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76
Review Article
IntroductIon
Hypertension (HTN) has reached a staggering gure all over
the world, and one in three adults in India is hypertensive.[1]
Resistant hypertension (RH) is dened as uncontrolled ofce
blood pressure (BP) >130/80 mmHg despite three different
groups of antihypertensive medications in optimum dose,
including one of the long-acting diuretics.[2] Studies show that
the prevalence of RH is 10% of total hypertensive patients.[3]
What are the caveatS of dIaGnoSIS of reSIStant
hyPertenSIon?
There are multiple caveats of diagnosis of RH.
1. SPRINT trial showed that benet of intensive lowering
of BP, especially in aged hypertensives with higher
cardiovascular risk,[4] has been the driving force behind
the American heart Association/ American College of
Cardiology (AHA/ACC) 2017 HTN guideline to set a
lower target (<130/80 mmHg) to achieve.[5] Accordingly,
the BP cutoff for diagnoses of RH has been changed from
<140/90 mmHg to <130/80 mmHg in 2017 guideline
2. Uncontrolled office BP has been used to define RH
according to the 2018 European Society of Cardiology
(ESC) guideline for HTN.[6] However, ambulatory BP
monitoring (ABPM) has revolutionized the essence of BP
lowering and stressed over 24-h control of BP including
at nighttime. ABPM has identied four subsets of RH
[Figure 1]. AHA/ACC and european society of cardiology
(ESC) suggest that ABPM is mandatory before diagnosing
RH to rule out white coat hypertension (WCH), which can
be as high as 20% of the RH group, and also to follow-up
the WCH patients.[6] Recently, there is growing evidence
Pseudo‑Resistant, Resistant, and Refractory Hypertension:
The Good, the Bad, and the Ugly
Dibbendhu Khanra, Bhanu Duggal
Department of Cardiology, All India Institution of Medical Sciences, Rishikesh, Uttarakhand, India
Resistant Hypertension (RH) not uncommon in daily clinical practice but is often loosely coined. Accuracy of BP measurement, Adherence to
prescribed medications and Adequacy of prescribed dosages are to be ensured before diagnosing RH. Ambulatory blood pressure monitoring
and home blood pressure monitoring are becoming standard of care in evaluation of RH patients. Management of RH in recent years has
been evolved and spiranolactone has become the fourth drug when combination of Renin-Angiotensin system blockers, calcium channel
blockers and long acting thiazide like diuretics fail. Scores like PFK comprising of Urinary pH>7, Female Sex, K<3.5 mg/dl has been handy
in decision making to start spiranolactone. However, Refractory Hypertension (RfH) has been dened when ve anti‑hypertensive drugs
including spiranolactone fail and has been emerging to be a novel phenotype. RH patients are known to be volume dependent whereas
RfH patients are known to have sympathetic overdrive. Management strategy of RfH is challenging and beta-blockers or alpha-blockers
may be of role in these subset. Renal artery denervation is being resurrected with newer evidence and denitely an option for RfH patients.
Novel therapies like Barroreceptor Activation Techniques and Central iliac arteriovenous anastomosis are being evaluated in resistant and
refractory hypertension patients.
Keywords: Ambulatory blood pressure monitoring, refractory hypertension, resistant hypertension
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DOI:
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Abstract
Address for correspondence: Dr. Dibbendhu Khanra,
Department of Cardiology, All India Institute of Medical Sciences,
Rishikesh, Uttarakhand, India.
E‑mail: ddk3987@gmail.com
How to cite this article: Khanra D, Duggal B. Pseudo-resistant, resistant,
and refractory hypertension: The good, the bad, and the ugly. J Pract
Cardiovasc Sci 2019;5:76-80.
This is an open access journal, and arcles are distributed under the terms of the Creave
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For reprints contact: reprints@medknow.com
Date of Submission : 02-May-2019
Date of Revision : 17-May-2019
Date of Acceptance : 28-May-2019
Date of Web Publication : 19-Aug-2019
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Khanra and Duggal: Resistant hypertension
Journal of the Practice of Cardiovascular Sciences ¦ Volume 5 ¦ Issue 2 ¦ May-August 2019 77
to support the use of home BP monitoring (HBPM)[7] for
6 times a day including nighttime BP and early morning
BP, which has been shown to have good correlation with
ABPM [Figure 2]
3. National Institute for Health and Care Excellence (NICE)
stressed upon using combination of angiotensin-converting
enzyme inhibitor/angiotensin receptor blockers, calcium
channel blockers, and diuretic (A + C + D) including a
long-acting thiazide. However, prescriptions of long-acting
thiazides such as chlorthalidone or spironolactone
have been found to be persistently low across the
spectrum of RH.[8] A recent study has reiterated the role
of chlorthalidone to reduce BP throughout the clock,
whereas hydrochlorothiazide (HCTZ) has turned resistant
hypertensive patients into masked HTN due to their
short-acting property.[8] PATHWAY 3 has shown that a
combination of amiloride with HCTZ was neutral for
glucose and K+ and reduced BP more than each single
diuretic.[9] Hence, in regard to a treatment RH, choosing
the correct diuretic is of supreme importance.
Secondary hyPertenSIon IS not aS Same aS
reSIStant hyPertenSIon
All hypertensive patients at the time of diagnosis must have a
thorough clinical history (for obstructive sleep apnea [OSA]
and history suggestive of pheochromocytoma), clinical
examinations (including peripheral pulses and abdominal mass),
and echocardiography (to rule out coarctation of the aorta)
and markers for connective tissue diseases (e.g., anti-nuclear
antibody). Figure 3 one of the most underrated causes of HTN is
OSA, and sleep study may clinch the diagnosis for the suspected
ones. Drugs such as nonsteroidal anti‑inammatory drugs and
oral contraceptive pills and other hormonal therapies including
steroids are also looked for while dealing with patients of RH.
Yamashita et al.[10] have developed PFK score which consists of
U pH >7, female sex, K <3.5, primary hyperaldosteronism can be
suspected if PFK scores are positive. Prescribing spironolactone ahs
been found to be useful in controlling hypertension in this subset.
It has been found that plasma renin is low across the
spectrum of RH, and PATHWAY 2 study demonstrated that
spironolactone was the most effective BP -lowering agent
throughout the distribution of baseline plasma renin, but it
was particularly effective in patients with lower rennin.[11]
However, changing antihypertensive medications according
to plasma rennin to plasma aldosterone ratio was intuitively
appealing but practically not feasible in most instances owing
to poor availability, standardization, and hyporeninemic
hypoaldosteronism in diabetes mellitus.
hoW to aPProach manaGement reSIStant
hyPertenSIon?
Studies have shown that 50% of the total RH patients are
actually having pseudo-RH and the rest 50% have true RH
(TRH), and it can be due to white coat effect, inaccurate BP
measurement, undertreatment, or medical nonadherence.[12]
Hence, whenever ofce BP is >140/90 with A + C + D regimen,
ABPM should be advised to rule out WCH and diuretics
should be changed to long-acting chlorthalidone. Accuracy
of BP measurement, adherence to prescribed medications, and
adequacy of prescribed dosages are to be ensured (Triple-A).
According to the NICE guideline, in RH patients, after A + C
+ D regimen, the fourth drug to be decided as per the serum
potassium (k) level. If k <4.5, a spironolactone has to be added,
whereas if k >4.5, either double the dose of thiazide or adding
a loop diuretic has been advised.[13]
can We IdentIfy the true reSIStant hyPertenSIon
and maSKed reSIStant hyPertenSIon at the
clInIc?
In a large community-based study of 8295 patients with RH
classied on the basis of ABPM, de la Sierra et al.[14] found that
Figure 2: Normal and abnormal pattern of ambulatory blood pressure
monitoring.
Figure 1: Spectrum of resistant hypertension as per ambulatory blood
pressure monitoring. RH: Resistant hypertension.
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Khanra and Duggal: Resistant hypertension
Journal of the Practice of Cardiovascular Sciences ¦ Volume 5 ¦ Issue 2 ¦ May-August 2019
78
true resistant hypertension patients who had longer duration
of uncontrolled hypertension and needed four or more drugs
to control BP, had a worse cardiovascular outcome. The group
included larger proportions of smokers, diabetics, target organ
damage (including left ventricular hypertrophy, impaired
renal function, and microalbuminuria), and documented
cardiovascular disease. Moreover, true resistant hypertensives
exhibited in a greater proportion of a riser pattern in ABPM.
In J-HOME study[15] proling of 3400 Japanese patients with
RH by HBPM, it has been found that compared to controlled
HTN, factors associated with isolated uncontrolled home HTN
included obesity, relatively higher ofce systolic BP (SBP),
habitual drinking, and the use of two or more prescribed
antihypertensive drugs. Compared to uncontrolled HTN,
factors associated with isolated uncontrolled ofce HTN
included female gender, lower body mass index, and relatively
lower ofce SBP. The presence of hypercholesterolemia was
found to have a signicant and independent association with
isolated ofce RH. Higher ofce SBP, past history of ischemic
heart disease, and lower prescription rate of potassium-sparing
diuretics were found to have a signicant and independent
association with isolated home RH. Patients with sustained RH
had a signicantly lower prescription rate of potassium‑sparing
diuretics than those with controlled HTN.
What IS “refractory hyPertenSIon:” IS It a
novel PhenotyPe?
One subset of TRH patients are not amenable to achievement of
target BP despite using ve different classes of antihypertensive
drugs, including a long-acting thiazide lke diuretic and
spironolactone. Acelajado et al. have coined them to have
'refractory hypertension (RfH).[16] They have found that 10% of
the truly RH patients are RfH and they have a dismal outcome
in terms of stroke and heart failure in comparison to TRH.
Dudenbostel et al. dened RfH as failure to achieve BP control
with treatment prescribed by HTN experts at a minimum of
three follow-up visits during at least 6 months of care, receiving
ve or more different antihypertensive medications, including
chlorthalidone and spironolactone. This stricter denition led
the researchers to have a prevalence of RfH as 4% in their
prospective study comprising 700 patients of TRH.[17]
Birmingham Hypertension Clinic at the University of Alabama
at has proposed a classication of HTN according to number
of drugs [Figure 4].[17] Dudenbostel et al. compared the prole
of RfH to TRH patients and found that RfH patients are younger
with low renin and high sympathetic activity [Figure 5].[17]
Figure 6 summarizes the approach to RH.
What can be the laSt reSort for refractory
hyPertenSIon PatIentS?
For the subset of RfH patients, transcatheter renal artery
denervation (RDN) has been studied. However, the surge
of initial enthusiasm was refuted in SIMPLICITY 3
study, where RDN was not found to be superior to a sham
procedure and medical therapy in reducing office and
ambulatory BP at 6 months. However, RDN has been found
to have greater benet in RfH patients with high mean BP
(>199 mmHg), age <65 years, and estimated glomerular
ltration rate >60 ml/min/m2.[18] However, recent studies such
as RADIANCE-HTN SOLO and REQUIRED and SPYRAL
HTN-ON MED and OFF MED showed the promising result of
Figure 4: Classification of hypertension according to number of drugs.
Figure 3: Causes of secondary hypertension.
Figure 5: Comparison of true resistant hypertension and refractory
hypertension.
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Khanra and Duggal: Resistant hypertension
Journal of the Practice of Cardiovascular Sciences ¦ Volume 5 ¦ Issue 2 ¦ May-August 2019 79
RDN, and the practice is rejuvenated with availability newer
SPYRAL catheter by Medtronic.[19,20]
Baroreceptor activation technique has been also studied in RfH
patients. Initial phase III Rheos Pivotal Trial on continuous
carotid baroreceptor pacing with RHEOS device for RH with
the rst‑generation baroreceptor pacemaker yielded equivocal
data on efcacy and adverse effects due to facial nerve injury
during surgical implantation.[21]
Creation of a central iliac arteriovenous anastomosis (cAV)
using a novel nitinol coupler device (ROX device) results in
an immediate, signicant reduction of BP. In ROX CONTROL
HTN study, extended follow-up of patients with uncontrolled
HTN treated with an iliac cAV anastomosis has demonstrated
durable ofce and ABP reduction with no newly identied
safety reports. The magnitude of ofce BP reduction that
was observed at 6-month follow-up was greater than that
reported after the use of renal denervation in TRH and also the
use of spironolactone as a fourth-line antihypertensive drug
strategy for TRH. However, after coupler therapy, one-third of
patients developed ipsilateral venous stenosis; all were treated
successfully with venous stenting.[22]
IndIan ScenarIo
In a study by Bharatia et al.,[23] 19.5% of hypertensive
patients were resistant to A + C + D combination. Eighty
percent of them were aged in the range of 46–65 years and
67.2% of patients were male. A higher proportion of patients
were residents of Andhra Pradesh (21.4% patients) and
Maharashtra (19.3% patients) in the aforesaid study. In a study
reported from Varanasi, the prevalence of HTN was found to
be staggering 32.9%. Out of the total hypertensive patients,
only 38.4% were aware of their HTN status; of those, 70.4%
were seeking treatment and 66% had their BP above target.[24]
In a study by Roy et al., it has been found that the prevalence
of HTN increased from 23.0% to 42.2% and 11.2% to 28.9%
in urban and rural National Capital Region, respectively,
over a span of two decades, irrespective of high education,
alcohol use, obesity, and high fasting blood glucose being
at a higher risk for HTN . Moreover, surprisingly, the study
showed that, overall, there was no improvement in awareness,
treatment, and control rates of HTN in the population.[25] In
a meta-analysis by Anchala et al., about 33% of urban and
25% of rural Indians were found to be hypertensive. Of these,
25% of rural and 42% of urban Indians were aware of their
hypertensive status. Only 25% of rural and 38% of urban
Indians were being treated for HTN. Only one-tenth of rural
and one‑fth of urban Indian hypertensive population had
their BP under control.[1] However, data on RH in India are
limited, and Narang and Srikant have elucidated the nuances
in the application of 2017 HTN guidelines for Indian patients
in their article.[26]
concluSIon
The actual prevalence of RH may be lower than what is
perceived in the literature when triple-A (accuracy of BP
measurement, adherence of medications, and adequacy
of anti-HTN medications) are ensured. It is important to
emphasize that the sea of RH starts when the shore of secondary
HTN is over and the island of RfH is still uncharted. RfH is
emerging as a novel phenotype, and growing evidence suggest
that these patients have sympathetic hyperactivity. However,
the role of beta-blockers and interventions such as RDN and
baroreceptor activation techniques is yet to be studied.
Ethics clearance
Ethical clearance taken.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conicts of interest.
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