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2018 ESC/ESH Guidelines for the management of arterial hypertension

August 2018
European Heart Journal 39(33)

DOI:10.1093/eurheartj/ehy339

Authors:

Bryan Williams

University College London

Wilko Spiering

University Medical Center Utrecht

Show all 161 authorsHide

Use of intima-media thickness in the assessment of the development of preclinical atherosclerosis R.N.N. Najafov

nitiation of blood pressure-lowering treatment (lifestyle changes and medication) at different initial office blood pressure levels. BP = blood pressure; CAD = coronary artery disease; CVD = cardiovascular disease; HMOD = hypertension-mediated organ damage.

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Classification of office blood pressure a and definitions of hypertension grade b

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Factors influencing cardiovascular risk in patients with hypertension

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Drug treatment strategy for hypertension and chronic kidney disease. ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BP = blood pressure; CCB = calcium channel blocker; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; MI = myocardial infarction; o.d. = omni die (every day). a CKD is defined as an eGFR <60 mL/min/1.72 m 2 with or without proteinuria. b Use loop diuretics when eGFR is <30 mL/min/1.72 m 2 , because thiazide/thiazide-like diuretics are much less effective/ineffective when eGFR is reduced to this level.

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+16

Drug treatment strategy for hypertension and hear failure with reduced ejection fraction. Do not use non-dihydropyridine CCBs (e.g. verapamil or diltiazem). ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; ESC = European Society of Cardiology; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist. a Consider an angiotensin receptor/neprilysin inhibitor instead of ACEi or ARB per ESC Heart Failure Guidelines. 136 b Diuretic refers to thiazide/thiazide-like diuretic. Consider a loop diuretic as an alternative in patients with oedema. c MRA (spironolactone or eplerenone).

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2018 ESC/ESH Guidelines for the management

of arterial hypertension

The Task Force for the management of arterial hypertension of the

European Society of Cardiology (ESC) and the European Society of

Hypertension (ESH)

Authors/Task Force Members: Bryan Williams* (ESC Chairperson) (UK),

Giuseppe Mancia* (ESH Chairperson) (Italy), Wilko Spiering (The Netherlands),

Enrico Agabiti Rosei (Italy), Michel Azizi (France), Michel Burnier (Switzerland),

Denis L. Clement (Belgium), Antonio Coca (Spain), Giovanni de Simone (Italy),

Anna Dominiczak (UK), Thomas Kahan (Sweden), Felix Mahfoud (Germany),

Josep Redon (Spain), Luis Ruilope (Spain), Alberto Zanchetti

†

(Italy), Mary Kerins

(Ireland), Sverre E. Kjeldsen (Norway), Reinhold Kreutz (Germany),

Stephane Laurent (France), Gregory Y. H. Lip (UK), Richard McManus (UK),

Krzysztof Narkiewicz (Poland), Frank Ruschitzka (Switzerland),

Roland E. Schmieder (Germany), Evgeny Shlyakhto (Russia), Costas Tsioufis

(Greece), Victor Aboyans (France), Ileana Desormais (France)

* Corresponding authors. Bryan Williams, Institute of Cardiovascular Science, University College London, Maple House, 1st Floor, Suite A, 149 Tottenham Court Road, London

W1T 7DN, UK, Tel: þ44 (0) 20 3108 7907, E-mail: bryan.williams@ucl.ac.uk. Giuseppe Mancia, University of Milano-Bicocca, Milan, Italy; and Hypertension Center Istituto

Universitario Policlinico di Monza, Verano (MB), Piazza dei Daini, 4 –20126 Milan, Italy, Tel: þ39 347 4327142, E-mail: giuseppe.mancia@unimib.it

†

Professor Zanchetti died towards the end of the development of these Guidelines, in March 2018. He contributed fully to the development of these Guidelines, as a member

of the Guidelines’ Task Force and as a section co-ordinator. He will be sadly missed by colleagues and friends.

The two chairpersons contributed equally to the document.

ESC Committee for Practice Guidelines (CPG), European Society of Hypertension (ESH) Council, ESC National Cardiac Societies having participated in

the review process, ESH National Hypertension Societies having participated in the review process: listed in the Appendix.

ESC entities having participated in the development of this document:

Associations: European Association of Cardiovascular Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous

Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).

Councils: Council for Cardiology Practice, Council on Cardiovascular Nursing and Allied Professions, Council on Cardiovascular Primary Care, Council on Hypertension,

Council on Stroke.

Working Groups: Cardiovascular Pharmacotherapy, Coronary Pathophysiology and Microcirculation, e-Cardiology.

Disclaimer. The ESC/ESH Guidelines represent the views of the ESC and ESH and were produced after careful consideration of the scientiﬁc and medical knowledge and the evidence

available at the time of their dating. The ESC and ESH are not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC/ESH Guidelines and any other

ofﬁcial recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are

encouraged to take the ESC/ESH Guidelines fully into account when exercising their clinical judgment as well as in the determination and the implementation of preventive, diagnostic, or

therapeutic medical strategies. However, the ESC/ESH Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate and accu-

rate decisions in consideration of each patient’s health condition, and in consultation with that patient and the patient’s caregiver where appropriate and/or necessary. Nor do the ESC/ESH

Guidelines exempt health professionals from taking careful and full consideration of the relevant ofﬁcial updated recommendations or guidelines issued by the competent public health

authorities in order to manage each patient’s case in light of the scientiﬁcally accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s

responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

The content of these European Society of Cardiology (ESC) and European Society of Hypertension (ESH) Guidelines has been published for personal and educational use only.

No commercial use is authorized. No part of the ESC/ESH Guidelines may be translated or reproduced in any form without written permission from the ESC or ESH.

Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle

such permissions on behalf of the ESC (journals.permissions@oup.com).

This article has been co-published in the European Heart Journal (doi: 10.1093/eurheartj/ehy339) and Journal of Hypertension (doi:10.1097/HJH. 10.1097/HJH.0000000000001940), and in

CEuropean Society of Cardiology and European Society of Hypertension 2018. The articles in European Heart Journal and

Journal of Hypertension are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Any citation can be used when citing this article.

European Heart Journal (2018) 00,1–98 ESC/ESH GUIDELINES

doi:10.1093/eurheartj/ehy339

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Document Reviewers: Guy De Backer (ESC Review Co-ordinator) (Belgium), Anthony M. Heagerty (ESH

Review Co-ordinator) (UK), Stefan Agewall (Norway), Murielle Bochud (Switzerland), Claudio Borghi

(Italy), Pierre Boutouyrie (France), Jana Brguljan (Slovenia), He´ ctor Bueno (Spain), Enrico G. Caiani (Italy),

Bo Carlberg (Sweden), Neil Chapman (UK), Renata C

ıfkov

a (Czech Republic), John G. F. Cleland (UK),

Jean-Philippe Collet (France), Ioan Mircea Coman (Romania), Peter W. de Leeuw (The Netherlands),

Victoria Delgado (The Netherlands), Paul Dendale (Belgium), Hans-Christoph Diener (Germany),

Maria Dorobantu (Romania), Robert Fagard (Belgium), Csaba Farsang (Hungary), Marc Ferrini (France),

Ian M. Graham (Ireland), Guido Grassi (Italy), Hermann Haller (Germany), F. D. Richard Hobbs (UK),

Bojan Jelakovic (Croatia), Catriona Jennings (UK), Hugo A. Katus (Germany), Abraham A. Kroon

(The Netherlands), Christophe Leclercq (France), Dragan Lovic (Serbia), Empar Lurbe (Spain),

Athanasios J. Manolis (Greece), Theresa A. McDonagh (UK), Franz Messerli (Switzerland), Maria Lorenza

Muiesan (Italy), Uwe Nixdorff (Germany), Michael Hecht Olsen (Denmark), Gianfranco Parati (Italy),

Joep Perk (Sweden), Massimo Francesco Piepoli (Italy), Jorge Polonia (Portugal), Piotr Ponikowski

(Poland), Dimitrios J. Richter (Greece), Stefano F. Rimoldi (Switzerland), Marco Rofﬁ (Switzerland),

Naveed Sattar (UK), Petar M. Seferovic (Serbia), Iain A. Simpson (UK), Miguel Sousa-Uva (Portugal),

Alice V. Stanton (Ireland), Philippe van de Borne (Belgium), Panos Vardas (Greece), Massimo Volpe (Italy),

Sven Wassmann (Germany), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain)

The disclosure forms of all experts involved in the development of these Guidelines are available on the

ESC website www.escardio.org/guidelines

........................................................................ ............. ............. ............. .................. ............. ............. .................. ......................

Keywords Guidelines •Hypertension •Blood pressure •Blood pressure measurement •Blood pressure treatment

thresholds and targets •Hypertension-mediated organ damage •Lifestyle interventions •Drug therapy •

Combination therapy •Device therapy •Secondary hypertension

Table of Contents

1Preamble ............. .............................................5

2Introduction ....................................................... 5

2.1 What is new and what has changed in the 2018 European

Society of Cardiology/European Society of Hypertension

arterialhypertensionGuidelines?...................................7

3 Definition, classification, and epidemiological aspects

ofhypertension.....................................................10

3.1Definitionofhypertension.....................................10

3.2Classificationofbloodpressure................................10

3.3Prevalenceofhypertension....................................10

3.4 Blood pressure relationship with risk of cardiovascular and

renalevents......................................................12

3.5 Hypertension and total cardiovascular risk assessment. . . . . . . . . .12

3.6 Importance of hypertension-mediated organ damage in

refining cardiovascular risk assessment in hypertensivepatients . . . . . 13

3.7 Challenges in cardiovascular risk assessment. . . . . . . . . . . . . . . . . . . . 14

4Bloodpressuremeasurement......................................15

4.1 Conventional office blood pressure measurement . . . . . . . . . . . . . . 15

4.2 Unattended office blood pressure measurement. . . . . . . . . . . . . . . . 15

4.3 Out-of-office blood pressure measurement . . . . . . . . . . . . . . . . . . . . 16

4.4Homebloodpressuremonitoring..............................16

4.5Ambulatorybloodpressuremonitoring........................16

4.6 Advantages and disadvantages of ambulatory blood pressure

monitoring and home blood pressure monitoring . . . . . . . . . . . . . . . . . . 17

4.7 White-coat hypertension and masked hypertension . . . . . . . . . . . . 17

4.7.1White-coathypertension...............................17

4.7.2Maskedhypertension...................................18

4.8Screeningforthedetectionofhypertension....................18

4.9Confirmingthediagnosisofhypertension.......................18

4.10 Clinical indications for out-of-office blood

pressuremeasurements...........................................18

4.11 Blood pressure during exercise and at high altitude . . . . . . . . . . . . 20

4.12Centralaorticpressure.......................................20

5 Clinical evaluation and assessment of hypertension-mediated

organdamageinpatientswithhypertension..........................21

5.1Clinicalevaluation.............................................21

5.2Medicalhistory................................................21

5.3 Physical examination and clinical investigations. . . . . . . . . . . . . . . . . . 22

5.4 Assessment of hypertension-mediated organ damage . . . . . . . . . . .22

5.4.1 Using hypertension-mediated organ damage to help

stratifyriskinhypertensivepatients...........................22

5.5 Characteristics ofhypertension-mediated organ damage . . . . . . . . 24

5.5.1Theheartinhypertension...............................24

5.5.2 The blood vessels in hypertension. . . . . . . . . . . . . . . . . . . . . . . 24

5.5.3Thekidneyinhypertension .. ...........................25

5.5.4Hypertensiveretinopathy...............................25

2ESC/ESH Guidelines

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5.5.5Thebraininhypertension...............................25

5.6 Hypertension-mediated organ damage regression and

cardiovascular risk reduction with antihypertensive treatment . . . . . . 25

5.7 When to refer a patient with hypertension for

hospital-basedcare...............................................26

6Geneticsandhypertension.........................................27

7Treatmentofhypertension ........................................28

7.1 Beneficial effects of blood pressure-lowering therapy

inhypertension...................................................28

7.2. When to initiate antihypertensive treatment . . . . . . . . . . . . . . . . . . . 28

7.2.1 Recommendations in previous guidelines . . . . . . . . . . . . . . . . 28

7.2.2 Drug treatment for patients with grade 1

hypertension at low–moderate cardiovascular risk . . . . . . . . . . . .28

7.2.3 Initiation of blood pressure-lowering drug

treatmentin older peoplewith grade 1 hypertension. . . . . . . . . . 29

7.2.4 Initiation of blood pressure-lowering drug

treatmentin patients with high–normal blood pressure. . . . . . . . 29

7.2.5 Should blood pressure-lowering drug treatment be

initiatedon the basis of blood pressure values orthe level

oftotalcardiovascularrisk?...................................30

7.2.6 Initiation of bloodpressure-lowering drug treatment . . . . .30

7.3Bloodpressuretreatmenttargets..............................32

7.3.1 New evidence on systolic blood pressure and

diastolicbloodpressuretreatmenttargets....................32

7.3.2 Blood pressure targets in specific subgroups of

hypertensivepatients........................................32

7.4Treatmentofhypertension....................................34

7.4.1Lifestylechanges........................................34

7.4.2Dietarysodiumrestriction..............................34

7.4.3 Moderation of alcohol consumption. . . . . . . . . . . . . . . . . . . . .35

7.4.4Otherdietarychanges..................................35

7.4.5Weightreduction .. ....................................35

7.4.6Regularphysicalactivity.................................36

7.4.7Smokingcessation......................................36

7.5.Pharmacologicaltherapyforhypertension.....................36

7.5.1 Drugs for the treatment of hypertension . . . . . . . . . . . . . . . . 36

7.5.2Hypertensiondrugtreatmentstrategy...................39

7.5.3 The drug treatment algorithm forhypertension . . . . . . . . . . 43

7.6Device-basedhypertensiontreatment .......... ...............47

7.6.1 Carotid baroreceptor stimulation

(pacemakerandstent).......................................47

7.6.2Renaldenervation......................................47

7.6.3 Creation of an arteriovenous fistula . . . . . . . . . . . . . . . . . . . . . 48

7.6.4Otherdevices..........................................48

8Hypertensioninspecificcircumstances.............................48

8.1Resistanthypertension........................................48

8.1.1 Definition of resistant hypertension . . . . . . . . . . . . . . . . . . . . . 48

8.1.2Pseudo-resistanthypertension..........................49

8.1.3 Diagnostic approach to resistant hypertension . . . . . . . . . . .49

8.1.4Treatmentofresistanthypertension.....................50

8.2Secondaryhypertension.......................................51

8.2.1 Drugs and other substances that may cause

secondaryhypertension......................................51

8.2.2 Genetic causes of secondary hypertension. . . . . . . . . . . . . . . 51

8.3Hypertensionurgenciesandemergencies ......................54

8.3.1 Acutemanagement ofhypertensive emergencies . . . . . . . . 55

8.3.2Prognosisandfollow-up ................................55

8.4White-coathypertension......................................56

8.5Maskedhypertension..........................................57

8.6Maskeduncontrolledhypertension ...... ......................57

8.7 Hypertension in younger adults (age <50 years) . . . . . . . . . . . . . . . . 57

8.7.1 Isolated systolic hypertension in the young. . . . . . . . . . . . . . .58

8.8 Hypertension in older patients (age >_65years).................58

8.9 Women, pregnancy, oral contraception, and

hormone-replacementtherapy....................................59

8.9.1Hypertensionandpregnancy............................59

8.9.2 Oral contraceptive pills and hypertension. . . . . . . . . . . . . . . . 61

8.9.3 Hormone-replacement therapy and hypertension . . . . . . . 61

8.10Hypertensionindifferentethnicgroups.......................61

8.11Hypertensionindiabetesmellitus.............................62

8.12 Hypertension and chronic kidney disease . . . . . . . . . . . . . . . . . . . . . 63

8.13 Hypertension and chronic obstructive pulmonary disease. . . . . . 64

8.14Hypertensionandheartdisease...............................64

8.14.1Coronaryarterydisease...............................64

8.14.2 Left ventricular hypertrophy and heart failure. . . . . . . . . . . 65

8.15Cerebrovasculardiseaseandcognition........................66

8.15.1Acuteintracerebralhaemorrhage......................66

8.15.2Acuteischaemicstroke................................66

8.15.3 Previous strokeor transient ischaemic attack . . . . . . . . . . . 66

8.15.4Cognitivedysfunctionanddementia....................67

8.16Hypertension,atrialfibrillation,andotherarrhythmias .........67

8.16.1 Oral anticoagulants and hypertension . . . . . . . . . . . . . . . . . . 68

8.17Hypertensionandvasculardisease............................68

8.17.1Carotidatherosclerosis................................68

8.17.2 Arteriosclerosis and increased arterial stiffness . . . . . . . . . 68

8.17.3Lowerextremityarterialdisease.......................69

8.18 Hypertension in valvular disease and aortopathy. . . . . . . . . . . . . . . 69

8.18.1Coarctationoftheaorta...............................69

8.18.2 Prevention of aortic dilation and dissection in

high-risksubjects ...................................... ......69

8.18.3 Hypertension bicuspid aortic valve-related

aortopathy..................................................69

8.19Hypertensionandsexualdysfunction .........................69

8.20Hypertensionandcancertherapy.............................70

8.21 Perioperative management of hypertension . . . . . . . . . . . . . . . . . . .70

9 Managing concomitant cardiovascular disease risk. . . . . . . . . . . . . . . . . . . 71

9.1Statinsandlipid-loweringdrugs................................71

9.2 Antiplatelet therapy and anticoagulant therapy. . . . . . . . . . . . . . . . . . 71

9.3. Glucose-lowering drugs and blood pressure . . . . . . . . . . . . . . . . . . . 72

10Patientfollow-up.................................................72

10.1Follow-upofhypertensivepatients............................72

10.2 Follow-up of subjects with high–normal blood pressure

andwhite-coathypertension......................................72

10.3Elevatedbloodpressureatcontrolvisits......................73

10.4 Improvement in blood pressure control in hypertension:

drugadherence...................................................73

10.5 Continued search for asymptomatic hypertension-mediated

organdamage ......................................... ...........74

10.6 Can antihypertensive medications be reduced or stopped?. . . . . 74

11Gapsintheevidence .............................................75

12Keymessages....................................................76

13 ‘What to do’ and ‘what not to do’ messages from the Guidelines . . . . .78

14Appendix........................................................80

15References.......................................................80

ESC/ESH Guidelines 3

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Abbreviations and acronyms

ABI Ankle–brachial index

ABPM Ambulatory blood pressure monitoring

ACCOMPLISH Avoiding Cardiovascular Events Through

Combination Therapy in Patients Living With

Systolic Hypertension

ACCORD Action to Control Cardiovascular Risk in

Diabetes

ACE Angiotensin-converting enzyme

ACEi Angiotensin-converting enzyme inhibitor

ACR Albumin:creatinine ratio

ADVANCE Action in Diabetes and Vascular Disease:

Preterax and Diamicron –MR Controlled

Evaluation

AF Atrial ﬁbrillation

ALLHAT Antihypertensive and Lipid-Lowering

Treatment to Prevent Heart Attack Trial

ALTITUDE Aliskiren Trial in Type 2 Diabetes Using

Cardiovascular and Renal Disease Endpoints

ARB Angiotensin receptor blocker

ASCOT Anglo-Scandinavian Cardiac Outcomes Trial

AV Atrioventricular

BMI Body mass index

BP Blood pressure

bpm Beats per minute

BSA Body surface area

CAD Coronary artery disease

CAPPP Captopril Prevention Project

CCB Calcium channel blocker

CHA2DS2-VASc Congestive heart failure, Hypertension, Age

>_75 years, Diabetes mellitus, Stroke, Vascular

disease, Age 65–74 years, Sex category

(female)

CKD Chronic kidney disease

CK-MB Creatinine kinase-muscle/brain

CMR Cardiac magnetic resonance

COLM Combination of OLMesartan and a calcium

channel blocker or diuretic in Japanese elderly

hypertensive patients

CONVINCE Controlled Onset Verapamil Investigation of

Cardiovascular End Points

COPD Chronic obstructive pulmonary disease

COPE Combination Therapy of Hypertension to

Prevent Cardiovascular Events

CT Computed tomography

CV Cardiovascular

CVD Cardiovascular disease

DBP Diastolic blood pressure

DENERHTN Renal Denervation for Hypertension

DHP Dihydropyridine

ECG Electrocardiogram

eGFR Estimated glomerular ﬁltration rate

ELSA European Lacidipine Study on Atherosclerosis

ENaC Epithelial sodium channel

ESC European Society of Cardiology

ESH European Society of Hypertension

FEVER Felodipine Event Reduction

HAS-BLED Hypertension, Abnormal renal/liver function

(1 point each), Stroke, Bleeding history or

predisposition, Labile INR, Elderly (>65),

Drugs/alcohol concomitantly (1 point each)

HbA1c Haemoglobin A1c

HBPM Home blood pressure monitoring

HDL-C HDL cholesterol

HELLP Haemolysis, elevated liver enzymes, and low

platelets

HFpEF Heart failure with preserved ejection fraction

HFrEF Heart failure with reduced ejection fraction

HMOD Hypertension-mediated organ damage

HOPE Heart Outcomes Prevention Evaluation

HYVET Hypertension in the Very Elderly Trial

i.v. Intravenous

IMT Intima-media thickness

INVEST International Verapamil-Trandolapril Study

ISH Isolated systolic hypertension

JUPITER Justiﬁcation for the Use of Statins in

Prevention: an Intervention Trial Evaluating

Rosuvastatin

LDH Lactate dehydrogenase

LDL-C LDL cholesterol

LEAD Lower extremity artery disease

LIFE Losartan Intervention For Endpoint reduction

in hypertension

LV Left ventricular

LVH Left ventricular hypertrophy

MAP Mean arterial pressure

MI Myocardial infarction

MR Magnetic resonance

MRA Mineralocorticoid receptor antagonist

MRI Magnetic resonance imaging

MUCH Masked uncontrolled hypertension

NORDIL Nordic Diltiazem

NS Non-signiﬁcant

NT-proBNP N-terminal pro-B natriuretic peptide

o.d. Omni die (every day)

ONTARGET Ongoing Telmisartan Alone and in

combination with Ramipril Global Endpoint

Trial

PAC Plasma aldosterone concentration

PAD Peripheral artery disease

PATHS Prevention and Treatment of Hypertension

Study

PRA Plasma renin activity

PRC Plasma renin concentration

PROGRESS Perindopril protection against recurrent stroke

study

PWV Pulse wave velocity

RAS Renin–angiotensin system

RCT Randomized controlled trial

RWT Relative wall thickness

SBP Systolic blood pressure

4ESC/ESH Guidelines

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SCOPE Study on Cognition and Prognosis in the

Elderly

SCORE Systematic COronary Risk Evaluation

SHEP Systolic Hypertension in the Elderly Program

SPC Single-pill combination

SPRINT Systolic Blood Pressure Intervention Trial

STOP-H Swedish Trial in Old Patients with

Hypertension

SUCH Sustained uncontrolled hypertension

Syst-China Systolic Hypertension in China

Syst-Eur Systolic Hypertension in Europe

TIA Transient ischaemic attack

TTE Transthoracic echocardiography

VALUE Valsartan Antihypertensive Long-term Use

Evaluation

VEGF Vascular endothelial growth factor

WUCH White-coat uncontrolled hypertension

1 Preamble

Guidelines summarize and evaluate available evidence with the aim of

assisting health professionals in selecting the best management strat-

egies for an individual patient with a given condition. Guidelines and

their recommendations should facilitate decision making of health

professionals in their daily practice. However, the final decisions con-

cerning an individual patient must be made by the responsible health

professional(s) in consultation with the patient and caregiver as

appropriate.

A great number of guidelines have been issued in recent years by

the European Society of Cardiology (ESC) and by the European

Society of Hypertension (ESH), as well as by other societies and

organisations. Because of the impact on clinical practice, quality crite-

ria for the development of guidelines have been established in order

to make all decisions transparent to the user. The recommendations

for formulating and issuing ESC Guidelines can be found on the

ESC website (http://www.escardio.org/Guidelines-&-Education/Clinical-

Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines).

ESC Guidelines represent the official position of the ESC on a given

topic and are regularly updated.

Members of this Task Force were selected by the ESC and ESH to

represent professionals involved with the medical care of patients

with this pathology. Selected experts in the field undertook a com-

prehensive review of the published evidence for management of a

given condition according to ESC Committee for Practice Guidelines

(CPG) policy and approved by the ESH. A critical evaluation of diag-

nostic and therapeutic procedures was performed, including assess-

ment of the risk–benefit ratio. The level of evidence and the strength

of the recommendation of particular management options were

weighed and graded according to predefined scales, as outlined in

Tables 1and 2.

The experts of the writing and reviewing panels provided declara-

tion of interest forms for all relationships that might be perceived as

real or potential sources of conflicts of interest. These forms were

compiled into one file and can be found on the ESC website (http://

www.escardio.org/guidelines). Any changes in declarations of interest

that arise during the writing period were notified to the ESC and ESH

and updated. The Task Force received its entire financial support

from the ESC and ESH without any involvement from the healthcare

industry.

The ESC CPG supervises and coordinates the preparation of new

Guidelines. The Committee is also responsible for the endorsement

process of these Guidelines. The ESC Guidelines undergo extensive

review by the CPG and external experts, and in this case by ESH -

appointed experts. After appropriate revisions the Guidelines are

approved by all the experts involved in the Task Force. The finalized

document is approved by the CPG and ESH for publication in the

European Heart Journal and in the Journal of Hypertension as well as

Blood Pressure. The Guidelines were developed after careful consid-

eration of the scientific and medical knowledge and the evidence

available at the time of their dating.

The task of developing ESC and ESH Guidelines also includes the

creation of educational tools and implementation programmes for

the recommendations including condensed pocket guideline ver-

sions, summary slides, booklets with essential messages, summary

cards for non-specialists and an electronic version for digital applica-

tions (smartphones, etc.). These versions are abridged and thus, if

needed, one should always refer to the full text version, which is

freely available via the ESC AND ESH websites and hosted on the

EHJ AND JOURNAL OF HYPERTENSION websites. The National

Societies of the ESC are encouraged to endorse, translate and imple-

ment all ESC Guidelines. Implementation programmes are needed

because it has been shown that the outcome of disease may be

favourably influenced by the thorough application of clinical

recommendations.

Surveys and registries are needed to verify that real-life daily prac-

tice is in keeping with what is recommended in the guidelines, thus

completing the loop between clinical research, writing of guidelines,

disseminating them and implementing them into clinical practice.

Health professionals are encouraged to take the ESC and ESH

Guidelines fully into account when exercising their clinical judgment,

as well as in the determination and the implementation of preventive,

diagnostic or therapeutic medical strategies. However, the ESC and

ESH Guidelines do not override in any way whatsoever the individual

responsibility of health professionals to make appropriate and accu-

rate decisions in consideration of each patient’s health condition and

in consultation with that patient or the patient’s caregiver where

appropriate and/or necessary. It is also the health professional’s

responsibility to verify the rules and regulations applicable to drugs

and devices at the time of prescription.

2 Introduction

Substantial progress has been made in understanding the epidemiol-

ogy, pathophysiology, and risk associated with hypertension, and a

wealth of evidence exists to demonstrate that lowering blood pres-

sure (BP) can substantially reduce premature morbidity and mortal-

ity.

1–10

A number of proven, highly effective, and well-tolerated

lifestyle and drug treatment strategies can achieve this reduction in

BP. Despite this, BP control rates remain poor worldwide and are far

from satisfactory across Europe. Consequently, hypertension

remains the major preventable cause of cardiovascular disease

(CVD) and all-cause death globally and in our continent.

11–14

ESC/ESH Guidelines 5

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These 2018 ESC/ESH Guidelines for the management of arterial

hypertension are designed for adults with hypertension, i.e. aged >_18

years. The purpose of the review and update of these Guidelines was

to evaluate and incorporate new evidence into the Guideline recom-

mendations. The specific aims of these Guidelines were to produce

pragmatic recommendations to improve the detection and treatment

of hypertension, and to improve the poor rates of BP control by pro-

moting simple and effective treatment strategies.

These joint 2018 Guidelines follow the same principles upon

which a series of hypertension Guidelines were jointly issued by the

two societies in 2003, 2007, and 2013. These fundamental principles

are: (i) to base recommendations on properly conducted studies,

identified from an extensive review of the literature; (ii) to give the

highest priority to data from randomized controlled trials (RCTs);

(iii) to also consider well-conducted meta-analyses of RCTs as strong

evidence (this contrasts with network meta-analyses, which we do

not consider to have the same level of evidence because many of the

comparisons are non-randomized); (iv) to recognize that RCTs can-

not address many important questions related to the diagnosis, risk

stratification, and treatment of hypertension, which can be addressed

by observational or registry-based studies of appropriate scientific

calibre; (v) to grade the level of scientific evidence and the strength of

recommendations according to ESC recommendations (see section

1); (vi) to recognize that opinions may differ on key recommenda-

tions, which are resolved by voting; and (vii) to recognize that there

are circumstances in which there is inadequate or no evidence, but

that the question is important for clinical practice and cannot be

ignored. In these circumstances, we resort to pragmatic expert opin-

ion and endeavour to explain its rationale.

Each member of the Task Force was assigned specific writing tasks,

which were reviewed by section co-ordinators and then by the two

chairs, one appointed by the ESC and the other by the ESH. The text

was developed over approximately 24 months, during which the

Task Force members met collectively and corresponded intensively

with one another between meetings. Before publication, the docu-

ment was reviewed by European reviewers selected by the ESC and

ESH, and by representatives of ESC National Cardiac Societies and

ESH National Hypertension Societies.

Table 2 ESC Levels of evidence

Table 1 ESC Classes of recommendations

©ESC 2018

Classes of

recommendations

Definition Suggested wording to use

Class I Evidence and/or general agreement

that a given treatment or procedure is

beneficial, useful, effective.

Is recommended/is

indicated

Class II Conflicting evidence and/or a

divergence of opinion about the

usefulness/efficacy of the given

treatment or procedure.

Class IIa Weight of evidence/opinion is in favour

of usefulness/efficacy.

Should be considered

Class IIb Usefulness/efficacy is less well

established by evidence/opinion.

May be considered

Class III Evidence or general agreement that

the given treatment or procedure is

not useful/effective, and in some cases

may be harmful.

Is not recommended

6ESC/ESH Guidelines

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2.1 What is new and what has changed in the 2018 ESC/ESH Arterial Hypertension

Guidelines?

Changes in recommendations

2013 2018

Diagnosis Diagnosis

Ofﬁce BP is recommended for screening and diagnosis of

hypertension.

It is recommended to base the diagnosis of hypertension on:

•Repeated ofﬁce BP measurements; or

•Out-of-ofﬁce BP measurement with ABPM and/or HBPM if logistically

and economically feasible.

Treatment thresholds

Highnormal BP (130 –139/85–89 mmHg): Unless the necessary

evidence is obtained, it is not recommended to initiate

antihypertensive drug therapy at high–normal BP.

Treatment thresholds

Highnormal BP (130 –139/85–89 mmHg): Drug treatment may be

considered when CV risk is very high due to established CVD, especially

CAD.

Treatment thresholds

Treatment of low-risk grade 1 hypertension:

Initiation of antihypertensive drug treatment should also be

considered in grade 1 hypertensive patients at low–moderate-risk,

when BP is within this range at several repeated visits or elevated by

ambulatory BP criteria, and remains within this range despite a

reasonable period of time with lifestyle measures.

Treatment thresholds

Treatment of low-risk grade 1 hypertension:

In patients with grade 1 hypertension at low– moderate-risk and without

evidence of HMOD, BP-lowering drug treatment is recommended if the

patient remains hypertensive after a period of lifestyle intervention.

Treatment thresholds

Older patients

Antihypertensive drug treatment may be considered in the elderly

(at least when younger than 80 years) when SBP is in the

140–159 mmHg range, provided that antihypertensive treatment is

well tolerated.

Treatment thresholds

Older patients

BP-lowering drug treatment and lifestyle intervention is recommended in

ﬁt older patients (>65 years but not >80 years) when SBP is in the

grade 1 range (140–159 mmHg), provided that treatment is well tolerated.

BP treatment targets BP treatment targets

An SBP goal of <140 mmHg is recommended. •It is recommended that the ﬁrst objective of treatment should be to

lower BP to <140/90 mmHg in all patients and, provided that the

treatment is well tolerated, treated BP values should be targeted to

130/80 mmHg or lower in most patients.

•In patients <65 years it is recommended that SBP should be lowered

to a BP range of 120–129 mmHg in most patients.

Continued

ESC/ESH Guidelines 7

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BP treatment targets in older

patients (65–80 years)

BP treatment targets in older patients (65–80 years)

An SBP target of between 140–150 mmHg

is recommended for older patients (65–80 years).

In older patients (>_65 years), it is recommended that SBP should be

targeted to a BP range of 130– 139 mmHg.

BP treatment targets in patients aged over 80 years BP treatment targets in patients aged over 80 years

An SBP target between 140–150 mmHg should be considered in

people older than 80 years, with an initial SBP >_160 mmHg, provided

that they are in good physical and mental condition.

An SBP target range of 130–139 mmHg is recommended for people older

than 80 years, if tolerated.

DBP targets DBP targets

A DBP target of <90 mmHg is always recommended, except in

patients with diabetes, in whom values <85 mmHg are

recommended.

A DBP target of <80 mmHg should be considered for all hypertensive

patients, independent of the level of risk and comorbidities.

Initiation of drug treatment Initiation of drug treatment

Initiation of antihypertensive therapy with a two-drug combination

may be considered in patients with markedly high baseline BP or

at high CV risk.

It is recommended to initiate an antihypertensive treatment with a

two-drug combination, preferably in a SPC. The exceptions are frail older

patients and those at low risk and with grade 1 hypertension (particularly

if SBP is <150 mmHg).

Resistant hypertension Resistant hypertension

Mineralocorticoid receptor antagonists, amiloride, and the alpha-1

blocker doxazosin should be considered if no contraindication

exists.

Recommended treatment of resistant hypertension is the addition of

low-dose spironolactone to existing treatment, or the addition of further

diuretic therapy if intolerant to spironolactone, with either eplerenone,

amiloride, higher-dose thiazide/thiazide-like diuretic or a loop diuretic,

or the addition of bisoprolol or doxazosin.

Device-based therapy for hypertension Device-based therapy for hypertension

In case of ineffectiveness of drug treatment, invasive procedures

such as renal denervation and baroreceptor stimulation may be

considered.

Use of device-based therapies is not recommended for the routine

treatment of hypertension, unless in the context of clinical studies and

RCTs, until further evidence regarding their safety and efﬁcacy becomes

available.

Recommendation Grading

Grade I Grade IIa Grade IIb Grade III

ABPM = ambulatory blood pressure monitoring; BP = blood pressure; CAD = coronary artery disease; CV = cardiovascular; CVD = cardiovascular disease; DBP = diastolic

blood pressure; HBPM = home blood pressure monitoring; HMOD = hypertension-mediated organ damage; RCT = randomized controlled trial; SBP = systolic blood pressure;

SPC = single-pill combination.

8ESC/ESH Guidelines

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New sections/recommendations

When to suspect and how to screen for the causes of secondary hypertension

Management of hypertension emergencies

Updated recommendations on the management of BP in acute stroke

Updated recommendations on the management of hypertension in women and pregnancy

Hypertension in different ethnic groups

The effects of altitude on BP

Hypertension and chronic obstructive pulmonary disease

Hypertension and AF and other arrhythmias

Oral anticoagulant use in hypertension

Hypertension and sexual dysfunction

Hypertension and cancer therapies

Perioperative management of hypertension

Glucose-lowering drugs and BP

Updated recommendations on CV risk assessment and management: (i) using the SCORE system to assess risk in

patients without CVD; (ii) the importance of HMOD in modifying CV risk; and (iii) the use of statins and aspirin for

CVD prevention

New concepts

BP measurement

•Wider use of out-of-ofﬁce BP measurement with ABPM and/or HBPM, especially HBPM, as an option to conﬁrm the diagnosis

of hypertension, detect white-coat and masked hypertension, and monitor BP control.

Less conservative treatment of BP in older and very old patients

•Lower BP thresholds and treatment targets for older patients, with emphasis on considerations of biological rather than

chronological age (i.e. the importance of frailty, independence, and the tolerability of treatment).

•Recommendation that treatment should never be denied or withdrawn on the basis of age, provided that treatment is tolerated.

A SPC treatment strategy to improve BP control

•Preferred use of two-drug combination therapy for the initial treatment of most people with hypertension.

•A single-pill treatment strategy for hypertension with the preferred use of SPC therapy for most patients.

•Simpliﬁed drug treatment algorithms with the preferred use of an ACE inhibitor or ARB, combined with a CCB and/or a

thiazide/thiazide-like diuretic, as the core treatment strategy for most patients, with beta-blockers used for speciﬁc indications.

New target ranges for BP in treated patients

•Target BP ranges for treated patients to better identify the recommended BP target and lower safety boundaries for treated BP,

according to a patient’s age and speciﬁc comorbidities.

Detecting poor adherence to drug therapy

•A strong emphasis on the importance of evaluating treatment adherence as a major cause of poor BP control.

A key role for nurses and pharmacists in the longer-term management of hypertension

•The important role of nurses and pharmacists in the education, support, and follow-up of treated hypertensive patients is

emphasized as part of the overall strategy to improve BP control.

ABPM = ambulatory blood pressure monitoring; ACE = angiotensin-converting enzyme; AF = atrial ﬁbrillation; ARB = angiotensin receptor blocker; BP = blood pressure; CCB

= calcium channel blocker; CV = cardiovascular; CVD = cardiovascular disease; HBPM = home blood pressure monitoring; HMOD = hypertension-mediated organ damage;

SCORE = Systematic COronary Risk Evaluation; SPC = single-pill combination.

ESC/ESH Guidelines 9

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3 Definition, classification, and

epidemiological aspects of

hypertension

3.1 Definition of hypertension

The relationship between BP and cardiovascular (CV) and renal

events is continuous, making the distinction between normotension

and hypertension, based on cut-off BP values, somewhat arbitrary.

2,4,8

However, in practice, cut-off BP values are used for pragmatic rea-

sons to simplify the diagnosis and decisions about treatment.

Epidemiological associations between BP and CV risk extend from

very low levels of BP [i.e. systolic BP (SBP) >115 mmHg]. However,

‘hypertension’ is defined as the level of BP at which the benefits of

treatment (either with lifestyle interventions or drugs) unequivocally

outweigh the risks of treatment, as documented by clinical trials. This

evidence has been reviewed (see section 7.2 for detailed discussion

of hypertension diagnostic thresholds) and provides the basis

for the recommendation that the classification of BP and definition

of hypertension remain unchanged from previous ESH/ESC

Guidelines (Table 3).

15,16,17

Hypertension is defined as office SBP values >_140 mmHg and/or

diastolic BP (DBP) values >_90 mmHg. This is based on evidence from

multiple RCTs that treatment of patients with these BP values is benefi-

cial (see section 7). The same classification is used in younger, middle-

aged, and older people, whereas BP centiles are used in children and

teenagers, in whom data from interventional trials are not available.

Details on BP classification in boys and girls <_16yearsofagecanbe

found in the 2016 ESH Guidelines for children and adolescents.

3.2 Classification of blood pressure

3.3 Prevalence of hypertension

Based on office BP, the global prevalence of hypertension was esti-

mated to be 1.13 billion in 2015,

with a prevalence of over 150 mil-

lion in central and eastern Europe. The overall prevalence of

hypertension in adults is around 30- 45%,

with a global age-

standardized prevalence of 24 and 20% in men and women, respec-

tively, in 2015.

This high prevalence of hypertension is consistent

across the world, irrespective of income status, i.e. in lower, middle,

and higher income countries.

Hypertension becomes progressively

more common with advancing age, with a prevalence of >60% in

people aged >60 years.

As populations age, adopt more sedentary

lifestyles, and increase their body weight, the prevalence of hyperten-

sion worldwide will continue to rise. It is estimated that the number

Table 3 Classiﬁcation of ofﬁce blood pressure

and deﬁnitions of hypertension grade

Category Systolic (mmHg) Diastolic (mmHg)

Optimal <120 and <80

Normal 120–129 and/or 80–84

High normal 130–139 and/or 85–89

Grade 1 hypertension 140–159 and/or 90–99

Grade 2 hypertension 160–179 and/or 100–109

Grade 3 hypertension >_180 and/or >_110

Isolated systolic hypertension

>_140 and <90

BP = blood pressure; SBP = systolic blood pressure.

BP category is deﬁned according to seated clinic BP and by the highest level of BP, whether systolic or diastolic.

Isolated systolic hypertension is graded 1, 2, or 3 according to SBP values in the ranges indicated.

The same classiﬁcation is used for all ages from 16 years.

Classiﬁcation of BP

Recommendation Class

Level

It is recommended that BP be classiﬁed as

optimal, normal, high–normal, or grades

1–3 hypertension, according to ofﬁce BP.

BP = blood pressure.

Class of recommendation

Level of evidence.

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Table 4 Factors inﬂuencing cardiovascular risk in patients with hypertension

Demographic characteristics and laboratory parameters

Sex

(men >women)

Age

Smoking (current or past history)

Total cholesterol

and HDL-C

Uric acid

Diabetes

Overweight or obesity

Family history of premature CVD (men aged <55 years and women aged <65 years)

Family or parental history of early-onset hypertension

Early-onset menopause

Sedentary lifestyle

Psychosocial and socioeconomic factors

Heart rate (resting values >80 beats/min)

Asymptomatic HMOD

Arterial stiffening:

Pulse pressure (in older people) >_60 mmHg

Carotid–femoral PWV >10 m/s

ECG LVH (Sokolow–Lyon index >35 mm, or R in aVL >_11 mm; Cornell voltage duration product >2440 mm.ms, or Cornell voltage >28 mm in

men or >20 mm in women)

Echocardiographic LVH [LV mass index: men >50 g/m

2.7

; women >47 g/m

2.7

(height in m

2.7

); indexation for BSA may be used in normal-weight

patients; LV mass/BSA g/m

>115 (men) and >95 (women)]

Microalbuminuria (30–300 mg/24 h), or elevated albumin–creatinine ratio (30– 300 mg/g; 3.4– 34 mg/mmol) (preferentially on morning spot urine)

Moderate CKD with eGFR >30–59 mL/min/1.73 m

(BSA) or severe CKD eGFR <30 mL/min/1.73 m

Ankle-brachial index <0.9

Advanced retinopathy: haemorrhages or exudates, papilloedema

Established CV or renal disease

Cerebrovascular disease: ischaemic stroke, cerebral haemorrhage, TIA

CAD: myocardial infarction, angina, myocardial revascularization

Presence of atheromatous plaque on imaging

Heart failure, including HFpEF

Peripheral artery disease

Atrial ﬁbrillation

BSA = body surface area; CAD = coronary artery disease; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease; ECG = electrocardiogram; eGFR

= estimated glomerular ﬁltration rate; HDL-C = HDL cholesterol; HFpEF = heart failure with preserved ejection fraction; HMOD = hypertension-mediated organ damage; LV

= left ventricular; LVH = left ventricular hypertrophy; PWV = pulse wave velocity; SCORE = Systematic COronary Risk Evaluation; TIA = transient ischaemic attack.

CV risk factors included in the SCORE system.

Proteinuria and reduced eGFR are independent risk factors.

See Table 6for CV risk modiﬁers.

ESC/ESH Guidelines 11

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of people with hypertension will increase by 15–20% by 2025, reach-

ing close to 1.5 billion.

3.4 Blood pressure relationship with risk

of cardiovascular and renal events

Elevated BP was the leading global contributor to premature death in

2015, accounting for almost 10 million deaths and over 200 million

disability-adjusted life years.

Importantly, despite advances in diagno-

sis and treatment over the past 30 years, the disability-adjusted life

years attributable to hypertension have increased by 40% since

1990.

SBP >_140 mmHg accounts for most of the mortality and dis-

ability burden (70%), and the largest number of SBP-related deaths

per year are due to ischaemic heart disease (4.9 million), haemor-

rhagic stroke (2.0 million), and ischaemic stroke (1.5 million).

Both office BP and out-of-office BP have an independent and con-

tinuous relationship with the incidence of several CV events [hae-

morrhagic stroke, ischaemic stroke, myocardial infarction, sudden

death, heart failure, and peripheral artery disease (PAD)], as well as

end-stage renal disease.

Accumulating evidence is closely linking

hypertension with an increased risk of developing atrial fibrillation

(AF),

and evidence is emerging that links early elevations of BP to

increased risk of cognitive decline and dementia.

21,22

The continuous relationship between BP and risk of events has

been shown at all ages

and in all ethnic groups,

24,25

and extends

from high BP levels to relatively low values. SBP appears to be a bet-

ter predictor of events than DBP after the age of 50 years.

23,26,27

High DBP is associated with increased CV risk and is more commonly

elevated in younger (<50 years) vs. older patients. DBP tends to

decline from midlife as a consequence of arterial stiffening; conse-

quently, SBP assumes even greater importance as a risk factor from

midlife.

In middle-aged and older people, increased pulse pressure

(the difference between SBP and DBP values) has additional adverse

prognostic significance.

28,29

3.5 Hypertension and total

cardiovascular risk assessment

Hypertension rarely occurs in isolation, and often clusters with other

CV risk factors such as dyslipidaemia and glucose intolerance.

30,31

Table 5 Ten year cardiovascular risk categories (Systematic COronary Risk Evaluation system)

Very high risk People with any of the following:

Documented CVD, either clinical or unequivocal on imaging.

•Clinical CVD includes acute myocardial infarction, acute coronary syndrome, coronary or other arterial revascula-

rization, stroke, TIA, aortic aneurysm, and PAD

•Unequivocal documented CVD on imaging includes signiﬁcant plaque (i.e. >_50% stenosis) on angiography or

ultrasound; it does not include increase in carotid intima-media thickness

•Diabetes mellitus with target organ damage, e.g. proteinuria or a with a major risk factor such as grade 3

hypertension or hypercholesterolaemia

•Severe CKD (eGFR <30 mL/min/1.73 m

)

•A calculated 10 year SCORE of >_10%

High risk People with any of the following:

•Marked elevation of a single risk factor, particularly cholesterol >8 mmol/L (>310 mg/dL), e.g. familial hyper-

cholesterolaemia or grade 3 hypertension (BP >_180/110 mmHg)

•Most other people with diabetes mellitus (except some young people with type 1 diabetes mellitus and with-

out major risk factors, who may be at moderate-risk)

Hypertensive LVH

Moderate CKD eGFR 30-59 mL/min/1.73 m

)

A calculated 10 year SCORE of 5-10%

Moderate risk People with:

•A calculated 10 year SCORE of 1to<5%

•Grade 2 hypertension

•Many middle-aged people belong to this category

Low risk People with:

•A calculated 10 year SCORE of <1%

BP = blood pressure; CKD = chronic kidney disease; CVD = cardiovascular disease; eGFR = estimated glomerular ﬁltration rate; LVH = left ventricular hypertrophy; TIA =

transient ischaemic attack; PAD = peripheral artery disease; SCORE = Systematic COronary Risk Evaluation.

12 ESC/ESH Guidelines

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This metabolic risk factor clustering has a multiplicative effect on CV

risk.

Consequently, quantification of total CV risk (i.e. the likelihood

of a person developing a CVevent over a defined period) is an impor-

tant part of the risk stratification process for patients with

hypertension.

Many CV risk assessment systems are available and most project

10 year risk. Since 2003, the European Guidelines on CVD preven-

tion have recommended use of the Systematic COronary Risk

Evaluation (SCORE) system because it is based on large, representa-

tive European cohort data sets (available at: http://www.escardio.org/

Guidelines-&-Education/Practice-tools/CVD-prevention-toolbox/SC

ORE-Risk-Charts). The SCORE system estimates the 10 year risk of

a first fatal atherosclerotic event, in relation to age, sex, smoking hab-

its, total cholesterol level, and SBP. The SCORE system also allows

calibration for different CV risk levels across numerous European

countries and has been externally validated.

A previous limitation

of the SCORE system was that it applied only to patients aged 40–65

years; however, the SCORE system has recently been adapted for

patients over the age of 65 years.

Detailed information on CV risk

assessment is available.

Factors influencing CV risk factors in patients with hypertension

are shown in Table 4. Hypertensive patients with documented

CVD, including asymptomatic atheromatous disease on imaging,

type 1 or type 2 diabetes, very high levels of individual risk factors

(including grade 3 hypertension), or chronic kidney disease (CKD;

stages 3 - 5), are automatically considered to be at very high (i.e.

>_10% CVD mortality) or high (i.e. 5 - 10% CVD mortality) 10 year

CV risk (Table 5). Such patients do not need formal CV risk estima-

tion to determine their need for treatment of their hypertension

and other CV risk factors. For all other hypertensive patients, esti-

mation of 10 year CV risk using the SCORE system is recom-

mended. Estimation should be complemented by assessment of

hypertension-mediated organ damage (HMOD), which can also

increase CV risk to a higher level, even when asymptomatic (see

Table 4and sections 3.6 and 4).

There is also emerging evidence that an increase in serum uric acid

to levels lower than those typically associated with gout is independ-

ently associated with increased CV risk in both the general popula-

tion and in hypertensive patients. Measurement of serum uric acid is

recommended as part of the screening of hypertensive patients.

The SCORE system only estimates the risk of fatal CV events.

The risk of total CV events (fatal and non-fatal) is approximately

three times higher than the rate of fatal CV events in men and

four times higher in women. This multiplier is attenuated to less than

three times in older people in whom a first event is more likely to be

fatal.

There are important general modifiers of CV risk (Table 6) as well

as specific CV risk modifiers for patients with hypertension. CV risk

modifiers are particularly important at the CV risk boundaries, and

especially for patients at moderate-risk in whom a risk modifier might

convert moderate-risk to high risk and influence treatment decisions

with regard to CV risk factor management. Furthermore, CV risk

estimates by the SCORE system may be modified in first-generation

immigrants to Europe and CV risk scores in such patients may be

adjusted by correction factors (Table 7). Further details of the impact

of CV risk modifiers are available from the ESC 2016 CVD preven-

tion Guidelines.

3.6 Importance of hypertension-

mediated organ damage in refining

cardiovascular risk assessment in

hypertensive patients

A unique and important aspect of CV risk estimation in hypertensive

patientsis the need to consider the impact of HMOD. This was previ-

ously termed ‘target organ damage’, but HMOD more accurately

Table 6 Risk modiﬁers increasing cardiovascular risk

estimated by the Systemic COronary Risk Evaluation

(SCORE) system

Social deprivation, the origin of many causes of CVD

Obesity (measured by BMI) and central obesity (measured by

waist circumference)

Physical inactivity

Psychosocial stress, including vital exhaustion

Family history of premature CVD (occurring at age <55 years in

men and <60 years in women)

Autoimmune and other inﬂammatory disorders

Major psychiatric disorders

Treatment for infection with human immunodeﬁciency virus

Atrial ﬁbrillation

LV hypertrophy

CKD

Obstructive sleep apnoea syndrome

BMI = body mass index; CKD = chronic kidney disease; CVD = cardiovascular

disease; LV = left ventricular.

Table 7 Correction factors for the Systemic

COronary Risk Evaluation (SCORE) cardiovascular risk

estimates in ﬁrst-generation immigrants to Europe

Region of origin Multiplication factor

Southern Asia 1.4

Sub-Saharan Africa 1.3

Caribbean 1.3

Western Asia 1.2

Northern Africa 0.9

Eastern Asia 0.7

Southern America 0.7

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describes hypertension-induced structural and/or functional changes

in major organs (i.e. the heart, brain, retina, kidney, and vasculature)

(Table 4). There are three important considerations: (i) not all fea-

tures of HMOD are included in the SCORE system (CKD and estab-

lished vascular disease are included) and several hypertensive

HMODs (e.g. cardiac, vascular, and retinal) have well-established

adverse prognostic significance (see section 5) and may, especially if

HMOD is pronounced, lead to a high CV risk even in the absence of

classical CV risk factors; (ii) the presence of HMOD is common and

often goes undetected;

and (iii) the presence of multiple HMODs

in the same patient is also common, and further increases CV

risk.

39–41

Consequently, the inclusion of HMOD assessment is

important in patients with hypertension and helps identify high-risk

or very high-risk hypertensive patients who may otherwise be mis-

classified as having a lower level of risk by the SCORE system.

This

is especially true for the presence of left ventricular hypertrophy

(LVH), CKD with albuminuria or proteinuria, or arterial stiffening

(see section 5). The impact of progression of the stages of

hypertension-associated disease (from uncomplicated through to

asymptomatic or established disease), according to different grades

of hypertension and the presence of CV risk factors, HMOD, or

comorbidities, is illustrated in Figure 1for middle-aged individuals.

3.7 Challenges in cardiovascular risk

assessment

CV risk is strongly influenced by age (i.e. older people are invariably

at high absolute CV risk). In contrast, the absolute risk of younger

people, particularly younger women, is invariably low, even in those

with a markedly abnormal risk factor profile. In the latter, relative risk

is elevated even if absolute risk is low. The use of ‘CV risk age’ has

been proposed as a useful way of communicating risk and making

treatment decisions, especially for younger people at low absolute

risk but with high relative risk.

This works by illustrating how a

younger patient (e.g. a 40-year-old) with risk factors but low absolute

risk has a CV risk equivalent to a much older person (60 years) with

optimal risk factors; thus, the CV risk age of the younger patient is 60

years. The CV risk age can be automatically calculated using

HeartScore (www.heartscore.org).

A second consideration is that the presence of concomitant dis-

ease is often recorded in a binary way in CV risk assessment systems

(e.g. diabetes, yes/no). This does not reflect the impact of the severity

or duration of concomitant diseases on total CV risk. For example,

long-standing diabetes is clearly associated with high risk, whereas

the risk is less certain for recent-onset diabetes.

A third conundrum specific to hypertension is what BP value to

use in CV risk assessment in a patient who is receiving treatment for

hypertension. If treatment was commenced recently, it seems appro-

priate to use the pre-treatment BP value. If treatment has been

long-standing, using the current treated BP value will invariably

underestimate risk because it does not reflect prior longer-term

exposure to higher BP levels, and antihypertensive treatment does

not completely reverse the risk even when BP is well controlled. If

treatment has been long-standing, then the ‘treated BP value’ should

be used, with the caveat that the calculated CV risk will be lower

than the patient’s actual risk. A fourth conundrum is how to impute

out-of-office BP values into risk calculators that have been calibrated

Hypertension

disease

staging

Other risk factors,

HMOD, or disease

BP (mmHg) grading

High normal

SBP 130–139

DBP 85–89

Grade 1

SBP 140–159

DBP 90–99

Grade 2

SBP 160–179

DBP 100–109

Grade 3

SBP 180

or DBP 110

Stage 1

(uncomplicated)

No other risk

factors Low risk Low risk Moderate risk High risk

1 or 2 risk factors Low risk Moderate risk Moderate to

high risk High risk

3 risk factors Low to

Moderate risk

Moderate to

high risk High Risk High risk

Stage 2

(asymptomatic

disease)

HMOD, CKD grade

3, or diabetes

mellitus without

organ damage

Moderate to

high risk High risk High risk High to

very high risk

Stage 3

(established

disease)

Established CVD,

CKD grade 4, or

diabetes mellitus

with organ damage

Very high risk Very high risk Very high risk Very high risk

©ESC/ESH 2018

Figure 1 Classification of hypertension stages according to blood pressure levels, presence of cardiovascular risk factors, hypertension-mediated

organ damage, or comorbidities. CV risk is illustrated for a middle-aged male. The CV risk does not necessarily correspond to the actual risk

at different ages. The use of the SCORE system is recommended for formal estimation of CV risk for treatment decisions. BP = blood pressure;

CKD = chronic kidney disease; CV = cardiovascular; DBP = diastolic blood pressure; HMOD = hypertension-mediated organ damage; SBP = systolic

blood pressure; SCORE = Systematic COronary Risk Evaluation.

14 ESC/ESH Guidelines

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according to office BP readings. These various limitations should be

kept in mind when estimating CV risk in clinical practice.

4 Blood pressure measurement

4.1 Conventional office blood pressure

measurement

Auscultatory or oscillometric semiautomatic or automatic sphyg-

momanometers are the preferred method for measuring BP in the

doctor’s office. These devices should be validated according to stand-

ardized conditions and protocols.

BP should initially be measured in

both upper arms, using an appropriate cuff size for the arm circumfer-

ence. A consistent and significant SBP difference between arms (i.e.

>15 mmHg) is associated with an increased CV risk,

most likely

due to atheromatous vascular disease. Where there is a difference in

BP between arms, ideally established by simultaneous measurement,

the arm with the higher BP values should be used for all subsequent

measurements.

In older people, people with diabetes, or people with other causes

of orthostatic hypotension, BP should also be measured 1 min and 3

min after standing. Orthostatic hypotension is defined as a reduction

in SBP of >_20 mmHg or in DBP of >_10 mmHg within 3 min of stand-

ing, and is associated with an increased risk of mortality and CV

events.

Heart rate should also be recorded at the time of BP meas-

urements because resting heart rate is an independent predictor of

CV morbid or fatal events,

although heart rate is not included in

any CV risk algorithm. Table 8summarizes the recommended proce-

dure for routine office BP measurement. It is emphasized that office

BP is often performed improperly, with inadequate attention to the

standardized conditions recommended for a valid measurement of

office BP. Improper measurement of office BP can lead to inaccurate

classification, overestimation of a patient’s true BP, and unnecessary

treatment.

4.2 Unattended office blood pressure

measurement

Automated multiple BP readings in the doctor’s office improve the

reproducibility of BP measurement, and if the patient is seated alone

and unobserved, the ‘white-coat effect’ (see section 4.7.1) can be

substantially reduced

or eliminated.

Moreover, the BP values are

lower than those obtained by conventional office BP measurement

and are similar to, or even less than, those provided by daytime

ambulatory blood pressure monitoring (ABPM) or home blood pres-

sure monitoring (HBPM).

Use of unattended office BP measure-

ment in a recent clinical trial [the Systolic Blood Pressure

Intervention Trial (SPRINT)]

generated controversy about its quan-

titative relationship to conventional office BP measurement (which

has been the basis for all previous epidemiological and clinical trial

Hypertension and CV risk assessment

Recommendation Class

Level

CV risk assessment with the SCORE system

is recommended for hypertensive patients

who are not already at high or very high risk

due to established CVD, renal disease, or

diabetes, a markedly elevated single risk fac-

tor (e.g. cholesterol), or hypertensive

LVH.

33,35

CVD = cardiovascular disease; LVH = left ventricular hypertrophy; SCORE =

Systematic COronary Risk Evaluation.

Class of recommendation.

Level of evidence.

Table 8 Ofﬁce blood pressure measurement

Patients should be seated comfortably in a quiet environment

for 5 min before beginning BP measurements.

Three BP measurements should be recorded, 1–2 min apart,

and additional measurements only if the ﬁrst two readings differ

by >10 mmHg. BP is recorded as the average of the last two BP

readings.

Additional measurements may have to be performed in patients

with unstable BP values due to arrhythmias, such as in patents

with AF, in whom manual auscultatory methods should be used

as most automated devices have not been validated for BP

measurement in patients with AF.

Use a standard bladder cuff (12–13 cm wide and 35 cm long)

for most patients, but have larger and smaller cuffs available for

larger (arm circumference >32 cm) and thinner arms,

respectively.

The cuff should be positioned at the level of the heart, with the

back and arm supported to avoid muscle contraction and iso-

metric exercise-dependant increases in BP.

When using auscultatory methods, use phase I and V (sudden

reduction/disappearance) Korotkoff sounds to identify SBP and

DBP, respectively.

Measure BP in both arms at the ﬁrst visit to detect possible

between-arm differences. Use the arm with the higher value as

the reference.

Measure BP 1 min and 3 min after standing from a seated posi-

tion in all patients at the ﬁrst measurement to exclude ortho-

static hypotension. Lying and standing BP measurements should

also be considered in subsequent visits in older people, people

with diabetes, and people with other conditions in which ortho-

static hypotension may frequently occur.

Record heart rate and use pulse palpation to exclude

arrhythmia.

AF = atrial ﬁbrillation; BP = blood pressure; DBP = diastolic blood pressure; SBP

= systolic blood pressure.

Most automatic devices are not validated for BP measurement in patients with

AF and will record the highest individual systolic pressure wave form rather than

an average of several cardiac cycles. This will lead to overestimation of BP.

ESC/ESH Guidelines 15

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data); its feasibility in routine clinical practice has also been ques-

tioned. Presently, the relationship between BP readings obtained

with conventional office BP measurement and unattended office BP

measurement remains unclear, but available evidence suggests that

conventional office SBP readings may be at least 5–15 mmHg higher

than SBP levels obtained by unattended office BP measurements.

There is also very limited evidence on the prognostic value of unat-

tended office BP measurements, i.e. whether they guarantee at least

the same ability to predict outcomes as conventional office BP

measurements.

4.3 Out-of-office blood pressure

measurement

Out-of-office BP measurement refers to the use of either HBPM or

ABPM, the latter usually over 24 h. It provides a larger number of BP

measurements than conventional office BP in conditions that are

more representative of daily life. Recent position papers and practice

guidelines provide comprehensive details for ABPM

and HBPM,

and are briefly summarized below.

54,56

4.4 Home blood pressure monitoring

Home BP is the average of all BP readings performed with a semiau-

tomatic, validated BP monitor, for at least 3 days and preferably for

6–7 consecutive days before each clinic visit, with readings in the

morning and the evening, taken in a quiet room after 5 min of rest,

with the patient seated with their back and arm supported. Two

measurements should be taken at each measurement session, per-

formed 1–2 min apart.

Compared with office BP, HBPM values are usually lower, and the

diagnostic threshold for hypertension is >_135/85 mmHg (equivalent

to office BP >_140/90 mmHg) (Table 9) when considering the average

of 3–6 days of home BP values. Compared with office BP, HBPM pro-

vides more reproducible BP data and is more closely related to

HMOD, particularly LVH.

Recent meta-analyses of the few

available prospective studies have further indicated that HBPM better

predicts cardiovascular morbidity and mortality than office BP.

There is alsoevidence that patient self-monitoring may have a benefi-

cial effect on medication adherence and BP control,

60,61

especially

when combined with education and counselling.

Telemonitoring

and smartphone applications may offer additional advantages,

63,64

such as an aid to memory to make BP measurements, and as a con-

venient wayto store and review BP data in a digital diary and transmit

them. We do not recommend the use of apps as a cuff-independent

means of measuring BP.

4.5 Ambulatory blood pressure

monitoring

ABPM provides the average of BP readings over a defined period,

usually 24 h. The device is typically programmed to record BP at

15 - 30 min intervals, and average BP values are usually provided for

daytime, night-time, and 24 h. A diary of the patient’s activities and

sleep time can also be recorded. A minimum of 70% usable BP

recordings are required for a valid ABPM measurement session.

ABPM values are, on average, lower than office BP values, and the

diagnostic threshold for hypertension is >_130/80 mmHg over 24 h,

>_135/85 mmHg for the daytime average, and >_120/70 for the night-

time average (all equivalent to office BP >_140/90 mmHg), see Table 9.

ABPM is a better predictor of HMOD than office BP.

Furthermore, 24 h ambulatory BP mean has been consistently shown

to have a closer relationship with morbid or fatal events,

66–68

and is a

more sensitive risk predictor than office BP of CV outcomes such as

coronary morbid or fatal events and stroke.

68–72

BP normally decreases during sleep. Although the degree of night-

time BP dipping has a normal distribution in a population setting, an

arbitrary cut-off has been proposed to define patients as ‘dippers’ if

their nocturnal BP falls by >10% of the daytime average BP value;

however, the ‘dipping’ status is often highly variable from day to day

and thus is poorly reproducible.

Recognised reasons for an absence

of nocturnal BP dipping are sleep disturbance, obstructive sleep

apnoea, obesity, high salt intake in salt-sensitive subjects, orthostatic

hypotension, autonomic dysfunction, CKD, diabetic neuropathy, and

old age.

Studies that accounted for daytime and night-time BP in

the same statistical model found that night-time BP is a stronger pre-

dictor of outcomes than daytime BP.

The night-to-day ratio is also a

significant predictor of outcome, and patients with a reduced night-

time dip in BP (i.e. <10% of the daytime average BP or a night-to-day

ratio >0.9) have an increased cardiovascular risk.

Moreover, in

those in whom there is no night-time dip in BP or a higher night-time

than daytime average BP, there is a substantially increase in risk.

Paradoxically, there is also some evidence of increased risk in patients

who have extreme dipping of their night-time BP,

although the lim-

ited prevalence and reproducibility of this phenomenon makes inter-

pretation of data difficult.

A number of additional indices derived from ABPM recordings

have some prognostic value, including 24 h BP variability,

morning

BP surge,

and the ambulatory arterial stiffness index.

However,

their incremental predictive value is not yet clear. Thus, these indices

should be regarded as research tools, with no current indication for

routine clinical use.

Table 9 Deﬁnitions of hypertension according to

ofﬁce, ambulatory, and home blood pressure levels

Category SBP

(mmHg)

DBP

(mmHg)

Ofﬁce BP

>_140 and/or >_90

Ambulatory BP

Daytime (or awake) mean >_135 and/or >_85

Night-time (or asleep) mean >_120 and/or >_70

24 h mean >_130 and/or >_80

Home BP mean >_135 and/or >_85

BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood

pressure.

Refers to conventional ofﬁce BP rather than unattended ofﬁce BP.

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4.6 Advantages and disadvantages of

ambulatory blood pressure monitoring

and home blood pressure monitoring

A major advantage of both ABPM and HBPM is that they enable the

diagnosis of white-coat and masked hypertension (see section 4.7).

The relative advantages and disadvantages of HBPM and ABPM are

shown in Table 10. A particularly important advantage of HBPM is

that it is much cheaper and thus more available than ABPM. Another

is that it provides multiple measurements over several days or even

longer periods, which is clinically relevant because day-to-day BP vari-

ability may have an independent prognostic value.

Unlike ABPM,

typical HBPM devices do not provide BP measurements during rou-

tine daily activities and during sleep, although recent technical advan-

ces may allow BP during sleep to be measured by HBPM. A further

consideration is the potential impact of impaired cognition on the

reliability of HBPM measurements and rare instances of obsessional

behaviour, circumstances that may favour the use of ABPM if out-of-

office BP readings are required. In general, both methods should be

regarded as complementary rather than absolute alternatives.

Despite the advances in out-of-office BP measurement over the

past 50 years, some fundamental questions remain, the most impor-

tant of which is whether HBPM- or ABPM-guided therapy results in

greater reductions in morbidity and mortality than conventional

office BP-guided treatment, which has been the diagnostic strategy

for all clinical outcome trials.

4.7 White-coat hypertension and masked

hypertension

White-coat hypertension refers to the untreated condition in which

BP is elevated in the office, but is normal when measured by ABPM,

HBPM, or both.

Conversely, ‘masked hypertension’ refers to

untreated patients in whom the BP is normal in the office, but is

elevated when measured by HBPM or ABPM.

The term ‘true nor-

motension’ is used when both office and out-of-office BP measure-

ments are normal, and ‘sustained hypertension’ is used when both

are abnormal. In white-coat hypertension, the difference between

the higher office and the lower out-of-office BP is referred to as the

‘white-coat effect’, and is believed to mainly reflect the pressor

response to an alerting reaction elicited by office BP measurements

byadoctororanurse,

although other factors are probably also

involved.

Although the terms white-coat and masked hypertension were

originally defined for people who were not being treated for hyper-

tension, they are now also used to describe discrepancies between

office and out-of-office BP in patients treated for hypertension, with

the terms masked uncontrolled hypertension (MUCH) (office BP

controlled but home or ambulatory BP elevated) and white-coat

uncontrolled hypertension (WUCH) (office BP elevated but home

or ambulatory BP controlled), compared with sustained uncontrolled

hypertension (SUCH)

(both office and home or ambulatory BP are

uncontrolled).

The white-coat effect is used to describe the difference between

an elevated office BP (treated or untreated) and a lower home or

ambulatory BP in both untreated and treated patients.

4.7.1 White-coat hypertension

Although the prevalence varies between studies, white-coat hyper-

tension can account for up to 30 - 40% of people (and >50% in the

very old) with an elevated office BP. It is more common with increas-

ing age, in women, and in non-smokers. Its prevalence is lower in

patients with HMOD, when office BP is based on repeated measure-

ments, or when a doctor is not involved in the BP measurement. A

significant white-coat effect can be seen at all grades of hypertension

(including resistant hypertension), but the prevalence of white-coat

hypertension is greatest in grade 1 hypertension.

Table 10 Comparison of ambulatory blood pressure monitoring and home blood pressure monitoring

ABPM HBPM

Advantages Advantages

•Can identify white-coat and masked hypertension

•Stronger prognostic evidence

•Night-time readings

•Measurement in real-life settings

•Additional prognostic BP phenotypes

•Abundant information from a single measurement session, including

short-term BP variability

•Can identify white-coat and masked hypertension

•Cheap and widely available

•Measurement in a home setting, which may be more relaxed than

the doctor’s ofﬁce

•Patient engagement in BP measurement

•Easily repeated and used over longer periods to assess day-to-day BP

variability

Disadvantages

•Expensive and sometimes limited availability

•Can be uncomfortable

Disadvantages

•Only static BP is available

•Potential for measurement error

•No nocturnal readings

ABPM = ambulatory blood pressure monitoring; BP = blood pressure; HBPM = home blood pressure monitoring.

Techniques are being developed to enable nocturnal BP measurement with home BP devices.

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HMOD is less prevalent in white-coat hypertension than in sus-

tained hypertension, and recent studies show that the risk of cardio-

vascular events associated withwhite-coat hypertension is also lower

than that in sustained hypertension.

68,85,86

Conversely, compared

with true normotensives, patients with white-coat hypertension have

increased adrenergic activity,

a greater prevalence of metabolic risk

factors, more frequent asymptomatic cardiac and vascular damage,

and a greater long-term risk of new-onset diabetes and progression

to sustained hypertension and LVH.

In addition, although the out-

of-office BP values are, by definition, normal in white-coat hyperten-

sion, they tend to be higher than those of true normotensive people,

which may explain the increased long-term risk of CV events

reported in white-coat hypertension by recent studies after adjust-

ment for demographic and metabolic risk factors.

85,86,88–90

White-

coat hypertension has also been shown to have a greater CV risk in

isolated systolic hypertension and older patients,

and does not

appear to be clinically innocent.

The diagnosis should be confirmed

by repeated office and out-of-office BP measurements, and should

include an extensive assessment of risk factors and HMOD. Both

ABPM and HBPM are recommended to confirm white-coat hyper-

tension, because the CV risk appears to be lower (and close to sus-

tained normotension) in those in whom both ABPM and HBPM are

both normal;

for treatment considerations see section 8.4.

4.7.2 Masked hypertension

Masked hypertension can be found in approximately 15% of patients

with a normal office BP.

The prevalence is greater in younger peo-

ple, men, smokers, and those with higher levels of physical activity,

alcohol consumption, anxiety, and job stress.

Obesity, diabetes,

CKD, family history of hypertension, and high–normal office BP are

also associated with an increased prevalence of masked hyperten-

sion.

Masked hypertension is associated with dyslipidaemia and dys-

glycaemia, HMOD,

adrenergic activation, and increased risk of

developing diabetes and sustained hypertension.

81,93

Meta-analyses

and recent studies

have shown that the risk of CV events is substan-

tially greater in masked hypertension compared with normotension,

and close to or greater than that of sustained hypertension.

68,93–96

Masked hypertension has also been found to increase the risk of CV

and renal events in diabetes, especially when the BP elevation occurs

during the night.

95,97

4.8 Screening for the detection of

hypertension

Hypertension is predominantly an asymptomatic condition that is

best detected by structured population screening programmes or

opportunistic measurement of BP. When structured population

screening programmes have been undertaken, an alarming number of

people (>50%) were unaware they had hypertension.

12,98

This high

rate of undetected hypertension occurred irrespective of the income

status of the countries studied across the world.

All adults should have their BP recorded in their medical record

and be aware of their BP, and further screening should be undertaken

at regular intervals with the frequency dependent on the BP level. For

healthy people with an optimal office BP (<120/80 mmHg), BP should

be remeasured at least every 5 years and more frequently when

opportunities arise. In patients with a normal BP (120–129/80–84),

BP should be remeasured at least every 3 years. Patients with

high–normal BP (130–139/85–89 mmHg) should have their BP

recorded annually because of the high rates of progression of

high–normal BP to hypertension. This is true also for people in

whom masked hypertension is detected.

4.9 Confirming the diagnosis of

hypertension

BP can be highly variable, thus the diagnosis of hypertension should

not be based on a single set of BP readings at a single office visit,

unless the BP is substantially increased (e.g. grade 3 hypertension)

and there is clear evidence of HMOD (e.g. hypertensive retinopathy

with exudates and haemorrhages, or LVH, or vascular or renal dam-

age). For all others (i.e. almost all patients), repeat BP measurements

at repeat office visits have been a long-standing strategy to confirm a

persistent elevation in BP, as well as for the classification of the hyper-

tension status in clinical practice and RCTs. The number of visits and

the time interval between visits varies according to the severity of the

hypertension, and is inversely related to the severity of hypertension.

Thus, more substantial BP elevation (e.g. grade 2 or more) requires

fewer visits and shorter time intervals between visits (i.e. a few days

or weeks), depending on the severity of BP elevation and whether

there is evidence of CVD or HMOD. Conversely, in patients with BP

elevation in the grade 1 range, the period of repeat measurements

may extend over a few months, especially when the patient is at low

risk and there is no HMOD. During this period of BP assessment, CV

risk assessment and routine screening tests are usually performed

(see section 3).

These Guidelines also support the use of out-of-office BP meas-

urements (i.e. HBPM and/or ABPM) as an alternative strategy to

repeated office BP measurements to confirm the diagnosis of hyper-

tension, when these measurements are logistically and economically

feasible (Figure 2).

This approach can provide important supple-

mentary clinical information, e.g. detecting white-coat hypertension

(see section 4.7.1), which should be suspected, especially in people

with grade 1 hypertension on office BP measurement and in whom

there is no evidence of HMOD or CVD

100

(Table 11). A particular

challenge is the detection of masked hypertension (see section 4.7.2).

Masked hypertension is more likely in people with a BP in the

high–normal range in whom out-of-office BP should be considered

to exclude masked hypertension (see Table 8). Out-of-office BP

measurements are also indicated in specific circumstances (see sec-

tion 4.10 and Table 11).

4.10 Clinical indications for out-of-office

blood pressure measurements

Out-of-office BP measurements are increasingly used, especially

HBPM but also ABPM, to confirm the diagnosis of hypertension.

Out-of-office BP measurement provides important complementary

information, as discussed above. The clinical indications for out-of-

office BP measurements are shown in Table 11. HBPM is also increas-

ingly used by patients to monitor their BP control, which increases

their engagement and may improve their adherence to treatment

and BP control.

61,101,102

It is likely that, with increased availability and

lower cost of these devices, this will become more commonplace.

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Figure 2 Screening and diagnosis of hypertension. ABPM = ambulatory blood pressure monitoring; BP = blood pressure; HBPM = home blood

pressure monitoring.

Table 11 Clinical indications for home blood pressure monitoring or ambulatory blood pressure monitoring

Conditions in which white-coat hypertension is more common, e.g.:

•Grade I hypertension on ofﬁce BP measurement

•Marked ofﬁce BP elevation without HMOD

Conditions in which masked hypertension is more common, e.g.:

•High–normal ofﬁce BP

•Normal ofﬁce BP in individuals with HMOD or at high total CV risk

Postural and post-prandial hypotension in untreated and treated patients

Evaluation of resistant hypertension

Evaluation of BP control, especially in treated higher-risk patients

Exaggerated BP response to exercise

When there is considerable variability in the ofﬁce BP

Evaluating symptoms consistent with hypotension during treatment

Speciﬁc indications for ABPM rather than HBPM:

•Assessment of nocturnal BP values and dipping status (e.g. suspicion of nocturnal hypertension, such as in sleep apnoea, CKD, diabetes, endo-

crine hypertension, or autonomic dysfunction)

ABPM = ambulatory blood pressure monitoring; BP = blood pressure; CKD = chronic kidney disease; CV = cardiovascular; HBPM = home blood pressure monitoring; HMOD

= hypertension-mediated organ damage.

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4.11 Blood pressure during exercise and

at high altitude

It is important to recognise that BP increases during dynamic and

static exercise, and that the increase is more pronounced for SBP

than for DBP,

103

although only SBP can be measured reliably with

non-invasive methods. There is currently no consensus on normal

BP response during exercise. The increase in SBP during exercise is

related to pre-exercise resting BP, age, arterial stiffness, and

abdominal obesity, and is somewhat greater in women than in men

and in unfit individuals. There is some evidence that an excessive

rise in BP during exercise predicts the development of hyperten-

sion, independently from BP at rest.

104

Nevertheless, exercise test-

ing is not recommended as part of the routine evaluation of

hypertension because of various limitations, including a lack of

standardization of methodology and definitions. Importantly,

except in the presence of very high BP values (grade 3 hyperten-

sion), patients, or athletes, with treated or untreated hypertension

should not be discouraged from regular exercise, especially aerobic

exercise, which is considered beneficial as part of lifestyle changes

to reduce BP (see section 7.4.1).

Evidence is available that BP increases with high altitude expo-

sure, especially above 3000 m and possibly above 2000 m.

105

This

is due to a number of factors including sympathetic activation.

Patients with grade 2 hypertension and increased CV risk should

check their BP values before and during high altitude (>2500 m)

exposure. Patients with grade 1 hypertension may reach very high

altitude (>4000 m) with adequate medical therapy; uncontrolled

severe hypertensive patients (grade 3) should avoid exposure to

very high altitude.

105

4.12 Central aortic pressure

Various techniques allow aortic BP (central BP) to be derived from

peripheral BP measurements using dedicated algorithms.

106,107

Some studies and meta-analyses have shown that in hypertensive

patients, central BP predicts CV events and that there is a differen-

tial effect of antihypertensive drugs on central compared with bra-

chial BP.

108

The incremental prognostic value of central vs.

conventional clinic BP measurement remains unclear.

109

An excep-

tion may be isolated systolic hypertension in the young, in whom

peripheral BP may be disproportionately elevated relative to a nor-

mal central BP. This occurs in a small fraction of younger people,

mainly men with isolated systolic hypertension, and it remains

unclear whether such patients are at lower risk than suggested by

their brachial office BP.

110,111

BP measurement

Recommendations Class

Level

Screening programmes for hypertension are

recommended. All adults (18 years or

older) should have their ofﬁce BP measured

and recorded in their medical ﬁle, and be

aware of their BP.

12,98

•Further BP recording is indicated, at least

every 5 years if BP remains optimal. IC

•Further BP recording is indicated, at least

every 3 years if BP remains normal. IC

•If BP remains high–normal, further BP

recording, at least annually, is

recommended.

•In older patients (>50 years), more fre-

quent screening of ofﬁce BP should be

considered for each BP category because

of the steeper rise in SBP with ageing.

IIa C

It is recommended that ofﬁce BP should be

measured in both arms at least at the ﬁrst

visit because a between-arm SBP difference

of >15 mmHg is suggestive of atheromatous

disease and is associated with an increased

CV risk.

If a between-arm difference in BP is

recorded, then it is recommended that all

subsequent BP readings use the arm with

the higher BP reading.

It is recommended that the diagnosis of

hypertension should be based on:

•Repeated ofﬁce BP measurements on

more than one visit, except when hyper-

tension is severe (e.g. grade 3 and espe-

cially in high-risk patients). At each visit,

three BP measurements should be

recorded, 1–2 min apart, and additional

measurements should be performed if

the ﬁrst two readings differ by >10

mmHg. The patient’s BP is the average of

the last two BP readings.

•Out-of-ofﬁce BP measurement with

ABPM and/or HBPM, provided that

these measurements are logistically and

economically feasible.

Continued

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5 Clinical evaluation and

assessment of hypertension-

mediated organ damage in

patients with hypertension

5.1 Clinical evaluation

The purpose of the clinical evaluation is to establish the diagnosis and

grade of hypertension, screen for potential secondary causes of

hypertension, identify factors potentially contributing to the develop-

ment of hypertension (lifestyle, concomitant medications, or family

history), identify concomitant CV risk factors (including lifestyle and

family history), identify concomitant diseases, and establish whether

there is evidence of HMOD or existing CV, cerebrovascular, or renal

disease.

5.2 Medical history

A thorough medical history (Table 12) should address in particular:

•Time of the first diagnosis of hypertension, including records of

any previous medical screening, hospitalization, etc.

•Record any current and past BP values

•Record current and past antihypertensive medications

•Record other medications

•Family history of hypertension, CVD, stroke, or renal disease

•Lifestyle evaluation, including exercise levels, body weight

changes, diet history, smoking history, alcohol use, recreational

drug use, sleep history, and impact of any treatments on sexual

function

•History of any concomitant CV risk factors

•Details and symptoms of past and present comorbidities

Out-of-ofﬁce BP (i.e. ABPM or HBPM) is

speciﬁcally recommended for a number of

clinical indications, such as identifying white-

coat and masked hypertension, quantifying

the effects of treatment, and identifying pos-

sible causes of side effects

17,54,62,68,72

(e.g.

symptomatic hypotension).

It is recommended that all hypertensive

patients undergo pulse palpation at rest to

determine heart rate and search for

arrhythmias such as AF.

20,47

Other BP measures and indices (pulse pres-

sure, BP variability, exercise BP, and central

BP) may be considered but are not often

used for routine clinical use at present.

They may provide useful additional informa-

tion in some circumstances and are valuable

tools for research.

IIb C

ABPM = ambulatory blood pressure monitoring; AF = atrial ﬁbrillation; BP =

blood pressure; CV = cardiovascular; HBPM = home blood pressure monitoring;

SBP = systolic blood pressure.

Class of recommendation.

Level of evidence.

Table 12 Key information to be collected in personal

and family medical history

Risk factors

Family and personal history of hypertension, CVD, stroke, or renal

disease

Family and personal history of associated risk factors (e.g. familial

hypercholesterolaemia)

Smoking history

Dietary history and salt intake

Alcohol consumption

Lack of physical exercise/sedentary lifestyle

History of erectile dysfunction

Sleep history, snoring, sleep apnoea (information also from partner)

Previous hypertension in pregnancy/pre-eclampsia

History and symptoms of HMOD, CVD, stroke, and renal

disease

Brain and eyes: headache, vertigo, syncope, impaired vision, TIA,

sensory or motor deﬁcit, stroke, carotid revascularization, cognitive

impairment, dementia (in the elderly)

Heart: chest pain, shortness of breath, oedema, myocardial infarc-

tion, coronary revascularization, syncope, history of palpitations,

arrhythmias (especially AF), heart failure

Kidney: thirst, polyuria, nocturia, haematuria, urinary tract infections

Peripheral arteries: cold extremities, intermittent claudication, pain-

free walking distance, pain at rest, peripheral revascularization

Patient or family history of CKD (e.g. polycystic kidney disease)

History of possible secondary hypertension

Young onset of grade 2 or 3 hypertension (<40 years), or sudden

development of hypertension or rapidly worsening BP in older

patients

History of renal/urinary tract disease

Recreational drug/substance abuse/concurrent therapies: corticoste-

roids, nasal vasoconstrictor, chemotherapy, yohimbine, liquorice

Repetitive episodes of sweating, headache, anxiety, or palpitations,

suggestive of Phaeochromocytoma

History of spontaneous or diuretic-provoked hypokalaemia, epi-

sodes of muscle weakness, and tetany (hyperaldosteronism)

Symptoms suggestive of thyroid disease or hyperparathyroidism

History of or current pregnancy and oral contraceptive use

History of sleep apnoea

Antihypertensive Drug Treatment

Current/past antihypertensive medication including effectiveness

and intolerance to previous medications

Adherence to therapy

AF = atrial ﬁbrillation; BP = blood pressure; CKD = chronic kidney disease; CVD

= cardiovascular disease; HMOD = hypertension-mediated organ damage; TIA =

transient ischaemic attack.

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•Specific history of potential secondary causes of hypertension

(see section 8.2)

•History of past pregnancies and oral contraceptive use

•History of menopause and hormone replacement therapy

•Use of liquorice

•Use of drugs that may have a pressor effect.

5.3 Physical examination and clinical

investigations

Physical examination provides important indications of potential

causes of secondary hypertension, signs of comorbidities, and

HMOD. Office BP and heart rate should be measured as summarized

in section 4. Measurements of office BP on more than one occasion

are usually required to confirm the diagnosis of hypertension unless

HBPM or ABPM is used to confirm the diagnosis (see section 4).

Details of the requirements for a comprehensive clinical examina-

tion are outlined in Table 13, and this should be adapted according to

the severity of hypertension and clinical circumstances. Suggested

routine clinical investigations are outlined in Table 14.

5.4 Assessment of hypertension-

mediated organ damage

HMOD refers to structural or functional changes in arteries or end

organs (heart, blood vessels, brain, eyes, and kidney) caused by an

elevated BP, and is a marker of pre-clinical or asymptomatic CVD.

112

HMOD is common in severe or long-standing hypertension, but can

also be found in less severe hypertension. With wider use of imaging,

HMOD is becoming increasingly apparent in asymptomatic

patients.

CV risk increases with the presence of HMOD, and more

so when damage affects multiple organs.

16,113,114

Some types of

HMOD can be reversed by antihypertensive treatment, especially

when used early, but with long-standing hypertension, HMOD may

become irreversible despite improved BP control.

115,116

Nevertheless, BP-lowering treatment is still important as it may delay

the further progression of HMOD and will reduce the elevated CV

risk of these patients.

116

Although poor technical provision and cost

may limit the search for HMOD in some countries, it is recom-

mended that basic screening for HMOD is performed in all hyperten-

sive patients and more detailed assessment is performed when the

presence of HMOD might influence treatment decisions. The various

investigations to establish HMOD are shown in Table 15.

5.4.1 Using hypertension-mediated organ damage to help

stratify risk in hypertensive patients

As discussed in section 3, hypertensive patients with documented

CVD, diabetes, CKD, grade 3 hypertension, or marked cholesterol

elevation (e.g. familial hypercholesterolaemia) are already at high or

very high CV risk (>_10% risk of a fatal event). Thus, the presence of

HMOD is unlikely to influence treatment, as these patients should

Table 14 Routine workup for evaluation of hyperten-

sive patients

Routine laboratory tests

Haemoglobin and/or haematocrit

Fasting blood glucose and glycated HbA

Blood lipids: total cholesterol, LDL cholesterol, HDL

cholesterol

Blood triglycerides

Blood potassium and sodium

Blood uric acid

Blood creatinine and eGFR

Blood liver function tests

Urine analysis: microscopic examination; urinary protein by dip-

stick test or, ideally, albumin:creatinine ratio

12-lead ECG

eGFR = estimated glomerular ﬁltration rate; ECG = electrocardiogram; HbA

haemoglobin A1c.

Table 13 Key steps in physical examination

Body habitus

Weight and height measured on a calibrated scale, with calcula-

tion of BMI

Waist circumference

Signs of HMOD

Neurological examination and cognitive status

Fundoscopic examination for hypertensive retinopathy

Palpation and auscultation of heart and carotid arteries

Palpation of peripheral arteries

Comparison of BP in both arms (at least once)

Secondary hypertension

Skin inspection: cafe-au-lait patches of neuroﬁbromatosis

(phaeochromocytoma)

Kidney palpation for signs of renal enlargement in polycystic kid-

ney disease

Auscultation of heart and renal arteries for murmurs or bruits

indicative of aortic coarctation, or renovascular hypertension

Comparison of radial with femoral pulse: to detect radio-femo-

ral delay in aortic coarctation

Signs of Cushing’s disease or acromegaly

Signs of thyroid disease

BMI = body mass index; BP = blood pressure; HMOD = hypertension-mediated

organ damage.

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already receive lifestyle interventions, BP-lowering medications, sta-

tins, and in some cases antiplatelet therapy, to reduce their risk

(see section 9).

The main advantage of detecting HMOD is that it may reclassify a

patient’s SCORE risk assessment from low to moderate or from

moderate to high risk.

117

The specific impact of HMOD

114

with

regard to the reclassification of risk estimation according to the

SCORE system has not been clearly defined. The SCORE system

already takes account of the grade of hypertension as SBP is included

in the risk calculation. Moreover, CKD and the presence of vascular

disease on imaging are already specified as high or very high risk

(Table 5). Conditioning of the risk score by the presence of HMOD

will be most important in middle-aged patients with hypertension,

many of whom will be at moderate-risk and at higher risk if HMOD is

detected. Moreover, a risk-conditioning effect of HMOD will also be

important in younger hypertensive patients who are invariably classi-

fied as low risk according to the SCORE system. In addition, detecting

HMOD in younger patients with grade 1 hypertension provides

unequivocal evidence of hypertension-mediated damage and indi-

cates a clear need for BP-lowering treatment in patients who may be

reluctant to be treated. For the same reason, the presence of

HMOD in a patient with high–normal BP would also provide a

rationale to consider BP-lowering treatment.

Another important consideration is whether the presence of a

specific manifestation of HMOD (e.g. LVH or CKD) might influence

the selection of drug treatment for hypertension. This was consid-

ered important in the previous guidelines,

but is now considered

less important. In patients more likely to have HMOD (i.e. those with

high grade 1 or grade 2–3 hypertension), we now recommend initial

treatment with a combination of two drugs, usually an angiotensin-

converting enzyme (ACE) inhibitor or angiotensin receptor blocker

(ARB) in combination with a calcium channel blocker (CCB) or

thiazide-type diuretic, which would be the optimal treatment for all

manifestations of HMOD (see section 7).

Table 15 Assessment of hypertension-mediated organ damage

Basic screening tests for HMOD Indication and interpretation

12-lead ECG Screen for LVH and other possible cardiac abnormalities, and to document heart rate and cardiac

rhythm

Urine albumin:creatinine ratio To detect elevations in albumin excretion indicative of possible renal disease

Blood creatinine and eGFR To detect possible renal disease

Fundoscopy To detect hypertensive retinopathy, especially in patients with grade 2 or 3 hypertension

More detailed screening for HMOD

Echocardiography To evaluate cardiac structure and function, when this information will inﬂuence treatment

decisions

Carotid ultrasound To determine the presence of carotid plaque or stenosis, particularly in patients with cerebrovas-

cular disease or vascular disease elsewhere

Abdominal ultrasound and Doppler studies •To evaluate renal size and structure (e.g. scarring) and exclude renal tract obstruction as pos-

sible underlying causes of CKD and hypertension

•Evaluate abdominal aorta for evidence of aneurysmal dilatation and vascular disease

•Examine adrenal glands for evidence of adenoma or phaeochromocytoma (CT or MRI pre-

ferred for detailed examination); see section 8.2 regarding screening for secondary

hypertension

•Renal artery Doppler studies to screen for the presence of renovascular disease, especially in

the presence of asymmetric renal size

PWV An index of aortic stiffness and underlying arteriosclerosis

ABI Screen for evidence of LEAD

Cognitive function testing To evaluate cognition in patients with symptoms suggestive of cognitive impairment

Brain imaging To evaluate the presence of ischaemic or haemorrhagic brain injury, especially in patients with a

history of cerebrovascular disease or cognitive decline

ABI = ankle-brachial index; CKD = chronic kidney disease; CT = computed tomography; ECG = electrocardiogram; eGFR = estimated glomerular ﬁltration rate; HMOD =

hypertension-mediated organ damage; LEAD = lower extremity artery disease; LVH = left ventricular hypertrophy; MRI = magnetic resonance imaging; PWV = pulse wave

velocity.

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5.5 Characteristics of hypertension-

mediated organ damage

5.5.1 The heart in hypertension

Chronically increased left ventricular (LV) workload in hypertensive

patients can result in LVH, impaired LV relaxation, left atrial enlarge-

ment, an increased risk of arrhythmias, especially AF, and an

increased risk of heart failure with preserved ejection fraction

(HFpEF) and heart failure with reduced ejection fraction (HFrEF).

5.5.1.1 Electrocardiogram

A 12-lead electrocardiogram (ECG) should be part of the routine

assessment in all hypertensive patients. The ECG is not a particularly

sensitive method of detecting LVH and its sensitivity varies according

to body weight. ECG LVH provides independent prognostic informa-

tion, even after adjusting for other CV risk factors and echocardio-

graphic LV mass.

118

In addition to LVH, the presence of a ‘strain

pattern’ on an ECG is associated with increased risk.

119

The preva-

lence of ECG LVH increases with the severity of hypertension.

120

The most commonly used criteria to define ECG LVH are shown in

Table 16.

The ECG cannot exclude LVH because it has poor sensitivity.

When detailed information on cardiac structure and function will

influence treatment decisions, echocardiography is recommended.

When LVH is present on the ECG, it can be used to detect changes

in LVH during follow-up in untreated and treated patients.

121,122

5.5.1.2 Transthoracic echocardiography in hypertension

Echocardiographic LVH is a potent predictor of mortality in both

hypertensive patients and the general population,

123,124

and regres-

sion of echocardiographic LVH due to treatment of hypertension

predicts an improved prognosis.

125

Two-dimensional transthoracic

echocardiography (TTE) also provides information about LV geome-

try, left atrial volume, aortic root dimensions, LV systolic and diastolic

function, pump performance, and output impedance.

123,126,127

Whether additional parameters other than evidence of increased LV

mass and left atrial dilatation are useful to help stratify CV risk is

uncertain.

123,126,128

The partition values recommended for the defini-

tion of LVH by echocardiography are shown in Table 17.

Three-dimensional TTE is a more reliable method for quantitative

analysis,

129

specifically for LV mass,

130

volumes, and ejection fraction,

and has superior reproducibility to two-dimensional TTE but much

less prognostic validation.

131

More detailed information on the use of

echocardiography to assess the hypertensive heart is available.

Cardiac magnetic resonance is the gold standard for cardiac anatomi-

cal and functional quantification.

132–134

Abnormal LV geometry in hypertensive patients is frequently asso-

ciated with diastolic dysfunction,

127,135

which can be further eval-

uated by a combination of transmitral flow and tissue Doppler

studies.

136

Left atrial size is also frequently increased in hypertensive

patients and is associated with adverse CV events

128,137

and incident

AF,

138

and is related to diastolic dysfunction.

139,140

During the diag-

nostic workup for secondary hypertension, a suprasternal view

should also be performed for the identification of aortic

coarctation.

141

5.5.2 The blood vessels in hypertension

5.5.2.1 Carotid artery

Carotid intima-media thickness (IMT) quantified by carotid ultra-

sound, and/or the presence of plaques, predicts CV risk.

42,142

This

holds true both for the IMT value at the carotid bifurcations (reflect-

ing primarily atherosclerosis) and for the IMT value at the level of the

common carotid artery (reflecting primarily hypertension-related

hypertrophy). A carotid IMT >0.9 mm is considered abnormal,

143

but the upper limit of normality varies with age. The presence of a

plaque can be identified by an IMT >_1.5 mm, or by a focal increase in

thickness of 0.5 mm or 50% of the surrounding carotid IMT value.

144

Stenotic carotid plaques have a strong predictive value for both

Table 16 The most commonly used simple criteria

and recognised cut-off points for deﬁnitions of electro-

cardiogram left ventricular hypertrophy

ECG voltage criteria Criteria for LVH

þR

(Sokolow–Lyon criterion) >35 mm

R wave in aVL >_11 mm

þR

aVL

(Cornell voltage)

Cornell duration product

>28 mm (men)

>20 mm (women)

>2440 mm.ms

ECG = electrocardiogram; LVH = left ventricular hypertrophy.

Sum of limb and precordial lead voltage.

Product of Cornell voltage x QRS duration (mm.ms).

Table 17 Echocardiographic deﬁnitions of left ventric-

ular hypertrophy, concentric geometry, left ventricular

chamber size, and left atrial dilatation

Parameter Measure Abnormality

threshold

LVH LV mass/height

2.7

(g/m

2.7

) >50 (men)

>47 (women)

LVH

LV mass/BSA (g/m

) >115 (men)

>95 (women)

LV concentric

geometry

RWT >_0.43

LV chamber size LV end-diastolic

diameter/height (cm/m)

>3.4 (men)

>3.3 (women)

Left atrial size

(elliptical)

Left atrial volume/height

(mL/m

)

>18.5 (men)

>16.5 (women)

BSA = body surface area; LV = left ventricular; LVH = left ventricular hypertro-

phy; RWT = relative wall thickness.

BSA normalization may be used in normal weight patients.

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stroke and myocardial infarction, independent of traditional CV risk

factors,

42,142

and confer superior prognostic accuracy for future myo-

cardial infarction compared with IMT.

145

The presence of carotid pla-

ques will automatically reclassify patients from intermediate to high

risk;

146,147

however, routine carotid imaging is not recommended

unless clinically indicated (i.e. presence of carotid bruit, previous TIA

or cerebrovascular disease, or as part of the assessment of patients

with evidence of vascular disease).

5.5.2.2 Pulse wave velocity

Large artery stiffening is the most important pathophysiological

determinant of isolated systolic hypertension and age-dependent

increase in pulse pressure.

148

Carotid-femoral pulse wave velocity

(PWV) is the gold standard for measuring large artery stiffness.

149

Reference values for PWV are available in healthy populations and

patients at increased CV risk.

150

A PWV >10 m/s is considered a con-

servative estimate of significant alterations of aortic function in

middle-aged hypertensive patients.

149

The additive value of PWV

above and beyond traditional risk factors, including SCORE and the

Framingham risk score, has been suggested by several studies.

151

However, routine use of PWV measurement is not practical and is

not recommended for routine practice.

5.5.2.3 Ankle–brachial index

Ankle-brachial index (ABI) may be measured either with automated

devices, or with a continuous wave Doppler unit and a BP sphyg-

momanometer. A low ABI (i.e. <0.9) indicates lowerextremity artery

disease (LEAD), is usually indicative of advanced atherosclerosis,

152

and has predictive value for CV events,

153

being associated with an

almost two-fold greater 10 year CV mortality and major coronary

event rate, compared with the overall rate in each Framingham cate-

gory.

153

Even asymptomatic LEAD, detected by a low ABI, is associ-

ated in men with a high incidence of CV morbid and fatal events,

approaching 20% in 10 years.

153,154

Routine use of ABI is not recom-

mended in hypertensive patients, but should be considered in

patients with symptoms or signs of LEAD, or in moderate-risk

patients in whom a positive test would reclassify the patient as high-

risk.

5.5.3 The kidney in hypertension

Hypertension is the second most important cause of CKD after dia-

betes. Hypertension may also be the presenting feature of asympto-

matic primary renal disease. An alteration of renal function is most

commonly detected by an increase in serum creatinine. This is an

insensitive marker of renal impairment because a major reduction in

renal function is needed before serum creatinine rises. Furthermore,

BP reduction by antihypertensive treatment often leads to an acute

increase in serum creatinine by as much as 20–30%, especially with

renin-angiotensin system (RAS) blockers, which has a functional basis

and does not usually reflect manifest renal injury, but the long-term

clinical significance is unclear.

155,156

The diagnosis of hypertension-

induced renal damage is based on the finding of reduced renal func-

tion and/or the detection of albuminuria. CKD is classified according

to estimated glomerular filtration rate (eGFR), calculated by the 2009

CKD-Epidemiology Collaboration formula.

157

The albumin:creatinine ratio (ACR) is measured from a spot urine

sample (preferably early morning urine), and is the preferred method

to quantify urinary albumin excretion. A progressive reduction in

eGFR and increased albuminuria indicate progressive loss of renal

function, and are both independent and additive predictors of

increased CV risk and progression of renal disease.

158

Serum creatinine, eGFR, and ACR should be documented in all

hypertensive patients, and if CKD is diagnosed, repeated at least

annually.

159

One negative urinary dipstick test does not rule out albu-

minuria, in contrast to a normal ACR.

160

5.5.4 Hypertensive retinopathy

The prognostic significance of hypertensive retinopathy by fundo-

scopy has been well documented.

161

Detection of retinal haemor-

rhages, microaneurysms, hard exudates, cotton wool spots, and

papilloedema is highly reproducible, indicates severe hypertensive

retinopathy, and is highly predictive of mortality.

161,162

In contrast,

evidence of arteriolar narrowing, either focal or general, and arterio-

venous nicking at early stages of hypertensive retinopathy have less

predictive value,

163

and limited interobserver and intraobserver

reproducibility, even with experienced observers.

164

Fundoscopy

should be performed in patients with grade 2 or 3 hypertension or

hypertensive patients with diabetes, in whom significant retinopathy

is more likely. Fundoscopy may be considered in other hypertensive

patients. The increasing emergence of new techniques to visualize

the fundus through smartphone technologies should increase the fea-

sibility of more routine fundoscopy.

165

5.5.5 The brain in hypertension

Hypertension increases the prevalence of brain damage, of which

transient ischaemic attack (TIA) and stroke are the most dramatic

acute clinical manifestations. In the asymptomatic phase, brain dam-

age can be detected by magnetic resonance imaging (MRI) as white

matter hyperintensities, silent microinfarcts, (most of which are small

and deep, i.e. lacunar infarctions), microbleeds, and brain atro-

phy.

166,167

White matter hyperintensities and silent infarcts are asso-

ciated with an increased risk of stroke and cognitive decline due to

degenerative and vascular dementia.

166–169

Availability and cost do

not permit the widespread use of brain MRI for the evaluation of

hypertensive patients, but white matter hyperintensity and silent

brain infarcts should be sought in all hypertensive patients with neu-

rological disturbances, cognitive decline, and, particularly, memory

loss.

168,169

A family history of cerebral haemorrhage at middle age

and early-onset dementia should prompt MRI. Cognitive impairment

in older patients is, at least in part, hypertension-related, and cogni-

tive evaluation tests should be considered in the clinical assessment

of hypertensive patients with a history suggestive of early cognitive

impairment. The Mini-Mental State Examination has been the most

widely used method in clinical trials, but is now being superseded by

more sophisticated cognitive tests that are more suitable for routine

clinic visits.

170

5.6 Hypertension-mediated organ

damage regression and cardiovascular

risk reduction with antihypertensive

treatment

As discussed above, HMOD assessment may play a role in stratifying

the risk of patients with hypertension. In post hoc analyses, BP

ESC/ESH Guidelines 25

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treatment-induced regression of some (but not all) manifestations of

asymptomatic HMOD, as a consequence of treatment, is associated

with a reduction in CV risk, thereby providing additional information

on the effectiveness of treatment in individual patients.

16,104,171

This

has been best illustrated for the treatment-induced regression of

LVH measured by either ECG or echocardiography.

125,172,173

reduced incidence of CV events and slower progression of renal dis-

ease has been reported with a treatment-induced reduction in uri-

nary protein excretion in both diabetic and non-diabetic patients,

especially for microalbuminuria,

174

but results are discordant.

175–179

There is also evidence that treatment-induced changes in eGFR pre-

dict CV events

180

and progression to end-stage renal disease.

181,182

Two meta-analyses

183,184

failed to document any predictive value of

treatment-induced reductions in carotid IMT for CV events.

Evidence on the predictive power of treatment-induced changes on

other measures of HMOD (PWV and ABI) are either limited or

absent. Regression of HMOD might not be possible even when BP is

controlled, particularly when HMOD is advanced, because some of

the changes become irreversible.

The information available on the sensitivity and timing of changes

in HMOD during antihypertensive treatment is summarized in

Table 18. If, when, and how often the assessment of HMOD should

be performed has not been validated in follow-up studies. HMOD

can also develop during the course of antihypertensive treatment,

185

and this may be accompanied by increased risk.

186–188

5.7 When to refer a patient with

hypertension for hospital-based care

Hypertension is a very common condition and most patients with

hypertension, in most healthcare systems, will be managed in the pri-

mary care setting. However, there are circumstances in which a

referral for routine hospital-based evaluation and treatment may be

required, keeping in mind that in some instances out-of-office or

office-based care of hypertensive patients depends on the healthcare

organization of a given country:

•Patients in whom secondary hypertension is suspected (see sec-

tion 8.2)

•Younger patients (<40 years) with grade 2 or more severe

hypertension in whom secondary hypertension should be

excluded

•Patients with treatment-resistant hypertension (see section 8.1)

•Patients in whom more detailed assessment of HMOD would

influence treatment decisions

•Patients with sudden onset of hypertension when BP has previ-

ously been normal

•Other clinical circumstances in which the referring doctor feels

more specialist evaluation is required.

There are also rarer circumstances in which a patient with hyper-

tension should be referred to hospital for emergency care, which will

often require inpatient care (see section 8.3).

Table 18 Sensitivity to detect treatment-induced changes, reproducibility and operator independence, time to

changes, and prognostic value of changes provided by markers of hypertension-mediated organ damage

CMR = cardiac magnetic resonance; ECG = electrocardiogram; eGFR = estimated glomerular ﬁltration rate; HMOD = hypertension-mediated organ damage; IMT = intima-

media thickness; LVH = left ventricular hypertrophy; PWV = pulse wave velocity.

26 ESC/ESH Guidelines

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6 Genetics and hypertension

A positive family history is a frequent feature in hypertensive

patients, with the heritability estimated to vary between 35 and

50% in most studies.

191,192

However, hypertension is a highly heter-

ogeneous disorder with a multifactorial aetiology. Several genome-

wide association studies and their meta-analyses have identified

120 loci that are associated with BP regulation, but together these

only explain about 3.5% of the trait variance.

193

Several rare,

monogenic forms of hypertension have been described such as

glucocorticoid-remediable aldosteronism, Liddle’s syndrome, and

others, where a single gene mutation fully explains the pathogenesis

of hypertension and dictates the best treatment modality.

194–196

There are also inherited forms of phaeochromocytoma and para-

ganglioma, which are also rare causes of hypertension.

197–200

Outside of specialist clinics evaluating patients for these rare causes

of secondary hypertension, there is no role for genetic testing in

hypertension in routine clinical care.

Clinical evaluation and HMOD assessment

Recommendations Class

Level

Heart

12-lead ECG is recommended for all hypertensive patients.

120

Echocardiography:

•Is recommended in hypertensive patients when there are ECG abnormalities or signs or symptoms of LV

dysfunction.

42,134

•May be considered when the detection of LVH may inﬂuence treatment decisions.

42,134

IIb B

Blood vessels

Ultrasound examination of the carotid arteries: IB

•May be considered for the detection of asymptomatic atherosclerotic plaques or carotid stenosis in patients with docu-

mented vascular disease elsewhere.

IIb B

Measurement of PWV may be considered for measuring arterial stiffness.

109,189

IIb B

Measurement of ABI may be considered for the detection of advanced LEAD.

153,190

IIb B

Kidney

Measurement of serum creatinine and eGFR is recommended in all hypertensive patients.

180

Measurement of urine albumin:creatinine ratio is recommended in all hypertensive patients.

43,180

Renal ultrasound and Doppler examination should be considered in patients with impaired renal function, albuminuria, or for

suspected secondary hypertension. IIa C

Fundoscopy

Is recommended in patients with grades 2 or 3 hypertension and all hypertensive patients with diabetes. IC

May be considered in other hypertensive patients. IIb C

Brain

In hypertensive patients with neurological symptoms and/or cognitive decline, brain MRI or CT should be considered for

detecting brain infarctions, microbleeds, and white matter lesions.

168,169

IIa B

ABI = ankle–brachial index; CT = computed tomography; ECG = electrocardiogram; eGFR = estimated glomerular ﬁltration rate; HMOD = hypertension-mediated organ dam-

age; LEAD = lower extremity arterial disease; LV = left ventricular; LVH = left ventricular hypertrophy; MRI = magnetic resonance imaging; PWV = pulse wave velocity; TIA =

transient ischaemic attack.

Class of recommendation.

Level of evidence.

ESC/ESH Guidelines 27

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7 Treatment of hypertension

7.1 Beneficial effects of blood pressure-

lowering therapy in hypertension

There are two well-established strategies to lower BP: lifestyle inter-

ventions and drug treatment. Device-based therapy is also emerging,

but is not yet proven as an effective treatment option. Lifestyle inter-

ventions can undoubtedly lower BP and in some cases CV risk (see

section 7.4.1), but most patients with hypertension will also require

drug treatment. The drug treatment of hypertension is founded on

very solid evidence, underpinned by the largest number of outcome-

based RCTs in clinical medicine. Meta-analyses of RCTs including

several hundred thousand patients have shown that a 10 mmHg

reduction in SBP or a 5 mmHg reduction in DBP is associated with

significant reductions in all major CV events by 20%, all-cause mor-

tality by 10- 15%, stroke by 35%, coronary events by 20%, and

heart failure by 40%.

2,8

These relative risk reductions are consis-

tent, irrespective of baseline BP within the hypertensive range, the

level of CV risk, comorbidities (e.g. diabetes and CKD), age, sex, and

ethnicity.

2,201

Relative outcome reductions calculated by two recent meta-

analyses are similar to those provided by the original meta-analysis of

the effects of BP lowering on outcomes in 1994.

202

Thus, the benefits

of antihypertensive treatment have not been attenuated by the wide-

spread concomitant prescription of lipid-lowering and antiplatelet

therapiesin contemporary medicine.

Another important objective of antihypertensive therapy is to

reduce the development of CKD; however, the slow rate of decline

in renal function in most hypertensive patients makes the demonstra-

tion of potential benefits of BP lowering difficult. Consequently, the

protective effect of BP reduction on kidney function can be less

obvious and has been restricted to patients with diabetes or CKD, in

whom there is a faster rate of disease progression.

203

Some, but not

all, RCTs have also shown a protective effective of BP lowering on

the progression of CKD towards end-stage renal disease in both dia-

betic and non-diabetic nephropathy.

The recommendations that follow are based on outcome evidence

from RCTs; however, it must be acknowledged that RCTs based on

clinical outcomes have limitations, the most important of which are

that the data are largely limited to older and high-risk patients, prefer-

entially recruited to increase statistical power, and over a relatively

short duration of follow-up, rarely beyond 5 years. This means that

recommendations for life-long treatment for younger and lower risk

patients are necessarily based on considerable extrapolation. Big

data, now being collected by national health system registries, health

insurance companies, and prolonged observational follow-up of

RCTs, are becoming an important source of long-term information

on the effects of chronic treatment,

204

which adds to that provided

by observational studies over several decades.

205–207

Such evidence

suggests that the benefit of continued treatment is maintained over

decades.

206

7.2. When to initiate antihypertensive

treatment

7.2.1 Recommendations in previous guidelines

All guidelines agree that patients with grade 2 or 3 hypertension

should receive antihypertensive drug treatment alongside lifestyle

interventions.

208

Guidelines are also consistent in recommending

that patients with grade 1 hypertension and high CV risk or HMOD

should be treated with BP-lowering drugs. There has been less con-

sistency about whether BP-lowering drugs should be offered to

patients with grade 1 hypertension and low–moderate CV risk or

grade 1 hypertension in older patients (>60 years), or the need for

BP-lowering drug treatment in patients with high–normal BP lev-

els.

17,209,210

This uncertainty relates to the fact that low-risk patients

with high–normal BP or grade 1 hypertension have rarely been

included in RCTs, and that in older patients, RCTs have invariably

recruited patients with at least grade 2 hypertension. New analyses

and RCT data have become available in these important areas and

are discussed below.

7.2.2 Drug treatment for patients with grade 1

hypertension at lowmoderate cardiovascular risk

Recent meta-analyses show significant treatment-induced reductions

in CV events and mortality in patients with grade 1 hyperten-

sion.

8,201,211

However, the first of these analyses included a substan-

tial number of patients who had grade 1 hypertension despite

existing treatment, and were therefore likely to have had initial BPs

above the grade 1 range. Furthermore, many of the patients had dia-

betes and were therefore at high CV risk.

211

The second meta-

analysis, limited to RCTs in patients with grade 1 hypertension and

low–moderate-risk (five RCTs, 8974 patients), demonstrated a signif-

icant reduction in all major CV eventsby BP-lowering drug treatment

[combined stroke and coronary artery disease (CAD) reduced by

34%, and all-cause mortality by 19% for an SBP reduction of 7

mmHg].

A third analysis demonstrated a benefit of BP lowering in

reducing death and CVD in patients with a baseline BP 140/90 mmHg

or higher, but not when baseline BP was lower.

201

These findings

have been supported by the results of a subgroup analysis of the

Genetic testing and hypertension

Recommendations Class

Level

Genetic testing should be considered in spe-

cialist centres for patients suspected to have

rare monogenic causes of secondary hyper-

tension or for those with

phaeochromocytoma.

198

IIa B

Routine genetic testing for hypertensive

patients is not recommended. III C

Class of recommendation.

Level of evidence.

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Heart Outcomes Prevention Evaluation (HOPE)-3 trial, showing a

significant 27% reduction in major CV outcomes in patients at inter-

mediate CV risk and baseline SBP values in the grade 1 hypertensive

range [i.e. >143.5 mmHg (mean 154 mmHg)] when SBP was lowered

by drug treatment by a mean of6 mmHg.

212

Based on these new data, this Task Force now recommends that

lifestyle advice should be accompanied by BP-lowering drug treat-

ment in patients with grade 1 hypertension at low–moderate CV

risk.

7.2.3 Initiation of blood pressure-lowering drug treat-

ment in older people with grade 1 hypertension

Discussion about the treatment of ‘the elderly’ or ‘older’ people has

been complicated by the various definitions of older age used in

RCTs. For example, older was defined as >60 years in the earliest tri-

als, then as 65, 70, and finally 75

or 80 years

213

in later trials.

Chronological age is often a poor surrogate for biological age, with

consideration of frailty and independence influencing the likely toler-

ability of BP-lowering medications. For the purposes of this guideline,

the ‘old’ are defined as >_65 years and the ‘very old’ as >_80 years. The

previous Guidelines

noted that all available evidence on CV event

reduction by BP lowering in older patients was obtained in patients

whose baseline SBP was >_160 mmHg, and there is strong evidence

that these patients should be offered BP-lowering drug

treatment.

210,214

Undoubtedly, there are RCTs showing outcome benefits with BP-

lowering treatment in older patients whose baseline BP was in a

lower SBP range, but these patients were often on background anti-

hypertensive treatment, thus they cannot be defined as having true

grade 1 hypertension. This is also the case for the data recently pub-

lished from the SPRINT trial, which included a cohort of patients

older than 75 years, in whom more intense BP lowering reduced the

risk of major CV events and mortality.

51,215

However, in most RCTs

showing a protective effect of BP-lowering treatment in patients with

an untreated baseline BP in the grade 1 hypertension range, older

patients were well represented. This was further supported by the

recent HOPE-3 trial, which showed beneficial effects of BP lowering

on CV outcomes in patients, many with grade 1 hypertension (SBP

>143 mmHg and mean BP = 154 mmHg), whose mean age was 66

years, and in whom only 22% had prior treatment of hypertension.

212

The evidence supports the recommendation that older patients

(>65 years, including patients over 80 years) should be offered BP-

lowering treatment if their SBP is >_160 mmHg. There is also justifica-

tion to now recommend BP-lowering treatment for old patients

(aged >65 but not >80 years) at a lower BP (i.e. grade 1 hypertension;

SBP = 140–159 mmHg).

201

BP-lowering drugs should not be with-

drawn on the basis of age alone. It is well established that BP-

lowering treatment withdrawal leads to a marked increase in CV risk.

This was exemplified in older patients by a recent subgroup analysis

of the Hypertension in the Very Elderly Trial (HYVET),

213

reporting

that in patients aged >_80 years, CV risk reduction was greatest in

those who continued treatment rather than in those whose treat-

ment was discontinued.

216

As stated above, all of the above recom-

mendations relate to relatively fit and independent older patients,

because physically and mentally frail and institutionalized patients

have been excluded in most RCTs of patients with hypertension.

214

Further details of the treatment of hypertension in older patients and

very old patients is provided in section 8.8.

7.2.4 Initiation of blood pressure-lowering drug

treatment in patients with highnormal blood pressure

The previous (2013) Guidelines

recommended not to initiate anti-

hypertensive treatment in people with high–normal BP and

low–moderate CV risk. This recommendation is further supported

by new evidence:

(1) In all RCTs (including SPRINT)

and meta-analyses

that have

reported reduced major outcomes by lowering ‘baseline’ BP in the

high–normal range, the ‘baseline’ BP was commonly measured on a

background of antihypertensive treatment. Therefore, these studies

do not provide evidence to support treatment initiation in patients

without hypertension.

(2) The HOPE-3 trial,

212

in which only22% of the patients at intermedi-

ate CV risk had background antihypertensive treatment, showed

that BP-lowering treatment did not reduce the risk of major CV

events in patients with baseline SBP values in the high–normal

range.

(3) A meta-analysis of 13 RCTs or RCT subgroups (involving 21 128

individuals) in patients at low–moderate CV risk and untreated

baseline BP in the high–normal and normal range, showed no effect

of BP-lowering treatment on any CV outcomes.

217

(4) Another recent analysis, including patients with high–normal BP,

concluded that primary preventive BP lowering was associated with

reduced risk for death and incident CVD if baseline SBP was 140

mmHg or higher, but at lower BP levels [i.e. high–normal BP (<140/

90 mmHg)], treatment was not associated with any benefit in pri-

mary prevention.

201

(5) The situation may be different in very high-risk patients with a

high–normal BP and established CVD. In a meta-analysis of 10

RCTs or RCT subgroups that also included individuals at high or

very high CV risk, mostly with previous CVD and untreated

high–normal and normal BP (n= 26 863), BP-lowering drug treat-

ment, achieving an SBP reduction of 4 mmHg, reduced the risk of

stroke but not any other CV events.

217

In another analysis of trials

including people with previous CAD and a mean baseline SBP of

138 mmHg, treatment was associated with reduced risk for major

CV events (relative risk 0.90; 95% confidence interval 0.84–0.97),

but was not associated with an increased survival (relative risk 0.98;

95% confidence interval 0.89–1.07).

201

Thus, the benefit for treating

people with high–normal BP appears marginal and, if present,

appears to be restricted to those at very high CV risk and estab-

lished CVD, especially CAD.

We recommend that patients with high–normal BP and

low–moderate CV risk should be offered lifestyle advice, because this

reduces their risk of progressing to established hypertension and may

further reduce their CV risk. These patients should not be offered BP-

lowering drug treatment. Nevertheless, based on the data from the

HOPE-3 trial, drug treatment may be considered in these patients if

ESC/ESH Guidelines 29

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their BP is close to the hypertension diagnostic threshold of 140/90

mmHg, after a prolonged attempt to control BP with lifestyle changes.

BP-lowering drugs may be considered for patients with

high–normal BP and established CVD, especially CAD. In these

patients, monotherapy may be sufficient.

7.2.5 Should blood pressure-lowering drug treatment be

initiated on the basis of blood pressure values or the level

of total cardiovascular risk?

Two recent meta-analyses of RCTs

8,218

have shown that when BP-

lowering data are stratified according to CV risk, the relative risk reduc-

tions do not differ across the various risk strata; not surprisingly, the

absolute risk reduction is greater with increasing baseline CV risk.

These data have been taken as support for the hypothesis that BP-

lowering treatment should be based on CV risk and target those at

greatest CV risk, irrespective of their BP.

218

However, it has recently

been made that whereas patients at high or very high CV risk exhibit

the greatest absolute reduction in CV outcomes with BP-lowering

treatment, they also have the highest residual risk, which means failure

of treatment to exert full protection.

It is the opinion of this Task

Force that these data support earlier treatment of patients with SBP or

DBP values >140/90 mmHg when their CV risk is still low–moderate,

to prevent the accumulation of HMOD and a high incidence of late

treatment failure (residual risk), which would otherwise occur if treat-

ment was delayed by a purely CV risk-based approach. The most

effective strategy to reduce risk is to prevent the development of high

CV-risk situations with earlier intervention. The assessment of CV risk

is at the core of the treatment strategy recommended by these

Guidelines because of the frequent coexistence of multiple CV risk fac-

tors in hypertensive patients, and to inform the use of concomitant

medications (e.g. statins, antiplatelet therapies, etc., see section 9) to

reduce CV risk. We conclude that, in general, the decision to use BP-

lowering treatment should not be based solely on the level of CV risk

because even in patients at the highest risk (with established CVD),

when baseline BP is below 140/90 mmHg, the benefits of BP-lowering

treatment are at best marginal and most evident in patients with CAD

at the upper end of the high– normal BP range.

201

7.2.6 Initiation of blood pressure-lowering drug

treatment

In patients with grade 2 or 3 hypertension, it is recommended that

BP-lowering drug treatment should be initiated alongside lifestyle

interventions. In patients with grade 1 hypertension at high risk or

with HMOD, drug treatment should also be initiated simultaneously

with lifestyle interventions. In lower-risk patients with grade 1 hyper-

tension, BP-lowering drug treatment should be initiated after 3–6

months if BP is not controlled by lifestyle interventions alone

(Figure 3). Recommended BP thresholds for the initiation of antihy-

pertensive drug treatment are shown in Table 19.

Figure 3 Initiation of blood pressure-lowering treatment (lifestyle changes and medication) at different initial office blood pressure levels. BP =

blood pressure; CAD= coronary artery disease; CVD = cardiovascular disease;HMOD = hypertension-mediated organ damage.

30 ESC/ESH Guidelines

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Initiation of hypertension treatment according to ofﬁce BP

Recommendations Class

Level

Prompt initiation of BP-lowering drug treatment is recommended in patients with grade 2 or 3 hypertension at any level of CV

risk, simultaneous with the initiation of lifestyle changes.

2,8

In patients with grade 1 hypertension:

Lifestyle interventions are recommended to determine if this will normalize BP.

219

II B

In patients with grade 1 hypertension at low–moderate-risk and without evidence of HMOD, BP-lowering drug treatment is

recommended if the patient remains hypertensive after a period of lifestyle intervention.

211,212

In patients with grade 1 hypertension and at high risk or with evidence of HMOD, prompt initiation of drug treatment is rec-

ommended simultaneously with lifestyle interventions.

211,212

In ﬁt older patients with hypertension (even if aged >80 years), BP-lowering drug treatment and lifestyle intervention are rec-

ommended when SBP is >_160 mmHg.

210,220,221

BP-lowering drug treatment and lifestyle intervention are recommended for ﬁt older patients (>65 years but not >80 years)

when SBP is in the grade 1 range (140–159 mmHg), provided that treatment is well tolerated.

212

Antihypertensive treatment may also be considered in frail older patients if tolerated.

215

IIb B

Withdrawal of BP-lowering drug treatment on the basis of age, even when patients attain an age of >_80 years, is not recom-

mended, provided that treatment is well tolerated.

213

III A

In patients with high–normal BP (130 –139/85–89 mmHg):

Lifestyle changes are recommended.

17,35

Drug treatment may be considered when their CV is very high due to established CVD, especially CAD.

217

IIb A

BP = blood pressure; CAD = coronary artery disease; CV = cardiovascular; CVD = cardiovascular disease; HMOD = hypertension-mediated organ damage; SBP = systolic

blood pressure.

Class of recommendation.

Level of evidence.

In patients with grade 1 hypertension and at low– moderate-risk, drug treatment may be preceded by a prolonged period of lifestyle intervention to determine if this approach

will normalize BP. The duration of the lifestyle intervention alone will depend on the level of BP within the grade 1 range, i.e. the likelihood of achieving BP control with lifestyle

intervention alone, and the opportunities for signiﬁcant lifestyle change in individual patients.

Table 19 Summary of ofﬁce blood pressure thresholds for treatment

Age group Ofﬁce SBP treatment threshold (mmHg) Ofﬁce DBP treatment

threshold (mmHg)

Hypertension 1Diabetes 1CKD 1CAD 1Stroke/TIA

18 - 65 years >_140 >_140 >_140 >_140

>_140

>_90

65 - 79 years >_140 >_140 >_140 >_140

>_140

>_90

>_80 years >_160 >_160 >_160 >_160 >_160 >_90

Ofﬁce DBP treatment

threshold (mmHg)

>_90 >_90 >_90 >_90 >_90

BP = blood pressure; CAD = coronary artery disease; CKD = chronic kidney disease; DBP = diastolic blood pressure; SBP = systolic blood pressure; TIA = transient

ischaemic attack.

Treatment may be considered in these very high-risk patients with high– normal SBP (i.e. SBP 130– 140 mmHg).

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7.3 Blood pressure treatment targets

7.3.1 New evidence on systolic blood pressure and

diastolic blood pressure treatment targets

The 2013 ESH/ESC hypertension Guidelines

recommended an

office BP treatment target of <140/90 mmHg, regardless of the num-

ber of comorbidities and level of CV risk. The Guidelines specifically

stated that evidence from RCTs, meta-analyses, and post hoc analysis

of large-scale RCTs all showed no obvious incremental benefit of

lowering BP to <130/80 mmHg. Since then, new information has

emerged from post hoc analyses of large outcome trials in patients at

high CV risk,

222–224

registries in patients with coronary disease, and,

more importantly, new RCTs and meta-analyses of all available RCT

evidence. In the post hoc RCT analyses and registry data, compared

with a target SBP of between 130 mmHg and 139 mmHg, lowering

SBP to <130 mmHg was, in general, associated with no further bene-

fit on major CV events, except perhaps for further reductions in the

risk of stroke. A consistent finding was that reducing SBP to <120

mmHg increased the incidence of CV events and death.

A recent RCT relevant to the issue of target BP is SPRINT, which

compared two different SBP targets (<140 or <120 mmHg) in

>9000 patients at high CV risk, but excluded patients with diabetes

or previous stroke. More intensive BP-lowering treatment (achieved

SBP 121 vs. 136 mmHg) was associated with a 25% reduction in

major CV events and a 27% reduction in all-cause death (but no sig-

nificant reduction in stroke or myocardial infarction).

This outcome

unquestionably provides strong support for the beneficial effects of

more vs. less intensive BP-lowering treatment strategies in higher risk

patients. However, this RCT does not clarify the optimal BP target

because the method used for office BP measurement in SPRINT

(unattended automatic measurement) had not been used in any pre-

vious RCTs that provide the evidence base for the treatment of

hypertension.

225

This is because unattended automated office BP

measurement results in lower BP values, relative to conventional

office BP measurement, due to the absence of the white-coat

effect.

52,54

Thus, it has been suggested that the BP values reported in

SPRINT may correspond to conventional office SBPs in the 130 –140

and 140 –150 mmHg ranges in the more vs. less intensive BP-

lowering groups, respectively.

Some new information onSBP and DBP targets for drug treatment

has been provided by two recent, large meta-analyses of RCTs of BP

lowering. In the first of these meta-analyses, achieved SBP was strati-

fied according to three SBP target ranges (149–140 mmHg, 139–130

mmHg, and <130 mmHg).

226

Lowering SBP to <140 mmHg reduced

the relative risk of all major CV outcomes (including mortality); simi-

lar benefits were seen when SBP was lowered to <130 mmHg (aver-

age 126 mmHg). Importantly, the latter was also true when the

achieved SBP in the comparator group was 130 - 139 mmHg.

Stratification of RCTs for achieved DBP, to either 89 - 80 mmHg or

<80 mmHg, also showed a reduction in all types of CV outcomes

compared with higher DBP values.

226

The second meta-analysis, which also included the SPRINT trial,

noted that every 10 mmHg reduction in SBP reduced the rate of

major CV events and death for baseline SBP values >160 mmHg to

baseline values between 130 and 139 mmHg, implying benefit at

achieved SBP values of <130 mmHg. Furthermore, a benefit of a 10

mmHg reduction in SBP was also reported for patients with a base-

line SBP of <130 mmHg, thereby achieving values <120 mmHg.

However, there were far fewer patients in these subgroups, and this

last set of data will have been heavily influenced by the unusually low

BP values in the SPRINT trial, due to the method of BP measurement

(see above). Importantly, this analysis showed consistent benefit

from intensive BP lowering in patients at all levels of risk, including

those with and without existing CVD, stroke, diabetes, and CKD.

Finally, in the first meta-analysis,

226

the incremental benefit of BP

lowering on events progressively decreased as the target BP was low-

ered. Furthermore, an additional meta-analysis by the same group

found that permanent treatment discontinuation because of

treatment-related adverse effects was significantly higher in those tar-

geted to lower BP values.

227

Therefore, advocating more intensive

BP-lowering targets for all has to be viewed in the context of an

increased risk of treatment discontinuation due to adverse events,

which might offset, in part or completely, the limited incremental

reduction in CV risk.

Whilst considering BP targets, it is important to acknowledge that

<50% of patients treated for hypertension currently achieve a target

office SBP of <140 mmHg.

11,12

This is a major missed opportunity for

CVD prevention in millions of people across the world.

This Task Force recommends that when BP-lowering drugs are

used, the first objective should be to lower BP to <140/90 mmHg in

all patients. Provided that the treatment is well tolerated, treated BP

values should be targeted to 130/80 mmHg or lower in most patients,

although in some groups the evidence is less compelling. In older

patients (>65 years), SBP should be targeted to between 130 and

140 mmHg, and DPB to <80 mmHg. Treated SBP should not be tar-

geted to <120 mmHg.

Importantly, we specify a target range because the lower safety

boundary assumes greater importance when BP is targeted to lower

levels. Furthermore, in general, when SBP is lowered to <120 mmHg

in patients included in RCTs (i.e. older and higher-risk patients, often

with comorbidities and CVD), the risk of harm appears to increase

and outweigh the benefits.

222

7.3.2 Blood pressure targets in specific subgroups of

hypertensive patients

7.3.2.1. Diabetes mellitus

RCTs in type 1 diabetes mellitus demonstrate that BP-loweringtreat-

ment has a renoprotective effect,

228

but because these patients tend

to be younger, previous RCTs have had inadequate power to study

CV outcomes and to establish optimal BP targets.

In contrast, there have been many BP-lowering treatment RCTs,

either exclusively dedicated to patients with type 2 diabetes or

hypertension trials that have included a large cohort of patients with

type 2 diabetes.

Most of these RCTs have shown that BP lowering

to <140/85 mmHg is beneficial in patients with type 2 diabetes and

hypertension. However, the results have been less clear about

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whether a lower BP target is associated with further benefits. The evi-

dence can be summarized as follows:

i. A large RCT in patients with type 2 diabetes has shown that an

achieved SBP of <135 mmHg, compared with 140 mmHg, was

associated with a significant reduction in cardiovascular and all-cause

mortality.

229

ii. Evidence from another large RCT in patients with type 2 diabetes

showed that, compared with patients with an on-treatment SBP of

135 mmHg, reducing SBP to 121 mmHg did not reduce CV mor-

bidity and mortality or all-cause death, but substantially reduced the

risk of stroke.

230

iii. Although one recent meta-analysis concluded that most ofthe bene-

fit associated with BP lowering was obtained at higher BP targets (i.e.

<150 mmHg but not <140 mmHg),

231

other large meta-analyses

have confirmed that in type 2 diabetes, lowering SBP to <140 mmHg

is associated with reductions in all major CV events.

1,232–234

iv. Two of the meta-analyses concluded that the overall benefit of low-

ering BP in patients with type 2 diabetes (unlike patients without

type 2 diabetes) largely disappears when SBP is lowered to <130/80

mmHg,

1,235

except for the continuing incremental benefit on stroke.

v. Similar evidence for stroke benefit from lower achieved SBP has also

been reported from post hoc analysis of diabetic patients in the

ONTARGET (Ongoing Telmisartan Alone and in combination with

Ramipril Global Endpoint Trial) study. In addition, reanalysis of the

Action to Control Cardiovascular Risk in Diabetes (ACCORD)

230

trial in type 2 diabetes, after removing the interaction fromthe inten-

sive glucose-lowering arm and thereby limiting the analysis to BP-

lowering effects, showed an overall reduction in CV events with

intensive SBP lowering to <130 mmHg.

236

vi. Further recent analysis of the ACCORD trial has shown that reduc-

ing SBP to <120 mmHg was associated with increased risk of major

CV events.

236

vii. With regard to DBP, earlier evidence suggested a benefit on major

CV events when DBP was lowered to <85 mmHg.

237,238

recently, in the Action in Diabetes and Vascular Disease: Preterax

and Diamicron – MR Controlled Evaluation (ADVANCE) trial,

229

the benefits on CV outcomes was observed at diastolic pressures of

75 mmHg. This is consistent with evidence from the meta-analyses

cited above, that it is safe and effective to lower DBP to <80 mmHg

in patients with type 2 diabetes.

In summary, In patients with diabetes receiving BP-lowering drugs,

it is recommended that office BP should be targeted to an SBP of 130

mmHg,

229

and lower if tolerated. In older patients (aged >_65 years)

the SBP target range should be 130–140 mmHg

213

if tolerated. SBP

should not be lowered to <120 mmHg and DBP should be lowered

to <80 mmHg. Attention should also be given to the consistency of

BP control, because visit-to-visit BP variability is associated with

increased CV and renal disease risk. Furthermore, CV protection has

been found to be greater when BP control is accompanied by fewer

visit-to-visit BP variations.

239–241

7.3.2.2. Older patients

The definition of ‘older’ is complex. As populations age, there is

increasingly wide variation between a patient’s chronological age and

their functional status, ranging from fit, active, and independent,

through to frail and dependent. The anticipated benefits vs. potential

harm of BP treatment in older patients will be influenced by the

patient’s ability to tolerate treatment and their health and functional

status. For the purposes of these Guidelines, ‘older’ patients are

defined as those aged >_65 years.

In the 2013 ESH/ESC hypertension Guidelines, the target SBP for

older hypertensive patients was set at 140–150 mmHg because this

was the range of systolic values achieved by major outcome trials

demonstrating a beneficial effect of antihypertensive treatment in

these patients. A similar SBP target was suggested by the HYVET trial,

in which treating to an SBP target of <150 mmHg (achieving a mean

SBP of 144 mmHg) in the very old (>80 years) demonstrated signifi-

cant reductions in mortality, fatal stroke, and heart failure, with the

caveat that the ‘very old’ patients in this study were active and inde-

pendent.

213

More recent evidence supports a lower SBP target for

older patients (>_65 years):

(1) The SPRINT trial included a high proportion of patients over

the age of 75 years (n= 2636) and demonstrated that more inten-

sive BP-lowering treatment (mean achieved BP = 124/62 mmHg)

significantly reduced the risk of major CV events, heart failure, and

all-cause death (all by >30%) compared with standard treatment

(mean achieved BP = 135/67 mmHg).

215

It has been noted above

that the BP measurement technique used in SPRINT generated

lower values than those provided by the conventional office

BP measurement.

225,242

Consequently, the SBP of 124 mmHg

achieved in the intensively treated older patients in the SPRINT

trial most probably reflects a conventional office SBP range of

130 –139 mmHg.

(2) Although HYVET and most other RCTs in older patients have

recruited relatively fit and independent patients, the SPRINT study

also suggested that there are benefits of more intensive treatment

being extended to older patients who are at the frailer end of the

spectrum of patients meeting the recruitment criteria, with reduced

gait speed.

215

Based on the new data, the targets suggested by the previous

Guidelines now appear too conservative for many old and very old

patients, especially those who are active and independent.

Consequently, we recommend that in older patients treated for

hypertension, BP should be lowered to <140/80 mmHg, but not

below an SBP of 130 mmHg. Importantly, the impact of BP-lowering

on the well-being of the patient should be closely monitored, because

the increased risk of adverse events (e.g. injurious falls) with lower BP

values could be more pronounced in older patients in the real-life

setting than in the closely monitored conditions of RCTs. Further

details on the approach to treatment of the frail older patient are dis-

cussed in section 8.8.

ESC/ESH Guidelines 33

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7.3.2.3 Office vs. home and ambulatory blood pressure targets

No outcome-based RCT has used ABPM or HBPM to guide the

treatment of hypertension. Thus, ABPM and HBPM BP targets are

based on extrapolation from observational data rather than on out-

come trials. Although we do not provide formal ABPM or HBPM BP

targets for treated patients, it should be noted that:

(1) In population studies, the difference between office and out-of-

office BP levels decreases as office BP decreases, to a point of

around 115- 120/70 mmHg, at which office and 24 h ABPM mean

BP values are usually similar.

(2) This convergence has also been confirmed in treated patients

243

whom the difference between office BP and ambulatory BP

values diminishes and becomes negligible at an SBP of approxi-

mately 120 mmHg.

(3) In treated patients, a target office SBP of 130 mmHg might therefore

correspond to a slightly lower mean 24 h SBP, i.e. approximately

125 mmHg.

(4) Although there are no available data, the home SBP target, to be

equivalent to an office SBP target of 130 mmHg, might also be lower

than 130 mmHg.

7.4 Treatment of hypertension

7.4.1 Lifestyle changes

Heathy lifestyle choices can prevent or delay the onset of hyperten-

sion and can reduce CV risk.

17,35

Effective lifestyle changes may be

sufficient to delay or prevent the need for drug therapy in patients

with grade 1 hypertension. They can also augment the effects of BP-

lowering therapy, but they should never delay the initiation of drug

therapy in patients with HMOD or at a high level of CV risk. A major

drawback of lifestyle modification is the poor persistence over

time.

245,246

The recommended lifestyle measures that have been

shown to reduce BP are salt restriction, moderation of alcohol con-

sumption, high consumption of vegetables and fruits, weight reduc-

tion and maintaining an ideal body weight, and regular physical

activity.

In addition, tobacco smoking has an acute prolonged

pressor effect that may raise daytime ambulatory BP, but smoking

cessation and other lifestyle measures are also important beyond BP

(i.e. for CVD and cancer prevention).

7.4.2 Dietary sodium restriction

There is evidence of a causal relationship between sodium intake and

BP, and excessive sodium consumption (>5 g sodium per day, e.g.

one small teaspoon of salt per day) has been shown to have a pressor

effect and be associated with an increased prevalence of hyperten-

sion and the rise in SBP with age.

247

Conversely, sodium restriction

has been shown to have a BP-lowering effect in many trials. A recent

meta-analysis of these trials showed that a reduction of 1.75 g

sodium per day (4.4 g salt/day) was associated with a mean 4.2/2.1

mmHg reduction in SBP/DBP, with a more pronounced effect (-5.4/

-2.8 mmHg) in people with hypertension.

248

The beneficial effect of a

reduced sodium intake on BP tends to diminish with time, in part due

to poor dietary persistence. The BP-lowering effect of sodium

restriction is greater in black people, in older patients, and in patients

with diabetes, metabolic syndrome, or CKD.

249

In people with

treated hypertension, effective sodium restriction may reduce the

number or dose of BP-lowering drugs that are necessary to control

BP.

250,251

The effect of reduced dietary sodium on CV events remains

unclear.

252–255

Prospective cohort studies have reported an over-

all increased risk of mortality and CV events on high sodium intake.

However, they also reported that reducing sodium intake below a

certain level (about 3 g of sodium per day) further reduced BP, but

paradoxically was associated with an increased risk of all-cause and

CV mortalities in both the general population and in hypertensive

people, suggesting a J-curve phenomenon.

256

The mechanism of

this apparent increased risk at low sodium intake is not well under-

stood and might be confounded by reverse causality. There is no

evidence from epidemiological studies that very low sodium intake

may cause harm.

257

Although a few trials and meta-analyses sug-

gest that reducing salt intake from high to moderate is accompa-

nied by a lower risk of CV events,

254,255,258

to date, no prospective

RCT has provided definitive evidence about the optimal sodium

intake to minimize CV events and mortality. Increased potassium

intake is associated with BP reduction and may have a protective

effect, thereby modifying the association between sodium intake,

BP, and CVD.

259

Ofﬁce BP treatment targets in hypertensive patients

Recommendations Class

Level

It is recommended that the ﬁrst objective of

treatment should be to lower BP to <140/

90 mmHg in all patients and, provided that

the treatment is well tolerated, treated BP

values should be targeted to 130/80 mmHg

or lower in most patients.

2,8

In patients <65 years receiving BP-lowering

drugs, it is recommended that SBP should

be lowered to a BP range of 120–129

mmHg in most patients.

c2,215,229

In older patients (aged >_65 years) receiving

BP-lowering drugs:

•It is recommended that SBP should be

targeted to a BP range of 130–139

mmHg.

2,235,244

•Close monitoring of adverse effects is

recommended. IC

•These BP targets are recommended for

patients at any level of CV risk and in patients

with and without established CVD.

2,8

A DBP target of <80 mmHg should be consid-

ered for all hypertensive patients, independent

of the level of risk and comorbidities.

226,235

IIa B

BP = blood pressure; CV = cardiovascular; CVD = cardiovascular disease; DBP =

diastolic blood pressure; SBP = systolic blood pressure.

Class of recommendation.

Level of evidence.

Less evidence is available for this target in low–moderate-risk patients.

34 ESC/ESH Guidelines

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Globally, usual sodium intake is between 3.5–5.5 g per day (which

corresponds to 9 - 12 g of salt per day), with marked differences

between countries and even between regions within countries. We

recommend sodium intake to be limited to approximately 2.0 g per

day (equivalent to approximately 5.0 g salt per day) in the general

population and to try to achieve this goal in all hypertensive

patients. Effective salt reduction is not easy and there is often poor

appreciation of which foods contain high salt levels. Advice should

be given to avoid added salt and high-salt foods. A reduction in pop-

ulation salt intake remains a public health priority but requires a

combined effort between the food industry, governments, and the

public in general, as 80% of salt consumption involves hidden salt in

processed foods.

7.4.3 Moderation of alcohol consumption

There is a long-established positive linear association between alco-

hol consumption, BP, the prevalence of hypertension, and CVD risk.

Binge drinking can have a strong pressor effect.

The Prevention and

Treatment of Hypertension Study (PATHS) investigated the effects

of alcohol reduction on BP; the intervention group had a modest 1.2/

0.7 mmHg lower BP than the control group at the end of the 6 month

period.

260

A Mendelian randomization meta-analysis of 56 epidemio-

logical studies suggested that reduction of alcohol consumption, even

for light–moderate drinkers, might be beneficial for CV health.

261

Hypertensive men who drink alcohol should be advised to limit their

consumption to 14 units per week and women to 8 units per week

(1 unit is equal to 125 mL of wine or 250 mL of beer). Alcohol-free

days during the week and avoidance of binge drinking

are also

advised.

7.4.4 Other dietary changes

Hypertensive patients should be advised to eat a healthy balanced

diet containing vegetables, legumes, fresh fruits, low-fat dairy prod-

ucts, wholegrains, fish, and unsaturated fatty acids (especially olive

oil), and to have a low consumption of red meat and saturated fatty

acids.

262–264

The Mediterranean diet includes many of these nutrients

and foods, with a moderate consumption of alcohol (mostly wine

with meals). A number of studies and meta-analyses

262–265

have

shown that the Mediterranean diet is associated with a reduction in

CV events and all-cause mortality. An RCT in high-risk individuals on

the Mediterranean diet over 5 years showed a 29% CV risk reduction

compared with a low-fat control diet, and a 39% reduction in

stroke.

265

The Mediterranean diet also significantly reduced ambula-

tory BP, blood glucose, and lipid levels.

266

The diet should be

accompanied by other lifestyle changes such as physical exercise and

weight loss.

With regard to coffee consumption, caffeine has been shown to

have an acute pressor effect.

267

Nevertheless, coffee consumption is

associated with CV benefits, as highlighted by a recent systematic

review of prospective cohort studies including more than 1 million

participants and 36 352 CV events.

267

Moreover, green or black tea

consumption may also have a small but significant BP-lowering

effect.

268,269

Regular consumption of sugar-sweetened soft drinks has been

associated with overweight, metabolic syndrome, type 2 diabetes,

and higher CV risk. The consumption of these drinks should be

discouraged.

Thus, adopting a healthy and balanced diet may assist in BP reduc-

tion and also reduce CV risk.

7.4.5 Weight reduction

Excessive weight gain is associated with hypertension, and reducing

weight towards an ideal body weight decreases BP.

270

In a meta-

analysis, the mean SBP and DBP reductions associated with an aver-

age weight loss of 5.1 kg were 4.4 and 3.6 mmHg, respectively.

271

Both overweight and obesity are associated with an increased risk of

CV death and all-cause mortality. Weight reduction is recommended

in overweight and obese hypertensive patients for control of meta-

bolic risk factors, but weight stabilization may be a reasonable goal

for many. The Prospective Studies Collaboration

272

concluded that

mortality was lowest at a body mass index (BMI) of approximately

22.5 - 25 k g/m

, whereas a more recent meta-analysis concluded that

mortality was lowest in subjects with overweight.

273,274

Although the

optimal BMI is unclear, maintenance of a healthy body weight (BMI of

approximately 20 - 25 kg/m

in people <60 years of age; higher in

older patients) and waist circumference (<94 cm for men and <80

cm for women) is recommended for non-hypertensive individuals to

prevent hypertension, and for hypertensive patients to reduce BP.

Weight loss can also improve the efficacy of antihypertensive medica-

tions and the CV risk profile. Weight loss should employ a multidisci-

plinary approach that includes dietary advice, regular exercise, and

motivational counselling.

35,275

Furthermore, short-term results are

often not maintained over the long-term. Weight loss can also be

promoted by anti-obesity drugs and, to a greater degree, bariatric

surgery, which appears to decrease CV risk in severely obese

patients. Further details are available in a recent document of the

ESH and the European Association for the Study of Obesity.

276

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7.4.6 Regular physical activity

Physical activity induces an acute rise in BP, especially SBP, followed

by a short-lived decline in BP below baseline. Epidemiological studies

suggest that regular aerobic physical activity may be beneficial for

both the prevention and treatment of hypertension, and to lower CV

risk and mortality. A meta-analysis of RCTs, which rely on self-

reported exercise and are by necessity unblinded, has shown that

aerobic endurance training, dynamic resistance training, and isometric

training reduce resting SBP and DBP by 3.5/2.5, 1.8/3.2, and 10.9/6.2

mmHg, respectively, in general populations.

277

Endurance training,

but not other types of training, reduces BP more in hypertensive par-

ticipants (8.3/5.2 mmHg). Regular physical activity of lower intensity

and duration lowers BP less than moderate- or high-intensity training,

but is associated with at least a 15% decrease in mortality in cohort

studies.

278,279

This evidence suggests that hypertensive patients

should be advised to participate in at least 30 min of moderate-

intensity dynamic aerobic exercise (walking, jogging, cycling, or swim-

ming) on 5–7 days per week. Performance of resistance exercises on

2 - 3 days per week can also be advised. For additional benefit in

healthy adults, a gradual increase in aerobic physical activity to 300

min a week of moderate intensity or 150 min a week of vigorous-

intensity aerobic physical activity, or an equivalent combination

thereof, is recommended.

The impact of isometric exercises on BP

and CV risk is less well established.

280

7.4.7 Smoking cessation

Smoking is a major risk factor for CVD and cancer. Although the

rate of smoking is declining in most European countries, especially

in men, it is still common in many regions and age groups, and over-

all the prevalence remains high at 20–35% in Europe.

281

There is

also evidence suggesting ill-health effects of passive smoking.

282

Studies using ABPM have shown that both normotensive subjects

and untreated hypertensive smokers present higher daily BP values

than non-smokers.

283

No chronic effect of smoking has been

reported for office BP,

284

which is not lowered by smoking cessa-

tion. Smoking is second only to BP in contributing risk to the global

burden of disease, and smoking cessation is probably the single

most effective lifestyle measure for the prevention of CVD, includ-

ing stroke, myocardial infarction, and PAD.

285,286

Therefore, the

history of tobacco use should be established at each patient visit

and hypertensive smokers should be counselled regarding smoking

cessation.

Brief advice from a physician has a small but significant effect of

1 - 3% over and above the unassisted 12 month quit rate.

287

This can

be improved by the use of pharmacological measures, with vareni-

cline and combination nicotine replacement therapy being superior

to bupropion or single nicotine replacement therapy.

288

In compari-

son with placebo, nicotine replacement therapy or treatment with

buproprion doubles the chance of quitting, whilst varenicline or

combination nicotine replacement therapy triples the chance of

quitting. Combining behavioural support with pharmacotherapy

increases the chance of success by 70 - 100% compared with brief

advice alone.

289

7.5. Pharmacological therapy for

hypertension

7.5.1 Drugs for the treatment of hypertension

Most patients will require drug therapy in addition to lifestyle meas-

ures to achieve optimal BP control. In the previous Guidelines, five

major drug classes were recommended for the treatment of hyper-

tension: ACE inhibitors, ARBs, beta-blockers, CCBs, and diuretics

(thiazides and thiazide-like diuretics such as chlortalidone and indapa-

mide), based on: (i) proven ability to reduce BP; (ii) evidence from

placebo-controlled studies that they reduce CV events; and (iii) evi-

dence of broad equivalence on overall CV morbidity and mortality,

with the conclusion that benefit from their use predominantly derives

from BP lowering. These conclusions have since been confirmed by

Lifestyle interventions for patients with hypertension or

high-normal BP

Recommendations Class

Level

Salt restriction to <5 g per day is

recommended.

248,250,255,258

It is recommended to restrict alcohol con-

sumption to:

•Less than 14 units per week for men.

•Less than 8 units per week for women.

It is recommended to avoid binge drinking. III C

Increased consumption of vegetables, fresh

fruits, ﬁsh, nuts, and unsaturated fatty acids

(olive oil); low consumption of red meat;

and consumption of low-fat dairy products

are recommended.

262,265

Body-weight control is indicated to avoid

obesity (BMI >30 kg/m

or waist circumfer-

ence >102 cm in men and >88 cm in

women), as is aiming at healthy BMI (about

20–25 kg/m

) and waist circumference val-

ues (<94 cm in men and <80 cm in women)

to reduce BP and CV risk.

262,271,273,290

Regular aerobic exercise (e.g. at least 30

min of moderate dynamic exercise on 5–7

days per week) is recommended.

262,278,279

Smoking cessation, supportive care, and

referral to smoking cessation programs are

recommended.

286,288,291

BMI = body mass index; BP = blood pressure; CV = cardiovascular.

Class of recommendation.

Level of evidence mostly based on the effect on BP and/or CV risk proﬁle.

36 ESC/ESH Guidelines

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recent meta-analyses.

1,2,217,292

These meta-analyses have reported

cause-specific differences on outcomes between some drugs (e.g.

less stroke prevention with beta-blockers, and less heart failure pre-

vention with CCBs); however, overall, major CV outcomes and mor-

tality were similar with treatment based on initial therapy with all five

major classes of treatment. These Guidelines thus recommend that

the same five major classes of drugs should form the basis of antihy-

pertensive therapy. There are compelling or possible contraindica-

tions for each class of drug (Table 20) and preferential use of some

drugs for some conditions, as discussed below. There is also evidence

that there are differences in the persistence and discontinuation rates

of the major drug classes.

293,294

Other classes of drugs have been less widely studied in event-

based RCTs or are known to be associated with a higher risk of

adverse effects [e.g. alpha-blockers, centrally acting agents, and min-

eralocorticoid receptor antagonists (MRAs)]. These are useful addi-

tions to the antihypertensive armamentarium in patients whose BP

cannot be controlled by proven combinations of the aforementioned

major drug classes.

7.5.1.1. Blockers of the reninangiotensin system (angiotensin-

converting enzyme inhibitors and angiotensin receptor blockers)

Both ACE inhibitors and ARBs are among the most widely used

classes of antihypertensive drugs. They have similar effective-

ness

295,296

as each other and other major drug classes on major CV

events and mortality outcomes.

2,292

ARBs are associated with signifi-

cantly lower treatment discontinuation rates for adverse events than

those of all other antihypertensive therapies,

297

and similar rates to

placebo.

294

ACE inhibitors and ARBs should not be combined for the

treatment of hypertension because there is no added benefit on out-

comes and an excess of renal adverse events.

298,299

Dual combina-

tion of RAS blockers also led to the premature cessation of another

trial due to adverse events,

291

when a renin inhibitor, aliskiren, was

combined with either an ACE inhibitor or an ARB in people with dia-

betes. This result halted further research into the clinicalutility of alis-

kiren for BP treatment.

Both ACE inhibitors and ARBs reduce albuminuria more than

other BP-lowering drugs and are effective at delaying the progression

of diabetic and non-diabetic CKD.

217

A recent meta-analysis shows

Table 20 Compelling and possible contraindications to the use of speciﬁc antihypertensive drugs

Drug Contraindications

Compelling Possible

Diuretics (thiazides/thiazide-like, e.g. chlortha-

lidone and indapamide)

•Gout •Metabolic syndrome

•Glucose intolerance

•Pregnancy

•Hypercalcaemia

•Hypokalaemia

Beta-blockers •Asthma

•Any high-grade sinoatrial or atrioventricular block

•Bradycardia (heart rate <60 beats per min)

•Metabolic syndrome

•Glucose intolerance

•Athletes and physically active patients

Calcium antagonists (dihydropyridines) •Tachyarrhythmia

•Heart failure (HFrEF, class III or IV)

•Pre-existing severe leg oedema

Calcium antagonists (verapamil, diltiazem) •Any high-grade sinoatrial or atrioventricular block

•Severe LV dysfunction (LV ejection fraction <40%)

•Bradycardia (heart rate <60 beats per min)

•Constipation

ACE inhibitors •Pregnancy

•Previous angioneurotic oedema

•Hyperkalaemia (potassium >5.5 mmol/L)

•Bilateral renal artery stenosis

•Women of child-bearing potential

without reliable contraception

ARBs •Pregnancy

•Hyperkalaemia (potassium >5.5 mmol/L)

•Bilateral renal artery stenosis

•Women of child-bearing potential

without reliable contraception

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; HFrEF = heart failure with reduced ejection fraction; LV = left ventricular.

ESC/ESH Guidelines 37

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that RAS blockers are the only antihypertensive agents for which evi-

dence is available of a reduced risk of end-stage renal disease.

217

ACE inhibitors and ARBs also appear effective in preventing or

regressing HMOD, such as LVH and small artery remodelling, for an

equivalent reduction in BP.

292

Both drugs reduce incident AF, which

may be related to improved LVfunction and more effective LV struc-

tural regression.

292

ACE inhibitors and ARBs are also indicated post-

myocardial infarction and in patients with chronic HFrEF, which are

frequent complications of hypertension.

ACE inhibitors are associated with a small increased risk of angio-

neurotic oedema, especially in people of black African origin and, in

such patients, when RAS blockers are used, an ARB may be preferred.

7.5.1.2. Calcium channel blockers

CCBs are widely used for the treatment of hypertension and have

similar effectiveness as other major drug classes on BP, major CV

events, and mortality outcomes.

2,292

CCBs have a greater effect on

stroke reduction than expected for the BP reduction achieved, but

may also be less effective at preventing HFrEF.

2,292

However, in anti-

hypertensive treatment trials, emergent heart failure is the event con-

sidered. Though clinically a very relevant event, it is a difficult

endpoint to quantify precisely, either because symptoms and signs

are relatively non-specific or because oedema due to CCBs may

result in misdiagnosis. Comparison with diuretics may also be difficult

because fluid loss may mask signs and symptoms of incipient heart

failure rather than preventing it. CCBs have also been compared with

other antihypertensive agents in HMOD-based trials, and are

reported to be more effective than beta-blockers in slowing the pro-

gression of carotid atherosclerosis, and in reducing LVH and

proteinuria.

CCBs are a heterogeneous class of agents. Most RCTs demon-

strating the benefits of CCBs on outcomes have used dihydropyri-

dines (especially amlodipine). A smaller number of RCTs have

compared non-dihydropyridines (verapamil and diltiazem) with other

drugs, and meta-analyses evaluating the two subclasses (vs. other

drugs) have not shown substantial differences in effectiveness.

292

7.5.1.3. Thiazide/thiazide-like diuretics (e.g. chlorthalidone and

indapamide)

Diuretics have remained the cornerstone of antihypertensive treat-

ment since their introduction in the 1960s. Their effectiveness in pre-

venting all types of CV morbidities and mortality has been confirmed

in RCTs and meta-analyses.

300

Diuretics also appear to be more

effective than other drug classes in preventing heart failure.

292

There

has been debate about whether thiazide-like diuretics such as chlor-

thalidone and indapamide should be given preference over classical

thiazide diuretics (e.g. hydrochlorothiazide and bendrofluazide), but

their superiority on outcomes has never been tested in head-to-head

RCTs. Chlorthalidone and indapamide have been used in a number

of RCTs showing CV benefits, and these agents are more potent per

milligram than hydrochlorothiazide in lowering BP, with a longer

duration of action compared with hydrochlorothiazide and no evi-

dence of a greater incidence of side effects.

301

Lower dose thiazide-

like diuretics (typical of modern antihypertensive treatment regi-

mens) also have more evidence from RCTs demonstrating reduc-

tions in CV events and mortality, when compared with lower dose

thiazide diuretics.

302

That said, hydrochlorothiazide, alone or in

combination with a potassium-sparing agent, has also been used in

BP-lowering RCTs, with positive results.

303

A recent meta-analysis of

placebo-controlled studies based on thiazides, chlorthalidone, and

indapamide reported similar effects on CV outcomes of the three

types of diuretics.

300

Therefore, in the absence of evidence from

direct comparator trials and recognizing that many of the approved

single-pill combinations (SPCs) are based on hydrochlorothiazide

(see below), we recommend that thiazides, chlorthalidone, and inda-

pamide can all be considered suitable antihypertensive agents. Both

thiazide and thiazide-like diuretics can reduce serum potassium and

have a side effect profile that is less favourable than RAS blockers,

which may account for their association with a higher rate of treat-

ment discontinuation.

293,300

They also exhibit dysmetabolic effects

that increase insulin resistance and the risk of new-onset diabetes.

Potassium may attenuate these effects,

304

and a recent study has

shown that the adverse effect of thiazides on glucose metabolism

may be reduced by the addition of a potassium-sparing diuretic.

305

Both thiazides and thiazide-like agents are less effective antihyperten-

sive agents in patients with a reduced GFR (eGFR <45 mL/min) and

become ineffective when the eGFR is <30 mL/min. In such circum-

stances, loop diuretics such as furosemide (or torasemide) should

replace thiazides and thiazide-like diuretics to achieve an antihyper-

tensive effect.

7.5.1.4. Beta-blockers

RCTs and meta-analyses demonstrate that when compared with pla-

cebo, beta-blockers significantly reduce the risk of stroke, heart fail-

ure, and major CV events in hypertensive patients.

300

When

compared with other BP-lowering drugs, beta-blockers are usually

equivalent in preventing major CV events, except for less effective

prevention of stroke, which has been a consistent finding.

1,2,217

It is

possible that the difference originated from small differences in

achieved BP (including central SBP

108

between different drug treat-

ments), to which cerebrovascular events may be especially sensitive.

RCTs based on HMOD have also indicated that beta-blockers are

somewhat less effective than RAS blockers and CCBs in preventing

or regressing LVH, carotid IMT, aortic stiffness, and small artery

remodelling.

In addition, a mortality benefit post-myocardial infarc-

tion is uncertain in patients without LV dysfunction.

306

Beta-blockers,

as well as diuretics, and particularly their combination, are also associ-

ated with increased risk of new-onset diabetes in predisposed sub-

jects (mostly those with the metabolic syndrome). They also exhibit

a somewhat lessfavourable side effect profile than that of RAS block-

ers, with a higher rate of treatment discontinuation when assessed in

real-life conditions.

293

Beta-blockers have been shown to be particu-

larly useful for the treatment of hypertension in specific situations

such as symptomatic angina, for heart rate control, post-myocardial

infarction, HFrEF, and as an alternative to ACE inhibitors or ARBs in

younger hypertensive women planning pregnancy or of child-bearing

potential.

Finally, beta-blockers are not a homogeneous class. In recent years,

the use of vasodilating beta-blockers—such as labetalol, nebivolol,

celiprolol, and carvedilol—has increased. Studies on nebivolol have

shown that it has more favourable effects on central BP, aortic stiff-

ness, endothelial dysfunction, etc. It has no adverse effect on the risk

of new-onset diabetes and a more favourable side effect profile than

classical beta-blockers,

307,308

including less adverse effects on sexual

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function. Bisoprolol, carvedilol, and nebivolol have been shown to

improve outcomes in RCTs in heart failure;

136

however, there are no

RCTs reporting patient outcomes with these beta-blockers in hyper-

tensive patients.

7.5.1.5. Other antihypertensive drugs

Centrally active drugs were widely used in the earliest decades of anti-

hypertensive treatment when other treatments were not available,

but are less frequently used now, principally because of their poorer

tolerability relative to the newer major classes of drugs. The alpha-

blocker doxazosin was effective in the Anglo-Scandinavian Cardiac

Outcomes Trial (ASCOT) as third-line therapy (with no increase in

the risk of heart failure),

309

and was more effective than placebo but

less effective than spironolactone at lowering BP in resistant hyperten-

sion in the Prevention And Treatment of Hypertension With

Algorithm-based therapY-2 (PATHWAY-2) study.

310

Alpha-blockers

may also be required in specific indications (e.g. the treatment of

symptomatic prostatic hypertrophy). Antihypertensive drugs, other

than the major classes already discussed above, are no longer recom-

mended for the routine treatment of hypertension, and are primarily

reserved for add-on therapy in rare cases of drug-resistant hyperten-

sion where all other treatment options have failed.

7.5.2 Drug treatment strategy for hypertension

Guidelines have generated a variety of different strategies to initiate

and escalate BP-lowering medication to improve BP control rates. In

previous Guidelines, the emphasis was on initial use of different

monotherapies, increasing their dose, or substituting for another

monotherapy. However, increasing the dose of monotherapy produ-

ces little additional BP lowering and may increase the risk of adverse

effects, whilst switching from one monotherapy to another is frus-

trating, time consuming, and often ineffective. For these reasons,

more recent Guidelines have increasingly focused on the stepped-

care approach, initiating treatment with different monotherapies and

then sequentially adding other drugs until BP control is achieved.

Despite this, BP control rates have remained poor worldwide. As

shown by recent observations, irrespective of the world region,

whether high- or low-income economies, or the level of sophistica-

tion of healthcare provision, only 40% of patients with hyperten-

sion are treated; of these, only 35% are controlled to a BP of <140/

90 mmHg.

This failure to achieve BP control in most hypertensive

patients,despite numerous iterations of previous Guidelines, suggests

that these treatment strategies are not working and that a different

approach is needed. This Task Force believes that one of the most

important issues to address in these Guidelines is ‘how do we

improve BP control in treated patients?’. This has become an even

more pressing matter because, based on new evidence, current

Guidelines are recommending more stringent BP targets (on-treat-

ment values of <_ 130/80 mmHg in the general population and <_ 140/

90mmHg in older hypertensive people), which will make the achieve-

ment of BP control even more challenging.

Several reasons need to be considered to identify why the current

treatment strategy has failed to achieve better BPcontrol rates:

(1) Efficacy of pharmacological therapies. Are the best available

treatments, in whatever combination, incapable of controlling BP in

most patients? The evidence from RCTs demonstrating that BP

control can be achieved in most recruited patients, and that no

more than 5 - 10% of these patients exhibit resistance to the

selected treatment regimen, suggests that ineffective drug therapy is

not the source of the problem.

(2) Physician or treatment inertia. (i.e. failure to adequately upti-

trate treatment). Evidence suggests that inertia

311

contributes to

suboptimal BP control, with many patients remaining on monother-

apy and/or suboptimal doses, despite inadequate BP control.

(3) Patient adherence to treatment. Evidence is accumulating that

adherence is a much more important factor than previously recog-

nised. Studies using urine or blood assays for the presence or

absence of medication have shown that adherence to treatment is

low. This is supported by studies in the general population in which

adherence to treatment, based on prescription refilling, was <50%

of the treatment in half of the patients.

312

Poor adherence has also

be shown to be associated with increased CV risk in various stud-

ies

313

(see section 10).

(4) Insufficient use of combination treatment. BP is a multiregu-

lated variable depending on many compensating pathways.

Consequently, combinations of drugs, working through different

mechanisms, are required to reduce BP in most people with hyper-

tension. Thus, monotherapy is likely to be inadequate therapy in

most patients. Indeed, almost all patients in RCTs have required

combinations of drugs tocontrol their BP.

314

(5) Complexity of current treatment strategies. There is also

evidence that adherence to treatment is adversely affected by the

complexity of the prescribed treatment regimen. In a recent study,

adherence to treatment was strongly influenced by the number of

pills that a patient was prescribed for the treatment of hyperten-

sion.

315

Non-adherence was usually <10% with a single pill, rising to

20% with two pills, 40% with three pills, and very high rates of

partial or complete non-adherence in patients receiving five or

more pills.

315

The above considerations suggest that the most effective

evidence-based treatment strategy to improve BP control is one that:

(i) encourages the use of combination treatment in most patients,

especially in the context of lower BP targets; (ii) enables the use of

SPC therapy for most patients, to improve adherence to treatment;

and (iii) follows a treatment algorithm that is simple, applies to all

patients, and is pragmatic, with the use of SPC therapy as initial ther-

apy for most patients, except those with BP in the high–normal range

and in frail older patients (see below).

7.5.2.1. Drug combinations for hypertension treatment

Among the large number of RCTs of antihypertensive therapy, only a

few have directly compared different two-drug combinations, with

systematic use of the two combinations in both arms. In other trials,

treatment was initiated using monotherapy in either arm and another

drug (and sometimes more than one drug) was added, usually in a

non-randomized fashion, according to a pre-specified treatment algo-

rithm. In a few trials, the design precluded the use of what might be

considered optimal combinations because multiple monotherapies

were being evaluated [e.g. the Antihypertensive and Lipid-Lowering

Treatment to Prevent Heart Attack Trial (ALLHAT), where the add-

on therapy to either a diuretic, CCB, ACE inhibitor, or alpha-blocker

was a beta-blocker, clonidine, or reserpine].

316

ESC/ESH Guidelines 39

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With this caveat, Table 21 shows that a variety of drug combina-

tions have been used in at least one active arm of placebo-controlled

trials and have been associated with significant benefit on major CV

events. In trials comparing different regimens (Table 22), all combina-

tions have been used in a larger or smaller proportion of patients,

without major differences in benefits. The only exceptions are two

trials in which a large proportion of the patients received either an

ARB–diuretic combination

317

or CCB–ACE inhibitor combina-

tion,

318

with both regimens being superior to a beta-blocker–diuretic

combination in reducing CV outcomes. However, in six other trials

(with seven comparisons), beta-blockers followed by diuretics or

diureticsfollowed by beta-blockers were not associated with a signifi-

cantly different risk of any CV outcome,

233,234,316,319–321

and the

beta-blocker diuretic combination was significantly more effective

than placebo in three trials.

322–324

It should be mentioned that the

beta-blocker–diuretic combination may result in more cases of new-

onset diabetes in susceptible individuals compared with other combi-

nations.

325

A rarely used combination of thiazide and potassium-

sparing diuretic (amiloride) has also been shown to be equivalent to

CCB-based treatment,

310,326

and was recently reported to be associ-

ated with fewer metabolic adverse effects compared with thiazide

alone (less hypokalaemia and glucose intolerance).

305

Table 21 Major drug combinations used in trials of antihypertensive treatment in a stepped approach or as a random-

ized combination (combinations vs. placebo or monotherapy)

Trial Comparator Type of patients SBP difference

(mmHg)

Outcomes [change in relative risk (%)]

ACE inhibitor and diuretic combination

PROGRESS

Placebo Previous stroke or TIA – 9 – 28% strokes (P<0.001)

ADVANCE

229

Placebo Diabetes –5.6 –9% micro/macrovascular events (P= 0.04)

HYVET

220

Placebo Hypertensive; >_80 years –15 –34% CV events (P<0.001)

ARB and diuretic combination

SCOPE

330

Diuretic þplacebo Hypertensive; >_70 years –3.2 –28% non-fatal strokes (P= 0.04)

CCB and diuretic combination

FEVER

331

Diuretic þplacebo Hypertensive –4 – 27% CV events (P<0.001)

ACE inhibitor and CCB combination

Syst-Eur

332

Placebo Older with ISH –10 –31% CV events (P<0.001)

Syst-China

333

Placebo Older with ISH –9 –37% CV events (P<0.004)

Beta-blocker and diuretic combination

Coope and Warrender

322

Placebo Older hypertensive –18 –42% strokes (P<0.03)

SHEP

323

Placebo Older with ISH –13 –36% strokes (P<0.001)

STOP-H

324

Placebo Older hypertensive –23 –40% CV events (P= 0.003)

STOP-H 2

334

ACE inhibitor or

conventional

antihypertensive

Hypertensive 0 NS difference in CV events

Combination of two RAS blockers/ACE inhibitor 1ARB or RAS blocker 1renin inhibitor)

ONTARGET

299

ACE inhibitor or ARB High-risk patients More renal events

ALTITUDE

291

ACE inhibitor or ARB High-risk diabetic patients More renal events

ACE = angiotensin-converting enzyme; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron – MR Controlled Evaluation; ALTITUDE = Aliskiren

Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; CV = cardiovascular; FEVER

= Felodipine Event Reduction; HYVET = Hypertension in the Very Elderly Trial; ISH = isolated systolic hypertension; NS = non-signiﬁcant; ONTARGET = Ongoing Telmisartan

Alone and in combination with Ramipril Global Endpoint trial; PROGRESS = perindopril protection against recurrent stroke study; RAS = renin-angiotensin system; SBP = sys-

tolic blood pressure; SCOPE = Study on Cognition and Prognosis in the Elderly; SHEP = Systolic Hypertension in the Elderly Program; STOP-H = Swedish Trial in Old Patients

with Hypertension; Syst-China = Systolic Hypertension in China; Syst-Eur = Systolic Hypertension in Europe; TIA = transient ischaemic attack.

40 ESC/ESH Guidelines

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Table 22 Major drug combinations used in trials of antihypertensive treatment in a stepped approach or as a random-

ized combination (combinations vs. other combinations)

Trial Comparator Type of patients SBP difference

(mmHg)

Outcomes [change in

relative risk (%)]

ACE inhibitor and diuretic combination

CAPPP

335

BB þdiuretic Hypertensive þ3þ5% CV events (NS)

ACCOMPLISH

327

ACE inhibitor þCCB Hypertensive with risk factors þ1þ21% CV events (P<0.001)

ARB and diuretic combination

LIFE

317

BB þdiuretic Hypertensive with LVH –1 –26% stroke (P<0.001)

CCB and diuretic combination

ELSA

336

BB þdiuretic Hypertensive 0 NS difference in CV events

CONVINCE

233

BB þdiuretic Hypertensive with risk factors 0 NS difference in CV events

VALUE

337

ARB þdiuretic High-risk hypertensive –2.2 –3% CV events (P= NS)

COPE

338

CCB þBB Hypertensive þ0.7 NS difference in CV events or stroke

ACE inhibitor and CCB combination

NORDIL

339

BB þdiuretic Hypertensive þ3 NS difference in CV events

INVEST

340

BB þdiuretic Hypertensive with CAD 0 NS difference in CV events

ASCOT

318

BB þdiuretic Hypertensive with risk factors – 3 –16% CV events (P<0.001)

ACCOMPLISH

327

ACE inhibitor þdiuretic Hypertensive with risk factors –1 –21% CV events (P<0.001)

Beta-blocker and diuretic combination

CAPPP

335

ACE inhibitor þdiuretic Hypertensive –3 –5% CV events (P= NS)

LIFE

317

ARB þdiuretic Hypertensive with LVH þ1þ26% stroke (P<0.001)

ALLHAT

316

ACE inhibitor þBB Hypertensive with risk factors –2 NS difference in CV events

ALLHAT

316

CCB þBB Hypertensive with risk factors –1 NS difference in CV events

CONVINCE

233

CCB þdiuretic Hypertensive with risk factors 0 NS difference in CV events

NORDIL

339

ACE inhibitor þCCB Hypertensive –3 NS difference in CV events

INVEST

340

ACE inhibitor þCCB Hypertensive with CAD 0 NS difference in CV events

ASCOT

318

ACE inhibitor þCCB Hypertensive with risk factors þ3þ16% CV events (P<0.001)

Beta-blocker and CCB combination

COPE

329

ARB þCCB Hypertensive þ0.8 NS difference in CV events or stroke

ARB and CCB combination

COPE

329

CCB þdiuretic Hypertensive –0.7 NS difference in CV events or stroke

COPE

329

CCB þBB Hypertensive –0.8 NS difference in CV events or stroke

COLM

328

ARB þdiuretic Older hypertensive 0 NS difference in CV events

ACCOMPLISH = Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension; ACE = angiotensin-converting enzyme;

ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ARB = angiotensin receptor blocker; ASCOT = Anglo-Scandinavian Cardiac

Outcomes Trial; BB = beta-blocker; CAD = coronary artery disease; CAPPP = Captopril Prevention Project; CCB = calcium channel blocker; COLM = Combination of

OLMesartan and a calcium channel blocker or diuretic in Japanese elderly hypertensive patients; CONVINCE = Controlled Onset Verapamil Investigation of Cardiovascular

End Points; COPE = Combination Therapy of Hypertension to Prevent Cardiovascular Events; CV = cardiovascular; ELSA = European Lacidipine Study on Atherosclerosis;

INVEST = International Verapamil-Trandolapril Study; LIFE = Losartan Intervention For Endpoint reduction in hypertension; LVH = left ventricular hypertrophy; NORDIL =

Nordic Diltiazem; NS = non-signiﬁcant; SBP = systolic blood pressure; VALUE = Valsartan Antihypertensive Long-term Use Evaluation.

ESC/ESH Guidelines 41

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Three outcome trials directly compared two different combina-

tions, each involving a combination of a RAS blocker (ACE inhibitor

or ARB) and a CCB with other combinations. In the Avoiding

Cardiovascular Events Through Combination Therapy in Patients

Living With Systolic Hypertension (ACCOMPLISH) trial, the ACE

inhibitor–CCB combination was superior to the same ACE inhibitor

in combination with a thiazide diuretic at preventing major CV out-

comes, despite no apparent BP difference between the two arms.

327

This finding was not confirmed in the Combination of OLMesartan

and a CCB or diuretic in Japanese older hypertensive patients

(COLM)

328

and Combination Therapy of Hypertension to Prevent

Cardiovascular Events (COPE) trials,

329

which reported no significant

differences in CV events when a RAS blocker-CCB combination was

compared with a RAS blocker–thiazide diuretic combination, but

both of these trials had insufficient statistical power.

Based on the results of outcome RCTs and recent meta-analyses,

and evidence of BP-lowering effectiveness, all five major drug classes

can, in principle, be combined with one another, except for ACE

inhibitors and ARBs, whose concomitant use may lead to no addi-

tional benefit but increased adverse effects and is thus discouraged.

We recommend that the treatment of hypertension should be pref-

erentially based on combinations of an ACE inhibitor or ARB with a

CCB and/or a thiazide/thiazide-like diuretic. These combinations are

now widely available in a single pill and in a range of doses, facilitating

simplification of treatment, flexible prescribing, and uptitration from

lower to higher doses. Combination therapy that includes an ACE

inhibitor or ARB with either a CCB or thiazide/thiazide-like diuretic

are complementary because both CCBs or diuretics activate the

RAS, which will be counteracted by their combination with an ACE

inhibitor or ARB. These combinations will also limit potential adverse

effects associated with diuretic or CCB monotherapy, reducing the

risk of hypokalaemia due to diuretics and reducing the prevalence of

peripheral oedema due to CCBs. These combinations also ensure

that the RAS is inhibited as part of the treatment strategy, which is an

important consideration for many patient groups (e.g. diabetes, LVH,

proteinuria).

Other combinations, such as CCB þdiuretic, also have evidence

from RCTs supporting their use.

233,329

These are much less widely

available as SPCs and do not include blockade of the RAS, which may

be desirable in many patient groups.

Beta-blockers in combination should be preferentially used when

there is a specific clinical indication for their use (e.g. in patients with

symptomatic angina, for patients requiring heart rate control, post-

myocardial infarction, chronic HFrEF, and as an alternative to ACE

inhibitors or ARBs in younger hypertensive women planning preg-

nancy or of child-bearing potential). SPCs of beta-blockers with an

ACE inhibitor, CCB, or diuretic are available.

7.5.2.2 Rationale for initial two-drug combination therapy for most

patients

As discussed above and with the emphasis in these Guidelines on

achieving a BP target in most patients of<130/80 mmHg, the majority

of patients will require combination therapy. Initial combination ther-

apy is invariably more effective at BP lowering than monotherapy,

indeed even low-dose combination therapy is usually more effective

than maximal dose monotherapy.

341

Furthermore, the combination

of medications targeting multiple mechanisms, such as blocking the

RAS as well as inducing vasodilatation and/or diuresis, reduces the

heterogeneity of the BP response to initial treatment and provides a

steeper dose response than is observed with escalating doses of

monotherapy.

342

Finally, two-drug combinations as initial therapy

have been shown to be safe and well tolerated, with no or only a

small increase in the riskof hypotensive episodes,

341

even when given

to patients with grade 1 hypertension,

343

in which adverse events

leading to treatment discontinuation are infrequent.

294

Although no RCT has compared major CV outcomes between ini-

tial combination therapy and monotherapy, observational evidence

suggests that the time taken to achieve BP control is an important

determinant of clinical outcomes, especially in higher risk patients,

with a shorter time to control associated with lower risk.

344

Furthermore, there is evidence from the more general hypertensive

population that, compared with patients on initial monotherapy,

those who start treatment with a two-drug combination exhibit

more frequent BP control after 1 year.

341,345

This is probably because

initial combination treatment is associated with a better long-term

adherence to the prescribed treatment regimen

346

and because initial

two-drug administration prevents therapeutic inertia (i.e. reluctance

or failure to upgrade treatment from one to more drugs when BP is

uncontrolled).

347

Studies from very large hypertension cohorts in

usual care have shown that initial combination treatment results in

reduced treatment discontinuation and a lower risk of CV events

than initial monotherapy followed by the traditional stepped-care

approach.

312,346

The usual-care settings for these studies may be

especially relevant to study the true impact of treatment strategies

on adherence and therapeutic inertia, because this can be difficult to

replicate in a conventional RCT in which the motivation of the clinical

staff and patients, and the monitoring of treatment, are very different

from usual care. In this regard, the outcome of these real-life studies

of the impact of initialcombinationtherapy on adherence, BPcontrol,

and CV outcomes may be especially relevant.

348

A consideration in the current Guidelines was to persist with the

current stepped-care approach to BP treatment, which has been

interpreted as recommending monotherapy as initial therapy for

most patients, reflecting current practice. In fact, the previous

Guidelines did acknowledge the possibility of initial combination ther-

apy for patients with grade 2 or 3 hypertension, or patients at high or

very high risk. In other words, initial monotherapy was only recom-

mended for grade 1 hypertension and low- or moderate-risk

patients. Thus, in reality, the shift in emphasis in this new guidance is

subtle. However, normalizing the concept of initiating therapy with a

two-drug combination for most patients with hypertension is likely

to have a majoreffect on clinical practice and the speed and quality of

BP control. We acknowledge that some low- or moderate-risk

patients with grade 1 hypertension may achieve their BP target with

monotherapy, but this is unlikely in patients with an initial SBP >150

mmHg who would require a BP reduction of >_20 mmHg. Moreover,

the possibility of starting with a low-dose combination of two antihy-

pertensive drugs, even in grade 1 hypertensive patients with

low–moderate-risk, is supported by the reduction of CV events

obtained by combination therapy in the upper tertile (grade 1 hyper-

tension) in the HOPE-3 trial.

212

In patients with high–normal BP and

a high CV risk or in frail older patients, treatment initiation with

monotherapy may be appropriate in the former because only a small

BP reduction may be required to achieve the BP target, and in the

42 ESC/ESH Guidelines

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latter because in older patients baroreflex sensitivity is frequently

impaired and the risk ofhypotension is greater.

7.5.2.3 Uptitration of treatment to three-drug combination therapy

Studies suggest that two-drug combination therapy will control BP in

approximately two-thirds of patients.

341

For patients whose BP is not

controlled by two-drug combination therapy, the logical option is to

increase treatment to three-drug combination therapy: usually a RAS

blocker, a CCB, and a diuretic. Studies suggest that a three-drug com-

bination should control BP in >80% of patients.

349,350

This rate of BP

control is much greater than the current rate of BP control across

Europe in treated hypertensive patients. We do not recommend

three-drug combinations as initial therapy.

7.5.2.4 Rationale for single-pill combination therapy as usual therapy for

hypertension

The 2013 ESH/ESC Guidelines

favoured the use of combinations of

two antihypertensive drugs in a single pill, because reducing the num-

ber of pills to be taken daily improves adherence and increases the

rate of BP control.

346,351

This recommendation is endorsed by the

current Guidelines. It is further supported by data from recent stud-

ies using various methods to assessadherence to treatment,including

the quantification of antihypertensive drugs in urine and blood,

352,353

and estimates such as pill counting or prescription refills, which,

although indirect, allow the measurement of adherence on a pro-

longed basis, thereby accounting for its time-variable nature.

347,354

These studies have unequivocally shown a direct inverse relationship

between the number of pills and the likelihood of adherence. This

approach is now facilitated by the availability of several SPCs with a

range of dosages, which eliminates the often-stated disadvantage of

SPC therapy (i.e. the inability to increase the dose of one drug inde-

pendently of the other). It is also convenient that the most widely

available SPCs mirror the major drug class combinations recom-

mended by these Guidelines. The major advantage of an SPC as the

usual therapeutic approach for hypertension is that patients can

progress from 1, 2, or 3 drug treatments whilst remaining on a simple

treatment regimen with a single pill throughout, increasing the likeli-

hood of adherence to therapy and achieving BP control. Such an

approach has the potential to double BP control rates in treated

patients from the present low level of 40%. Although, at present,

the availability of two-drug SPCs is largely limited to a RAS blocker

with either a CCB or diuretic, it would be desirable to see the devel-

opment of an expanded range of low-cost SPCs in different drug for-

mulations, tailored to different clinical requirements.

Polypills have also emerged as SPCs (i.e. a fixed-dose combination

of one or more antihypertensive agents with a statin and low-dose

aspirin), with the rationale that hypertensive patients are often at suffi-

cient CV risk to benefit from statin therapy. Studies of bioequivalence

suggest that when combined in the polypill, different agents maintain

all or most of their expected effect.

355

Furthermore, studies per-

formed in the setting of secondary prevention, particularly in patients

with a previous myocardial infarction, have shown that use of the pol-

ypill is accompanied by a better adherence to treatment compared

with separate medications.

356

The ESC Guidelines for the manage-

ment of myocardial infarction have recommended polypill use to

improve long-term adherence to prescribed therapy (class IIa, level

B).

353

No data are available for primary prevention in patients with

hypertension. Nevertheless, the advantage of treatment simplification

and adherence suggests that use of the polypill may be considered in

patients with hypertension as substitution therapy, when the need and

effectiveness of each polypill component has been previously estab-

lished by their administration in separate tablets.

355

7.5.2.5 Further uptitration of antihypertensive therapy

When BP remains uncontrolled with three-drug combination therapy,

the patient is classified as having resistant hypertension, assuming that

secondary causes of hypertension and poor adherence to treatment

have been excluded, and that the elevation in BP has been confirmed

by repeated office BP measurement, ABPM, or HBPM (see section 8.1).

Such patients should be considered for specialist evaluation. Additional

treatment options include the addition of low-dose spironolactone

(25 - 50 mg daily)

310

or another additional diuretic therapy [higher-

dose amiloride 10 - 20 mg daily,

357

higher dose thiazide or thiazide-like

diuretics, loop diuretics in patients with significant renal impairment

(eGFR <45 mL/min/m

), beta-blockers, alpha-blockers, centrally acting

agents (e.g. clonidine), or, rarely, minoxidil] (see section 8.1).

7.5.3 The drug treatment algorithm for hypertension

Reflecting on the evidence above, and recognizing the urgent need to

address the factors contributing to the poor control of BP in treated

hypertensive patients (see section 7.5.1), this drug treatment algo-

rithm has been developed to provide a simple and pragmatic treat-

ment recommendation for the treatment of hypertension, based on

a few key recommendations:

(1) The initiation of treatment in most patients with an SPC comprising

two drugs, to improve the speed, efficiency, and predictability of BP

control.

(2) Preferred two-drug combinations are a RAS blocker with a CCB or

a diuretic. A beta-blocker in combination with a diuretic or any drug

from the other major classes is an alternative when there is a spe-

cific indication for abeta-blocker, e.g. angina, post-myocardialinfarc-

tion, heart failure, or heart rate control.

(3) Use monotherapy for low-risk patients with stage 1 hypertension

whose SBP is <150 mmHg, very high-risk patients with high–normal

BP, or frail older patients.

(4) The use of a three-drug SPC comprising a RAS blocker, a CCB, and

a diuretic if BP is not controlled by a two-drug SPC.

(5) The addition of spironolactone for the treatment of resistant hyper-

tension, unless contraindicated (see section 8.1.4).

(6) The use of other classes of antihypertensive drugs in the rare cir-

cumstances in which BP is not controlled by the above treatments.

(7) Information on availability and recommended doses of individual

drugs, as well as SPCs and free combinations, can be found in

national formularies.

This treatment algorithm focuses on the five major classes of

drugs: ACE inhibitors, ARBs, CCBs, thiazide or thiazide-like diuretics,

and beta-blockers. The algorithm recommends initial therapy for

most patients with a two drug-combination, ideally as an SPC.

Variations from the core drug treatment algorithm for uncomplicated

hypertension shown in Figure 4are specified in Figures 5to 8.

Recommended BP target ranges for treated hypertension are shown

in Table 23.

ESC/ESH Guidelines 43

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©ESC/ESH 2018

Initial therapy

Dual combination

Step 2

Triple combination

Step 3

Triple combination +

spironolactone or

other drug

very old ( 80 years) or frailer patients

Consider initiating therapy

when systolic BP is

130 mmHg in these very

high risk patients with

established CVD

Consider referral to a specialist centre

for further investigation

1 Pill

ACEi or ARB + beta-blocker or CCB

or CCB + diuretic or beta-blocker

or beta-blocker + diuretic

Triple combination of above

Resistant hypertension

Add spironolactone (25–50 mg o.d.)

or other diuretic, alpha-blocker or beta-blocker

2 Pills

1 Pill

Consider monotherapy in low risk

grade 1 hypertension

(systolic BP

150mmHg), or in

Figure 5 Drug treatment strategy for hypertension and coronary artery disease. ACEi = angiotensin-converting enzyme inhibitor;

ARB = angiotensin receptor blocker; BP = blood pressure; CCB = calcium channel blocker; CVD = cardiovascular disease; o.d. = omni die (every day).

©ESC/ESH 2018

Initial therapy

Dual combination

Step 2

Triple combination

Step 3

Triple combination +

spironolactone or

other drug

Beta-blockers

Consider beta-blockers at any treatment step, when there is a specific

indication for their use, e.g. heart failure, angina, post-MI, atrial fibrillation,

or younger women with, or planning, pregnancy

Consider monotherapy in

low risk grade 1 hypertension

(systolic BP <150mmHg), or in

very old ( 80 years) or frailer patients

Consider referral to a specialist centre

for further investigation

1 Pill

ACEi or ARB + CCB or diuretic

ACEi or ARB + CCB + diuretic

Resistant hypertension

Add spironolactone (25–50 mg o.d.)

or other diuretic, alpha-blocker or beta-blocker

2 Pills

1 Pill

Figure 4 Core drug treatment strategy for uncomplicated hypertension. The core algorithm is also appropriate for most patients with

HMOD, cerebrovascular disease, diabetes, or PAD. ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB =

calcium channel blocker; HMOD = hypertension-mediated organ damage; MI = myocardial infarction; o.d. = omni die (every day); PAD = peripheral

artery disease.

44 ESC/ESH Guidelines

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Figure 7 Drug treatment strategy for hypertension and hear failure with reduced ejection fraction. Do not use non-dihydropyridine

CCBs (e.g. verapamil or diltiazem). ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel

blocker; ESC = European Society of Cardiology; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist.

Consider an angiotensin receptor/neprilysin inhibitor instead of ACEi or ARB per ESC Heart Failure Guidelines.

136

Diuretic refers to thiazide/thiazide-like diuretic. Consider a loop diuretic as an alternative in patients with oedema.

MRA (spironolactone or eplerenone).

Figure 6 Drug treatment strategy for hypertension and chronic kidney disease. ACEi = angiotensin-converting enzyme inhibitor;

ARB = angiotensin receptor blocker; BP = blood pressure; CCB = calcium channel blocker; CKD = chronic kidney disease; eGFR = estimated

glomerular filtration rate; MI = myocardial infarction; o.d. = omni die(every day).

CKD is deﬁned as an eGFR <60 mL/min/1.72 m

with or without proteinuria.

Use loop diuretics when eGFR is <30 mL/min/1.72 m

, because thiazide/thiazide-like diuretics are much less effective/ineffective when

eGFR is reduced to this level.

Caution: risk of hyperkalaemia with spironolactone, especially when eGFR is <45 mL/min/1.72 m

or baseline K

>_4.5 mmol/L.

ESC/ESH Guidelines 45

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The drug treatment strategy for patients with hypertension

should be based on the algorithm shown (Figures 4to 8),

unless there are contraindications to these drugs (Table 20), or

concomitant conditions or diseases are present that require spe-

cific modification of the drugs, as outlined in the recommendations

below.

©ESC/ESH 2018

Initial therapy

Dual combination

Step 2

Triple combination

Add oral anticoagulation when indicated according to the CHA

-VASc score, unless contraindicated.

Routine combination of beta-blockers with non-dihydropyridine CCBs (e.g. verapamil or diltiazem) is not recommended due to a potential

marked reduction in heart rate.

ACEi or ARB + beta-blocker

or non-DHP CCBa,

or beta-blocker + CCB

ACEi or ARB + beta-blocker

+ DHP CCB or diuretic

or beta-blocker + DHP CCB + diuretic

Figure 8 Drug treatment strategy for hypertension and atrial fibrillation. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial

fibrillation; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; CHA

-VASc = CHA

-VASc = Cardiac failure,

Hypertension, Age >_75 (Doubled), Diabetes, Stroke (Doubled) – Vascular disease, Age 65–74 and Sex category (Female); DHP = dihydropyridine.

Non-DHP CCB (non-DHP CCB, e.g. verapamil or diltiazem).

Table 23 Ofﬁce blood pressure treatment target range

Age group Ofﬁce SBP treatment target ranges (mmHg) Ofﬁce DBP

treatment

target range

(mmHg)

Hypertension 1Diabetes 1CKD 1CAD 1Stroke

/TIA

18 - 65 years Target to 130

or lower if tolerated

Not <120

Target to 130

or lower if tolerated

Not <120

Target to <140 to

130 if tolerated

Target to 130

or lower if tolerated

Not <120

Target to 130

or lower if tolerated

Not <120

70–79

65 - 79 years

Target to 130-139

if tolerated

Target to 130-139

if tolerated

Target to 130-139

if tolerated

Target to 130-139

if tolerated

Target to 130-139

if tolerated

70–79

>_80 years

Target to 130-139

if tolerated

Target to 130-139

if tolerated

Target to 130-139

if tolerated

Target to 130-139

if tolerated

Target to 130-139

if tolerated

70–79

Ofﬁce DBP

treatment

target range

(mmHg)

70–79 70 –79 70–79 70–79 70– 79

CAD = coronary artery disease; CKD = chronic kidney disease (includes diabetic and non-diabetic CKD); DBP = diastolic blood pressure; SBP = systolic blood pressure; TIA =

transient ischaemic attack.

Refers to patients with previous stroke and does not refer to blood pressure targets immediately after acute stroke.

Treatment decisions and blood pressure targets may need to be modiﬁed in older patients who are frail and independent.

46 ESC/ESH Guidelines

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7.6 Device-based hypertension

treatment

Various device-based therapies have emerged, principally targeted at

the treatment of resistant hypertension. These are discussed below.

7.6.1 Carotid baroreceptor stimulation (pacemaker and

stent)

Carotid baroreceptor stimulation or baroreflex amplification

therapy—externally via an implantable pulse generator or internally

via an implantable device designed to increase the strain on the caro-

tid bulb—can lower BP in patients with resistant hypertension. An

RCT with the first generation of an implantable pulse generator

showed sustained BP-lowering efficacy (and sympathetic nervous sys-

tem inhibition), but with some concerns about procedural and longer

term safety.

358

A second-generation unilateral device has been devel-

oped to improve safety and sustained efficacy. A propensity score-

matched comparison of the first- and second-generation systems

revealed that BP at 12 months post-implantation was similar, with a

better safety profile for the second-generation device.

359

However,

no RCT is currently available with this second-generation device.

Another consideration is that implantation is costly and requires a

complex surgical intervention. This has led to the development of an

endovascular carotid baroreflex amplification device using a dedi-

cated stent-like device designed to stretch the carotid bulb and

increase baroreflex sensitivity. Preliminary data in humans have

shown evidence of BP-lowering efficacy of this new approach,

360

but

data from ongoing RCTs are needed to definitively understand its

longer-term efficacy and safety.

7.6.2 Renal denervation

The rationale for renal denervation lay with the importance of sym-

pathetic nervous system influences on renal vascular resistance, renin

release, and sodium reabsorption,

361

the increased sympathetic tone

to the kidney and other organs in hypertensive patients,

361

and the

pressor effect of renal afferent fibres documented in experimental

animals.

362

Catheter-based renal denervation using radiofrequency,

ultrasound, or perivascular injection of neurotoxic agents such as

alcohol has been introduced as a minimally invasive treatment option

for patients with resistant hypertension.

363

However, the clinical evi-

dence in support of renal denervation as an effective BP-lowering

technique is conflicting. Several observational studies and national

and international registries

364

support the BP-lowering efficacy of

Drug treatment strategy for hypertension

Recommendations Class

Level

Among all antihypertensive drugs, ACE inhibitors, ARBs, beta-blockers, CCBs, and diuretics (thiazides and thiazide-like

drugs such as chlorthalidone and indapamide) have demonstrated effective reduction of BP and CV events in RCTs, and thus

are indicated as the basis of antihypertensive treatment strategies.

Combination treatment is recommended for most hypertensive patients as initial therapy. Preferred combinations should

comprise a RAS blocker (either an ACE inhibitor or an ARB) with a CCB or diuretic. Other combinations of the ﬁve major

classes can be used.

233,318,327,329,341–345

It is recommended that beta-blockers are combined with any of the other major drug classes when there

are speciﬁc clinical situations, e.g. angina, post-myocardial infarction, heart failure, or heart rate control.

300,341

It is recommended to initiate an antihypertensive treatment with a two-drug combination, preferably in an SPC.

Exceptions are frail older patients and those at low risk and with grade 1 hypertension (particularly if SBP is

<150 mmHg).

342,346,351

It is recommended that if BP is not controlled

with a two-drug combination, treatment should be increased to a

three-drug combination, usually a RAS blocker with a CCB and a thiazide/thiazide-like diuretic, preferably

as an SPC.

349,350

It is recommended that if BP is not controlled

with a three-drug combination, treatment should be increased by the addition

of spironolactone or, if not tolerated, other diuretics such as amiloride or higher doses of other diuretics, a beta-blocker, or

an alpha-blocker.

310

The combination of two RAS blockers is not recommended.

291,298,299

III A

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; CCB = calcium channel blocker; CV = cardiovascular; RAS=

renin-angiotensin system; RCT = randomized controlled trial; SBP = systolic blood pressure; SPC = single-pill combination.

Class of recommendation.

Level of evidence.

Adherence should be checked.

ESC/ESH Guidelines 47

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renal denervation originally reported in the Symplicity HTN-1 and

HTN-2 trials.

365

A reduction in sympathetic activity following renal

denervation has also been observed.

366

However, two RCTs with a

sham procedure control

367,368

failed to document the superiority of

renal denervation compared with the sham procedure in reducing

BP, but did confirm the safety of the procedure. Another RCT, the

Renal Denervation for Hypertension (DENERHTN) trial,

369

showed

the superiority of renal denervation in combination with optimized

pharmacotherapy compared with pharmacotherapy alone. The

PRAGUE-15 study

370

documented similar effects between renal

denervation and optimized pharmacotherapy (mainly by adding spi-

ronolactone) with respect to BP-lowering efficacy; however, the lat-

ter was associated with more side effects and high discontinuation

rates. Beyond resistant hypertension, interim data in the first 80

patients treated with renal denervation but with no background anti-

hypertensive therapy showed a modest effect of renal denervation

vs. sham control on 24 h ambulatory BP after 3 months.

366

This study

is ongoing.

Evaluating the efficacy of renal denervation has been challenging

because the procedure needs to be applied to a population with a

high probability of BP response. This is complicated by (i) the com-

plex pathophysiology of hypertension, (ii) the lack of clinically applica-

ble measures of sympathetic activity, (iii) the absence of predictors of

the long-term BP response following renal denervation, and (iv) the

absence of reliable markers of procedural success to immediately

establish whether denervation has been achieved.

371

There is evi-

dence indicating that isolated systolic hypertension, characterized by

increased aortic stiffness, is associated with a limited response to

renal denervation

372,373

and baroreceptor stimulation (see above).

Except for rare problems related to the catheterization procedure

(access site complications, vessel dissection, etc.), no major complica-

tions or deterioration of renal function have been reported.

Major uncertainties remain as to the clinical role of renal denerva-

tion outside of clinical studies, which should be performed in carefully

selected patients at specialist hypertension centres and by experi-

enced operators.

7.6.3 Creation of an arteriovenous fistula

The central iliac arteriovenous anastomosis creates a fixed-calibre (4

mm) conduit between the external iliac artery and vein using a stent-

like nitinol device (ROX arteriovenous coupler).

374,375

Device

deployment can be verified and is reversible,resulting in the diversion

of arterial blood (0.8–1 L/min) into the venous circuit with immedi-

ate, verifiable reductions in BP.

374,375

The BP-lowering effect of arte-

riovenous anastomosis was first observed in a study of patients with

chronic obstructive pulmonary disease (COPD), in whom a moder-

ate improvement in the 6 min walking test was shown.

376

In the ROX

CONTROL HTN trial, patients with resistant hypertension were

randomized to receive either standard care or insertion of an arterio-

venous coupler in combination with standard care.

377

At 6 months,

office and ambulatory BP were significantly reduced in the coupler

group compared with the control group. Some important safety

aspects need to be considered. Ipsilateral venous stenosis, which

needed venoplasty and/or stenting, occurred in 29% of patients.

There were no reports of right heart failure or high-output cardiac

failure after device implantation over the short-term, but longer

follow-up is clearly needed.

377,378

7.6.4 Other devices

The carotid body is located at the bifurcation of the common carotid.

It is innervated by nerve fibres from the vagus nerve through the cer-

vical ganglion and the carotid sinus nerve.

379

Stimulation of the caro-

tid body drives sympathetic tone, resulting in an increase in BP and

minute ventilation. Surgical resection of the carotid body is associated

with reductions in BP

380

and sympathetic overactivity in patients with

heart failure.

381

Devices for endovascular carotid body modification

by ultrasound-guided ablation have been developed and are currently

under investigation.

In summary, device-based therapy for hypertension is a fast-

moving field. Further sham-controlled studies are needed before

device-based therapies can be recommended for the routine treat-

ment of hypertension outside of the framework of clinical trials.

8 Hypertension in specific

circumstances

8.1 Resistant hypertension

8.1.1 Definition of resistant hypertension

Hypertension is defined as resistant to treatment when the recom-

mended treatment strategy fails to lower office SBP and DBP values

to <140 mmHg and/or <90 mmHg, respectively, and the inadequate

control of BP is confirmed by ABPM or HBPM in patients whose

adherence to therapy has been confirmed. The recommended treat-

ment strategy should include appropriate lifestyle measures and

treatment with optimal or best-tolerated doses of three or more

drugs, which should include a diuretic, typically an ACE inhibitor or

an ARB, and a CCB. Pseudo-resistant hypertension (see below) and

secondary causes of hypertension should also have been excluded

(see section 8.2).

Prevalence studies of resistant hypertension have been limited by

variation in the definition used, and reported prevalence rates range

from 5–30% in patients with treated hypertension. After applying a

strict definition (see above) and having excluded causes of pseudo-

resistant hypertension (see section 8.1.2), the true prevalence of

resistant hypertension is likely to be <10% of treated patients.

Patients with resistant hypertension are at higher risk of HMOD,

CKD, and premature CV events.

382

Device-based therapies for hypertension

Recommendation Class

Level

Use of device-based therapies is not recom-

mended for the routine treatment of hyperten-

sion, unless in the context of clinical studies

and RCTs, until further evidence regarding their

safety and efﬁcacy becomes available.

367,368

III B

RCT = randomized controlled trial.

Class of recommendation.

Level of evidence.

48 ESC/ESH Guidelines

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8.1.2 Pseudo-resistant hypertension

Several possible causes of pseudo-resistant hypertension should be

evaluated and ruled out before concluding that the patient has resist-

ant hypertension:

(1) Poor adherence to prescribed medicines is a frequent cause

of pseudo-resistant hypertension, occurring in <_50% of patients

assessed by therapeutic drug monitoring, and is directly related to

the number of tablets prescribed

315

(see section 10).

(2) White-coat phenomenon (in which office BP is elevated but BP

is controlled at ABPM or HBPM) is not uncommon in these

patients,hence the recommendationto confirm office hypertension

with ABPM or HBPM before confirming the diagnosis of resistant

hypertension.

(3) Poor office BP measurement technique, including the use of

cuffs that are too small relative to the arm circumference, can result

in a spurious elevation of BP.

(4) Marked brachial artery calcification, especially in older

patients with heavily calcified arteries.

(5) Clinician inertia, resulting in inadequate doses or irrational com-

binations of BP-lowering drug therapies.

Other causes of resistant hypertension

(1) Lifestyle factors, such as obesity or large gains in weight, excessive

alcohol consumption, and high sodium intake.

(2) Intake of vasopressor or sodium-retaining substances, drugs pre-

scribed for conditions other than hypertension, some herbal

remedies, or recreational drug use (cocaine, anabolic steroids, etc.)

(see Table 24).

(3) Obstructive sleep apnoea (usually, but not invariably, associated

with obesity).

(4) Undetected secondary forms of hypertension (see section 8.2).

(5) Advanced HMOD, particularly CKD or large-artery stiffening.

Resistant hypertension is associated with older age (especially >75

years), male sex, black African origin, higher initial BP at diagnosis of

hypertension, highest BP ever reached during the patient’s lifetime,

frequent outpatient visits, obesity, diabetes, atherosclerotic disease

and HMOD, CKD, and a Framingham 10 year coronary risk score

>20%.

383,384

8.1.3 Diagnostic approach to resistant hypertension

Diagnosis of resistant hypertension requires detailed information

about:

(1) The patient’s history, including lifestyle characteristics, alcohol and

dietary sodium intake, interfering drugs or substances, and sleep

history.

(2) The nature and dosing of the antihypertensive treatment.

(3) A physical examination, with a particular focus on determining the

presence of HMOD and signs of secondary hypertension.

(4) Confirmation of treatment resistance by out-of-office BP measure-

ments (i.e. ABPM or HBPM).

Table 24 Resistant hypertension characteristics, secondary causes, and contributing factors (adapted from

reference

385

)

Characteristics of patients with

resistant hypertension

Causes of secondary resistant

hypertension

Drugs and substances that may

cause raised BP

Demographics

•Older age (especially >75 years)

•Obesity

•More common in black people

•Excess dietary sodium intake

•High baseline BP and chronicity of uncon-

trolled hypertension

More common causes

•Primary hyperaldosteronism

•Atherosclerotic renovascular disease

•Sleep apnoea

•CKD

Prescribed drugs

•Oral contraceptives

•Sympathomimetic agents (e.g. decon-

gestants in proprietary cold

remedies)

•Non-steroidal anti-inﬂammatory drugs

•Cyclosporin

•Erythropoietin

•Steroids (e.g. prednisolone and

hydrocortisone)

•Some cancer therapies

Concomitant disease

•HMOD: LVH and/or CKD

•Diabetes

•Atherosclerotic vascular disease

•Aortic stiffening and isolated systolic

hypertension

Uncommon causes

•Phaeochromocytoma

•Fibromuscular dysplasia

•Aortic coarctation

•Cushing’s disease

•Hyperparathyroidism

Non-prescription drugs

•Recreational drugs (e.g. cocaine,

amphetamines, and anabolic

steroids)

•Excessive liquorice ingestion

•Herbal remedies (e.g. ephedra and ma

huang)

BP = blood pressure; CKD = chronic kidney disease; HMOD = hypertension-mediated organ damage; LVH = left ventricular hypertrophy.

ESC/ESH Guidelines 49

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(5) Laboratory tests to detect electrolyte abnormalities (hypokalae-

mia), associated risk factors (diabetes), organ damage (advanced

renal dysfunction), and secondary hypertension.

(6) Confirmation of adherence to BP-lowering therapy.

Patients should be screened for a secondary cause of hyperten-

sion, especially primary aldosteronism

386

or atherosclerotic renal

artery stenosis, particularly in older patients or patients with CKD.

Poor adherence to treatment should be considered, but its identifica-

tion may be challenging in routine clinical practice.

387

Some methods

are easy to use but of limited value (e.g. standardized questionnaires),

whereas others, such as drug screening of urine or blood, show con-

siderable promise but are not yet widely available.

388

Other methods

include the measurement of BP after directly observed treatment

intake,

389

which has been used in clinical trials,

390

but may be more

difficult to implement in routine clinical practice.

8.1.4 Treatment of resistant hypertension

Effective treatment combines lifestyle changes (especially the reduc-

tion of sodium intake), discontinuation of interfering substances, and

the sequential addition of antihypertensive drugs to the initial triple

therapy. Ultimately, replacing all current drugs by a simpler treatment

regimen using SPC treatment is recommended to reduce pill burden

and improve adherence to treatment. The optimal drug treatment of

resistant hypertension has been poorly studied. The most effective

strategy seems to be additional diuretic treatment to decrease vol-

ume overload, together with the restriction of salt intake, particularly

in patients with CKD. BP control may be improved by increasing the

dose of the existing diuretic or by switching to a more potent

thiazide-like diuretic (chlorthalidone or indapamide). A loop diuretic

should replace thiazides/thiazide-like diuretics if the eGFR is <30 mL/

min. Although resistant hypertension may show a BP reduction if the

existing diuretic dose is further increased, most patients require the

administration of additional drugs. There is growing evidence to sug-

gest that the fourth-line treatment should involve a blockade of the

biological effects of aldosterone through the use of MRAs

391

(spiro-

nolactone up to 50 mg/day), as shown in the PATHWAY 2 study

357

and supported by other studies and their meta-analysis.

392–394

Not

all patients will be able to tolerate spironolactone due to antiandro-

genic side effects resulting in breast tenderness or gynaecomastia (in

6%), impotence in men, and menstrual irregularities in women.

Moreover, the efficacy and safety of spironolactone for thetreatment

of resistant hypertension has not yet been established in patients

with significant renal impairment. As such, the use of spironolactone

for resistant hypertension should usually be restricted to patients

with an eGFR >_45 mL/min and a plasma potassium concentration of

<_ 4.5 mmol/L. Moreover, electrolytes and eGFR should be moni-

tored soon after initiation and at least annually thereafter. On theo-

retical grounds, alternative additional diuretic therapy to

spironolactone (when it is not tolerated due to androgen-like side

effects) could include the MRA eplerenone (50 - 100 mg/day).

Amiloride (10 - 20 mg/day) has recently been shown to be as effec-

tive as spironolactone 25–50 mg daily) in reducing BP in the

PATHWAY2 study.

357

It is emphasized that the same cautions about

the use of these agents should be considered in patients with reduced

eGFR and baseline potassium levels >4.5 mmol/L. The PATHWAY-2

study also evaluated bisoprolol (5- 10 mg/day) or doxazosin modified

release (4 - 8 mg/day) as alternatives to spironolactone. Neither was

as effective as spironolactone, but they did reduce BP significantly vs.

placebo when added to background treatment in resistant hyperten-

sion.

310

Thus, bisoprolol and doxazosin have an evidence base for the

treatmentof resistant hypertension when spironolactone is contrain-

dicated or not tolerated. Direct vasodilators, such as hydralazine or

minoxidil, are infrequently used because they may cause severe fluid

retention and tachycardia.

New BP-lowering drugs (nitric oxide donors, vasopressin antago-

nists, aldosterone synthase inhibitors, neutral endopeptidase inhibi-

tors, and endothelin antagonists) are all under investigation.

388

Resistant hypertension

Recommendations Class

Level

It is recommended that hypertension be

deﬁned as resistant to treatment (i.e. resist-

ant hypertension) when:

•Optimal doses (or best-tolerated doses) of

an appropriate therapeutic strategy, which

should include a diuretic (typically an ACE

inhibitor or an ARB with a CCB and a thia-

zide/thiazide-type diuretic), fails to lower

clinic SBP and DBP values to <140 mmHg

and/or <90 mmHg, respectively; and

•The inadequate control of BP has been

conﬁrmed by ABPM or HBPM; and

•After exclusion of various causes of

pseudo-resistant hypertension (espe-

cially poor medication adherence) and

secondary hypertension.

Recommended treatment of resistant

hypertension is:

•Reinforcement of lifestyle measures,

especially sodium restriction.

395

•Addition of low-dose spironolactone

existing treatment;

310,392,394

•Or the addition of further diuretic ther-

apy if intolerant to spironolactone, with

either eplerenone,

amiloride,

a higher-

dose thiazide/thiazide-like diuretic, or a

loop diuretic;

d357

•Or the addition of bisoprolol or

doxazosin.

310

ABPM = ambulatory blood pressure monitoring; ACE = angiotensin-converting

enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; CCB = cal-

cium channel blocker; DBP = diastolic blood pressure; HBPM = home blood

pressure monitoring.

Class of recommendation.

Level of evidence.

When spironolactone is not tolerated, replace with amiloride or eplerenone.

The use of these drugs should be restricted to patients with an estimated glomer-

ular ﬁltration rate >_45 mL/min and a plasma potassium concentration of <_ 4.5

mmol/L, because of the risk of hyperkalaemia.

A loop diuretic should replace thiazides/thiazide-like diuretics if the estimated

glomerular ﬁltration rate is <30 mL/min.

50 ESC/ESH Guidelines

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8.2 Secondary hypertension

Secondary hypertension is hypertension due to an identifiable cause,

which may be treatable with an intervention specific to the cause. A

high index of suspicion and early detection of secondary causes of

hypertension are important because interventions may be curative,

especially in younger patients [e.g. corrective surgery for aortic

coarctation, renal angioplasty in younger patients with renal artery

fibromuscular dysplasia, reversal of an endocrine cause of hyperten-

sion (e.g. by removal of an adrenal adenoma), or drug treatment of a

monogenic disorder affecting a specific drug-sensitive ion channel

(e.g. selective use of amiloride in Liddle’s syndrome)]. Interventions

that treat the cause of secondary hypertension later in life are less

likely to be curative (i.e. remove the need for antihypertensive medi-

cation) because longstanding hypertension results in vascular and

other organ damage that sustains the elevated BP, but intervention is

still important because it will often result in much better BP control

with less medication.

The prevalence of secondary hypertension is reported to be

5–15%

396

of people with hypertension. Screening all hypertensive

patients for secondary hypertension is not feasible or cost-effective;

however, there are some general patient characteristics that suggest

those more likely to have secondary hypertension and in whom

screening should be considered after confirming that BP is elevated

with ABPM (Table 25).

It is beyond the scope of these Guidelines to describe the detailed

clinical management of specific causes of secondary hypertension.

However, the commoner causes of secondary hypertension, clinical

history, and screening tests are described in Table 26,andthetypical

age distribution of these causes of secondary hypertension is shown in

Table 27. Review of these tables demonstrates that most screening can

be undertaken with blood and urine tests, abdominal ultrasound, and

echocardiography. Referral to a specialist centre is recommended for

additional investigations to confirm a suspected diagnosis of secondary

hypertension and for clinical management. Other causes of secondary

hypertension due to drugs and substances, and rarer monogenic

causes, are described below and are summarized inTables 28 and 29.

8.2.1 Drugs and other substances that may cause

secondary hypertension

Medications and other substances may cause a sufficient increase in

BP to raise the suspicion of secondary hypertension

397

(Table 28).

Consequently, a careful drug history is important when considering a

diagnosis of secondary hypertension. Moreover, other commonly

used drugs such as non-steroidal anti-inflammatory drugs or gluco-

corticoids can antagonize the BP-lowering effect of antihypertensive

medications in patients treated for hypertension, and may contribute

to a loss of BP control.

8.2.2 Genetic causes of secondary hypertension

Genetic causes of secondary hypertension are usually due to single-

gene disorders (see section 6).

194,195

They are rare but important

causes of secondary hypertension because identifying the cause can

point to a specific drug treatment (Table 29).

194,195

Common features

of these genetic disorders are that they usually present with hyper-

tension in children, adolescents, or young adults, and most mono-

genic disorders induce hypertension by increasing the renal tubular

reabsorption of sodium. Thus, they are usually associated with a sup-

pressed plasma renin concentration (PRC) or plasma renin activity

(PRA), which is unusual in younger patients and especially those

treated with antihypertensive medications (e.g. RAS blockers, CCBs,

or diuretics), that would be expected to increase PRC or PRA. Thus,

the finding of a suppressed PRC or PRA, especially whilst taking these

drugs, should raise the suspicion of secondary hypertension due a

salt-retaining state. Importantly, beta-blockers in particular, but also

non-steroidal anti-inflammatory drugs, alpha-methyl dopa, or cloni-

dine, suppress PRC and PRA. These drugs should be discontinued (if

clinically feasible) for at least 2 weeks before measuring PRC or PRA.

Table 25 Patient characteristics that should raise the suspicion of secondary hypertension

Characteristic

Younger patients (<40 years) with grade 2 hypertension or onset of any grade of hypertension in childhood

Acute worsening hypertension in patients with previously documented chronically stable normotension

Resistant hypertension (see section 8.1)

Severe (grade 3) hypertension or a hypertension emergency (see section 8.3)

Presence of extensive HMOD

Clinical or biochemical features suggestive of endocrine causes of hypertension or CKD

Clinical features suggestive of obstructive sleep apnoea

Symptoms suggestive of phaeochromocytoma or family history of phaeochromocytoma

CKD = chronic kidney disease; HMOD = hypertension-mediated organ damage.

ESC/ESH Guidelines 51

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Table 26 Common causes of secondary hypertension

Cause Prevalence in

hypertensive

patients

Suggestive symptoms and signs Screening Investigations

Obstructive sleep apnoea 5–10% Snoring; obesity (can be present in non-

obese); morning headache; daytime

somnolence

Epworth score and ambulatory

polygraphy

Renal parenchymal disease 2–10% Mostly asymptomatic; diabetes; haematu-

ria, proteinuria, nocturia; anaemia, renal

mass in adult polycystic CKD

Plasma creatinine and electrolytes,

eGFR; urine dipstick for blood and pro-

tein, urinary albumin:creatinine ratio;

renal ultrasound

Renovascular disease

Atherosclerotic renovascular disease 1–10% Older; widespread atherosclerosis (espe-

cially PAD); diabetes; smoking; recurrent

ﬂash pulmonary oedema; abdominal bruit

Duplex renal artery Doppler or CT

angiography or MR angiography

Fibromuscular dysplasia Younger; more common in women;

abdominal bruit

Endocrine causes

Primary Aldosteronism 5 - 15% Mostly asymptomatic; muscle weakness

(rare)

Plasma aldosterone and renin, and

aldosterone:renin ratio; hypokalaemia

(in a minority): note hypokalaemia can

depress aldosterone levels

Phaeochromocytoma <1% Episodic symptoms (the 5 ‘Ps’): paroxysmal

hypertension, pounding headache, perspi-

ration, palpitations, and pallor; labile BP; BP

surges precipitated by drugs (e.g. beta-

blockers, metoclopramide, sympathomi-

metics, opioids, and tricyclic

antidepressants)

Plasma or 24 h urinary fractionated

metanephrines

Cushing’s syndrome <1% Moon face, central obesity, skin atrophy,

striae and bruising; diabetes; chronic ste-

roid use

24 h urinary-free cortisol

Thyroid disease (hyper- or

hypothyroidism)

1 - 2% Signs and symptom of hyper- or

hypothyroidism

Thyroid function tests

Hyperparathyroidism <1% Hypercalcaemia, hypophosphataemia Parathyroid hormone, Ca

2þ

Other causes

Coarctation of the aorta <1% Usually detected in children or adoles-

cence; different BP (>_20/10 mmHg)

between upper–lower extremities and/or

between right–left arm and delayed radial-

femoral femoral pulsation; low ABI inter-

scapular ejection murmur; rib notching on

chest X-ray

Echocardiogram

ABI = ankle-brachial index; BP = blood pressure; CKD = chronic kidney disease; CT = computed tomography; eGFR = estimated glomerular ﬁltration rate; MR = magnetic res-

onance; PAD = peripheral artery disease.

52 ESC/ESH Guidelines

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Table 27 Incidence and typical causes of secondary hypertension according to age

Age group Per cent with underlying cause Typical causes

Young children (<12 years) 70 - 85 •Renal parenchymal disease

•Coarctation of the aorta

•Monogenic disorders

Adolescents (12–18 years) 10–15 •Renal parenchymal disease

•Coarctation of the aorta

•Monogenic disorders

Young adults (19–40 years) 5–10 •Renal parenchymal disease

•Fibromuscular dysplasia (especially in women)

•Undiagnosed monogenic disorders

Middle-aged adults (41–65 years) 5–15 •Primary aldosteronism

•Obstructive sleep apnoea

•Cushing’s syndrome

•Phaeochromocytoma

•Renal parenchymal disease

•Atherosclerotic renovascular disease

Older adults (>65 years) 5–10 •Atherosclerotic renovascular disease

•Renal parenchymal disease

•Thyroid disease

Table 28 Medications and other substances that may increase blood presssure

397

Medication/substance

Oral contraceptive pill Especially oestrogen containing; cause hypertension in 5% of women, usually mild but can be severe

Diet pills For example, phenylpropanolamine and sibutramine

Nasal decongestants For example, phenylephrine hydrochloride and naphazoline hydrochloride

Stimulant drugs Amphetamine, cocaine, and ecstasy; these substances usually cause acute rather than chronic

hypertension

Liquorice Chronic excessive liquorice use mimics hyperaldosteronism by stimulating the mineralocorticoid recep-

tor and inhibiting cortisol metabolism

Immunosuppressive medications For example, cyclosporin A (tacrolimus has less effect on BP and rapamycin has almost no effect on BP)

and steroids (e.g. corticosteroids and hydrocortisone)

Antiangiogenic cancer therapies Antiangiogenic drugs such as VEGF inhibitors (e.g. bevacizumab), tyrosine kinase inhibitors (e.g. suniti-

nib), and sorafenib have been reported to increase BP

Other drugs and substances

that may raise BP

Anabolic steroids, erythropoietin, non-steroidal anti-inﬂammatory drugs, and herbal remedies (e.g. ephe-

dra and ma huang)

BP = blood pressure; VEGF = vascular endothelial growth factor.

ESC/ESH Guidelines 53

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8.3 Hypertension urgencies and

emergencies

Hypertension emergencies are situations in which severe hyperten-

sion (grade 3) is associated with acute HMOD, which is often life-

threatening and requires immediate but careful intervention to lower

BP, usually with intravenous (i.v.) therapy.

398

The rate and magnitude

of an increase in BP may be at least as important as the absolute level

of BP in determining the magnitude of organ injury.

399

Typical presen-

tations of a hypertension emergency are:

•Patients with malignant hypertension, characterized by

severe hypertension (usually grade 3) associated with fundu-

scopic changes (flame haemorrhages and/or papilloedema),

microangiopathy, and disseminated intravascular coagulation, and

can be associated with encephalopathy (in about 15% of

cases),

400

acute heart failure, and acute deterioration in renal

function. The hallmark of this condition is small artery fibrinoid

necrosis in the kidney, retina, and brain. The term ‘malignant’

reflects the very poor prognosis for this condition if

untreated.

401–404

•Patients with severe hypertension associated with other

clinical conditions who are likely to require an urgent reduc-

tion of BP, e.g. acute aortic dissection, acute myocardial ischae-

mia, or acute heart failure.

•Patients with sudden severe hypertension due to phaeo-

chromocytoma, associated with organ damage.

•Pregnant women with severe hypertension or pre-

eclampsia (see section 8.9.1).

The most common emergency symptoms will depend of the

organs affected but may include headache, visual disturbances, chest

pain, dyspnoea, dizziness, and other neurological deficits. In patients

with hypertensive encephalopathy, the presence of somnolence,

lethargy, tonic clonic seizures, and cortical blindness may precede a

loss of consciousness; however, focal neurological lesions are rare

and should raise the suspicion of stroke.

Acute stroke, especially intracerebral haemorrhage, when

associated with severe hypertension has often been termed a

Table 29 Rare genetic causes of secondary hypertension

Condition Phenotype Mechanism and effect

Liddle syndrome Hypokalaemia, metabolic alkalosis, low PRA or

PRC, low PAC

Increased renal tubular ENaC activity:

responds to treatment with amiloride

Apparent mineralocorticoid

excess

Hypokalaemia, metabolic alkalosis, low PRA or

PRC, low PAC

Decreased 11b-dehydrogenase isoenzyme 2

Gordon syndrome Hypokalaemia, metabolic acidosis, low PRA or

PRC, low PAC

Overactivity of sodium chloride co-

transporter

Geller syndrome Pregnancy-exacerbated hypertension, low PRA or

PRC, low PAC

Agonist effect of progesterone on the min-

eralocorticoid receptor

Glucocorticoid remediable

hypertension

Hypokalaemia, metabolic alkalosis, low PRC or

PRA, and increased PAC

Chimeric CYP11b1 to CYP11b2 gene:

response to treatment with glucocorticoids

ENaC = epithelial sodium channel; PAC = plasma aldosterone concentration; PRA = plasma renin activity; PRC = plasma renin concentration.

Table 30 Diagnostic workup for patients with a sus-

pected hypertension emergency

Common tests for all potential causes

Fundoscopy is a critical part of the diagnostic workup

12-lead ECG

Haemoglobin, platelet count, ﬁbrinogen

Creatinine, eGFR, electrolytes, LDH, haptoglobin

Urine albumin:creatinine ratio, urine microscopy for red cells,

leucocytes, casts

Pregnancy test in women of child-bearing age

Speciﬁc tests by indication

Troponin, CK-MB (in suspected cardiac involvement, e.g. acute

chest pain or acute heart failure) and NT-proBNP

Chest X-ray (ﬂuid overload)

Echocardiography (aortic dissection, heart failure, or ischaemia)

CT angiography of thorax and/or abdomen in suspected acute

aortic disease (e.g. aortic dissection)

CT or MRI brain (nervous system involvement)

Renal ultrasound (renal impairment or suspected renal artery

stenosis)

Urine drug screen (suspected methamphetamine or cocaine

use)

CK-MB = creatinine kinase-muscle/brain; CT = computed tomography; ECG =

electrocardiogram; eGFR = estimated glomerular ﬁltration rate; LDH = lactate

dehydrogenase; MRI = magnetic resonance imaging; NT-proBNP = N-terminal

pro-B natriuretic peptide.

54 ESC/ESH Guidelines

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hypertension emergency, but a more cautious approach is now rec-

ommended for acute BP lowering in the emergency setting of acute

stroke (see section 8.15).

The term ‘hypertension urgency’ has also been used to describe

severe hypertension in patients presenting to the emergency depart-

ment in whom there is no clinical evidence of acute HMOD.

405

Whilst these patients require BP reduction, they do not usually

require admission to hospital, and BP reduction is best achieved with

oral medication according to the drug treatment algorithm presented

in Figure 4. However, these patients will require urgent outpatient

review to ensure that their BP is coming under control.

Acute and severe increases in BP can sometimes be precipitated

by ingestion of sympathomimetics such as meta-amphetamine or

cocaine. This can result in a hypertension emergency when there is

evidence of acute HMOD.

It is emphasized that many patients in an emergency

department with acute pain or distress may experience an acute ele-

vation in BP that will be restored to normal when the pain and dis-

tress are relieved, rather than requiring any specific intervention to

lower BP.

For patients with a suspected hypertension emergency, a diagnos-

tic workup is shown in Table 30.

8.3.1 Acute management of hypertensive emergencies

Apart from acute BP lowering in stroke, there are no RCTs evaluating

different treatment strategies for hypertensive emergencies. The key

considerations in defining the treatment strategy are:

(1) Establishing the target organs that are affected, whether they

require any specific interventions other than BP lowering, and

whether there is a precipitating cause for the acute rise in BP that

might affect the treatment plan (e.g. pregnancy);

(2) The recommended timescale and magnitude of BP lowering

required for safe BP reduction;

(3) The type of BP-lowering treatment required. With regard to drug

treatment, in a hypertension emergency, i.v. treatment with a drug

with a short half-life is ideal to allow careful titration of the BP

response to treatment in a higher dependency clinical area with

facilities for continuous haemodynamic monitoring.

Recommended drug treatments for specific hypertension emer-

gencies

398,406

are shown in Table 31 and an expanded range of possi-

ble drug choices

398

is shown in Table 32. Rapid uncontrolled BP

lowering is not recommended as this can lead to complications.

397

Although i.v. drug administration is recommended for most hyper-

tension emergencies, oral therapy with ACE inhibitors, ARBs, or

beta-blockers is sometimes very effective in malignant hypertension

because the renin system is activated by renal ischaemia. However,

low initial doses should be used because these patients can be very

sensitive to these agents and treatment should take place in hospital.

Further comprehensive details on the clinical management of hyper-

tension emergencies are available.

398

8.3.2 Prognosis and follow-up

The survival of patients with hypertension emergencies has improved

dramatically over past decades,

407

but these patients remain at high

risk

408,409

and should be screened for secondary hypertension (see

section 8.2). After discharge from hospital, when BP has reached a

safe and stable level on oral therapy, we recommend frequent, at

least monthly, visits in a specialized setting until the optimal target BP

is achieved and long-term specialist follow-up thereafter.

Table 31 Hypertensive emergencies requiring immediate blood pressure lowering with intravenous drug therapy

Clinical presentation Timeline and target for BP

reduction

First-line treatment Alternative

Malignant hypertension with or

without acute renal failure

Several hours

Reduce MAP by 20–25%

Labetalol

Nicardipine

Nitroprusside

Urapidil

Hypertensive encephalopathy Immediately reduce MAP by

20–25%

Labetalol, nicardipine Nitroprusside

Acute coronary event Immediately reduce SBP to <140

mmHg

Nitroglycerine, labetalol Urapidil

Acute cardiogenic pulmonary

oedema

Immediately reduce SBP to <140

mmHg

Nitroprusside or nitroglycerine

(with loop diuretic)

Urapidil (with loop diuretic)

Acute aortic dissection Immediately reduce SBP to <120

mmHg AND heart rate to <60

bpm

Esmolol and nitroprusside or

nitroglycerine or nicardipine

Labetalol OR metoprolol

Eclampsia and severe pre-

eclampsia/HELLP

Immediately reduce SBP to <160

mmHg AND DBP to <105 mmHg

Labetalol or nicardipine and

magnesium sulfate

Consider delivery

BP = blood pressure; bpm = beats per min; DBP = diastolic blood pressure; HELLP = haemolysis, elevated liver enzymes, and low platelets; i.v. = intravenous; MAP = mean

arterial pressure; SBP = systolic blood pressure.

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8.4 White-coat hypertension

As discussed in section 4, white-coat hypertension is defined as an

elevated office BP despite a normal out-of-office BP. White-coat

hypertension may be present in many people with an increased office

BP, with a maximum in grade 1 hypertension, and very old people

(>50%). Compared with normotensive people, white-coat hyperten-

sion is associated with an increased prevalence of dysmetabolic risk

factors and asymptomatic organ damage. It is also associated with a

greater risk of developing type 2 diabetes and sustained hypertension,

as well as an overall increased risk of CV events.

68,410–412

It is recom-

mended that people with white-coat hypertension should have an

accurate assessment of their CV risk profile, including a search for

HMOD. Office and out-of-office BP (both home and ambulatory BP)

should be measured frequently, e.g. no less than every 2 years.

Treatment should consider lifestyle changes to reduce the elevated

CV risk.

85,86,89

Whether or not patients with white-coat hypertension should

receive antihypertensive drugs is unresolved. In white-coat

Table 32 Drug types, doses, and characteristics for treatment of hypertension emergencies

Drug Onset of action Duration

of action

Dose Contraindications Adverse effects

Esmolol 1–2 min 10–30 min 0.5–1 mg/kg as bolus; 50–300

mg/kg/min as continuous

infusion

Second or third-degree AV

block, systolic heart failure,

asthma, bradycardia

Bradycardia

Metoprolol 1–2 min 5 –8 h 15 mg i.v., usually given as 5 mg

i.v., and repeated at 5 min inter-

vals as needed

Second or third-degree AV

block, systolic heart failure,

asthma, bradycardia

Bradycardia

Labetalol 5–10 min 3–6 h 0.25–0.5 mg/kg; 2–4 mg/min

until goal BP is reached, there-

after 5–20 mg/h

Second or third-degree AV

block; systolic heart failure,

asthma, bradycardia

Bronchoconstriction,

foetal bradycardia

Fenoldopam 5–15 min 30–60 min 0.1 mg/kg/min, increase every

15 min until goal BP is reached

Caution in glaucoma

Clevidipine 2–3 min 5–15 min 2 mg/h, increase every 2 min

with 2 mg/h until goal BP

Headache, reﬂex

tachycardia

Nicardipine 5–15 min 30–40 min 5–15 mg/h as continuous infu-

sion, starting dose 5 mg/h,

increase every 15–30 min with

2.5 mg until goal BP, thereafter

decrease to 3 mg/h

Liver failure Headache, reﬂex

tachycardia

Nitroglycerine 1–5 min 3–5 min 5– 200 mg/min, 5 mg/min

increase every 5 min

Headache, reﬂex

tachycardia

Nitroprusside Immediate 1–2 min 0.3–10 mg/kg/min, increase by

0.5 mg/kg/min every 5 min until

goal BP

Liver/kidney failure

(relative)

Cyanide intoxication

Enalaprilat 5–15 min 4–6 h 0.62–1.25 mg i.v. History of angioedema

Urapidil 3–5 min 4–6 h 12.5–25 mg as bolus injection;

5–40 mg/h as continuous

infusion

Clonidine 30 min 4 –6 h 150–300 mg i.v. over 5–10 min Sedation, rebound

hypertension

Phentolamine 1–2 min 10–30 min 0.5–1 mg/kg bolus injections

OR 50–300 mg/kg/min as con-

tinuous infusion

Tachyarrhythmias,

chest pain

AV = atrioventricular; BP = blood pressure; i.v. = intravenous.

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hypertension, antihypertensive drugs have been shown to effectively

and persistently lower office BP, with no concomitant reduction

(indeed, even a small increase) of ambulatory BP values.

413,414

Whether these BP changes lead to CV protection has not been inves-

tigated with adequately powered outcome studies and remains

unknown. However, it should be considered that people with white-

coat hypertension have inevitably been well represented in trials doc-

umenting the protective effect of antihypertensive drugs,

415

particu-

larly those addressing conditions in which white-coat hypertension is

more common, such as grade 1 hypertension or hypertension in

older patients. In a recent subanalysis of the HYVET trial of the very

old with hypertension, white-coat hypertension was reported to

account for 55% of the trial population.

416

Thus, antihypertensive

drug treatment cannot definitively be excluded for patients with

white-coat hypertension and may be considered, in particular, in

white-coat hypertensive people with a higher CV risk profile, such as

those with HMOD, an uncertain out-of-office BP normality pattern

(i.e. ambulatory but not home BP normality or vice versa), or a persis-

tent office BP elevation at repeated visits.

417–420

No CV risk excess

has been reported in patients in whom white-coat hypertension

results from treatment-dependant normalization of out-of-office BP

only.

418,421

Thus, whether this condition benefits from an uptitration

of the existing drug treatment regimen (to also achieve office BP nor-

malization) remains to be determined.

8.5 Masked hypertension

As reported in section 4.7.2, masked hypertension is defined in people

whose BP is normal in the office but elevated on out-of-office BP meas-

urements. Such people usually have dysmetabolic risk factors and

asymptomatic organ damage, which are substantially more frequent

than in people who are truly normotensive.

93,410–412,422

The challenge

is how to diagnose masked hypertension, because most hypertension

screening programmes use office BP measurement, which is normal in

these people. Masked hypertension is commoner in younger rather

than older individuals, and in those with an office BP in the borderline

hypertension range (i.e. 130 - 139/80 - 89 mmHg). It is uncommon in

people whose office BP is <130/80 mmHg. Masked hypertension is

associated with progression to sustained office hypertension, increased

frequency of developing type 2 diabetes, and the presence of HMOD.

The long-term risk of fatal and non-fatal CV events approaches that of

patients with sustained hypertension.

68,81,93,95,423

Patients with masked

hypertension should have an accurate initial assessment of their CV

risk profile. CV risk factors (including organ damage and ideally both

home and ambulatory BP) should then be periodically monitored.

Factors contributing to the out-of-office BP elevation (e.g. smoking)

should be discouraged and lifestyle interventions implemented to

improve out-of-office BP levels. The impact of antihypertensive drug

treatment on CV outcomes in people with masked hypertension has

never been studied. Nevertheless, treatment with BP-lowering medica-

tion should be considered because these patients are at high CV risk,

often have HMOD, and the adverse prognostic importance of out-of-

office BP elevations has been well documented.

68,74

8.6 Masked uncontrolled hypertension

MUCH occurs in some treated patients in whom the office BP

appears controlled to recommended BP targets, but BP is elevated

and thus uncontrolled according to out-of-office BP measurements

(ABPM or HBPM).

Registry-based studies in Spain have suggested

that MUCH occurs in as many as 30% of treated hypertensive

patients,

and is more common with comorbidities such as diabetes

and CKD and in those at highest risk. Moreover, MUCH was more

commonly due to poorly controlled nocturnal rather than daytime

pressures on ABPM. Presently, no data are available from outcome

trials for patients with MUCH; however, mindful of their high CV

risk, treatment uptitration should be considered to ensure that that

both office and out-of-office BP are controlled.

8.7 Hypertension in younger adults

(age <50 years)

The prevalence of hypertension increases with age. Most hyperten-

sion across the age span is due to systolic hypertension; however, ele-

vations of DBP and isolated diastolic hypertension, when they occur,

Management of white coat and masked hypertension

Management of white-coat hypertension

Recommendations Class

Level

In white-coat hypertensive patients, it is rec-

ommended to implement lifestyle changes

aimed at reducing CV risk as well as regular

follow-up with periodic out-of-ofﬁce BP

monitoring.

In patients with white-coat hypertension:

•Drug treatment may be considered in

people with evidence of HMOD or in

whom CV risk is high or very high.

IIb C

•Routine drug treatment is not indicated. III C

Management of masked hypertension

Recommendations

In masked hypertension, lifestyle changes

are recommended to reduce CV risk, with

regular follow-up, including periodic out-of-

ofﬁce BP monitoring.

Antihypertensive drug treatment should be

considered in masked hypertension to nor-

malize the out-of-ofﬁce BP, based on the

prognostic importance of out-of-ofﬁce BP

elevation.

IIa C

Antihypertensive drug uptitration should be

considered in treated patients whose out-

of-ofﬁce BP is not controlled (i.e. masked

uncontrolled hypertension), because of the

high CV risk of these patients.

IIa C

BP = blood pressure; CV = cardiovascular; HMOD = hypertension-mediated

organ damage.

Class of recommendation.

Level of evidence.

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are more common in younger rather than older patients.

211

There is

a greater likelihood of detecting secondary hypertension in younger

patients (<50 years), where the prevalence of secondary hyperten-

sion may be as high as 10% and should be considered, especially in

those with more severe hypertension (see section 3).

All younger adults with grade 2 or more severe hypertension

should be offered lifestyle advice and drug treatment, as well as high-

risk younger adults with grade 1 hypertension (i.e. with HMOD,

CVD, diabetes, CKD, or those at high CVD risk, although CV risk is

often underestimated in younger adults over shorter-term projec-

tions, such as 10 years).

There is controversy about whether younger adults with uncom-

plicated grade 1 hypertension should be treated because of the

obvious difficulty in conducting conventional clinical outcome trials in

younger adults in whom the outcomes only occur after many

years.

424

There is little doubt that treating stage 1 hypertension in

older patients, even those at low–moderate-risk, reduces CV mor-

bidity and mortality.

425

Moreover, long-term epidemiological studies

have demonstrated a clear relationship between BP and longer-term

risk of CV events and mortality in young adults with a BP >130/80

mmHg.

424,426

Furthermore, earlier treatment

can prevent more

severe hypertension

427

and the development of HMOD, which may

not be completely reversible with later treatment. Thus, despite the

absence of RCT evidence demonstrating the benefits of antihyper-

tensive treatment in younger adults with uncomplicated grade 1

hypertension, treatment with BP-lowering drugs may be considered

prudent. If a decision is taken not to offer treatment or treatment is

declined, lifestyle advice should be prescribed, and longer-term fol-

low-up is essential as BP will invariably rise. In younger patients with

hypertension treated with BP-lowering medication, office BP should

be reduced to <_ 130/80 mmHg if treatment is well tolerated.Other

interventions, e.g. statins or antiplatelet therapy, should also be con-

sidered for higher-risk patients (see section 7.2.5).

8.7.1 Isolated systolic hypertension in the young

Some young, healthy people, and men in particular, may present with

isolated grade 1 systolic hypertension (i.e. brachial SBP >_140 - 159

mmHg and a normal DBP <90 mmHg), and this may be associated

with a normal central aortic SBP due to excessive peripheral systolic

pressure amplification.

428

It is unclear whether isolated systolic

hypertension in the context of a normal aortic pressure is benign. A

recent examination of prospective data from the Chicago Heart

Association Detection Project found that young men with isolated

systolic hypertension had a CV risk similar to that of individuals with

high–normal BP and that isolated systolic hypertension in the young

was closely associated with smoking.

429

On the basis of current evi-

dence, these young individuals should receive recommendations on

lifestyle modification (particularly cessation of smoking); whether

they should receive drug treatment is unclear, but they do require

longer-term follow-up as many will develop sustained

hypertension.

430

8.8 Hypertension in older patients

(age 65 years)

The prevalence of hypertension increases with age, with a prevalence

of 60% over the age of 60 years and 75% over the age of 75 years.

For the purposes of these Guidelines, older is defined as >_65 years

and the very old as >_80 years.

For many years, advanced age has been a barrier to the treatment

of hypertension because of concerns about potential poor tolerabil-

ity, and even harmful effects of BP-lowering interventions in people in

whom mechanisms preserving BP homeostasis and vital organ perfu-

sion may be more frequently impaired. This approach is not appro-

priate, because evidence from RCTs has shown that in old and very

old patients, antihypertensive treatment substantially reduces CV

morbidity and CV and all-cause mortality

220,431

(see section 7).

Moreover, treatment has been found to be generally well tolerated.

However, older patients are more likely to have comorbidities such

as renal impairment, atherosclerotic vascular disease, and postural

hypotension, which may be worsened by BP-lowering drugs. Older

patients also frequently take other medications, which may negatively

interact with those used to achieve BP control. A further important

caveat is that RCTs have not included very frail patients, dependent

patients, and patients with postural hypotension. It is thus uncertain

whether, and to what extent, such patients would benefit from BP-

lowering treatment inthe context of their comorbidities and reduced

life expectancy. Thus, in older hypertensive patients, treatment

presents more difficulties than in younger people, because the deci-

sion to treathypertension must take into accountthe patient’sclinical

condition, concomitant treatments, and frailty. That said, age alone

must never be a barrier to treatment because high BP is an important

risk factor even at the most advanced ages. Furthermore, a recent

study of a cohort of older patients from the general population (thus

including those with frailty) has shown that better adherence to anti-

hypertensive treatment was associated with a reduced risk of CV

events and mortality, even when age was >85 years (mean 90

years).

432

It is recommended that older patients are treated according to the

treatment algorithm outlined in section 7. In very old patients, it may

be appropriate to initiate treatment with monotherapy. In all older

patients, when combination therapy is used, it is recommended that

this is initiated at the lowest available doses. In all older patients, and

especially very old or frail patients, the possible occurrence of pos-

tural BP should be closely monitored and symptoms of possible

hypotensive episodes checked by ABPM. Unless required for con-

comitant diseases, loop diuretics and alpha-blockers should be

avoided because of their association with injurious falls.

433,434

Renal

function should be frequently assessed to detect possible increases in

serum creatinine and reductions in eGFR as a result of BP-related

reductions in renal perfusion. When treated, BP should be lowered

to a systolic value of 130–139 mmHg and a diastolic value of <80

mmHg if tolerated. Treated SBP values of <130 mmHg should be

avoided. A key emphasis in treating older patients, and especially the

very old, is to carefully monitor for any adverse effects or tolerability

problems associated with BP-lowering treatment, keeping in mind

that adverse effects can be more frequent than reported in RCTs, in

which specific medical expertise and close patient supervision may

minimize adverse effects and tolerability problems.

An important consideration is frail, dependent older patients,

including those with orthostatic hypotension. These have been

excluded from RCTs. The SPRINT trial showed the benefits of BP-

lowering treatment being extended to recruited patients who were

at the frailer end of the spectrum, including those with reduced gait

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speed.

215

This suggests that the benefit of treatment is not limited to

fit and independent older patients; however, to what extent BP-

lowering treatment benefits the very frail

214

and institutionalized

patients remains to be determined.

In some patients, the best achievable BP may be higher than the rec-

ommended target, but it should be recognised that any amount of BP

lowering is likely to be worthwhile and associated with a reduced risk

of major CV events (especially stroke and heart failure) and mortality.

8.9 Women, pregnancy, oral

contraception, and hormone-

replacement therapy

8.9.1 Hypertension and pregnancy

Hypertensive disorders in pregnancy affect 5–10% of pregnancies

worldwideand remain a major cause of maternal, foetal, and neonatal

morbidity and mortality. Maternal risks include placental abruption,

stroke, multiple organ failure, and disseminated intravascular coagula-

tion. The foetus is at high risk of intrauterine growth retardation

(25% of cases of pre-eclampsia), prematurity (27% of cases of pre-

eclampsia), and intrauterine death (4% of cases of pre-eclampsia).

435

8.9.1.1 Definition and classification of hypertension in pregnancy

The definition of hypertension in pregnancy is based on office BP val-

ues, SBP >_140 mmHg and/or DBP >_90 mmHg,

436,437

and is classified

as mild (140–159/90–109 mmHg) or severe (>_160/110 mmHg), in

contrast to the conventional hypertension grading.

Hypertension in pregnancy is not a single entity but comprises:

•Pre-existing hypertension: precedes pregnancy or develops

before 20 weeks of gestation, and usually persists for more than

6 weeks post-partum and may be associated with proteinuria.

•Gestational hypertension: develops after 20 weeks of gesta-

tion and usually resolves within 6 weeks post-partum.

•Pre-existing hypertension plus superimposed gesta-

tional hypertension with proteinuria.

•Pre-eclampsia: gestational hypertension with significant protei-

nuria (>0.3 g/24 h or >_30 mg/mmol ACR). It occurs more fre-

quently during the first pregnancy, in multiple pregnancy, in

hydatidiform mole, in antiphospholipid syndrome, or with pre-

existing hypertension, renal disease, or diabetes. It is often associ-

ated with foetal growth restriction due to placental insufficiency

and is a common cause of prematurity.

438

The only cure for pre-

eclampsia is delivery. As proteinuria may be a late manifestation

of pre-eclampsia, it should be suspected when de novo hyperten-

sion is accompanied by headache, visual disturbances, abdominal

pain, or abnormal laboratory tests, specifically low platelets and/

or abnormal liver function.

•Antenatally unclassifiable hypertension: this term is used

when BP is first recorded after 20 weeks of gestation and it is

unclear if hypertension was pre-existing. Reassessment 6 weeks

post-partum will help distinguish pre-existing from gestational

hypertension.

8.9.1.2 Blood pressure measurement in pregnancy

BP in pregnancy should be measured in the sitting position (or the left

lateral recumbent during labour) with an appropriately sized arm cuff at

heart level and using Korotkoff V for DBP. Manual auscultation remains

the gold standard for BP measurement in pregnancy, because automated

devices tend to under-record the BP and are unreliable in severe pre-

eclampsia. Only validated devices should be used in pregnancy.

439

ABPM

is superior to office BP measurement for the prediction of pregnancy

outcome.

440

ABPM devices recommended for use in pregnancy are

more accurate than those used for office measurement or HBPM.

ABPM helps avoid unnecessary treatment of white-coat hypertension,

and is useful in the management of high-risk pregnant women with

hypertension and those with diabetic or hypertensive nephropathy.

8.9.1.3 Investigation of hypertension in pregnancy

Basic laboratory investigations recommended for monitoring preg-

nant hypertensive women include urine analysis, blood count, haema-

tocrit, liver enzymes, serum creatinine, and serum uric acid

(increased in clinically evident pre-eclampsia). Hyperuricaemia in

hypertensive pregnancies identifies women at increased risk of

adverse maternal and foetal outcomes.

441

All pregnant women should be assessed for proteinuria in early

pregnancy to detect pre-existing renal disease and, in the second half

of pregnancy, to screen for pre-eclampsia. A dipstick test of >_1þ

should prompt evaluation of ACR in a single spot urine sample and a

value <30 mg/mmol can reliably rule outproteinuria in pregnancy.

442

In addition to basic laboratory tests, the following investigations

may be considered:

•Ultrasound investigation of the kidneys and adrenals, and plasma

or urinary fractionated metanephrine assays in pregnant women

with a history suggestive of phaeochromocytoma.

•Doppler ultrasound of uterine arteries (performed after 20

weeks of gestation) to detect those at higher risk of gestational

hypertension, pre-eclampsia, and intrauterine growth

retardation.

443

•A soluble fms-like tyrosine kinase 1:placental growth factor ratio

of <_ 38 can be used to exclude the development of pre-

eclampsia in the next week when suspected clinically.

444

8.9.1.4 Prevention of hypertension and pre-eclampsia

Women at high or moderate-risk of pre-eclampsia should be advised

to take 100–150 mg of aspirin daily from weeks 12–36.

445

High risk

of pre-eclampsia includes any of the following:

•Hypertensive disease during a previous pregnancy

•CKD

•Autoimmune disease such as systemic lupus erythematosus or

antiphospholipid syndrome

•Type 1 or type 2 diabetes

•Chronic hypertension.

Moderate-risk of pre-eclampsia includes one or more of the fol-

lowing risk factors:

•First pregnancy

•Age >_40 years

•Pregnancy interval of >10 years

•BMI of >_35 kg/m

at first visit

•Family history of pre-eclampsia

•Multiple pregnancy.

8.9.1.5 Clinical management of hypertension in pregnancy

Mild hypertension of pregnancy (BP 140159/90 109 mmHg). The

goal of drug treatment of hypertension in pregnancy is to reduce

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maternal risk; however, the agents selected must be safe for the foetus.

The benefits of drug treatment for mother and foetus in hypertension

in pregnancy have not been extensively studied, with the best data

from a single trial using alpha-methyldopa, performed 40 years

ago.

446–448

A further study suggested that tighter vs. less tight control

of BP in pregnancy showed no difference in the risk of adverse perinatal

outcomes and overall serious maternal complications. However, sec-

ondary analysis suggested that tighter control of BP may reduce the

risk of developing more severe hypertension and pre-eclampsia.

446

Most women with pre-existing hypertension and normal renal

function will not have severe hypertension and are a low risk for

developing complications during pregnancy. Indeed, some of these

women may be able to withdraw their medication in the first half of

pregnancy because of the physiological fall in BP. Despite the paucity

of evidence, European Guidelines

17,449,450

have recommended initiat-

ing drug treatment:

(1) In all women with persistent elevation of BP >_150/95 mmHg;

(2) In women with gestational hypertension (with or without proteinu-

ria), pre-existing hypertension with the superimposition of gesta-

tional hypertension, or hypertension with subclinical HMOD, when

BP is >140/90 mmHg.

Women with pre-existing hypertension may continue their cur-

rent antihypertensive medication, but ACE inhibitors, ARBs, and

direct renin inhibitors are contraindicated due to adverse foetal and

neonatal outcomes. Methyldopa, labetalol, and CCBs are the drugs of

choice. Beta-blockers may induce foetal bradycardia; consequently, if

used, their type and dose should be carefully selected, with atenolol

best avoided. Diuretic therapy is generally avoided because plasma

volume is reduced in women who develop pre-eclampsia.

There are no data to define the optimal BP treatment target in

pregnant women. Nevertheless, for pragmatic reasons, if treatment is

initiated it is important to suggest a treatment target to calibrate how

much treatment to give. A BP target of <140/90 is suggested for preg-

nant women receiving antihypertensive therapy.

Severe hypertension of pregnancy (160/110 mmHg). There is

no agreed definition of severe hypertension, with values ranging

between 160–180 mmHg/>110 mmHg. The 2018 ESC Task Force

on cardiovascular disease during pregnancy

435

considers an SBP

>_170 mmHg or DBP >_110 mmHg an emergency in a pregnant

woman, who should be immediately admitted to hospital for treat-

ment. The selection of the antihypertensive drug and its route of

administration depends on the expected time of delivery.

Pharmacological treatment with i.v. labetalol, oral methyldopa, or

CCB should be initiated. Intravenous hydralazine is no longer the

drug of choice as it is associated with more perinatal adverse effects

than other drugs.

451

However, hydralazine is still used when other

treatment regimens fail to achieve adequate BP control. Intravenous

urapidil can also be considered.

In hypertensive crises, i.e. in patients with eclampsia or severe pre-

eclampsia (with or without haemolysis, elevated liver enzymes, and

low platelets syndrome), hospitalization and BP-lowering therapy is

essential, and delivery needs to be considered after the maternal con-

dition has stabilized.

435

Intravenous magnesium sulfate is recom-

mended for the prevention of eclampsia and treatment of seizures.

The consensus is to lower BP to <160/105 mmHg to prevent acute

hypertensive complications in the mother. Both labetalol and nicardi-

pine have shown to be safe and effective for the treatment of severe

pre-eclampsia if i.v. BP-lowering therapy is necessary.

452

In both

cases, monitoring of foetal heart rate is necessary. To prevent foetal

bradycardia, the cumulative dose of labetalol should not exceed 800

mg/24 h. Intravenous sodium nitroprusside iscontraindicated in preg-

nancy because of an increased risk of foetal cyanide poisoning. The

drug of choice when pre-eclampsia is associated with pulmonary

oedema is nitroglycerin (glyceryl trinitrate), given as an i.v. infusion of

5lg/min, and gradually increased every 3–5 min to a maximum dose

of 100 lg/min.

Delivery is indicated (i) urgently in pre-eclampsia with visual distur-

bances or haemostatic disorders, and (ii) at 37 weeks in asympto-

matic women.

453

Blood pressure post-partum. Post-partum hypertension is common

in the first week. Any drug recommended can be used according to

the hypertension treatment algorithm shown in Figure 4,withthecav-

eats: (i) methyldopa should be avoided because of the risk of post-

partum depression and (ii) consideration should be given to drug

choice in breastfeeding women.

8.9.1.6 Hypertension and breastfeeding

All antihypertensive drugs taken by the nursing mother are excreted

into breast milk. Most are present at very low concentrations except

for propranolol and nifedipine, with breast milk concentrations simi-

lar to those in maternal plasma. Reference to prescribing information

in breastfeeding women is important.

8.9.1.7 Risk of recurrence of hypertensive disorders in a subsequent

pregnancy

Women experiencing hypertension in their first pregnancy are at

increased risk in a subsequent pregnancy. The earlier the onset of

hypertension in the first pregnancy, the higher the risk of recurrence

in a subsequent pregnancy.

8.9.1.8 Long-term cardiovascular consequences of gestational

hypertension

Women who develop gestational hypertension or pre-eclampsia are

at increased risk of hypertension, stroke, and ischaemic heart disease

in later adult life.

454,455

Lifestyle modifications are indicated to avoid

complications in subsequent pregnancies and to reduce maternal CV

risk in the future. Therefore, annual visits to a primary care physician

to check BP and metabolic factors are recommended for these

patients.

Further detail on the management of hypertension and other CV

disorders in pregnancy is available.

435

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8.9.2 Oral contraceptive pills and hypertension

Combined oestrogen–progesterone oral contraceptive pills can be

associated with a small but significant increase in BP and the develop-

ment of hypertension in about 5% of users.

456,457

BP usually

decreases promptly following cessation of these pills; consequently,

BP should be monitored before and during oral contraceptive pill

treatment. The rise in BP appears to be related to the oestrogen con-

tent and may be less likely with the progestogen-only oral contracep-

tive pill. Older studies have demonstrated a relationship between the

oral contraceptive pill and venous thrombosis and venous throm-

boembolism, and, to a lesser extent, myocardial infarction (especially

with concomitant smoking history) and stroke.

458

More recent stud-

ies with newer-generation oral contraceptive pills have reported

conflicting results. Thus, the use of oral contraceptives should con-

sider the risks and benefits for the individual patient. Changes in BP

should be carefully evaluated with follow-up readings.

459

Concomitant CV risk factors (e.g. smoking history) should be

assessed and oral contraceptive pill use is not recommended if BP is

elevated. In such patients, alternative forms of contraception should

be offered. Discontinuation of combined oestrogen–progestin oral

contraceptives in women with hypertension may improve their BP

control.

460

8.9.3 Hormone-replacement therapy and hypertension

Cross-sectional studies have long established that menopause dou-

bles the risk of developing hypertension, even after adjusting for fac-

tors such as age and BMI.

461

Although hormone-replacement

therapy contains oestrogens, there is no convincing evidence that sig-

nificant rises in BP will occur in otherwise normotensive menopausal

women due to this therapy, or that BP will increase further due to

hormone-replacement therapy in menopausal hypertensive

women.

462

Hormone-replacement therapy and selective oestrogen

receptor modulators should not be used for primary or secondary

prevention of CVD. In summary, current evidence suggests that the

use of hormone-replacement therapy is not associated with an

increase in BP. Moreover, it is not contraindicated in women with

hypertension, and women with hypertension may be prescribed

hormone-replacement therapy as long as BP levels can be controlled

by antihypertensive medication.

8.10 Hypertension in different ethnic

groups

In comparison with the non-black population, hypertension is more

prevalent in the black population living in Europe,

463

similarly to that

reported for the USA.

464

As for the European white population, the

Management of hypertension in pregnancy

Recommendations Class

Level

In women with gestational hypertension, pre-existing hypertension superimposed by gestational hyperten-

sion, or with hypertension and subclinical organ damage or symptoms, initiation of drug treatment is recom-

mended when SBP is >_140 mmHg or DBP >_90 mmHg.

In all other cases, initiation of drug treatment is recommended when SBP is >_150 mmHg or DBP is >_95

mmHg. IC

Methyldopa, labetalol, and CCBs are recommended as the drugs of choice for the treatment of hypertension in

pregnancy.

447,448

(methyldopa)

(labetalol or CCBs)

ACE inhibitors, ARBs, or direct renin inhibitors are not recommended during pregnancy. III C

SBP >_170 mmHg or DBP >_110 mmHg in a pregnant woman is an emergency, and admission to hospital is

recommended. IC

In severe hypertension, drug treatment with i.v. labetalol, oral methyldopa, or nifedipine is recommended. IC

The recommended treatment for hypertensive crisis is i.v. labetalol or nicardipine and magnesium. IC

In pre-eclampsia associated with pulmonary oedema, nitroglycerin given as an i.v. infusion is recommended. IC

In women with gestational hypertension or mild pre-eclampsia, delivery is recommended at 37 weeks.

453

It is recommended to expedite delivery in pre-eclampsia with adverse conditions, such as visual disturbances

or haemostatic disorders. IC

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; DBP = diastolic blood pressure; i.v. = intravenous; SBP = systolic

blood pressure.

Class of recommendation.

Level of evidence.

ESC/ESH Guidelines 61

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black European population is heterogenous in nature,

463

although in

almost all European countries the largest ethnic group originates from

the Sub-Saharan African region.

463

Hypertension epidemiology, diag-

nosis, and treatment have been thoroughly studied in black (i.e. Afro-

American) US patients,

464

in contrast to the much scarcer database

available for European black people, and thus we extrapolate from US

data. However, this extrapolation requires some caution as differences

betweentheNorthAmericanandtheEuropeanblackpopulation

exist, especially with regard to socioeconomic status, CV risk,

465,466

and the response to antihypertensive drug treatment.

467

BP-related

HMOD, as well as CV and renal complications, are more common and

severe in black patients compared with age-matched white patients at

any BP level.

464

Black hypertensive patients exhibit a similar propor-

tional reduction of CV and renal events in response to BP-lowering

treatment as white patients, with somewhat different treatment modal-

ities. However, to achieve an effective BP reduction and BP control,

salt restriction is particularly important in black patients, in whom it

may lead to greater BP falls and more favourably impact on the effec-

tiveness of BP-lowering drug treatment.

468

Hypertensive black patients

also show a reduced antihypertensive response to RAS-blocker mono-

therapy, whereas they usually respond more effectively to thiazide or

thiazide-like diuretics and CCBs,

316,469,470

which in black patients may

be combined with each other or with a RAS blocker, making the latter

more effective. Angioedema appears more common with ACE inhibi-

tors in black patients, which may favour the preferred use of ARBs in

this population. Despite some progress in recent years, data on hyper-

tension prevalence, management, and control in European black

patients (and in other immigrant populations such as European individ-

uals from South Asia) are still scarce,

463,471

which makes this field an

important area for future research. There is no evidence that the BP

response to treatment in other ethnic groups differs from that

reported in the general population in Europe.

8.11 Hypertension in diabetes

mellitus

High BP is a common feature of type 1 and, particularly, type 2

diabetes. Moreover, masked hypertension and a blunted noctur-

nal fall in BP are not infrequent in people with diabetes.

472

Recording 24 h ABPM in apparently normotensive people with

diabetes may be a useful diagnostic procedure, especially in those

with HMOD. Substantial evidence supports the benefits of BP

reduction in people with diabetes to reduce major macrovascular

and microvascular complications of diabetes, as well as reducing

mortality. Proven benefits of BP-lowering treatment in diabetes

also include a significant reduction in the rate of end-stage renal

disease,

231,235

retinopathy,

and albuminuria.

Diabetic neuropa-

thy has never been included as an outcome in RCTs of BP-

lowering treatment.

When considering treatment for hypertension, it is important to

exclude significant postural hypotension, which can be marked in

people with diabetes due to autonomic neuropathy.

235

Initiation of

antihypertensive drug therapy is recommended when the office BP

is >140/90 mmHg. Alongside lifestyle interventions, treatment

should usually be initiated with a two-drug combination of an ACE

inhibitor or ARB with a CCB or thiazide/thiazide-like diuretic, and

treatment escalated according to the recommended treatment

algorithm (see section 7). This approach ensures that the treat-

ment strategy includes an ACE inhibitor or ARB, which has been

shown to reduce albuminuria and the appearance or progression

of diabetic nephropathy more effectively than other drug

classes.

235

Combination of an ACE inhibitor with an ARB is contra-

indicated because it is accompanied by an excess of renal adverse

events.

298,473,474

Recent RCTs have shown that some antidiabetes agents (the

selective inhibitors of sodium glucose cotransporter 2 in the kidney)

can reduce office and ambulatory BP by several mmHg,

475,476

and

that this occurs even when people are treated with antihypertensive

drugs. This may help improve BP control (see below), which is espe-

cially difficult in diabetes,

477

and may reduce the progression of

CKD

478–481

(see also section 8.12).

There has been considerable debate about the target BP

that should be achieved in people with diabetes (see section 7).

We recommend that in people with diabetes, the first objective

should be to lower BP to <140/80 mmHg, aiming at an SBP of 130

mmHg. Provided that the treatment is well tolerated, treated

SBP values of <130 mmHg should be considered because of the

benefits on stroke prevention. Achieved SBP values of <120

mmHg should always be avoided. BP targets for renoprotection

for patients with diabetic kidney disease are discussed in

section 8.12.

Hypertension in ethnic groups

Recommendations Class

Level

It is recommended that a two-drug combi-

nation, usually as an SPC, is used as initial

therapy for most black patients.

In black patients, initial antihypertensive

treatment should include a diuretic or a

CCB, either in combination or with a RAS

blocker.

d316,469

In other ethnic groups, BP-lowering treat-

ment may be based on the core treatment

algorithm (see Figure 4).

IIb C

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP

= blood pressure; CCB = calcium channel blocker; RAS = renin –angiotensin sys-

tem; SPC = single-pill combination.

Class of recommendation.

Level of evidence.

Except in patients with low grade 1 hypertension or frail older patients, in whom

initial treatment with a single drug may be more appropriate.

Angioedema is more common with ACE inhibitors and thus ARBs may be

preferred.

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8.12 Hypertension and chronic kidney

disease

Hypertension is a major risk factor for the development and progres-

sion of CKD, irrespective of the cause of CKD. In patients with CKD,

resistant hypertension, masked hypertension, and elevated night-

time BP are common, and are associated with a lower eGFR, higher

levels of albuminuria, and HMOD.

483,484

The effects of lowering BP in patients with CKD have been the

subject of many meta-analyses. A recent meta-analysis has shown

that BP lowering significantly reduced end-stage renal disease in

patients with CKD, but only in those with albuminuria and without

any beneficial effect on CV events.

203

However, a more recent and

larger meta-analysis has shown a significant reduction in all-cause

mortality following BP reduction in patients with CKD.

485

Reduction of albuminuria has also been considered as a therapeu-

tic target. Analyses of data from RCTs have reported that changes in

urinary albumin excretion are predictors of renal and CV

events.

186,486

However, there are also studies in which treatment

that was less effective at reducing albuminuria was more effective at

reducing CV events

175

and vice versa.

176,291

Thus, whether reducing

albuminuria per se is a proxy for CVD prevention remains

unresolved.

Patients with CKD should receive lifestyle advice, especially

sodium restriction, and drug treatment when their office BP is >140/

90 mmHg. Achieving recommended BP targets in CKD usually

requires combination therapy, which should be initiated as a combi-

nation of a RAS blocker with a CCB or diuretic in these patients. The

combination of two RAS blockers is not recommended.

291

Loop diu-

retics should replace thiazide diuretics when the estimated GFR is

<30 mL/min/1.73 m

The evidence with respect to BP targets in patients with CKD is

complex. In patients with non-diabetic CKD, one meta-analysis

showed that the slowest progression on CKD was obtained with a

treated SBP in the range of 110 -119 mmHg in patients with albumi-

nuria >1 g/day.

487

In contrast, in patients with a proteinuria <1 g/day,

the lowest risk of developing CKD (not CV risk) was obtained with

an SBP of <140 mmHg.

487

Another systematic review failed to dem-

onstrate that a BP target of <130/80 mmHg improved clinical out-

comes more than a target of <140/90 mmHg in non-diabetic

CKD.

488

In a large retrospective cohort containing 398 419 treated

hypertensive patients (30% with diabetes), the nadir SBP and DBP for

the lowest risk of end-stage renal disease and mortality were 137 and

71 mmHg, respectively, with a clear increase in mortality risk at SBP

<120 mmHg.

489

Current evidence suggests that in patients with CKD, BP should be

lowered to <140/90 mmHg and towards 130/80 mmHg. Lifestyle

advice, especially sodium restriction, may be especially effective at

aiding BP lowering in patients with CKD. Because BP lowering

reduces renal perfusion pressure, it is expected and not unusual for

eGFR to be reduced by 10 - 20% in patients treated for hypertension.

Thus, careful monitoring of blood electrolytes and eGFR is essential,

but clinicians should not be alarmed by the anticipated decline in GFR

when treatment is initiated. This decline usually occurs within the first

few weeks of treatment and stabilizes thereafter. If the decline in

GFR continues or is more severe, the treatment should be stopped,

and the patient investigated to determine the presence of renovascu-

lar disease.

Treatment strategies in people with diabetes

Recommendations Class

Level

Antihypertensive drug treatment is recom-

mended for people with diabetes when

ofﬁce BP is >_140/90 mmHg.

1,226,235,482

In people with diabetes receiving BP-lower-

ing drugs it is recommended:

•To target SBP to 130 mmHg and

<130mmHg if tolerated, but not

<120 mmHg.

1,231,235

•In older people (aged >_65 years aged), to

target to an SBP range of 130–139

mmHg.

1,205,235

•To target the DBP to <80 mmHg, but

not <70 mmHg. IC

It is recommended to initiate treatment

with a combination of a RAS blocker with a

CCB or thiazide/thiazide-like diuretic.

1,175,205

Simultaneous administration of two RAS

blockers, e.g. an ACE inhibitor and ARB, is

not indicated.

291,298,299

III A

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP

= blood pressure; CCB = calcium channel blocker; DBP = diastolic blood pres-

sure; eGFR = estimated glomerular ﬁltration rate; RAS = renin-angiotensin sys-

tem; SBP = systolic blood pressure.

Class of recommendation.

Level of evidence.

When eGFR <30 mL/min/1.73 m

, avoid thiazide/thiazide-like diuretics and con-

sider using a loop diuretic when a diuretic is required.

ESC/ESH Guidelines 63

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8.13 Hypertension and chronic

obstructive pulmonary disease

Hypertension is the most frequent comorbidity in patients with

COPD, and coincidence of the two diseases may affect 2.5% of the

adult population.

490

Patients with hypertension and COPD are at

particularly high CV risk.

490,491

Both conditions share similar environ-

mental risks and, in addition, hypoxia may exacerbate risk.

490,491

Treatment of COPD with anticholinergic agents and long-acting

beta-2 adrenoceptor agonists may adversely affect the CV system

(increase heart rate and BP). The presence of COPD also has an

impact on the selection of antihypertensive drugs, which should con-

sider their effects on pulmonary function. Concern has been pre-

dominantly directed to the use of beta-blockers, although there is

evidence that in COPD these drugs maintain their CV-protective

effects.

492,493

Beta-blockers may negatively affect the reduced basal

lung function in patients with COPD, diminish the effectiveness of

emergency beta-agonist administration, reduce the benefit of long-

acting beta-agonist treatment, and make the discrimination of asthma

and COPD more difficult. That said, when tolerated, the use of car-

diac beta1-selective beta-blockers in patients with COPD has proven

to be safe in different settings, including hypertension.

494

It should

also be noted that diuretics may decrease the plasma level of potas-

sium (in addition to the hypokalaemic effects of glucocorticoids and

beta2-adrenoceptor agonists), worsen carbon dioxide retention

(including metabolic alkalosis-related hypoxia in hypoventilated

patients), increase haematocrit, and deteriorate mucus secretion in

bronchi. Therefore, in general, diuretics are not recommended for

widespread use in hypertensive patients with COPD.

490,495

In conclusion, management of hypertensive patients with COPD

should include lifestyle changes, among which cessation of smoking is

essential. CCBs, ARBs or ACEIs, or the CCB/RAS blocker combina-

tion are recommended as the initial drugs of choice. If the BP

response is poor, or depending on other comorbidities, thiazides or

thiazide-like diuretics and beta1-selective beta-blockers can be

considered.

8.14 Hypertension and heart disease

8.14.1 Coronary artery disease

There are strong epidemiological relationships between CAD and

hypertension. The INTERHEART study showed that 50% of the

population-attributable risk of a myocardial infarction can be

accounted for by lipids, with hypertension accounting for 25%.

Another registry-based study of over 1 million patients showed that

ischaemic heart disease (angina and myocardial infarction) accounted

for most (43%) of the CVD-free years of life lost due to hypertension

from the age of 30 years.

More compelling is the beneficial effect of BP treatment on reduc-

ing the risk of myocardial infarction. A recent meta-analysis of RCTs

of antihypertensive therapy showed that for every 10 mmHg reduc-

tion in SBP, CAD was reduced by 17%.

A similar risk reduction has

been reported by otherswith more intensive BP control.

496

The ben-

efits of reducing cardiac events are also evident in high-risk groups,

such as those with diabetes.

231,425

There remains some inconsistency over the optimal BP target in

hypertensive patients with overt CAD, and especially whether there

is a J-curve relationship between achieved BP and CV outcomes in

CAD.

497–500

A recent analysis

501

of 22 672 patients with stable CAD

who were treated for hypertension found that, after a median

follow-up of 5.0 years, an SBP of >_140 mmHg and a DBP of >_80

mmHg were each associated with increased risk of CV events. An

SBP of <120 mmHg was also associated with increased risk, as was a

DBP of <70 mmHg. Similar findings were also reported from another

analysis of RCT data evaluating the relationships between achieved

BP and risks of CV outcomes.

222

Whether a J-curve phenomenon

exists in patients with CAD who have been revascularized remains

uncertain. Other analyses do not support the existence of a J-curve,

even in hypertensive patients at increased CV risk.

239

For example, in

patients with CAD and initially free from congestive heart failure

enrolled in ONTARGET, a BP reduction from baseline over the

Therapeutic strategies for treatment of hypertension in

CKD

Recommendations Class

Level

In patients with diabetic or non-diabetic

CKD, it is recommended that an ofﬁce BP

of >_140/90 mmHg be treated with lifestyle

advice and BP-lowering medication.

9,203,485

In patients with diabetic or non-diabetic

CKD:

•It is recommended to lower SBP to a

range of 130–139 mmHg.

9,487,489

•Individualized treatment should be con-

sidered according to its tolerability and

impact on renal function and electrolytes.

IIa C

RAS blockers are more effective at reducing

albuminuria than other antihypertensive

agents, and are recommended as part of the

treatment strategy in hypertensive patients

in the presence of microalbuminuria or

proteinuria.

487,489

A combination of a RAS blocker with a

CCB or a diuretic

is recommended as initial

therapy.

175

A combination of two RAS blockers is not

recommended.

298

III A

BP = blood pressure; CCB = calcium channel blocker; CKD = chronic kidney dis-

ease; eGFR = estimated glomerular ﬁltration rate; RAS = renin-angiotensin sys-

tem; SBP = systolic blood pressure.

Class of recommendation.

Level of evidence.

In case of eGFR <30 mL/min/1.73 m

, avoid thiazide/thiazide-like diuretics and

consider using a loop diuretic if required.

64 ESC/ESH Guidelines

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examined BP range had little effect on the risk of myocardial infarc-

tion and predicted a lower risk of stroke.

502

Thus, a target BP of

approximately <130/80 mmHg in patients with CAD appears safe

and can be recommended, but achieving a BP <120/80 mmHg is not

recommended.

In hypertensive patients with CAD, beta-blockers and RAS block-

ers may improve outcomes post-myocardial infarction.

503

In patients

with symptomatic angina, beta-blockers and calcium antagonists are

the preferred components of the drug treatment strategy.

8.14.2 Left ventricular hypertrophy and heart failure

Hypertension is the leading risk factor for the development of heart

failure,

and most patients with heart failure will have an antecedent

history of hypertension. This may be a consequence of CAD, which

results in HFrEF. Hypertension also causes LVH, which impairs LV

relaxation (so-called diastolic dysfunction) and is a potent predictor

of heart failure, even when LV systolic function is normal and there is

no preceding myocardial infarction (HFpEF). Hypertension-

dependent fibrosis and structural alteration of large and small arteries

(microvascular disease) also contribute.

Treating hypertension has a major impact on reducing the risk of

incident heart failure and heart failure hospitalization, especially in old

and very old patients.

51,213,316

This has been observed using diuretics,

beta-blockers, ACE inhibitors, or ARBs, with CCBs being less effec-

tive in comparative trials.

504

Reducing BP can also lead to the regression of LVH, which has

been shown to be accompanied by a reduction of CV events and

mortality.

125

The magnitude of LVH regression is associated with

baseline LV mass, duration of therapy, the SBP reduction,

505,506

and

the drugs used, with ARBs, ACE inhibitors, and CBBs causing more

effective LVH regression than beta-blockers

173

or diuretics.

In patients with HFrEF, antihypertensive drug treatment should

start (if not already initiated) when BP is >140/90 mmHg. It is

unclear how low BP should be lowered in patients with heart fail-

ure. Outcomes for patients with heart failure have repeatedly

been shown to be poor if BP values are low, which suggests

(although data interpretation is made difficult by the possibility of

reversed causality) that it may be wise to avoid actively lowering

BP to <120/70 mmHg. However, some patients may achieve even

lower BP levels than this because of the desirability to remain on

treatment with guideline-directed heart failure medications, which,

if tolerated, should be continued because of their protective

effect.

136

Heart failure guideline-directed medications are recommended for

the treatment of hypertension in patients with HFrEF.

136

ACE inhibi-

tors, ARBs, beta-blockers, and MRAs (e.g. spironolactone and eplero-

none) are all effective in improving clinical outcome in patients with

established HFrEF, whereas for diuretics, evidence is limited to symp-

tomatic improvement. If further BP lowering is required, a dihydro-

pyridine CCB may be considered. Sacubutril/valsartan lowers BP, has

also been shown to improve outcomes in patients with HFrEF, and is

indicated for the treatment of HFrEF as an alternative to ACE inhibi-

tors or ARBs.

507

Non-dihydropiridine CCBs (diltiazem and verapa-

mil), alpha-blockers, and centrally acting agents, such as moxonidine,

should not be used.

Antihypertensive treatment is commonly needed in patients with

HFpEF; the same BP threshold and target for drug treatment indi-

cated for HFrEF should be used. The optimal treatment strategy for

hypertensive patients with HFpEF is not known, but the strategy out-

lined above for HFrEF patients might also be the one to adopt in

HFpEF patients. HFpEF patients commonly have multiple comorbid-

ities that may adversely affect outcomes and complicate

management.

Therapeutic strategies in hypertensive patients with

CAD

Recommendations Class

Level

In patients with CAD receiving BP-lowering drugs, it is

recommended:

•To target SBP to <_ 130 mmHg if toler-

ated, but not <120 mmHg.

2,496

•In older patients (aged >_65 years), to tar-

get to an SBP range of 130–140

mmHg.

2,496

•To target DBP to <80 mmHg, but not

<70 mmHg. IC

In hypertensive patients with a history of

myocardial infarction, beta-blockers and

RAS blockers are recommended as part of

treatment.

503

In patients with symptomatic angina, beta-

blockers and/or CCBs are

recommended.

503

BP = blood pressure; CAD = coronary artery disease; CCB = calcium channel

blocker; DBP = diastolic blood pressure; RAS = renin–angiotensin system; SBP =

systolic blood pressure.

Class of recommendation.

Level of evidence.

ESC/ESH Guidelines 65

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8.15 Cerebrovascular disease and

cognition

Hypertension is a major risk factor for haemorrhagic and ischaemic

stroke, and a risk factor for recurrent stroke. BP management during

the acute phase of haemorrhagic and ischaemic stroke remains an

area of uncertainty. BP is often elevated at presentation with acute

stroke, but often declines without intervention.

508

8.15.1 Acute intracerebral haemorrhage

In acute intracerebral haemorrhage, an increased BP is common and is

associated with a greater risk of haematoma expansion, increased risk

of death, and a worse prognosis for neurological recovery.

509,510

Results from an RCT suggested that immediate BP lowering (within

6 h) to <140/90 mmHg did not show benefit on the primary outcome

of disability or death at 3 months, but might reduce haematoma expan-

sion and improve functional recovery, and was generally safe.

511

A subsequent RCT, in which SBP was immediately reduced (<4.5 h)

from a mean of 200 mmHg to two different target intervals (140–170

vs. 110–139 mmHg), showed that more intensive BP lowering had no

benefit on the same primary outcome and was associated with more

renal adverse events.

512

Thus, we do not recommend treatment to

immediately lower BP in patients with acute intracerebral haemor-

rhage. One possible caveat to this recommendation is patients with

acute intracerebral haemorrhage and very severe hypertension (SBP

>_220 mmHg), for whom there are much fewer data. A meta-analy-

sis

513

and secondary outcome data from one RCT

511

have suggested a

possible benefit on functional recovery at 3 months, and that acute

lowering of SBP to <180 mmHg in these patients might be beneficial.

Thus, careful lowering of BP via i.v. infusion may be considered in

patients with markedly elevated BP (SBP >_220 mmHg).

8.15.2 Acute ischaemic stroke

The beneficial effects of BP reduction are even less clear in acute

ischaemic stroke. A key consideration is whether the patient will

receive thrombolysis, because observational studies have reported

an increased risk of intracerebral haemorrhage in patients with a

markedly elevated BP who received thrombolysis.

514,515

In patients

receiving i.v. thrombolysis, BP should be lowered and maintained at

<180/105 mmHg for at least the first 24 h after thrombolysis. The

benefit of acute BP lowering in patients with acute ischaemic stroke

who do not receive thrombolysis is uncertain. A meta-analysis sug-

gested that BP lowering early after acute ischaemic stroke had a neu-

tral effect on the prevention of death or dependency.

516,517

In such

patients with markedly elevated SBP or DBP (i.e. >_220 or >_120

mmHg, respectively), clinical judgement should define whether to

intervene with drug therapy, in which case a reasonable goal may be

to lower BP by 15%, with close monitoring, during the first 24 h after

stroke onset.

516,518–520

Patients with acute ischaemic stroke and a BP

lower than this in the first 72 h after stroke do not seem to benefit

from the introduction or reintroduction of BP-lowering medica-

tion.

516,521

For stable patients who remain hypertensive (>_140/90

mmHg) >3 days after an acute ischaemic stroke, initiation or reintro-

duction of BP-lowering medication should be considered.

522

8.15.3 Previous stroke or transient ischaemic attack

RCTs of antihypertensive treatment (placebo controlled) in patients

with a previous stroke or TIA, in a stable clinical condition, and with

BP >140/90 mmHg, have shown that BP lowering reduces the risk of

recurrent stroke.

338,523

No evidence is yet available that recurrent

stroke is prevented by initiating therapy when BP is in the

high–normal range. We recommend resumption of BP-lowering

therapy several days after stroke, or immediately after TIA, for previ-

ously treated or untreated patientswith hypertension, for prevention

of both recurrent stroke and other CV events.

The appropriate BP targets to prevent recurrent stroke are uncer-

tain, but should be considered in the context of a consistent finding in

many meta-analyses that stroke is the one major CV event that is

reduced at lower achieved BP levels. This is supported by the results

from the recent Secondary Prevention of Small Subcortical Strokes 3

study

244,524

in patients with a recent lacunar stroke, which suggested

an SBP target of <130 mmHg,

525

and other studies.

526

Prevention of stroke is a consistent benefit of antihypertensive

therapy and has been observed in all large RCTs using different drug

Therapeutic strategies in hypertensive patients with

heart failure or LVH

Recommendations Class

Level

In hypertensive patients with heart failure

(with reduced or preserved ejection frac-

tion), BP-lowering treatment should be con-

sidered if BP is >_140/90 mmHg.

c136

IIa B

In patients with HFrEF, it is recommended

that BP-lowering treatment comprises an

ACE inhibitor or ARB, and a beta-blocker

and diuretic and/or MRA if required.

136

Dihydropyridine CCBs may be added if BP

control is not achieved.

IIb C

In patients with HFpEF, BP treatment

threshold and target values should be the

same as for HFrEF.

136

IIa B

Because no speciﬁc drug has proven its

superiority, all major agents can be used. IC

In all patients with LVH:

•It is recommended to treat with an RAS

blocker in combination with a CCB or

diuretic.

504

•SBP should be lowered to a range of

120–130 mmHg.

504,506

IIa B

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP

= blood pressure; CCB = calcium channel blocker; HFrEF = heart failure with

reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction;

LVH = left ventricular hypertrophy; MRA = mineralocorticoid receptor antago-

nist; RAS = renin–angiotensin system; SBP = systolic blood pressure.

Class of recommendation.

Level of evidence.

A lowest safety BP value is not given as many patients receiving intensive treatment

for heart failure may achieve much lower BP levels than recommended BP targets.

Non-dihydropyridines are not recommended in HFrEF but may be used in HFpEF.

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regimens. However, individual RCTs comparing modern treatment

regimens

317,527

and meta-analyses suggest that beta-blockers are less

effective at stroke prevention than other classes of antihypertensive

agents.

2,528

Although the beta-blocker in these studies was atenolol,

there are no data with more modern beta-blockers with regards to

stroke prevention in hypertension. Thus, optimal antihypertensive

treatment for stroke prevention should not include beta-blockers

unless there is a compelling indication for their use, mindful of the

fact that the most common recurrent event after stroke is a further

stroke rather than myocardial infarction.

529

8.15.4 Cognitive dysfunction and dementia

Several epidemiological and clinical studies have shown that hyper-

tension in midlife predicts cognitive decline and dementia (both

Alzheimer’s disease and vascular dementia) in older patients.

530–533

However, evidence on the beneficial effects of BP lowering on cogni-

tive decline is scant and conflicting. A meta-analysis

534

of 12 studies

investigating the impact of different antihypertensive drugs on

dementia and cognitive function concluded that BP lowering reduced

the incidence and risk of cognitive impairment and dementia by 9%.

One study showed that achieving better BP control over 4 years

reduced the progression of cerebral white matter lesions and the

decrease in global cognitive performance.

535

Trials are urgently needed to better define the potential impact of

BP lowering on preventing cognitive decline or in delaying dementia

when cognitive dysfunction is already present.

8.16 Hypertension, atrial fibrillation, and

other arrhythmias

Hypertension predisposes to cardiac arrhythmias, including ventricu-

lar arrhythmias, but most commonly AF,

536–538

which should be con-

sidered a manifestation of hypertensive heart disease.

539

Even

high–normal BP is associated with incident AF,

540,541

and hyperten-

sion is the most prevalent concomitant condition in AF patients. AF

adds to the risk of stroke and heart failure. AF necessitates stroke

prevention with oral anticoagulation, with monitoring of the associ-

ated risks and prevention of bleeding.

542

Most patients show a high ventricular rate with AF

542

and, in such

patients, beta-blockers or non-dihydropyridine calcium antagonists

(e.g. diltiazem and verapamil) are recommended as antihypertensive

agents. Non-dihydropyridine CCBs should be avoided in patients

with reduced LV systolic function and may precipitate heart failure in

some patients. Beta-blockers are often indicated in these patients,

and may need to be combined with digoxin to gain rate control.

542

In RCTs of hypertensive patients with LVH and/or high CV

risk,

543,544

RAS blockers have been shown to reduce first occurrence

of AF, compared with beta-blockers or CCBs, consistent with similar

effects of RAS blockers in patients with heart failure.

545–547

RAS

blockers do not prevent recurrence of paroxysmal or persistent

AF.

548–550

In patients with heart failure, beta-blockers

551

and

MRAs

552

may also prevent AF. The preventive effect of RAS blockers

against the development of AF is indirectly supported by a general

practice database in the UK, with approximately 5 million patient

Therapeutic strategies in hypertensive patients with acute stroke and cerebrovascular disease

Recommendations Class

Level

In patients with acute intracerebral haemorrhage:

•Immediate BP lowering is not recommended for patients with SBP <220 mmHg.

509–513

III A

•In patients with SBP >_220 mmHg, careful acute BP lowering with i.v. therapy to <180 mmHg should be considered.

509–513

IIa B

In acute ischaemic stroke, routine BP lowering with antihypertensive therapy is not recommended,

516,517

with the exceptions: III A

•In patients with acute ischaemic stroke who are eligible for i.v. thrombolysis, BP should be carefully lowered and maintained

at <180/105 mmHg for at least the ﬁrst 24 h after thrombolysis.

514,515

IIa B

•In patients with markedly elevated BP who do not receive ﬁbrinolysis, drug therapy may be considered, based on clinical

judgement, to reduce BP by 15% during the ﬁrst 24 h after the stroke onset. IIb C

In hypertensive patients with an acute cerebrovascular event, antihypertensive treatment is recommended:

•Immediately for TIA.

526

•After several days in ischaemic stroke.

526

In all hypertensive patients with ischaemic stroke or TIA, an SBP target range of 120–130 mmHg should be

considered.

244,524,526

IIa B

The recommended antihypertensive drug treatment strategy for stroke prevention is a RAS blocker plus a CCB or a thiazide-

like diuretic.

338

BP = blood pressure; CCB = calcium channel blocker; i.v. = intravenous; RAS = renin –angiotensin system; SBP = systolic blood pressure; TIA = transient ischaemic attack.

Class of recommendation.

Level of evidence.

ESC/ESH Guidelines 67

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records, which has reported that ACE inhibitors, ARBs, and beta-

blockers are associated with a lower risk of AF compared with

CCBs.

553

Hence, RAS blockers should be considered as part of the

antihypertensive treatment strategy in hypertensive patients with a

high risk of AF (e.g. LVH), to prevent incident AF.

8.16.1 Oral anticoagulants and hypertension

Many patients requiring oral anticoagulants (e.g. with AF) will be

hypertensive. Hypertension is not a contraindication to oral anticoa-

gulant use. However, although its role has been unappreciated in

most old and more recent RCTs on anticoagulant treatment,

537

hypertension does substantially increase the risk of intracerebral hae-

morrhage when oral anticoagulants are used, and efforts should be

directed towards achieving a BP goal of <130/80 mmHg in patients

receiving oral anticoagulants. Detailed information on hypertension

and oral anticoagulants has been published recently.

526,536

Anticoagulants should be used to reduce the risk of stroke in most

AF patients with hypertension, including those with AF in whom

hypertension is the single additional stroke risk factor.

554,555

BP con-

trol is important to minimize the risks of AF-related stroke and oral

anticoagulant-related bleeding. Until more data are available, BP val-

ues in AF patients taking oral anticoagulants should be at least <140

mmHg for SBP and <90 mmHg for DBP. Oral anticoagulants should

be used with caution in patients with persistent uncontrolled hyper-

tension (SBP >_180 mmHg and/or DBP >_100 mmHg), and urgent

efforts to control BP should be made.

8.17 Hypertension and vascular disease

8.17.1 Carotid atherosclerosis

A small number of studies have reported the effects of the various

pharmacological classes of antihypertensive drugs on carotid IMT,

and very few on carotid plaques. Reducing BP regresses carotid IMT

and may delay the intimal atherosclerotic process. There appear to

be differential drug effects on IMT regression, with CCBs having

greater efficacy than diuretics and beta-blockers,

146

and ACE inhibi-

tors more than diuretics.

557

However, the relevance of these findings

is unclear because most patients receive combinations of treatment

and the progression or treatment-induced changes in carotid IMT are

poorly predictive of future CV events.

184,558

Patients with carotid pla-

ques are at high risk of atheroembolic stroke and CV events, and BP

lowering should be complemented by lifestyle advice and treatment

with statins and antiplatelet therapy. A common conundrum faced by

clinicians is the hypertensive patient with a tight carotid stenosis,

especially when bilateral. No study has addressed this scenario and

therefore advice is necessarily pragmatic, and we recommend a more

cautious approach to BP lowering, initiating with monotherapy and

carefully monitoring for adverse effects.

8.17.2 Arteriosclerosis and increased arterial stiffness

Large artery stiffening is a major factor contributing to the rise in SBP

and fall in DBP with ageing. Arterial stiffness is usually measured in

studies as PWV. Arterial stiffening results from arteriosclerotic struc-

tural changes in large conduit arteries, leading to a loss of arterial

Therapeutic strategies in hypertensive patients with AF

Recommendation Class

Level

In patients with AF, screening for hypertension is recommended.

536

A beta-blocker or non-dihydropyridine CCB should be considered as part of the treatment of hypertension if rate control is

needed.

536

IIa B

Stroke prevention with oral anticoagulation is recommended in patients with AF and hypertension, and a CHA

-VASc

score of >_2 in men and >_3 in women.

536,556

Stroke prevention with oral anticoagulants should be considered in AF patients with hypertension, even when hypertension is

the single additional risk factor (CHA

-VASc score of 1).

536,556

IIa B

Oral anticoagulants should be used with caution in patients with marked BP elevation (SBP >_180 mmHg and/or DBP

>_100 mmHg); the aim should be to lower SBP to at least <140 mmHg, and SBP lowering to <130 should be considered.

If this is not possible, then patients should make an informed decision that they accept that the stroke protection

provided by the anticoagulant will be associated with higher bleeding risk.

536

IIa B

AF = atrial ﬁbrillation; BP = blood pressure; CCB = calcium channel blocker; CHA

-VASc = Congestive heart failure, Hypertension, Age >_75 years, Diabetes mellitus,

Stroke, Vascular disease, Age 65–74 years, Sex category (female); DBP = diastolic blood pressure; SBP = systolic blood pressure

Class of recommendation.

Level of evidence.

68 ESC/ESH Guidelines

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elasticity, and the distending force resulting from the pressure

exerted on the arterial wall. Thus, all antihypertensive drugs, by

reducing BP, reduce arterial stiffness, as the reduction in BP unloads

the stiff components of the arterial wall, leading to a passive decrease

in PWV. Pharmacodynamic RCTs

559

and meta-analyses

560,561

suggest

that ACE inhibitors and ARBs may reduce PWV beyond the effect of

BP lowering on a long-term basis. Whether RAS blockers are more

effective than other antihypertensive drugs in this regard has not

been demonstrated. Moreover, whether any long-term reduction in

aortic stiffness

562

translates into a reduction in CV events beyond the

impact of BP lowering alone

563

has not been demonstrated.

8.17.3 Lower extremity arterial disease

LEAD is often a manifestation of more widespread atherosclerosis

and especially atherosclerotic renal artery disease,

564

and these

patientsareatveryhighCVrisk.

190

BP control is an important part of

the CV risk-reduction strategy in these patients. Beta-blockers have

not been shown to worsen the symptoms of claudication in two

meta-analyses.

565,566

Thus, beta-blockers remain a treatment option

in hypertensive patients with LEAD when there is a specific indication

for their use. When critical limb ischaemia is present, BP reduction

should be instituted slowly as it may worsen ischaemia. In patients

with LEAD, antihypertensive treatment should be complemented by

lifestyle changes and especially smoking cessation, as well as statin

and antiplatelet therapy.

190

8.18 Hypertension in valvular disease and

aortopathy

8.18.1 Coarctation of the aorta

When feasible, treatment of aortic coarctation is predominantly sur-

gical and usually done in childhood. Even after surgical correction,

these patients may develop systolic hypertension at a young age and

require long-term follow-up. Few patients with aortic coarctation

remain undetected until adult life, and by then often have severe

hypertension, HMOD (especially LVH and LV dysfunction), and an

extensive collateral circulation below the coarctation. Such patients

should be evaluated in a specialist centre. The medical therapy for

hypertension in patients with aortic coarctation should follow the

treatment algorithm outlined in section 7, as there have been no for-

mal RCTs to define optimal treatment strategies.

567

8.18.2 Prevention of aortic dilation and dissection in high-

risk subjects

Chronic hypertension can be associated withmodest aortic root dila-

tation. When more extensive aortic root dilatation is present or the

dilatation extends beyond the aortic root, an additional cause for

aortopathy should be sought. All hypertensive patients with aortic

dilatation, whether associated with Marfan syndrome, bicuspid aortic

valve disease, or not, should have their BP controlled <_ 130/80

mmHg.

568

In patients with Marfan syndrome, prophylactic use of

ACE inhibitors, ARBs, or beta-blockers seems to be able to reduce

either the progression of the aortic dilation or the occurrence of

complications.

568–570

However, there is no evidence for the specific

efficacy of these treatments in aortic disease of other aetiologies.

8.18.3 Hypertension bicuspid aortic valve-related

aortopathy

Bicuspid aortic valve disease occurs in 1 in 100 people, more often

men, and is associated with coexistent aortic coarctation, which

should be excluded in patients with bicuspid aortic valve disease.

Bicuspid aortic valve disease is associated with an aortopathy, and the

risk of development of aortic dilation is higher in patients with bicus-

pid aortic valve disease than in the normal population

571

and is prob-

ably exacerbated by hypertension. Beyond aortic dilation and

aneurysm formation, bicuspid aortic valve disease is also a risk factor

for dissection and rupture.

572

Thus, BP should be tightly controlled in

patients with bicuspid aortic valve disease and targeted <_ 130/80

mmHg if tolerated. There is popular misconception that BP-lowering

treatment has deleterious effects in patients with aortic stenosis and

hypertension, when in fact it is well tolerated even in patients with

severe aortic stenosis. Moreover, vasodilating drugs (including RAS

blockers) also appear to be well tolerated. Thus, treatment of hyper-

tension should be considered in these patients.

573

8.19 Hypertension and sexual

dysfunction

Sexual dysfunction may have an important negative effect on the

quality of life of both men and women. Compared with the normo-

tensive population, the prevalence of sexual dysfunction is greater in

hypertensive individuals, in whom it presents an important cause of

low adherence to or discontinuation of antihypertensive treat-

ment.

574

A large meta-analysis of prospective cohort studies has pro-

vided strong evidence that in men, erectile dysfunction (i.e.

inadequate penile erection) is a significant independent risk factor for

CV events and mortality,

575

which means that it may be viewed as an

early marker of vascular damage.

576

Sexual dysfunction may be trig-

gered or aggravated by treatment with thiazide or thiazide-like diu-

retics, conventional beta-blockers, or centrally acting agents (e.g.

clonidine), while ACE inhibitors, ARBs, CCBs, or vasodilating beta-

blockers may have neutral or even beneficial effects.

574,577

Phosphodiesterase-5 inhibitors are effective against erectile dysfunc-

tion in patients with hypertension. They should be given only in the

absence of nitrate administration, but prescription also appears to be

Therapeutic strategies in hypertensive patients with

LEAD

Recommendations Class

Level

BP-lowering treatment is recommended to

reduce CV risk.

2,190,503

A combination of a RAS blocker, CCB, or

diuretic should be considered as initial

therapy.

IIa B

Beta-blockers may also be considered.

566

IIb C

BP = blood pressure; CCB = calcium channel blocker; CV = cardiovascular;

LEAD = lower extremity arterial disease; RAS = renin –angiotensin system.

Class of recommendation.

Level of evidence.

ESC/ESH Guidelines 69

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safe in patients with multidrug BP-lowering treatment,

578

with some

caution if treatment includes alpha-blockers.

577

However, it seems

prudent for unstable patients with high CV risk or severe uncon-

trolled hypertension to defer sexual activity until their condition is

stabilized and treatment for erectile dysfunction can be initiated.

575

Overall, studies on the effects of hypertension and antihypertensive

therapy on female sexual dysfunction are limited, and the situation is

thus less clear than in men,

577,579

although in a recent cross-sectional

analysis among middle-aged and older treated hypertensive women

in the SPRINT trial, neither BP values nor antihypertensive medica-

tion was associated with sexual dysfunction.

579

It is recommended that information on sexual dysfunction is col-

lected in all hypertensive patients at diagnosis and regularly at the

follow-up visits, with special attention to its possible relationship with

reluctance to start or adherence to drug treatment. In men reporting

sexual dysfunction, the antihypertensive agents more likely to be

associated with this effect (e.g. beta-blockers and thiazide diuretics)

should be avoided or replaced, unless strictly necessary for the

patient’s clinical condition.

8.20 Hypertension and cancer therapy

Hypertension is the most common CV comorbidity reported in can-

cer registries, in which an elevated BP is usually found in more than

one-third of the patients.

580

This can be due to the high prevalence of

hypertension at an age in which cancer is also common. However, it

is also due to the pressor effect of two groups of widely used anti-

cancer drugs, the inhibitors of the vascular endothelial growth factor

signalling pathway (bevacizumab, sorafenib, sunitinib, and pazopanib)

and the proteasome inhibitors (carfilzomib). While the former group

of drugs inhibits the production of nitric oxide in the arterial wall, the

latter reduces the vasodilator response to acetylcholine, favouring

vasoconstriction and vasospasm.

581

In patients under treatment with the above-mentioned anti-

cancer drugs, a BP increase has been reported in a variable but

overall high per cent of patients (<_ 30%). The increase frequently

occurs during the first months after starting the anticancer therapy,

the temporal association providing evidence for the anticancer

drug’s pathophysiological role. It follows that office BP should be

measured weekly during the initial part of the first cycle of therapy

and at least every 2–3 weeks thereafter.

582

After the first cycle is

completed and BP values appear to be stable, BP can be measured

at the time of the routine clinical evaluations or assessed by HBPM.

Patients developing hypertension (>_140/90 mmHg), or showing an

increase in DBP >_20 mmHg compared with pretreatment values,

should initiate or optimize antihypertensive therapy, for which RAS

blockers and CCBs may be considered the preferred drugs, and a

RAS blocker-CCB combination is a frequently needed strategy.

CCBs should only be of the dihydropiridine type, because diltiazem

and verapamil block the CYP3A4 isoenzyme, which is involved in

the metabolic pathway of sorafenib, increasing the drug’s levels and

leading to potential toxicity.

583

Although anticancer therapy takes

an obvious priority, its temporary discontinuation may be consid-

ered when BP values are exceedingly high despite multidrug treat-

ment, in the presence of severe hypertension-generated

symptoms, or when there is a CV event requiring an immediate

effective BP control.

584

8.21 Perioperative management of

hypertension

With the increasing number of patients undergoing surgery, manage-

ment of hypertension in the perioperative period (a term that

includes the intraoperative phase) has emerged as an important issue

in clinical practice.

585

ESC Guidelines have been issued for the assess-

ment of CV variables, risk, and disease management of patients

undergoing non-cardiac surgery.

586

While a BP elevation is per se not

a strong risk factor for CV complications in non-cardiac surgery,

overall CV risk assessment, including the search for HMOD, is impor-

tant in treated and untreated hypertensive patients, and mandatory

when a BP elevation is newly detected.

537,586

Postponing necessary

surgery is usually not warranted in patients with grade 1 or 2 hyper-

tension, whereas in those with an SBP >_180 mmHg and/or DBP

>_110 mmHg, deferring the intervention until BP is reduced or con-

trolled is advisable, except for emergency situations. What seems to

be also important is to avoid large perioperative BP fluctua-

tions.

537,586

This approach is supported by the findings from a recent

RCT that has shown that in patients undergoing abdominal surgery,

an individualized intraoperative treatment strategy, which kept BP

values within a 10% difference from the preoperative office SBP,

resulted in reduced risk of postoperative organ dysfunction.

587

There

is no clear evidence in favour or againstone vs. another antihyperten-

sive treatment mode in patients undergoing non-cardiac surgery, and

thus the general drug treatment algorithms apply to these patients as

well.

588,589

However, the perioperative use of beta- blockers has

been the object of controversy for many years, and the concern has

recently been revived by meta-analyses showing some increase in the

risk of hypotension, stroke, and mortality in patients on perioperative

beta-blockers vs. placebo.

586,588,589

Continuation of beta-blockers is

nevertheless recommended in hypertensive patients on chronic

beta-blocker treatment

586

in whom their abrupt discontinuation may

lead to BP or heart rate rebounds.

537

This may also occur with the

abrupt discontinuation of central agents such as clonidine. More

recently, the question has been raised whether RAS blockers should

be discontinued before surgery to reduce the risk of intraoperative

hypotension.

586,590

Preoperative discontinuation of these drugs has

also been supported by a recent international prospective cohort

study, in a heterogenous group of patients, in which withholding ACE

inhibitors or ARBs 24 h before non-cardiac surgery was associated

with a significant reduction in CV events and mortality 30 days after

the intervention.

591

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9 Managing concomitant

cardiovascular disease risk

9.1 Statins and lipid-lowering drugs

Patients with hypertension, and more so those with type 2 diabetes

or metabolic syndrome, often have atherogenic dyslipidaemia charac-

terized by elevated triglycerides and LDL cholesterol (LDL-C), and

low HDL cholesterol (HDL-C).

595

The benefit of adding a statin to

antihypertensive treatment was well established in the ASCOT-Lipid

Lowering Arm study

596

and further studies, as summarized in pre-

vious European Guidelines.

16,35

The beneficial effect of statin adminis-

tration to patients without previous CV events [targeting an LDL-C

value of <3.0 mmol/L (115 mg/dL)] has been strengthened by the

findings from the Justification for the Use of Statins in Prevention: an

Intervention Trial Evaluating Rosuvastatin (JUPITER)

597

and HOPE-3

studies,

343,598

showing that lowering LDL-C in patients with baseline

values <3.4 mmol/L (130 mg/dL) reduced the incidence of CV events

by between 44 and 24%. This justifies the use of statins in hyperten-

sive patients who have moderate–high CV risk.

599

As detailed in the recent ESC/EAS Guidelines,

599

when overt CVD

is present and the CV risk is very high, statins should be administered

to achieve LDL-C levels of <1.8 mmol/L (70 mg/dL) or a reduction of

>_50% if the baseline LDL-C is between 1.8 and 3.5 mmol/L (70 and

135 mg/dL).

600–602

In patients at high CV risk, an LDL-C goal of <2.6

mmol/L (100 mg/dL) or a reduction of >_50% if the baseline LDL-C is

between 2.6 and 5.2 mmol/L (100 and 200 mg/dL) is recom-

mended.

602

Beneficial effects of statin therapy have also been shown

in patients with a previous stroke with LDL-C targets <2.6 mmol/L

(100 mg/dL).

525

Whether they also benefit from a target of <1.8

mmol/L (70 mg/dL) is open to future research. The summary of the

available evidence suggests that many patients with hypertension

would benefit from statin therapy.

9.2 Antiplatelet therapy and

anticoagulant therapy

The most common complications of hypertension are related to

thrombosis.

603

Hypertension predisposes to a prothrombotic

state,

603

and also predisposes to LEAD, heart failure, or AF, which

are common conditions associated with thromboembolism, whether

systemic or venous.

Antiplatelet and anticoagulant therapy use in patients with

hypertension was addressed in a Cochrane systematic review,

604

which included four randomized trials with a combined total of 44

012 patients. The authors concluded that overall acetylsalicylic

acid (aspirin) did not reduce stroke or CV events compared

with placebo in primary prevention patients with elevated BP and

no previous CVD.

604

For secondary prevention, antiplatelet ther-

apy in patients with elevated BP was reported as causing an abso-

lute reduction in vascular events of 4.1% compared with

placebo.

604

Benefit has not been demonstrated for anticoagulation therapy,

alone or in combination with aspirin, in patients with hypertension in

the absence of other indications requiring anticoagulants, such as AF

or venous thromboembolism.

604

In anticoagulated patients, uncon-

trolled hypertension is one of the independent risk factors for intra-

cranial haemorrhage and major bleeding.

605

In such patients,

attention to modifiable bleeding risk factors should be made during

all patient contacts. Bleeding risk assessment with clinical risk scores

such as the HAS-BLED [Hypertension, Abnormal renal/liver function

(1 point each), Stroke, Bleeding history or predisposition, Labile INR,

Older (>65), Drugs/alcohol concomitantly (1 point each)] score,

includes uncontrolled hypertension (defined as SBP >160 mmHg) as

one of the risk factors for bleeding;

606

theseshouldbeusedto‘flag

up’ patients at particularly high risk (e.g. HAS-BLED >_3) for more

regular review and follow-up.

607

Perioperative management of hypertension

Recommendations Class

Level

It is recommended that newly diagnosed hypertensive patients who are scheduled for elective surgery should be preoperatively

screened for HMOD and CV risk. IC

It is recommended to avoid large perioperative BP ﬂuctuations during the perioperative period.

587

Non-cardiac surgery may not be deferred in patients with grade 1 or 2 hypertension (SBP <180 mmHg; DBP <110 mmHg). IIb C

Perioperative continuation of beta-blockers is recommended in hypertensive patients on chronic treatment with these

drugs.

592,593

Abrupt discontinuation of beta-blockers or centrally acting agents (e.g. clonidine) is potentially harmful and is not

recommended.

589,594

III B

Transient preoperative discontinuation of RAS blockers should be considered in patients with hypertension undergoing non-

cardiac surgery. IIa C

BP = blood pressure; CV = cardiovascular; DBP = diastolic blood pressure; HMOD = hypertension-mediated organ damage; RAS = renin– angiotensin system; SBP = systolic

blood pressure.

Class of recommendation.

Level of evidence.

ESC/ESH Guidelines 71

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In summary, aspirin is not recommended for primary prevention in

hypertensive patients without CVD.

For secondary prevention, the

benefit of antiplatelet therapy in patients with hypertension may be

greater than the harm.

35,604

Ticlopidine, clopidogrel, and newer anti-

platelet agents such as prasugrel and ticagrelor have not been suffi-

ciently evaluated in patients with high BP.

9.3. Glucose-lowering drugs and blood

pressure

The impact of new glucose-lowering drugs on BP and the reduction

in CV and renal risk, beyond their effect of glucose control, have

received attention after the publication of the US Food and Drug

Administration recommendations for evaluating CV risk in new

therapies to treat type 2 diabetes. New generations of antidiabetes

drugs, i.e. dipeptidyl peptidase 4 inhibitors and glucagon-like peptide

1 agonists, slightly reduce BP, and also body weight with glucagon-like

peptide 1 agonists. Two glucagon-like peptide 1 agonists (liraglutide

and semaglutide) reduced CV and total mortality, but not heart fail-

ure, in patients with type 2 diabetes.

608,609

More data are required

with respect to the capacity of glucagon-like peptide 1 agonists and

dipeptidyl peptidase 4 inhibitors to prevent heart failure.

Inhibitors of sodium-glucose co-transporter-2 are the only

glucose-lowering drug class to reduce BP beyond the projected

impact of weight reduction on BP. Empaglifozine

475

and canagliflo-

zin

476

have demonstrated a reduction in heart failure and total and

CV mortality, and a protective effect on renal function. Several mech-

anisms may account for these effects, and increased sodium excre-

tion and improvements in tubuloglomerular balance reducing

hyperfiltration are suggested mechanisms for the observed CV and

renal protection, respectively.

10 Patient follow-up

10.1 Follow-up of hypertensive patients

After the initiation of antihypertensive drug therapy, it is important to

review the patient at least once within the first 2 months to evaluate

the effects on BP and assess possible side effects until BP is under

control. The frequency of review will depend on the severity of

hypertension, the urgency to achieve BP control, and the patient’s

comorbidities. SPC therapy should reduce BP within 1 - 2 weeks and

may continue to reduce BP over the next 2 months. Once the BP tar-

get is reached, a visit interval of a few months is reasonable and evi-

dence has been obtained that no difference exists in BP control

between3and6monthintervals.

610

Depending on the local organi-

zation of health resources, many of the later visits may be performed

by non-physician health workers such as nurses.

611

For stable

patients, HBPM and electronic communication with the physician

may also provide an acceptable alternative to reduce the frequency

of visits.

60,612,613

It is nevertheless advisable to assess risk factors and

asymptomatic organ damage at least every 2 years.

10.2 Follow-up of subjects with

high–normal blood pressure and white-

coat hypertension

Patients with high–normal BP or white-coat hypertension frequently

have additional risk factors, including HMOD, and have a higher risk

of developing sustained hypertension

427,614–618

(see section 4). Thus,

even when untreated, they should be scheduled for regular follow-up

(at least annual visits) to measure office and out-of-office BP, as well

as to check the CV risk profile. At annual visits, recommendations on

Treatment of CV risk factors associated with

hypertension

Recommendations Class

Level

CV risk assessment with the SCORE system

is recommended for hypertensive patients

who are not already at high or very high risk

due to established CVD, renal disease, or

diabetes.

For patients at very high CV risk, statins are

recommended to achieve LDL-C levels of

<1.8 mmol/L (70 mg/dL), or a reduction of

>_50% if the baseline LDL-C is 1.8–3.5

mmol/L (70–135 mg/dL).

596,599,602

For patients at high CV risk, statins are rec-

ommended to achieve an LDL-C goal of

<2.6 mmol/L (100 mg/dL), or a reduction of

>_50% if the baseline LDL-C is 2.6–5.2

mmol/L (100–200 mg/dL).

599,602

For patients at low–moderate CV risk, sta-

tins should be considered to achieve an

LDL-C value of <3.0 mmol/L (115 mg/

dL).

598

IIa C

Antiplatelet therapy, in particular low-dose

aspirin, is recommended for secondary pre-

vention in hypertensive patients.

35,604

Aspirin is not recommended for primary

prevention in hypertensive patients without

CVD.

35,604

III A

CV = cardiovascular; CVD = cardiovascular disease; LDL-C = LDL cholesterol;

SCORE = Systematic COronary Risk Evaluation.

Class of recommendation.

Level of evidence.

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lifestyle changes, which represent the appropriate treatment in many

of these patients, should be reinforced.

10.3 Elevated blood pressure at control

visits

The finding of an elevated BP should always lead physicians to search

for the cause(s), particularly the most common ones such as poor

adherence to the prescribed treatment regimen, persistence of a

white-coat effect, and occasional or more regular consumption of salt,

drugs, or substances that raise BP or oppose the antihypertensive

effect of treatment (e.g. alcohol or non-steroidal anti-inflammatory

drugs). This may require tactful but stringent questioning of the patient

(and his/her relatives) to identify interfering factors, as well as repeated

measurements of BP in the following weeks to ensure that BP has

returned to controlled values. If ineffective treatment is regarded as

the reason for inadequate BP control, the treatment regimen should

be uptitrated in a timely fashion (see section 7); this avoids clinical iner-

tia, a major contributor to poor BP control worldwide.

311

10.4 Improvement in blood pressure

control in hypertension: drug adherence

There is growing evidence that poor adherence to treatment—in

addition to physician inertia (i.e. lack of therapeutic action when the

patient’s BP is uncontrolled)—is the most important cause of poor

BP control.

293,619–621

Non-adherence to antihypertensive therapy

correlates with higher risk of CV events.

312,622

Early discontinuation of treatment and suboptimal daily use of the

prescribed regimens are the most common facets of poor adherence.

After 6 months, more than one-third, and after 1 year, about one-half

of patients may stop their initial treatment.

623

Studies based on the

detection of antihypertensive medications in blood or urine have

shown that low adherence to the prescribed medications can affect

<_ 50% of patients with apparently resistant hypertension,

352,624

and

that poor adherence is strongly and inversely correlated with the

number of pills prescribed. Early recognition of a lack of adherence

might reduce the number of costly investigations and procedures

(including interventional treatment), and avoid the prescription of

unnecessary drugs.

625

A major emphasis of these Guidelines has been to simplify the

treatment strategy to try and improve adherence to treatment and

BP control, by prescribing a single pill to most patients with hyperten-

sion. This is a response to the fact that despite the clear-cut benefits

of BP treatment in trials, most treated patients do not achieve recom-

mended BP targets in real life. The lower BP targets recommended in

these Guidelines will mean that BP control rates will be even worse

unless action is taken to ensure that patients are more likely to

adhere to logical combinations of treatment.

Several methods are available to detect poor adherence, but

most are indirect, poorly reliable, and provide little information

on the most important issue: dosing history. Today, the most

accurate methods that can be recommended, despite their limita-

tions, are the detection of prescribed drugs in blood or urine sam-

ples. Directly observed treatment, followed by BP measurement

over subsequent hours via HBPM or ABPM, can also be very useful

to determine if BP really is poorly controlled despite witnessed

consumption of medication in patients with apparent resistant

hypertension. In contrast, questionnaires frequently overestimate

drug adherence. The assessment of adherence should be

improved with the development of cheaper and more reliable

methods of detection that are easily applicable in daily

practice.

354,626

Barriers to optimal adherence may be linked with physician atti-

tudes, patient beliefs and behaviour, the complexity and tolerability

of drug therapies, the healthcare system, and several other factors.

Therefore, the assessment of adherence should always be conducted

in a no-blame approach, and should favour an open discussion to

identify the specific barriers limiting the patient’s ability to follow the

therapeutic recommendations. Individualized solutions should be

found. Patients should be encouraged to take responsibility for their

own CV health.

Patient adherence to therapy can be improved by several interven-

tions. The most useful interventions are those linking drug intake

with habits,

347

those giving adherence feedback to patients, self-

monitoring of BP

using pill boxes and other special packaging, and

motivational interviewing. Increasing the integration among health-

care providers with the involvement of pharmacists and nurses

increases drug adherence. Using multiple components has a greater

effect on adherence, as the effect size of each intervention is generally

modest. Recent data suggest that adherence to treatment may also

be improved with the use of telemetry for transmission of recorded

home values, maintaining contact between patients and physicians,

and studies are ongoing.

627

Prescription of an appropriate therapeutic regimen is crucial.

389

This might be achieved through: (i) possible drug-related adverse

events, (ii) using long-acting drugs that require once daily dos-

age,

628,629

(iii) avoiding complex dosing schedules, (iv) using SPCs

whenever possible, and (v) taking into consideration the effect of

treatment on a patient’s budget.

Compared with the large number of trials for individual drugs and

treatments, there are only a limited number of rigorous trials on

adherence interventions. Thus, the level of evidence indicating that a

sustained improvement in medication adherence can be achieved

within the resources available today in clinical practice is low. This is

essentially due to the short duration of most studies, their heteroge-

neity, and their questionable designs. Whether available interventions

ameliorate treatment outcomes remains to be demonstrated in

adequate trials.

A list of the interventions associated with improved patient adher-

ence to treatment is shown in Table 33.

ESC/ESH Guidelines 73

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10.5 Continued search for asymptomatic

hypertension-mediated organ damage

The importance and need to detect HMOD at initial assessment to

help risk stratify the patient, and to review the progression or regres-

sion of HMOD during follow-up, have been described in section 4.

The presence of HMOD demonstrates that BP is elevated and that

the patient would benefit from treatment. The regression of asymp-

tomatic organ damage occurring during treatment can often indicate

an improved prognosis (see section 5).

10.6 Can antihypertensive medications

be reduced or stopped?

In some patients in whom treatment is accompanied by effective BP

control for an extended period, it may be possible to reduce the

number and/or dosage of drugs. This may particularly be the case if

BP control is accompanied by healthy lifestyle changes such as weight

loss, exercise habit, and a low-fat and low-salt diet, which remove

environmental pressor influences. A reduction of medications should

be made gradually, and the patient should be checked frequently

Table 33 Interventions that may improve drug adherence in hypertension

Physician level

Provide information on the risks of hypertension and the beneﬁts of treatment, as well as agreeing a treatment strategy to achieve and maintain BP

control using lifestyle measures and a single-pill-based treatment strategy when possible (information material, programmed learning, and com-

puter-aided counselling)

Empowerment of the patient

Feedback on behavioural and clinical improvements

Assessment and resolution of individual barriers to adherence

Collaboration with other healthcare providers, especially nurses and pharmacists

Patient level

Self-monitoring of BP (including telemonitoring)

Group sessions

Instruction combined with motivational strategies

Self-management with simple patient-guided systems

Use of reminders

Obtain family, social, or nurse support

Provision of drugs at worksite

Drug treatment level

Simpliﬁcation of the drug regimen favouring the use of SPC therapy

Reminder packaging

Health system level

Supporting the development of monitoring systems (telephone follow-up, home visits, and telemonitoring of home BP)

Financially supporting the collaboration between healthcare providers (e.g. pharmacists and nurses)

Reimbursement of SPC pills

Development of national databases, including prescription data, available for physicians and pharmacists

Accessibility to drugs

BP = blood pressure; SPC = single-pill combination.

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because reappearance of hypertension can occur quickly, within

weeks, or may take many months. Patients with prior HMOD or pre-

vious accelerated hypertension should not have their treatment

withdrawn.

11 Gaps in the evidence

Gaps in the evidence and need for further studies

What is the optimal population screening programme for detecting hypertension?

What is the optimal method to measure BP in patients with AF?

What is the incremental beneﬁt for CV risk prediction of the addition of out-of-ofﬁce BP (HBPM and ABPM) to ofﬁce BP measurement?

What is the incremental beneﬁt, over the SCORE system, of measures of HMOD in reclassifying the CV risk of patients with hypertension?

What are the appropriate BP thresholds and targets for drug treatment in younger hypertensive patients?

What are the optimal BP treatment targets according to HBPM and ABPM?

What are the outcome beneﬁts associated with antihypertensive treatment in patients with resistant hypertension?

What are the beneﬁts of BP treatment for patients with BP in the high–normal range?

What baseline level of CV risk predicts treatment beneﬁt?

More data on the beneﬁts of BP treatment in the very elderly and the inﬂuence of frailty

Outcome-based comparison between ofﬁce BP- and out-of-ofﬁce BP-guided treatment

Outcome-based comparison between treatments guided by BP control and by HMOD reductions, especially in younger patients

More outcome studies of the optimal SBP treatment target for patients at different levels of baseline CV risk and with different comorbidities,

including diabetes and CKD

More outcome studies of the optimal DBP treatment target

Impact of single-pill vs. multidrug treatment strategies on adherence to treatment, BP control, and clinical outcomes

Outcome-based comparison between treatment strategies based on initial monotherapy vs. initial combination therapy

What is the optimal salt intake to reduce CV and mortality risk?

What are the long-term outcome beneﬁts resulting from the recommended lifestyle changes?

Outcome-based comparison between treatments based on thiazide vs. thiazide-like diuretics

Incremental value of central vs. peripheral BP in risk estimation and risk reduction by treatment

Outcome-based comparison of BP treatment with classical vs. vasodilator beta-blockers

Optimal BP treatment targets in speciﬁc clinical conditions (e.g. diabetes, CKD, and post-stroke)

Protective effect of antihypertensive treatment in patients with cognitive dysfunction or dementia

Role of antihypertensive treatment in white-coat hypertension

Role of antihypertensive treatment in masked hypertension

Optimal treatment of hypertension in different ethnic groups

ABPM = ambulatory blood pressure monitoring; AF = atrial ﬁbrillation; BP = blood pressure; CKD = chronic kidney disease; CV = cardiovascular; DBP = diastolic blood pressure; HBPM

= home blood pressure monitoring; HMOD = hypertension-mediated organ damage; SBP = systolic blood pressure; SCORE = Systematic COronary Risk Evaluation.

ESC/ESH Guidelines 75

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12 Key messages

(1) BP, epidemiology, and risk. Globally, over 1 billion people

have hypertension. As populations age and adopt more sedentary

lifestyles, the worldwide prevalence of hypertension will continue

to rise towards 1.5 billion by 2025. Elevated BP is the leading global

contributor to premature death, accounting for almost 10 million

deaths in 2015, 4.9 million due to ischaemic heart disease and 3.5

million due to stroke. Hypertension is also a major risk factor for

heart failure, AF, CKD, PAD, and cognitive decline.

(2) Definition of hypertension. The classification of BP and the

definition of hypertension is unchanged from previous European

Guidelines, and is defined as an office SBP >_140 and/or DBP >_90

mmHg, which is equivalent to a 24 h ABPM average of >_130/80

mmHg, or a HBPM average >_135/85 mmHg.

(3) Screening and diagnosis of hypertension. Hypertension is

usually asymptomatic (hence the term ‘silent killer’). Because of its

high prevalence, screening programmes should be established to

ensure that BP is measured in all adults at least every 5 years, and

more frequently in people with a high–normal BP. When hyper-

tension is suspected because of an elevated screening BP, the diag-

nosis of hypertension should be confirmed either by repeated

office BP measurements overa number of visits or by out-of-office

BP measurement using 24 h ABPM or HBPM.

(4) The importance of cardiovascular risk assessment and

detection of HMOD. Other CV risk factors such as dyslipidae-

mia and metabolic syndrome frequently cluster with hypertension.

Thus, unless the patient is already at high or very high risk due to

established CVD, formal CV risk assessment is recommended

using the SCORE system. However, it is important to recognise

that the presence of HMOD, especially LVH, CKD, or advanced

retinopathy, further increases the risk of CV morbidity and mortal-

ity, and should be screened for as part of risk assessment in hyper-

tensive patients because the SCORE system alone may

underestimate their risk.

(5) Think: could this patient have secondary hypertension?

For most people with hypertension, no underlying cause will be

detected. Secondary (and potentially remediable) causes of hyper-

tension are more likely to be present in people with young onset

of hypertension (<40 years), people with severe or treatment-

resistant hypertension, or people who suddenly develop significant

hypertension in midlife on a background of previously normal BP.

Such patients should be referred for specialist evaluation.

(6) Treatment of hypertension: importance of lifestyle inter-

ventions. The treatment of hypertension involves lifestyle inter-

ventions and drug therapy. Many patients with hypertension will

require drug therapy, but lifestyle interventions are important

because they can delay the need for drug treatment or comple-

ment the BP-lowering effect of drug treatment. Moreover, lifestyle

interventions such as sodium restriction, alcohol moderation,

healthy eating, regular exercise, weight control, and smoking cessa-

tion all have health benefits beyond their impact on BP.

(7) When to consider drug treatment of hypertension. The

treatment thresholds for hypertension are now less conservative

than they were in previous Guidelines. We now recommend that

patients with low-moderate-risk grade 1 hypertension (office BP

140–159/90–99), even if they do not have HMOD, should now

receive drug treatment if their BP is not controlled after a period

of lifestyleintervention alone. For higher-risk patients with grade 1

hypertension, including those with HMOD, or patients with higher

grades of hypertension (e.g. grade 2 hypertension, >_160/100

mmHg), we recommend initiating drug treatment alongside life-

style interventions. These recommendations apply to all adults

aged <80 years.

(8) Special considerations in frail and older patients. It is

increasingly recognised that biological rather than chronological

age, as well as consideration of frailty and independence, are

important determinants of the tolerability of and likely benefit

from BP-lowering medications. It is important to note that even in

the very old (i.e. >80 years), BP-lowering therapy reduces mortal-

ity, stroke, and heart failure. Thus, these patients should not be

denied treatment or have treatment withdrawn simply on the

basis of age. For people >80 years who have not yet received

treatment for their BP, treatment is recommended when their

office SBP is >_160 mmHg, provided that the treatment is well

tolerated.

(9) How low should SBP be lowered? This has been a hotly

debated topic. A key discussion point is the balance of potential

benefits vs. potential harm or adverse effects. This is especially

important whenever BP targets are lowered, as there is a greater

potential for harm to exceed benefit. Thus, in these Guidelines, we

recommend a target range. The evidence strongly suggests that

lowering office SBP to <140 mmHg is beneficial for all patient

groups, including independent older patients. There is also evi-

dence to support targeting SBP to 130 mmHg for most patients, if

tolerated. Even lower SBP levels (<130 mmHg) will be tolerated

and potentially beneficial for some patients, especially to further

reduce the risk of stroke. SBP should not be targeted to <120

mmHg because the balance of benefit vs. harm becomes concern-

ing at these levels of treated SBP.

(10) BP targets in old and very old patients. As discussed above,

independence, frailty, and comorbidities will all influence treatment

decisions, especially in older (>_65 years) and very old (>80 years)

patients. The desired SBP target range for all patients aged >65

years is 130–139 mmHg. This is lower than in previous Guidelines

and may not be achievable in all older patients, but any BP lowering

towards this target is likely to be beneficial provided that the treat-

ment is well tolerated.

(11) BP targets in patients with diabetes and/or CKD. The BP

treatment targets for patients with diabetes or kidney disease have

been a moving target in previous Guidelines because of seemingly

contradictory results from major outcome trials and meta-

analyses. For diabetes, targeting the SBP to <140 mmHg and

towards 130 mmHg, as recommended for all other patient groups,

is beneficial on major outcomes. Moreover, targeting SBP to <130

mmHg, for those who will tolerate it, may further reduce the risk

of stroke but not other major outcomes. SBP should not be <120

mmHg. For patients with CKD, the evidence suggests that the tar-

get BP range should be 130–139 mmHg.

(12) How low should DBP be lowered? The optimal DBP target

has been less well defined, but a DBP target of <80 mmHg is rec-

ommended. Some patients with stiff arteries and isolated systolic

hypertension will already have DBP levels below this target. These

are high-risk patients and the low DBP should not discourage

76 ESC/ESH Guidelines

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treatment of their elevated SBP to the recommended target, pro-

vided that treatment is well tolerated.

(13) The need to do better on BP control. A key message in these

Guidelines is the need to do better at improving BP control rates.

Despite the overwhelming evidence of treatment benefit, on aver-

age, <50% of patients with treated hypertension achieve an SBP

target of <140 mmHg. Physician inertia (inadequate uptitration of

treatment, especially from monotherapy) and poor patient adher-

ence to treatment (especially when based on multiple pills) are

now recognised as the major factors contributing to poor BP

control.

(14) Start treatment in most patients with two drugs, not

one. Monotherapy is usually inadequate therapy for most people

with hypertension; this will be especially true now that the BP

treatment targets for many patients are lower than in previous

Guidelines. These Guidelines have set out to normalize the con-

cept that initial therapy for the majority of patients with hyperten-

sion should be with a combination of two drugs, not a single drug.

The only exception would be in a limited number of patients with

a lower baseline BP close to their recommended target, who might

achieve that target with a single drug, or in some frailer old or very

old patients in whom more gentle reduction of BP may be desir-

able. Evidence suggests that this approach will improve the speed,

efficiency, and consistency of initial BP lowering and BP control,

and is well tolerated by patients.

(15) A single-pill strategy to treat hypertension. Poor adher-

ence to longer-term BP-lowering medication is now recognised

as a major factor contributing to poor BP control rates.

Research has shown a direct correlation between the number

of BP-lowering pills and poor adherence to medications.

Moreover, SPC therapy has been shown to improve adherence

to treatment. SPC therapy is now the preferred strategy for ini-

tial two-drug combination treatment of hypertension and for

three-drug combination therapy when required. This will con-

trol the BP of most patients with a single pill and could trans-

form BP control rates.

(16) A simplified drug treatment algorithm. We have simplified

the treatment strategy so that patients with uncomplicated hyper-

tension and many patients with a variety of comorbidities (e.g.

HMOD, diabetes, PAD, orcerebrovascular disease) receive similar

medication. We recommend a combination of an ACE inhibitor or

ARB with a CCB or thiazide/thiazide-like diuretic as initial therapy

for most patients. For those requiring three drugs, we recommend

a combination of an ACE inhibitor or ARB with a CCB and a

thiazide/thiazide-like diuretic. We recommend that beta-blockers

be used when there is a specific indication for their use (e.g. angina,

post-myocardial infarction, HFrEF, or when heart rate control is

required).

(17) Hypertension in women and in pregnancy. In women with

hypertension who are planning pregnancy, ACE inhibitors or

ARBs and diuretics should be avoided, and the preferred medica-

tions to lower BP, if required, include alpha-methyl dopa, labetalol,

or CCBs. The same drugs are suitable if BP lowering is required in

pregnant women. ACE inhibitors or ARBs should not be used in

pregnant women.

(18) Is there a role fordevice-based therapy for the treatment

of hypertension? A number of device-based interventions have

been developed and studied for the treatment of hypertension.To

date, the results from these studies have not provided sufficient

evidence to recommend their routine use. Consequently, the use

of device-based therapies is not recommended for the routine

treatment of hypertension, unless in the context of clinical studies

and RCTs, until further evidence regarding their safety and efficacy

becomes available.

(19) Managing cardiovascular disease risk in hypertensive

patients beyond BP: statins. For hypertensive patients at mod-

erate CVD risk or higher, or those with established CVD, BP low-

ering alone will not optimally reduce their risk. These patients

would also benefit from statin therapy, which further reduces the

risk of a myocardial infarction by approximately one-third and

stroke by approximately one-quarter, even when BP is controlled.

Similar benefits have been seen in hypertensive patients at thebor-

der between low and moderate-risk. Thus, many more hyperten-

sive patients would benefit from statin therapy than are currently

receiving this treatment.

(20) Managing cardiovascular disease risk in hypertensive

patients beyond BP : antiplatelet therapy. Antiplatelet ther-

apy, especially low-dose aspirin, is recommended for secondary

prevention in hypertensive patients, but is not recommended for

primary prevention (i.e. in patients without CVD).

ESC/ESH Guidelines 77

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13 ‘What to do’ and ‘what not to do’ messages from the Guidelines

Recommendations Class

Level

Classiﬁcation of BP

It is recommended that BP be classiﬁed as optimal, normal, or high–normal, or grades 1–3 hypertension, according to ofﬁce

BP. IC

Screening for hypertension

Screening programmes for hypertension are recommended. All adults (>_18 years) should have their ofﬁce BP measured and

recorded in their medical ﬁle, and be aware of their BP. IB

Diagnosis of hypertension

It is recommended to base the diagnosis of hypertension on:

•Repeated ofﬁce BP measurements on more than one visit, except when hypertension is severe (e.g. grade 3 and especially

in high-risk patients). At each visit, three BP measurements should be recorded, 1–2 min apart, and additional measure-

ments performed if the ﬁrst two readings differ by >10 mmHg. The patient’s BP is the average of the last two BP readings.

•Out-of-ofﬁce BP measurement with ABPM and/or HBPM, provided that these measurements are logistically and economi-

cally feasible.

Ofﬁce BP thresholds for the initiation of drug treatment for hypertension

Prompt initiation of BP-lowering drug treatment is recommended in patients with grade 2 or 3 hypertension at any level of CV

risk, simultaneously with the initiation of lifestyle changes. IA

In patients with grade 1 hypertension:

•Lifestyle interventions are recommended to determine if this will normalize BP. IB

•In patients with grade 1 hypertension at low-moderate-risk and without evidence of HMOD, BP-lowering drug treatment is

recommended if the patient remains hypertensive after a period of lifestyle intervention.

•In patients with grade 1 hypertension at high risk or with evidence of HMOD, prompt initiation of drug treatment is recom-

mended simultaneously with lifestyle interventions. IA

In ﬁt older patients with hypertension (even if aged >80 years), BP-lowering drug treatment and lifestyle intervention are rec-

ommended when SBP is >_160 mmHg. IA

BP-lowering drug treatment and lifestyle intervention are recommended in ﬁt older patients (>65 years but not >80 years)

when SBP is in the grade 1 range (140–159 mmHg), provided that treatment is well tolerated. IA

In patients with high–normal BP (130–139/85 –89 mmHg), lifestyle changes are recommended. IA

Withdrawal of BP-lowering drug treatment on the basis of age, even when patients attain an age of >_80 years, is not recom-

mended, provided that treatment is well tolerated. III A

Ofﬁce BP treatment targets

It is recommended that the ﬁrst objective of treatment should be to lower BP to <140/90 mmHg in all patients, and provided

that the treatment is well tolerated, treated BP values should be targeted to 130/80 mmHg or lower in most patients. IA

In patients <65 years receiving BP-lowering drugs, it is recommended that SBP should be lowered to a BP range of 120–129

mmHg in most patients.

In older patients (aged >_65 years) receiving BP-lowering drugs, it is recommended that SBP should be targeted to a BP range of

130–139 mmHg. IA

Continued

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Treatment of hypertension: lifestyle interventions

Salt restriction to <5 g per day is recommended. IA

It is recommended to restrict alcohol consumption to <14 units per week for men and <8 units per week for women. IA

Increased consumption of vegetables, fresh fruits, ﬁsh, nuts, unsaturated fatty acids (olive oil); low consumption of red meat;

and consumption of low-fat dairy products are recommended. IA

Body weight control is indicated to avoid obesity (BMI >30 kg/m

, or waist circumference >102 cm in men and >88 cm in

women) and aim for healthy BMI (about 20–25 kg/m

) and waist circumference values (<94 cm in men and <80 cm in women)

to reduce BP and CV risk.

Regular aerobic exercise (e.g. >_30 min of moderate dynamic exercise on 5– 7 days per week) is recommended. IA

Smoking cessation and supportive care and referral to smoking cessation programmes are recommended. IB

It is recommended to avoid binge drinking. III A

Treatment of hypertension: drug treatment

Combination treatment is recommended for most hypertensive patients as initial therapy. Preferred combinations should com-

prise a RAS blocker (either an ACE inhibitor or an ARB) with a CCB or diuretic. Other combinations of the ﬁve major classes

can be used.It is recommended that beta-blockers are combined with any of the other major drug classes when there are spe-

ciﬁc clinical situations (e.g. angina, post-myocardial infarction, heart failure, or heart rate control).

It is recommended to initiate antihypertensive treatment with a two-drug combination, preferably in an SPC. Exceptions are

frail older patients and those at low risk and with grade 1 hypertension (particularly if SBP is <150 mmHg).

342,346,351

It is recommended that if BP is not controlled

with a two-drug combination, treatment should be increased to a three-drug

combination, usually a RAS blocker with a CCB and thiazide/thiazide-like diuretics, preferably as an SPC. IA

It is recommended that if BP is not controlled

with a three-drug combination, treatment should be increased by the addition

of spironolactone or, if not tolerated, other diuretics such as amiloride or higher doses of other diuretics, a beta-blocker, or an

alpha-blocker.

The combination of two RAS blockers is not recommended. III A

Treatment of hypertension: device-based therapies

Use of device-based therapies is not recommended for the routine treatment of hypertension, unless in the context of clinical

studies and RCTs, until further evidence regarding their safety and efﬁcacy becomes available. III B

Management of CVD risk in hypertensive patients

CV risk assessment with the SCORE system is recommended for hypertensive patients who are not already at high or very

high risk due to established CVD, renal disease, or diabetes. IB

For patients at high or very high CV risk, statins are recommended. IB

Antiplatelet therapy, in particular low-dose aspirin, is recommended for secondary prevention in hypertensive patients. IA

Aspirin is not recommended for primary prevention in hypertensive patients without CVD. III A

Routine genetic testing for hypertensive patients is not recommended. III C

ABPM = ambulatory blood pressure monitoring; ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BMI = body mass index; BP = blood pressure;

CCB = calcium channel blocker; CV = cardiovascular; CVD = cardiovascular disease; HBPM = home blood pressure monitoring; HMOD = hypertension-mediated organ dam-

age; RAS = renin–angiotensin system; RCT = randomized controlled trial; SBP = systolic blood pressure; SCORE = Systematic COronary Risk Evaluation; SPC = single-pill

combination.

Class of recommendation.

Level of evidence.

In patients with grade 1 hypertension and low-moderate-risk, drug treatment may be preceded by a prolonged period of lifestyle intervention to determine if this will normalize

BP. The duration of the lifestyle intervention alone will depend on the level of BP within the grade 1 range (i.e. the likelihood of achieving BP control with lifestyle intervention

alone) and the opportunities for signiﬁcant lifestyle change in individual patients.

Less evidence is available for this target in low-moderate-risk patients.

Adherence to medication should be checked.

ESC/ESH Guidelines 79

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14 Appendix

ESC Committee for Practice Guidelines (CPG): Stephan

Windecker (Chairperson) (Switzerland), Victor Aboyans (France),

Stefan Agewall (Norway), Emanuele Barbato (Italy), He´ctor Bueno

(Spain), Antonio Coca (Spain), Jean-Philippe Collet (France), Ioan

Mircea Coman (Romania), Veronica Dean (France), Victoria Delgado

(The Netherlands), Donna Fitzsimons (UK), Oliver Gaemperli

(Switzerland), Gerhard Hindricks (Germany), Bernard Iung (France),

Peter Ju¨ ni (Canada), Hugo A. Katus (Germany), Juhani Knuuti

(Finland), Patrizio Lancellotti (Belgium), Christophe Leclercq

(France), Theresa A. McDonagh (UK), Massimo Francesco Piepoli

(Italy), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece),

Marco Roffi (Switzerland), Evgeny Shlyakhto (Russia), Iain A. Simpson

(UK), Miguel Sousa-Uva (Portugal), Jose Luis Zamorano (Spain).

ESH Council: Costas Tsioufis (President) (Greece), Empar

Lurbe (Spain), Reinhold Kreutz (Germany), Murielle Bochud

(Switzerland), Enrico Agabiti Rosei (Italy), Bojan Jelakovic (Croatia),

Michel Azizi (France), Andrzej Januszewics (Poland), Thomas Kahan

(Sweden), Jorge Polonia (Portugal), Philippe van de Borne (Belgium),

Bryan Williams (UK), Claudio Borghi (Italy), Giuseppe Mancia (Italy),

Gianfranco Parati (Italy), Denis L. Clement (Belgium), Antonio Coca

(Spain), Athanasios Manolis (Greece), Dragan Lovic (Serbia)

ESC National Cardiac Societies actively involved in the

review process of the 2018 ESC/ESH Guidelines for the management

of arterial hypertension: Algeria: Algerian Society of Cardiology,

Salim Benkhedda; Armenia: Armenian Cardiologists Association,

Parounak Zelveian; Austria: Austrian Society of Cardiology, Peter

Siostrzonek; Azerbaijan: Azerbaijan Society of Cardiology, Ruslan

Najafov; Belarus: Belorussian Scientific Society of Cardiologists,

Olga Pavlova; Belgium: Belgian Society of Cardiology, Michel De

Pauw; Bosnia and Herzegovina: Association of Cardiologists of

Bosnia and Herzegovina, Larisa Dizdarevic-Hudic; Bulgaria:

Bulgarian Society of Cardiology, Dimitar Raev; Cyprus:Cyprus

Society of Cardiology, Nikos Karpettas; Czech Republic:Czech

Society of Cardiology, Ale

s Linhart; Denmark: Danish Society of

Cardiology, Michael Hecht Olsen; Egypt: Egyptian Society of

Cardiology, Amin Fouad Shaker; Estonia: Estonian Society of

Cardiology, Margus Viigimaa; Finland: Finnish Cardiac Society, Kaj

Mets€

arinne; The Former Yugoslav Republic of Macedonian:

Macedonian FYR Society of Cardiology, Marija Vavlukis; France:

French Society of Cardiology, Jean-Michel Halimi; Georgia:

Georgian Society of Cardiology, Zurab Pagava; Germany:German

Cardiac Society, Heribert Schunkert; Greece: Hellenic Society of

Cardiology, Costas Thomopoulos; Hungary: Hungarian Society of

Cardiology, De´nesP

all; Iceland: Icelandic Society of Cardiology, Karl

Andersen; Israel: Israel Heart Society, Michael Shechter; Italy:

Italian Federation of Cardiology, Giuseppe Mercuro; Kosovo:

Kosovo Society of Cardiology, Gani Bajraktari; Kyrgyzstan: Kyrgyz

Society of Cardiology, Tatiana Romanova; Latvia: Latvian Society of

Cardiology, K

arlis Tru

sinskis; Lebanon:LebaneseSocietyof

Cardiology, Georges A. Saade; Lithuania: Lithuanian Society of

Cardiology, Gintare Sakalyte; Luxembourg: Luxembourg Society

of Cardiology, Ste´phanie Noppe; Malta: Maltese Cardiac Society,

Daniela Cassar DeMarco; Moldova: Moldavian Society of

Cardiology, Alexandru Caraus; The Netherlands:Netherlands

Society of Cardiology, Janneke Wittekoek; Norway: Norwegian

Society of Cardiology, Tonje Amb Aksnes; Pola n d : Polish Cardiac

Society, Piotr Jankowski; Portugal: Portuguese Society of

Cardiology, Jorge Polonia; Romania: Romanian Society of

Cardiology, Dragos Vinereanu; Russian Federation: Russian

Society of Cardiology, Elena I. Baranova; San Marino:SanMarino

Society of Cardiology, Marina Foscoli; Serbia: Cardiology Society of

Serbia, Ana Djordjevic Dikic; Slovakia: Slovak Society of Cardiology,

Slavomira Filipova; Slovenia: Slovenian Society of Cardiology, Zlatko

Fras; Spain: Spanish Society of Cardiology, Vicente Bertomeu-

Mart



ınez; Sweden: Swedish Society of Cardiology, Bo Carlberg;

Switzerland: Swiss Society of Cardiology, Thilo Burkard; Tu n i s i a:

Tunisian Society of Cardiology and Cardio-Vascular Surgery, Wissem

Sdiri; Tu r k e y : Turkish Society of Cardiology, Sinan Aydogdu;

Ukraine: Ukrainian Association of Cardiology, Yuriy Sirenko;

United Kingdom: British Cardiovascular Society, Adrian Brady.

ESH National Hypertension Societies actively involved in

the review process of the 2018 ESC/ESH Guidelines for the manage-

ment of arterial hypertension: Austria: Austrian Society of

Hypertension, Thomas Weber; Belarus: Belarussian Hypertension

League, Irina Lazareva; Belgium: Belgian Hypertension Committee,

Tine De Backer; Bosnia and Herzegovina: Bosnia and

Herzegovina Society of Hypertension, Sekib Sokolovic; Croatia:

Croatian Society of Hypertension, Bojan Jelakovic; Czech

Republic: Czech Society of Hypertension, Jiri Widimsky; Estonia:

Estonian Society of Hypertension, Margus Viigimaa; Finland: Finnish

Hypertension Society, Ilkka Po¨ rsti; France:FrenchSocietyof

Hypertension, Thierry Denolle; Germany: German Hypertension

Society, Bernhard K. Kr€

amer; Greece: Hellenic Society of

Hypertension, George S. Stergiou; Italy: Italian Society of

Hypertension, Gianfranco Parati; Latvia: Latvian Society of

Hypertension and Atherosclerosis, K

arlis Tru

sinskis; Lithuania:

Lithuanian Hypertension Society, Marius Miglinas; Norway:

Norwegian Society of Hypertension, Eva Gerdts; Poland: Polish

Society of Hypertension, Andrzej Tykarski; Portugal: Portuguese

Society of Hypertension, Manuel de Carvalho Rodrigues; Romania:

Romanian Society of Hypertension, Maria Dorobantu; Russian

Federation: Russian Society of Hypertension, Irina Chazova;

Serbia: Serbian Society of Hypertension, Dragan Lovic; Slovakia:

Slovak Society of Hypertension, Slavomira Filipova; Slovenia:

Slovenian Hypertension Society, Jana Brguljan; Spain:Spanish

Society of Hypertension, Julian Segura; Sweden: Swedish Society of

Hypertension, Stroke and Vascular Medicine, Anders Gotts€

ater;

Switzerland: Swiss Society of Hypertension, Antoinette Peche`re-

Bertschi; Tu r k e y : Turkish Society of Hypertension and

Atherosclerosis, Serap Erdine; Ukraine: Ukrainian Antihypertensive

Society, Yuriy Sirenko; United Kingdom: British and Irish

Hypertension Society, Adrian Brady.

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Bioequivalence of China- and Germany-manufactured bisoprolol (Concor) tablets in fasted and fed healthy Chinese participants: a randomized, open-label, two-way, crossover study

Article

Full-text available

Mar 2025

Background The bioequivalence of Concor® (Merck Healthcare KGaA, Darmstadt, Germany), a bisoprolol-containing tablet, manufactured in China and Concor® tablets manufactured in Germany has not been previously reported. Methods This single-center, open-label, randomized, two-period, two-sequence, crossover trial (28 February 2023–19 May 2023) compared the pharmacokinetics and safety of bisoprolol 5-mg tablets manufactured in China (test product) with those of bisoprolol 5-mg tablets manufactured in Germany (reference product) in healthy Chinese adults under fasted and fed conditions. Primary endpoints were Cmax, AUC0–tlast, and AUC0– ∞ . Result The mean (coefficient of variation percentage) Cmax in the fasted group was 21.2 (15.0) ng/mL (test product) and 22.1 (17.0) ng/mL (reference product). Under fed conditions, the respective Cmax values were 22.7 (18.8) ng/mL and 22.8 (15.2) ng/mL. The mean and coefficient of variation percentage for AUC were also similar between the two products. The geometric least squares mean ratio (90% confidence interval) for the test/reference product was 0.9565 (0.9006–1.0158) ng/mL for Cmax, 0.9761 (0.9370–1.0168) h·ng/mL for AUC0–tlast, and 0.9807 (0.9429–1.0200) h·ng/mL for AUC0– ∞ in fasted conditions and 0.9966 (0.9289–1.0691) ng/mL for Cmax, 0.9672 (0.9220–1.0145) h·ng/mL for AUC0–tlast, and 0.9693 (0.9253–1.0155) h·ng/mL for AUC0– ∞ in fed conditions, which met the pre-defined criteria for bioequivalence. No serious treatment-emergent adverse events or deaths were observed. Conclusion This study compared the bioequivalence of bisoprolol 5-mg tablets manufactured in China to that of the tablets manufactured in Germany among healthy Chinese adults. Systematic Review Registration identifier CTR20230391

Inflammatory and Fibrosis Parameters Predicting CPET Performance in Males with Recent Elective PCI for Chronic Coronary Syndrome

Article

Full-text available

Mar 2025

Functional capacity (FC), ideally determined by a cardiopulmonary exercise test (CPET), is a valuable prognostic marker in chronic coronary syndrome (CCS). As CPET has limited availability, biomarkers of inflammation and/or fibrosis could help predict diminished FC. Our objective was to assess the value of galectin-3 (gal-3) and that of three inflammatory markers easily obtained from a complete blood count (NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio) and MLR (monocyte-to-lymphocyte ratio) in predicting diminished FC in males with recent elective percutaneous coronary intervention (PCI) for CCS. Our prospective study enrolled 90 males who had undergone elective PCI in the previous 3 months (mean age 60.39 ± 10.39 years) referred to a cardiovascular rehabilitation (CR) clinic between February 2023 and December 2024. All subjects received clinical examination, a cardiopulmonary stress test, transthoracic echocardiography and bloodwork. Based on percentage of predicted oxygen uptake (%VO2max), patients were classified in two subgroups—impaired FC (≤70%, n = 50) and preserved FC (>70%, n = 40). NLR, PLR and gal-3 were elevated in patients with poor FC and were significant predictors of diminished FC in multivariate analysis. PLR, NLR and gal-3 could guide referrals for CR for high-risk males with recent elective PCI.

Adverse Pregnancy Outcomes and Cardiovascular Disease: A Spanish Cohort

Article

Mar 2025

Background and Aims: Emerging evidence suggests adverse pregnancy outcomes (APOs) may increase future cardiovascular risk. This study aimed to assess in a Spanish cohort the long-term risk of cardiovascular disease in women with APOs compared to those without such complications. Methods: A retrospective longitudinal cohort study was conducted at Hospital Vall d’Hebron (Barcelona, Spain), including pregnant women delivering between January 2010 and December 2015. Women with pre-existing medical conditions were excluded. APOs included preeclampsia, gestational diabetes, preterm birth, late miscarriage, and stillbirth. Cardiovascular events were defined as acute myocardial infarction or stroke. Both APO and non-APO groups were compared for their risk of cardiovascular events in the years following delivery, using unadjusted and adjusted models. Results: Out of 12,071 pregnant women delivered at Hospital Vall d’Hebron during the study period. 10,734 met the inclusion criteria (8234 in the non-APO group and 2500 in the APO group). The adjusted model revealed a significant association between APOs and cardiovascular events post-delivery (HR 2.5; 95% CI 1.4–4.4). Furthermore, an increased number of APOs (≥2) correlated with a higher risk of post-delivery cardiovascular events (HR 8.6; 95% CI 2.8–26.8). Conclusions: Women with adverse pregnancy outcomes (APOs), particularly those experiencing preeclampsia, preterm birth, and late miscarriage, exhibit an elevated long-term risk of cardiovascular events. Our findings highlight that these associations persist even after adjusting for traditional cardiovascular risk factors, indicating that APOs may independently influence long-term cardiovascular health. This underscores the importance of recognizing pregnancy as a critical window for early cardiovascular health interventions and counseling. Addressing these risks proactively could improve long-term health outcomes for women with a history of APOs.

Changes in non-high-density lipoprotein to high-density lipoprotein ratio (NHHR) and cardiovascular disease: insights from CHARLS

Article

Full-text available

Mar 2025
LIPIDS HEALTH DIS

Background The established association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and cardiovascular disease (CVD) risk has been well-documented. Nevertheless, the relationship between changes in NHHR and CVD events remains to be elucidated. The present study aims to clarify the correlation between NHHR change patterns and the incidence of CVD across a broad population. Methods The current study recruited participants from the China Health and Retirement Longitudinal Study (CHARLS). The NHHR index was calculated using the formula: NHHR = (TC-HDL-c)/HDL-c. Temporal changes in NHHR were assessed with latent profile analysis, and cumulative NHHR was also evaluated. Multivariable Cox proportional hazards regression models and multivariate-adjusted restricted cubic spline (RCS) analyses were employed to examine the association between the NHHR index and incident CVD. Results A total of 4,629 individuals were recruited for the study. The average age of the participants was 57.47 years, with 53.7% being female. Over the follow-up period, 879 cases of CVD were documented. Compared to participants in the lowest tertile, those in the highest tertile for both baseline NHHR and cumulative NHHR exhibited a significantly increased risk of CVD, with adjusted hazard ratios (HRs) of 1.43 (95% confidence interval [CI]: 1.21–1.70) and 1.45 (95% CI: 1.23–1.72), respectively. Participants classified in Class 2 demonstrated a 27% higher risk of CVD, while those in Class 3 showed a 41% greater risk compared to the Class 1 group. Further analysis revealed that this relationship was linear. Stratified analyses corroborated the primary findings. Conclusion Baseline NHHR, cumulative NHHR, and changes in NHHR are significantly associated with an increased risk of CVD among individuals aged 45 years and older, thereby confirming their potential as valuable tools for risk stratification in CVD.

Correlation between different types of obesity and hypertension in perimenopausal working women

Article

Full-text available

Mar 2025

Hypertension (HTN) can lead to a series of target organ damage and is associated with increased cardiovascular disease incidence and mortality. Perimenopause implies an important physiological transition. Previous studies have confirmed that obesity is a risk factor for the development of HTN. Nevertheless, few studies have investigated the prevalence of HTN in perimenopausal women and the relationships between peripheral or abdominal obesity and HTN. Therefore, we analysed the influencing factors of HTN in perimenopausal working women and the correlation between different types of obesity and HTN to provide evidence for the need to prevent HTN in perimenopausal women. Perimenopausal women who underwent physical examination at Shanghai Health and Medical Center from January 2021 to October 2021 were selected as subjects. A multivariate logistic regression model was used to analyse the associations between different types of obesity and HTN in perimenopausal women. Five hundred eighty-two perimenopausal women were included in this study; 124 cases of HTN were detected (incidence rate 21.31%), 23 of which were isolated systolic HTN (18.55% of total HTN cases). Multivariate logistic regression analysis revealed that age and BMI were the influencing factors of HTN in perimenopausal women. Compared with that of perimenopausal women without peripheral obesity, HTN in overweight (OR = 1.84, 95% CI: 1.13–2.98) and peripheral obesity (OR = 4.36, 95% CI: 1.52–12.54) women increased with increasing body weight. Perimenopausal women with abdominal obesity had a greater risk of developing HTN (OR = 2.69, 95% CI: 1.16–6.21) (P < 0.05). Age and BMI are risk factors for the development of HTN in perimenopausal working women. Both abdominal obesity and peripheral obesity are positively associated with HTN in perimenopausal women. The BMI and abdominal circumference of perimenopausal women need to be monitored as early as possible to prevent obesity and reduce the occurrence of HTN.

Masked hypertension in patients with irritable bowel syndrome

Article

Mar 2025
Indian J Gastroenterol

The pathophysiology of irritable bowel syndrome (IBS) and masked hypertension (mHT) exhibits shared characteristics, including factors such as anxiety and stress. Consequently, the aim of this study was to investigate the frequency of mHT in patients with IBS. Patients diagnosed with IBS in 2020-2023 were re-evaluated using the Rome IV criteria. Patients who did not have sustained HT, as evidenced by repeated in-office blood pressure (BP) measurements and who did not meet the exclusion criteria (chronic renal failure, heart failure, diabetes, cerebrovascular events, pregnancy or puerperium) were included in the study group. A control group was also constituted with the same number of age and gender-matched healthy individuals. The participants were connected to a 24-hour ambulatory BP monitor and the results were analyzed. Total 128 participants, including 64 IBS patients and 64 healthy individuals, were included in our study. The age (36.9 ± 7.3 years; 37.3 ± 7.7 years) and gender (62.5% female; 62.5% female) distributions and the baseline clinical characteristics of the study and control groups were similar. The in-office systolic BP measurements of the IBS patients were significantly higher than those of the control group (124.7 ± 5.4 mmHg compared to 121.8 ± 5.2 mmHg, p = 0.02). The IBS patients also had a higher frequency of mHT (n = 21, 32.8% compared to n = 10, 15.6%, p = 0.02), higher 24-hour daytime systolic BP (127.5 ± 7.6 mmHg compared to 124.8 ± 5.22 mmHg, p = 0.02) and higher nighttime diastolic BP (62.2 ± 7.5 mmHg compared to 59.6 ± 6.1 mmHg, p = 0.03) than the control group. The study group included all four sub-types of IBS: diarrhea-dominant (IBS-D), constipation-dominant (IBS-C), mixed type (IBS-M) and unclassified (IBS-U). It was determined that 57.9% of the IBS-C patients, 27.8% of the IBS-M patients, 23.5% of the IBS-D patients and 10% of the IBS-U patients in the study group had mHT. To the best of our knowledge, this is the first study demonstrating a relationship between IBS and mHT. The frequency of mHT was higher among patients with IBS compared to healthy controls (p = 0.02). Studies on larger patient groups are needed to evaluate the frequency of mHT for the IBS sub-types.

Blood pressure variability associated with in-hospital and 30-day mortality in heart failure patients: a multicenter cohort study

Article

Full-text available

Mar 2025

To investigate the association between blood pressure variability (BPV) and mortality (in-hospital and 30-day) among heart failure (HF) patients, and to examine these associations across patient subgroups. This multicenter retrospective cohort study analyzed 25,591 heart failure patients from two intensive care databases (eICU Collaborative Research Database [eICU-CRD] and the Medical Information Mart for Intensive Care IV [MIMIC-IV]). BPV was assessed using coefficient of variation of systolic (SBPV), diastolic (DBPV), and mean (MBPV) blood pressure measurements. Multivariable logistic regression and Cox proportional hazards models evaluated mortality associations, adjusting for clinical parameters. The observed mortality rates were 14.7% (in-hospital) and 17.3% (30-day). Higher BPV demonstrated significant associations with increased mortality risk, with SBPV showing the strongest relationship. For in-hospital mortality, each standard deviation increase in SBPV, DBPV, and MBPV corresponded to adjusted odds ratios of 1.56 (95% CI 1.51–1.62), 1.21 (95% CI 1.16–1.25), and 1.42 (95% CI 1.37–1.48), respectively. For 30-day mortality, adjusted hazard ratios were 1.37 (95% CI 1.33–1.41) for SBPV, 1.15 (95% CI 1.12–1.19) for DBPV, and 1.30 (95% CI 1.27–1.34) for MBPV. These associations remained robust across all patient subgroups. Increased blood pressure variability during hospitalization independently predicts higher in-hospital (14.7%) and 30-day mortality (17.3%) in HF patients, with SBPV showing the strongest association (OR: 1.56, 95% CI 1.51–1.62). BPV may serve as a valuable prognostic marker for risk stratification in hospitalized heart failure patients.

The adverse effect of metabolic syndrome on left ventricular global strains and myocardial energetic efficiency in non-ischemic dilated cardiomyopathy patients: a cardiac magnetic resonance study

Article

Full-text available

Mar 2025
CARDIOVASC DIABETOL

Background Metabolic syndrome (MetS) is a known risk factor for cardiovascular dysfunction; however, its impact on left ventricular (LV) global strains and myocardial energetic efficiency in non-ischemic dilated cardiomyopathy (NIDCM) remains inadequately understood. This study aimed to investigate the effect of MetS on LV dysfunction in NIDCM patients using cardiovascular magnetic resonance (CMR) imaging. Methods A total of 557 NIDCM patients (378 without MetS and 179 with MetS) who underwent CMR examination were included. CMR-derived LV strains, remodeling index (LVRI), global function index (LVGFI), and indexed myocardial energetic efficiency (MEEI) were assessed and compared between the groups. The independent determinants of LV global longitudinal peak strain (GLPS), LVRI, LVGFI, and MEEI were evaluated using multivariable linear regression analyses. Results Compared to NIDCM patients without MetS, those with MetS had significantly lower LVSVI, LVEF, and LVGFI, along with higher LVMI and LVRI (all p < 0.05). However, no significant differences were found in LVEDVI and LVESVI (both p > 0.05). In terms of LV strain, the NIDCM(MetS+) group exhibited worse global peak strain and peak diastolic strain rate in all three directions, as well as decreased radial and longitudinal peak systolic strain rate (PSSR) compared to the NIDCM (MetS−) group (all p < 0.05), while circumferential PSSR did not differ significantly (p > 0.05). The MEEI was significantly lower in the NIDCM(MetS+) group compared to the NIDCM(MetS−) group (0.30 [0.20, 0.45] ml/s/g vs. 0.39 [0.25, 0.58] ml/s/g, p < 0.001). Multivariable analysis identified the presence of MetS as an independent determinant of LV GLPS (β = 0.211, p < 0.001), LVRI (β = 0.147, p = 0.003), and MEEI (β = − 0.160, p < 0.001). Conclusion The presence of MetS worsens LV function, remodeling, and myocardial energetic efficiency in patients with NIDCM, as evidenced by declines in LV strain, global function parameters, and indexed myocardial energetic efficiency. These findings suggest that addressing metabolic abnormalities may be crucial for improving LV function and outcomes for patients with NIDCM.

Thoughts on the European Society of Cardiology 2024 guidelines for the management of elevated blood pressure and hypertension

Article

Mar 2025
ARCH CARDIOVASC DIS

Long-term event rates, risk factors, and treatment pattern in 1.4 million individuals qualifying for dual blood pressure lowering therapy

Article

Mar 2025
J Hypertens

Objectives We assessed rates of cardiovascular events, all-cause death, baseline risk factors, and treatment patterns in a population qualifying for initiation of dual combination blood pressure (BP)-lowering therapy. We also evaluated the association between dual versus monotherapy during follow-up and incidence of cardiovascular events. Methods This study utilized integrated databases in England: Clinical Practice Research Datalink, Hospital Episode Statistics, and Office for National Statistics. Individuals aged at least 18 years qualifying for dual therapy were identified during 15-year period (2005–2019). The primary endpoint was composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, and cardiovascular death. The secondary endpoint was all-cause death. Results Total 1 426 079 individuals met selection criteria. The 15-year event rates for the primary and secondary endpoints were 27.1 and 32.6%, respectively. Atherosclerotic cardiovascular disease, diabetes on insulin therapy, heart failure, atrial fibrillation, chronic kidney disease, and advanced age were associated with two to four-fold higher risk of primary and secondary endpoints. The estimated hazard ratio for dual versus monotherapy as a time-varying covariate was 0.82 (95% confidence interval 0.81–0.83) for the primary endpoint. At variance with guidelines, monotherapy was most common treatment pattern over 5-year follow-up. Conclusion Baseline characteristics conveying a multifold higher risk for cardiovascular events and all-cause death mostly represented nonmodifiable risk factors. Treatment with dual therapy as compared to monotherapy was associated with reduction in cardiovascular events. Monotherapy remained most common BP-lowering treatment indicating substantial opportunity for risk reduction by treatment intensification.

Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial

Article

Full-text available

Apr 2003

Context. Hypertensive patients are often given a calcium antagonist to reduce cardio-vascular disease risk, but the benefit compared with other drug classes is controversial. Objective. To determine whether initial therapy with controlled-onset extended- release (COER) verapamil is equivalent to a physician’s choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease. Design, Setting, and Participants. Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed the study before unblinding the results. Intervention. Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic, beta-blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed. Main Outcome Measures. First occurrence of stroke, myocardial infarction, or cardiovascular disease–related death. Results. Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 nomm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease–related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P=.77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease–related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease–related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Non-stroke hemorrhage was more common with participants in the COER-verapamil group (n=118) compared with the atenolol or hydrochlorothiazide group (n=79) (HR, 1.54[95% CI, 1.16-2.04]; P=.003). More cardiovascular disease–related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53). Conclusions. The CONVINCE trial did not demonstrate equivalence of a COER verapamil–based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or �beta-blocker treatment.

ESC Council on hypertension position document on the management of hypertensive emergencies

Article

Full-text available

Aug 2018

Hypertensive emergencies are those situations where very high blood pressure (BP) values are associated with acute organ damage, and therefore, require immediate, but careful, BP reduction. The type of acute organ damage is the principal determinant of: (i) the drug of choice, (ii) the target BP, and (iii) the timeframe in which BP should be lowered. Key target organs are the heart, retina, brain, kidneys, and large arteries. Patients who lack acute hypertension-mediated end organ damage do not have a hypertensive emergency and can usually be treated with oral BP-lowering agents and usually discharged after a brief period of observation.

Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies

Article

Full-text available

Apr 2018

Background: In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. Methods: PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081. Findings: Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3-22·5), compared with a reduction of 18·3 mm Hg (16·2-20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95-4·08) on placebo to 4·50 (4·44-4·57) on amiloride (p<0·0001). Interpretation: Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension. Funding: British Heart Foundation and UK National Institute for Health Research.

Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial

Article

Jun 1998

Background Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension. Methods 18 790 patients, from 26 countries, aged 50–80 years (mean 61·5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure ⩽90 mm Hg, 6264 to ⩽85 mm Hg, and 6262 to ⩽80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo. Findings Diastolic blood pressure was reduced by 20·3 mm Hg, 22·3 mm Hg, and 24·3 mm Hg, in the ⩽90 mm Hg, ⩽85 mm Hg, and ⩽80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82·6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86·5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group ⩽80 mm Hg compared with target group ⩽90 mm Hg (p for trend=0·005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0·03) and all myocardial infarction by 36% (p=0·002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0·001). Interpretation Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82·6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.

Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial

Article

Feb 2015

Background High blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to lower their blood pressure. Methods In our multicentre, partial-factorial trial, we randomly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure (systolic 140–220 mm Hg) to 7 days of transdermal glyceryl trinitrate (5 mg per day), started within 48 h of stroke onset, or to no glyceryl trinitrate (control group). A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. The primary outcome was function, assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment. This study is registered, number ISRCTN99414122. Findings Between July 20, 2001, and Oct 14, 2013, we enrolled 4011 patients. Mean blood pressure was 167 (SD 19) mm Hg/90 (13) mm Hg at baseline (median 26 h [16–37] after stroke onset), and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls (difference −7·0 [95% CI −8·5 to −5·6] mm Hg/–3·5 [–4·4 to −2·6] mm Hg; both p<0·0001), and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients randomised to stop them (difference −9·5 [95% CI −11·8 to −7·2] mm Hg/–5·0 [–6·4 to −3·7] mm Hg; both p<0·0001). Functional outcome at day 90 did not differ in either treatment comparison—the adjusted common odds ratio (OR) for worse outcome with glyceryl trinitrate versus no glyceryl trinitrate was 1·01 (95% CI 0·91–1·13; p=0·83), and with continue versus stop antihypertensive drugs OR was 1·05 (0·90–1·22; p=0·55). Interpretation In patients with acute stroke and high blood pressure, transdermal glyceryl trinitrate lowered blood pressure and had acceptable safety but did not improve functional outcome. We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke. Funding UK Medical Research Council.

Ambulatory Blood Pressure Monitoring and Development of Cardiovascular Events in High-Risk Patients Included in the Spanish ABPM Registry. The Cardiorisc Event Study

Article

Apr 2012

Ambulatory blood pressure monitoring (ABPM) is superior to conventional BP measurement in predicting outcome, with baseline 24-h, daytime and night-time absolute values, as well as relative nocturnal decline, as powerful determinants of prognosis. We aimed to evaluate ABPM estimates on the appearance of cardiovascular events and mortality in a cohort of high-risk treated hypertensive patients. A total of 2115 treated hypertensive patients with high or very high added risk were evaluated by means of office and 24-h ABPM. Cardiovascular events and mortality were assessed after a median follow-up of 4 years. Two hundred and sixty-eight patients (12.7%) experienced a primary event (nonfatal coronary or cerebrovascular event, heart failure hospitalization or cardiovascular death) and 114 died (45 from cardiovascular causes). In a multiple Cox regression model, and after adjusting for baseline cardiovascular risk and office BP, night-time SBP predicted cardiovascular events [hazard ratio for each SD increase: 1.45; 95% confidence interval (CI) 1.29-1.59]. Values above 130 mmHg increased the risk by 52% in comparison to values less than 115 mmHg. In addition to clinical determinants of cardiovascular risk and conventional BP, ABPM performed during treatment adds prognostic significance on the development of cardiovascular events in high-risk hypertensive patients. Among different ABPM-derived values, night-time SBP is the most potent predictor of outcome.

Antihypertensive drug therapy for mild to moderate hypertension during pregnancy

Article

Oct 2018

Background: Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent progression to more severe disease, and thereby improve pregnancy outcome. This Cochrane Review is an updated review, first published in 2001 and subsequently updated in 2007 and 2014. Objectives: To assess the effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy. Search methods: We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 September 2017), and reference lists of retrieved studies. Selection criteria: All randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy, defined as systolic blood pressure 140 to 169 mmHg and/or diastolic blood pressure 90 to 109 mmHg. Comparisons were of one or more antihypertensive drug(s) with placebo, with no antihypertensive drug, or with another antihypertensive drug, and where treatment was planned to continue for at least seven days. Data collection and analysis: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Main results: For this update, we included 63 trials (data from 58 trials, 5909 women), with moderate to high risk of bias overall. We carried out GRADE assessments for the main 'antihypertensive drug versus placebo/no antihypertensive drug' comparison only. Evidence was graded from very low to moderate certainty, with downgrading mainly due to design limitations and imprecision.For many outcomes, trials contributing data evaluated different hypertensive drugs; while we did not downgrade for this indirectness, results should be interpreted with caution. Antihypertensive drug versus placebo/no antihypertensive drug (31 trials, 3485 women) Primary outcomes: moderate‐certainty evidence suggests that use of antihypertensive drug(s) probably halves the risk of developing severe hypertension (risk ratio (RR) 0.49; 95% confidence interval (CI) 0.40 to 0.60; 20 trials, 2558 women), but may have little or no effect on the risk of proteinuria/pre‐eclampsia (average risk ratio (aRR) 0.92; 95% CI 0.75 to 1.14; 23 trials, 2851 women; low‐certainty evidence). Moderate‐certainty evidence also shows that antihypertensive drug(s) probably have little or no effect in the risk of total reported fetal or neonatal death (including miscarriage) (aRR 0.72; 95% CI 0.50 to 1.04; 29 trials, 3365 women), small‐for‐gestational‐age babies (aRR 0.96; 95% CI 0.78 to 1.18; 21 trials, 2686 babies) or preterm birth less than 37 weeks (aRR 0.96; 95% CI 0.83 to 1.12; 15 trials, 2141 women). Secondary outcomes: we are uncertain of the effect of antihypertensive drug(s) on the risk of maternal death, severe pre‐eclampsia, or eclampsia, orimpaired long‐term growth and development of the baby in infancy and childhood, because the certainty of this evidence is very low. There may be little or no effect on the risk of changed/stopped drugs due to maternal side‐effects, or admission to neonatal or intensive care nursery (low‐certainty evidence). There is probably little or no difference in the risk of elective delivery (moderate‐certainty evidence). Antihypertensive drug versus another antihypertensive drug (29 trials, 2774 women) Primary outcomes: beta blockers and calcium channel blockers together in the meta‐analysis appear to be more effective than methyldopa in avoiding an episode of severe hypertension (RR 0.70; 95% CI 0.56 to 0.88; 11 trials, 638 women). There was also an increase in this risk when other antihypertensive drugs were compared with calcium channel blockers (RR 1.86; 95% CI 1.09 to 3.15; 5 trials, 223 women), but no evidence of a difference when methyldopa and calcium channel blockers together were compared with beta blockers (RR1.18, 95% CI 0.95 to 1.48; 10 trials, 692 women). No evidence of a difference in the risk of proteinuria/pre‐eclampsia was found when alternative drugs were compared with methyldopa (aRR 0.78; 95% CI 0.58 to 1.06; 11 trials, 997 women), with calcium channel blockers (aRR: 1.24, 95% CI 0.70 to 2.19; 5 trials, 375 women), or with beta blockers (aRR 1.21, 95% CI 0.88 to 1.67; 12 trials, 1107 women). For the babies, we found no evidence of a difference in the risk oftotal reported fetal or neonatal death (including miscarriage) when comparing other antihypertensive drugs with methyldopa (aRR 0.77, 95% CI 0.52 to 1.14; 22 trials, 1791 babies), with calcium channel blockers (aRR 0.90, 95% CI 0.52 to 1.57; nine trials, 700 babies), or with beta blockers (aRR: 1.23, 95% CI 0.81 to 1.88; 19 trials, 1652 babies); nor in the risk for small‐for‐gestational age in the comparison with methyldopa (aRR 0.79, 95% CI 0.52 to 1.20; seven trials, 597 babies), with calcium channel blockers (aRR 1.05, 95% CI 0.64 to 1.73; four trials, 200 babies), or with beta blockers (average RR 1.13, 95% CI 0.80 to 1.60; 7 trials, 680 babies). No evidence of an overall difference among groups in the risk of preterm birth (less than 37 weeks) was found in the comparison with methyldopa (aRR: 0.91; 95% CI 0.68 to 1.22; 11 trials, 835 women), with calcium channel blockers (aRR 0.85, 95% CI 0.59 to 1.23; six trials, 330 women), or with beta blockers (aRR 1.22, 95% CI 0.90 to 1.66; 9 trials, 806 women). Secondary outcomes: There were no cases of maternal death andeclampsia. There is no evidence of a difference in the risk of severe pre‐eclampsia, changed/stopped drug due to maternal side‐effects, elective delivery, admission to neonatal or intensive care nursery when other antihypertensive drugs are compared with methyldopa, calcium channel blockers or beta blockers. Impaired long‐term growth and development in infancy and childhood was not reported for these comparisons. Authors' conclusions: Antihypertensive drug therapy for mild to moderate hypertension during pregnancy reduces the risk of severe hypertension. The effect on other clinically important outcomes remains unclear. If antihypertensive drugs are used, beta blockers and calcium channel blockers appear to be more effective than the alternatives for preventing severe hypertension. High‐quality large sample‐sized randomised controlled trials are required in order to provide reliable estimates of the benefits and adverse effects of antihypertensive treatment for mild to moderate hypertension for both mother and baby, as well as costs to the health services, women and their families.

Non-invasive cardiovascular imaging for evaluating subclinical target organ damage in hypertensive patients: A consensus paper from the European Association of Cardiovascular Imaging (EACVI), the European Society of Cardiology Council on Hypertension, and the European Society of Hypertension (ESH)

Article

Sep 2017

Arterial hypertension (HTN) accounts for the largest amount of attributable cardiovascular (CV) mortality worldwide, and risk stratification in hypertensive patients is of crucial importance to manage treatment and prevent adverse events. Asymptomatic involvement of different organs in patients affected by HTN represents an independent determinant of CV risk and the identification of target organ damage (TOD) is recommended to further reclassify patients' risk. Non-invasive CV imaging is progressively being used and continues to provide new technological opportunities to TOD evaluation at early stage. The aim of this article is to provide the community of cardiology with an update on appropriate and justified use of non-invasive imaging tests in the growing population of hypertensive patients.

Self-monitoring of blood pressure in hypertension: A systematic review and individual patient data meta-analysis.

Article

Sep 2017

Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality

Article

Apr 2018
NEW ENGL J MED

Background Evidence for the influence of ambulatory blood pressure on prognosis derives mainly from population-based studies and a few relatively small clinical investigations. This study examined the associations of blood pressure measured in the clinic (clinic blood pressure) and 24-hour ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of patients in primary care. Methods We analyzed data from a registry-based, multicenter, national cohort that included 63,910 adults recruited from 2004 through 2014 in Spain. Clinic and 24-hour ambulatory blood-pressure data were examined in the following categories: sustained hypertension (elevated clinic and elevated 24-hour ambulatory blood pressure), “white-coat” hypertension (elevated clinic and normal 24-hour ambulatory blood pressure), masked hypertension (normal clinic and elevated 24-hour ambulatory blood pressure), and normotension (normal clinic and normal 24-hour ambulatory blood pressure). Analyses were conducted with Cox regression models, adjusted for clinic and 24-hour ambulatory blood pressures and for confounders. Results During a median follow-up of 4.7 years, 3808 patients died from any cause, and 1295 of these patients died from cardiovascular causes. In a model that included both 24-hour and clinic measurements, 24-hour systolic pressure was more strongly associated with all-cause mortality (hazard ratio, 1.58 per 1-SD increase in pressure; 95% confidence interval [CI], 1.56 to 1.60, after adjustment for clinic blood pressure) than the clinic systolic pressure (hazard ratio, 1.02; 95% CI, 1.00 to 1.04, after adjustment for 24-hour blood pressure). Corresponding hazard ratios per 1-SD increase in pressure were 1.55 (95% CI, 1.53 to 1.57, after adjustment for clinic and daytime blood pressures) for nighttime ambulatory systolic pressure and 1.54 (95% CI, 1.52 to 1.56, after adjustment for clinic and nighttime blood pressures) for daytime ambulatory systolic pressure. These relationships were consistent across subgroups of age, sex, and status with respect to obesity, diabetes, cardiovascular disease, and antihypertensive treatment. Masked hypertension was more strongly associated with all-cause mortality (hazard ratio, 2.83; 95% CI, 2.12 to 3.79) than sustained hypertension (hazard ratio, 1.80; 95% CI, 1.41 to 2.31) or white-coat hypertension (hazard ratio, 1.79; 95% CI, 1.38 to 2.32). Results for cardiovascular mortality were similar to those for all-cause mortality. Conclusions Ambulatory blood-pressure measurements were a stronger predictor of all-cause and cardiovascular mortality than clinic blood-pressure measurements. White-coat hypertension was not benign, and masked hypertension was associated with a greater risk of death than sustained hypertension. (Funded by the Spanish Society of Hypertension and others.)