ArticlePDF AvailableLiterature Review

Four pillars of heart failure: contemporary pharmacological therapy for heart failure with reduced ejection fraction

March 2021
Open Heart 8(1)

DOI:10.1136/openhrt-2021-001585

License
CC BY 4.0

Authors:

Melanie McGinlay

University of Leeds

Klaus Witte

University of Leeds

Initiation and optimisation of the Four Pillars of Heart Failure. All agents are initiated in parallel. This is followed by up-titration in one, two or three steps, as required. Additional therapies are then considered as a final step. ARNI, angiotensin receptor-neprilysin inhibitors; BB, beta-blocker; MRA, mineralocorticoid receptor antagonists;SGLT2i, sodium-glucose co-transporter 2inhibitors.

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Straw S, etal. Open Heart 2021;8:e001585. doi:10.1136/openhrt-2021-001585

To cite: Straw S, McGinlay M,

Witte KK. Four pillars of heart

failure: contemporary

pharmacological therapy for

heart failure with reduced

ejection fraction. Open Heart

2021;8:e001585. doi:10.1136/

openhrt-2021-001585

Accepted 11 February 2021

1Leeds Institute of

Cardiovascular and Metabolic

Medicine, University of Leeds,

Leeds, UK

2Cardiorespiratory Clinical

Services Unit, Leeds Teaching

Hospitals NHS Trust, Leeds, UK

Correspondence to

Dr Klaus K Witte; k. k. witte@

leeds. ac. uk

Four pillars of heart failure:

contemporary pharmacological therapy

for heart failure with reduced

ejection fraction

Sam Straw ,1 Melanie McGinlay,2 Klaus K Witte1

Viewpoint

employer(s)) 2021. Re- use

permitted under CC BY.

Published by BMJ.

INTRODUCTION

The past two decades have heralded dramatic

improvements in outcomes for people living

with heart failure with reduced ejection

fraction (HFrEF).1 The more widespread

implementation of disease modifying phar-

macological therapies,2 supported by land-

mark trials of renin- angiotensin system

inhibitors3 and beta- blockers4 have improved

longevity despite a background of an ageing

and increasingly multimorbid population.

Although the benefits of comprehensive

pharmacological therapies are clear, the

real- world attainment of target doses5 6 and

utilisation of novel agents such as angio-

tensin receptor- neprilysin inhibitors (ARNI)7

remain low. Furthermore, HFrEF remains a

disease associated with significant morbidity

and reduced survival relative to those without

HFrEF, even after taking into account comor-

bidities.8 Recently, trials have demonstrated

improved outcomes in people with HFrEF

receiving sodium- glucose co- transporter

2 inhibitors (SGLT2i).9 10 However, it is

currently unclear how these agents will be

used alongside established therapies. Now

is therefore an opportune moment to pause

and reflect on our current practice, barriers

to further progress and how future guide-

lines might work better for our patients. In

this viewpoint we summarise how our current

linear approach, on a background of increas-

ingly complex pharmacotherapy has the

potential to cause confusion and consequent

delays which could lead to even worse attain-

ment of optimal therapies. On the other

hand, a more parallel approach to the initi-

ation and optimisation of the Four Pillars of

Heart Failure would simplify our approach,

yielding benefits for our patients and health-

care systems.

HOW DID WE GET HERE?

Heart failure guidelines are based around

inhibition of the renin- angiotensin and

sympathetic nervous systems, two funda-

mental pathways which drive the pathophys-

iology of HFrEF using ACE inhibitors (ACEi)

and beta- blockers. In both European2 and

American guidelines11 additional therapies

are recommended for patients who ‘remain

symptomatic’ with persistently impaired left

ventricular (LV) function despite maximally

tolerated doses of ACEi and beta- blockers.

These guidelines differ subtly regarding the

timing of mineralocorticoid receptor antag-

onists (MRA) relative to other therapies but

are otherwise broadly similar, advocating

a linear approach. This attempts to avoid

‘unnecessary’ treatments in patients who

‘respond’ but has several important limita-

tions. First, while guidelines do not stipulate

a time interval between alterations to therapy,

the need for further assessment and re- eval-

uation of LV function inevitably results in

delays initiating additional agents as well as

contributing further follow- up and imaging

costs. In clinical practice it typically takes

many months before patients receive opti-

mised doses of these medications, and many

never do, even where integrated hospital

and community care is available.5 Second,

the barrier of ‘response’ is confusing and

misplaced: does ‘response’ mean asympto-

matic or merely improved? In our experi-

ence, while patients often feel better, they

rarely become asymptomatic (NYHA (New

York Heart Association) class 1),12 an obser-

vation supported by real- world data even

in those receiving ARNI.13 14 Moreover, we

should consider whether a highly subjec-

tive and poorly reproducible assessment is

appropriate to determine our allocation

of life- saving treatments.15 Hence, criteria

Open Heart

2Straw S, etal. Open Heart 2021;8:e001585. doi:10.1136/openhrt-2021-001585

requiring repeat assessment act as a barrier to initiating

additional therapies such as MRA or ARNI,7 which are

regarded as ‘second- line’ due to the hierarchical frame-

work which places greater emphasis on therapies based

on the chronological sequence in which the trials were

performed. There is no logical basis to assume that drug

classes trialled earliest would be the most beneficial, yet

this is what guidelines imply. Therefore, if we are to make

progress, future guidelines must address these limitations

and incorporate the Four Pillars of Heart Failure into a

comprehensive disease modifying programme for all

people living with HFrEF.

LEARNING LESSONS FROM ARNI

The PARADIGM- HF trial showed that a combination

of angiotensin receptor blocker and a neprilysin inhib-

itor (sacubitril- valsartan) was superior to an ACEi in

preventing cardiovascular deaths or hospitalisation

for heart failure (HR 080, 95% CI 0.73 to 0.87) and

reducing all- cause mortality (HR 0.84, 95% CI 0.76 to

0.93).16 Despite overwhelming efficacy which led to the

trial being stopped early, the utilisation of ARNI in the

real- world has been suboptimal, with less than 1% pene-

tration in eligible patients. The reluctance of physicians

to prescribe ARNI may in part be that, unusually, the

recommendations are based on a single trial, studied

in an ‘A+B vs C’ fashion. Furthermore, the comparator

was a submaximal dose of enalapril compounded by

lower blood pressure in those allocated ARNI suggesting

undertreatment in the control arm.16 It has also been

suggested that the trial was additionally biased in favour

of the novel agent due to a double drug run- in period of

unequal times, in which those randomised to ARNI had

already received an ACEi and were therefore pre- selected

(20% of patients were lost during the run- in period).17

Drug doses are related to outcomes in HFrEF18–20 and

the HR for the composite outcome in PARADIGM- HF

between sacubitril- valsartan and enalapril was similar to

the comparison of high and low dosing of lisinopril in

the ATLAS trial.21 However, post- hoc analysis has shown

that the point estimates for the benefit of low dose ARNI

compared with low dose ACEi were identical to the point

estimate of the overall trial,22 and real- world data have

shown clear improvements in outcomes, symptoms and

quality of life compared with standard of care ACEi.23

Another difficulty employing ARNI across the board

includes the wash- out period required following cessation

of ACEi due to risks of angioedema. Although not insur-

mountable, such requirements challenge heart failure

programmes facing reduced face- to- face appointments

due to service redesign and the current pandemic. Hence,

if the benefits of the activity are perceived (whether

correctly or incorrectly) to be minimal, physician inertia

may prevail. To counter this, initiating ARNI at the point

of diagnosis would mitigate the risk of inertia while also

providing a more effective treatment to patients during

the period of highest risk.

IMPLEMENTING NOVEL AGENTS INTO HEART FAILURE

PATHWAYS

The efficacy of SGLT2i in addition to standard therapies

for people with HFrEF has been confirmed with consistent

and near identical 25% risk reduction of the primary end

point of cardiovascular death or hospitalisation for heart

failure from both dapagliflozin and empagliflozin.10 24

Both trials also demonstrated a slow of decline in renal

function; EMPEROR- Reduced showed a 50% relative risk

reduction for the composite renal endpoint10 (although

this was non- significant in DAPA- HF).24

It is anticipated that more than four out of five people

with HFrEF in contemporary registries25 will be eligible

based on the inclusion criteria of these trials. The bene-

ficial effects on renal outcomes are particularly attractive

in a disease process typically associated with progressive

decline of kidney function which often prevents the initi-

ation or intensification of renin- angiotensin system inhib-

itors. Furthermore, SGLT2i are safe, with a low incidence

of serious side effects (no patients without diabetes devel-

oped ketoacidosis in DAPA- HF or EMPEROR- Reduced),

a lack of dosing considerations and minimal effects on

blood pressure.

Given the somewhat simpler approach taken in trials of

SGLT2i, the ease of use and clear benefits, it is likely that

uptake among physicians will be enthusiastic, although

it is yet unclear how these agents might fit into our

current practice. There is a risk that SGLT2i become an

additional agent for patients who do not ‘respond’ with

conventional pharmacological therapy, rather than a

fundamental Pillar of Heart Failure. The totality of the

available evidence suggests the benefits of SGLT2i are

consistent across subgroups, including diabetes status,

baseline ARNI and symptoms. SGLT2i must therefore

be regarded as a unique class of medication with a novel

mechanism of action to be used in all eligible patients.

THE POSSIBILITIES OF A COMPREHENSIVE APPROACH

The four drug classes are complementary to each other

and cross- trial comparisons have shown that a compre-

hensive disease modification strategy beyond the treat-

ments which most patients receive (ACEi and beta-

blocker) with ARNI, MRA and SGLT2i are associated with

improved outcomes. A typical patient aged 65 years can

expect to live an additional 5 years if receiving a compre-

hensive strategy with the Four Pillars, compared with

conventional therapy.26

INERTIA: KNOW YOUR ENEMY

Drugs, trial design and side effects aside, the key obstacle

to therapy intensification is physician inertia in patients

who are deemed to have stabilised or ‘responded’ to

treatment. For some with a recent decompensation this

might be appropriate,27 28 but the relevant clinical trials

were carried out in ambulatory patients receiving stable

doses of previous generations of medical therapy, most

Straw S, etal. Open Heart 2021;8:e001585. doi:10.1136/openhrt-2021-001585

Viewpoint

of which had class II symptoms.10 16 24 Of particular rele-

vance to SGLT2i, a striking result from DAPA- HF was the

early benefit from dapagliflozin, with a reduction in wors-

ening heart failure events observed within 28 days.24

SIMPLIFY TO PROGRESS

We propose a novel conceptual framework for the imple-

mentation of pharmacological therapies in HFrEF, in

which the Four Pillars of Heart Failure are introduced

in parallel, very early in the patient pathway with subse-

quent optimisation of dosing where required (figure 1).24

The rate of dose increments can be tailored to the patient

and the service. For most patients, low dose ARNI and

SGLT2i could be started simultaneously, followed within

a few days by low dose beta- blocker and MRA, followed

by up- titration. While others have suggested that initia-

tion with beta- blocker alongside SGLT2i might be more

optimal,29 we believe that the exact sequent of initiation

is unimportant, as long as all Four Pillars are introduced

within the first few weeks of diagnosis—although with the

lack of dosing considerations and clear evidence from

randomised trials of an early beneficial effect,27 SGLT2i

are an obvious first choice.

This approach is at odds with current practice and a

fundamental shift away from the linear approach advo-

cated by guidelines, including the recent technology

appraisal of dapagliflozin from the UK.30 Nevertheless, it

remains the case, that very few patients become asymp-

tomatic with even optimal doses of disease- modifying

therapy suggesting that slow up- titration, followed by a

decision to embark on the next step based on symptoms

is folly.

It seems likely that impairment of renal function

following up- titration of ARNI and MRA will become

lesser concerns following the introduction of SGLT2i

into care pathways, however, real- world data are vital to

confirm the safety and feasibility of this approach. Those

caring for people with heart failure must be cognisant

that early increases in creatinine with SGLT2i are tran-

sient and be reassured that in the long- term the less rapid

decline in renal function in patients receiving SGLT2i will

allow more complete renin- angiotensin system blockade.

CONCLUSION

The introduction of SGLT2i to the treatment of HFrEF

is a chance for us to revisit whether current guidelines

for the treatment of HFrEF are fit for purpose. Many

patients have waited for weeks or months before ever

seeing a cardiologist and receiving a diagnosis, and

further delays to treatments have the potential to cause

great harm. Moving forwards, we must recognise heart

failure for what it is, an incurable disease with a mortality

rate similar to many forms of cancer, where any delays

cost lives. Once we have done so we need to implement

pathways that offer rapid initiation and, where required,

up- titration of life- extending therapies.

Twitter Sam Straw @DrSamStraw

Contributors All authors contributed equally.

Funding This work was supported by the British Heart Foundation: CH/13/1/30086.

Competing interests KKW has received speakers’ fees and honoraria from

Medtronic, Cardiac Dimensions, Novartis, Abbott, BMS, Pzer, Bayer and has

received an unconditional research grant from Medtronic.

Patient consent for publication Not required.

Provenance and peer review Not commissioned; externally peer reviewed.

Data availability statement No data are available.

Open access This is an open access article distributed in accordance with the

Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits

others to copy, redistribute, remix, transform and build upon this work for any

purpose, provided the original work is properly cited, a link to the licence is given,

and indication of whether changes were made. See:https:// creativecommons. org/

licenses/ by/ 4. 0/.

ORCID iD

SamStraw http:// orcid. org/ 0000- 0002- 2942- 4574

REFERENCES

1 Cubbon RM, Gale CP, Kearney LC, etal. Changing characteristics

and mode of death associated with chronic heart failure caused by

left ventricular systolic dysfunction: a study across therapeutic eras.

Circ Heart Fail 2011;4:396–403.

2 Ponikowski P, Voors AA, Anker SD, etal. 2016 ESC Guidelines for

the diagnosis and treatment of acute and chronic heart failure: The

Task Force for the diagnosis and treatment of acute and chronic

heart failure of the European Society of Cardiology (ESC)Developed

with the special contribution of the Heart Failure Association (HFA) of

the ESC. Eur Heart J 2016;37:2129–200.

3 SOLVD Investigators, Yusuf S, Pitt B, etal. Effect of enalapril on

survival in patients with reduced left ventricular ejection fractions

and congestive heart failure. N Engl J Med 1991;325:293–302.

4 The cardiac insufciency bisoprolol study II (CIBIS- II): a randomised

trial. Lancet 1999;353:9–13.

5 Greene SJ, Fonarow GC, DeVore AD, etal. Titration of medical

therapy for heart failure with reduced ejection fraction. J Am Coll

Cardiol 2019;73:2365–83.

6 Brunner- La Rocca H- P, Linssen GC, Smeele FJ, etal. Contemporary

Drug Treatment ofChronic Heart Failure With ReducedEjection

Fraction: The CHECK- HF Registry. JACC Heart Fail 2019;7:13–21.

Figure 1 Initiation and optimisation of the Four Pillars

of Heart Failure. All agents are initiated in parallel. This

is followed by up- titration in one, two or three steps, as

required. Additional therapies are then considered as a

nal step. ARNI, angiotensin receptor- neprilysin inhibitors;

BB, beta- blocker; MRA, mineralocorticoid receptor

antagonists;SGLT2i, sodium- glucose co- transporter

2inhibitors.

Open Heart

4Straw S, etal. Open Heart 2021;8:e001585. doi:10.1136/openhrt-2021-001585

7 Greene SJ, Butler J, Albert NM, etal. Medical Therapy for Heart

Failure WithReduced Ejection Fraction: The CHAMP- HF Registry. J

Am Coll Cardiol 2018;72:351–66.

8 Drozd M, Relton SD, Walker AMN, etal. Association of heart failure

and its comorbidities with loss of life expectancy. Heart 2020.

doi:10.1136/heartjnl-2020-317833. [Epub ahead of print: 05 Nov

2020].

9 Colombo G, Casella R, Cazzaniga A, etal. Dapagliozin in patients

with heart failure and reduced ejection fraction. Intern Emerg Med

2020;15:515–7.

10 Packer M, Anker SD, Butler J, etal. Cardiovascular and renal

outcomes with Empagliozin in heart failure. N Engl J Med

2020;383:1413–24.

11 Yancy CW, Jessup M, Bozkurt B, etal. 2017 ACC/AHA/HFSA

focused update of the 2013 ACCF/AHA guideline for the

management of heart failure: a report of the American College of

Cardiology/American heart association Task force on clinical practice

guidelines and the heart failure Society of America. Circulation

2017;136:e137–61.

12 Koshy AO, Gallivan ER, McGinlay M, etal. Prioritizing symptom

management in the treatment of chronic heart failure. ESC Heart Fail

2020;7:2193–207.

13 Polito MV, Silverio A, Rispoli A, etal. Clinical and echocardiographic

benet of Sacubitril/Valsartan in a real- world population with HF with

reduced ejection fraction. Sci Rep 2020;10:6665.

14 Lau CW, Martens P, Lambeets S, etal. Effects of sacubitril/valsartan

on functional status and exercise capacity in real- world patients.

Acta Cardiol 2019;74:405–12.

15 Blacher M, Zimerman A, Engster PHB, etal. Revisiting heart failure

assessment based on objective measures in NYHA functional

classes I and II. Heart 2020. doi:10.1136/heartjnl-2020-317984.

[Epub ahead of print: 23 Dec 2020].

16 McMurray JJV, Packer M, Desai AS, etal. Angiotensin- neprilysin

inhibition versus enalapril in heart failure. N Engl J Med

2014;371:993–1004.

17 Haslam A, Prasad V. Conrmatory trials for drugs Approved on a

single trial. Circ Cardiovasc Qual Outcomes 2019;12:e005494.

18 Witte KK, Drozd M, Walker AMN, etal. Mortality reduction

associated with β-adrenoceptor inhibition in chronic heart failure is

greater in patients with diabetes. Diabetes Care 2018;41:136–42.

19 Straw S, McGinlay M, Relton SD, etal. Effect of disease- modifying

agents and their association with mortality in multi- morbid patients

with heart failure with reduced ejection fraction. ESC Heart Fail

2020;7:3859–70.

20 Bristow MR, Gilbert EM, Abraham WT, etal. Carvedilol produces

dose- related improvements in left ventricular function and survival in

subjects with chronic heart failure. MOCHA Investigators. Circulation

1996;94:2807–16.

21 Packer M, Poole- Wilson PA, Armstrong PW, ATLAS study group.

Comparative effects of low and high doses of the angiotensin-

converting enzyme inhibitor, lisinopril, on morbidity and mortality in

chronic heart failure. Circulation 1999;100:2312–8.

22 Vardeny O, Claggett B, Packer M, etal. Efcacy of sacubitril/

valsartan vs. enalapril at lower than target doses in heart failure with

reduced ejection fraction: the PARADIGM- HF trial. Eur J Heart Fail

2016;18:1228–34.

23 Khariton Y, Fonarow GC, Arnold SV, etal. Association Between

Sacubitril/Valsartan Initiation and Health Status Outcomes

inHeartFailure With Reduced EjectionFraction. JACC Heart Fail

2019;7:933–41.

24 McMurray JJV, Solomon SD, Inzucchi SE, etal. Dapagliozin in

patients with heart failure and reduced ejection fraction. N Engl J

Med 2019;381:1995–2008.

25 Sharma A, Zhao X, Hammill BG, etal. Trends in Noncardiovascular

comorbidities among patients hospitalized for heart failure: insights

from the get with the Guidelines- Heart failure registry. Circ Heart Fail

2018;11:e004646.

26 Vaduganathan M, Claggett BL, Jhund PS, etal. Estimating lifetime

benets of comprehensive disease- modifying pharmacological

therapies in patients with heart failure with reduced ejection fraction:

a comparative analysis of three randomised controlled trials. Lancet

2020;396:121–8.

27 Bhatt DL, Szarek M, Steg PG, etal. Sotagliozin in patients

with diabetes and recent worsening heart failure. N Engl J Med

2021;384:117-128:117–28.

28 Wachter R, Senni M, Belohlavek J, etal. Initiation of sacubitril/

valsartan in haemodynamically stabilised heart failure patients in

hospital or early after discharge: primary results of the randomised

TRANSITION study. Eur J Heart Fail 2019;21:998–1007.

29 McMurray JJV, Packer M. How should we sequence the treatments

for heart failure and a reduced ejection fraction? A redenition of

evidence- based medicine. Circulation 2020;100.

30 National Institute of Health and Care Excelence. Dapagliozin for

treating chronic heart failure with reduced ejection fraction, 2020.

Available: https://www. nice. org. uk/ guidance/ gid- ta10560/ documents/

nal- appraisal- determination- document [Accessed 08 Feb 2021].

Available via license: CC BY 4.0

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Dec 2024
IN VIVO

Background/Aim Atrial fibrillation (AF) and heart failure (HF) commonly co-occur, significantly increasing morbidity and mortality. Poorly controlled AF can contribute to complications like HF and is associated with conditions, such as stroke and pulmonary embolism (PE). This report involves a man with AF who had persistent respiratory symptoms and left-sided chest pain, initially suspected to be PE, but eventually diagnosed as HF. Case Report A 43-year-old male experienced increasing breathlessness, cough, and fatigue. Initially suspected to have a respiratory infection, his persistent symptoms raised concern for PE. The patient had a history of AF, unsuccessful cardioversion, and long-term non-adherence to beta blockers. Initial assessment revealed persistent respiratory symptoms and elevated levels of C-reactive protein, D-dimer, N-terminal pro-B-type natriuretic peptide, and Troponin T. Chest X-ray showed pulmonary congestion, and echocardiogram confirmed a severely impaired ejection fraction (EF <20%). While the differential diagnosis included community-acquired pneumonia, PE, and HF, the final diagnosis was worsening AF and HF with reduced EF, not PE. Conclusion PE symptoms can overlap with HF, making careful differential diagnosis essential, particularly in AF patients with elevated D-dimer levels, where false positives necessitate caution. This case underscores the importance of thorough differential diagnosis and clinical judgment before ordering tests to avoid misdiagnosis. Long-term non-adherence to beta blockers exacerbated the patient’s symptoms, emphasising the critical role of consistent medication use in managing AF and preventing complications like HF. This case report also highlights the importance of thorough investigations, guideline-based treatments and multidisciplinary care in complex AF-HF cases.

KDIGO 2024 clinical practice guideline on evaluation and management of chronic kidney disease: A primer on what pharmacists need to know

Article

Apr 2025
AM J HEALTH-SYST PH

Purpose To review the key updates in the 2024 KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease (CKD) and highlight the essential role of pharmacists in implementing these recommendations. Summary The updated guideline introduces significant changes in CKD management, including the use of validated equations for estimating glomerular filtration rate (GFR) for drug dosing, with incorporation of serum cystatin C into GFR estimates for specific patient populations, and an emphasis on a comprehensive approach to delay disease progression. The guideline recommends sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy for kidney disease with proteinuria, with or without diabetes, renin-angiotensin-aldosterone system inhibitors (RAASi) blood pressure control and proteinuria management, and statins to reduce the risk of atherosclerotic cardiovascular disease. New evidence supports the use of finerenone in patients with type 2 diabetes and CKD, and GLP-1 receptor agonists for their kidney-protective effects. The guidelines also emphasize the importance of nephrotoxin stewardship and prevention of acute kidney injury through patient education on sick day medication management. Conclusion Pharmacists play a crucial role in implementing these updated guidelines through comprehensive medication management, nephrotoxin stewardship, drug dosing adjustments, and patient education. Their involvement in interprofessional care teams is essential for optimizing health outcomes in patients with CKD.

15-Year trends, predictors, and outcomes of heart failure hospitalization complicating first acute myocardial infarction in the modern percutaneous coronary intervention era

Article

Feb 2025

Aims Heart failure (HF) following acute myocardial infarction (AMI) is a global health concern, but data on risk factors associated with HF hospitalization post-AMI are limited. Methods and results We analysed data from the Myocardial Ischaemia National Audit Project, including patients admitted with AMI from 1 January 2006 to 31 March 2019. Data linkage with Hospital Episode Statistics Admitted Patient Care and the Office for National Statistics facilitated a longitudinal analysis. High-risk patients were identified using dapagliflozin in patients without diabetes mellitus with acute myocardial infarction (DAPA-MI) and EMPAgliflozin on Hospitalization for Heart Failure and Mortality in Patients With aCuTe Myocardial Infarction (EMPACT-MI) criteria. We assessed clinical outcomes, adherence to European Society of Cardiology quality indicators, and predictors of HF-related hospitalizations. Out of 1 046 480 AMI patients, 9.1% overall, 17.2% in the DAPA-MI cohort, and 16.6% in the EMPACT-MI cohort experienced HF hospitalization within a year post-AMI. High-risk patients, defined by the presence of five risk factors, had nearly one in four hospitalizations with HF at 1-year follow-up. The predicted adjusted incidence rate for heart failure within 1 year almost doubled from 64.5 cases per 1000 person-years [95% confidence interval (CI): 51.1 to 78.0] in 2005, to 118.2 cases per 1000 person-years in 2019 (95% CI: 115.0 to 121.5). Heart failure hospitalization was associated with a three-fold increase in 1-year mortality (hazard ratio 3.01, 95% CI 2.95–3.13). Conclusion One in 10 AMI patients experienced HF hospitalization within the first-year post-AMI, with rising trends in high-risk subgroups. These findings highlight the need for targeted post-AMI care strategies to improve outcomes and address the increasing burden of HF in the modern percutaneous coronary intervention era.

Inpatient initiation of sodium-glucose cotransporter-2 inhibitors: the prescribing learning curve

Article

Jan 2024

Pharmacological and Device-Based Intervention for Preventing Heart Failure After Acute Myocardial Infarction ― A Clinical Review ―

Article

Full-text available

Sep 2024

In patients with acute myocardial infarction (MI), heart failure (HF) is one of the most common complications that is associated with a significant burden of mortality and healthcare resources. The clinical benefits of key HF drugs, the so-called “4 pillars” or “fantastic 4”, namely β-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitor, and sodium-glucose cotransporter 2 inhibitors, have been established in patients with HF with reduced ejection fraction, whereas the effects of these drugs are not comprehensively appreciated in patients with acute MI. This review summarizes current evidence on pharmacological and device-based interventions for preventing HF after acute MI.

Association of heart failure and its comorbidities with loss of life expectancy Heart failure and cardiomyopathies

Article

Full-text available

Nov 2020

Objective: Estimating survival can aid care planning, but the use of absolute survival projections can be challenging for patients and clinicians to contextualise. We aimed to define how heart failure and its major comorbidities contribute to loss of actuarially predicted life expectancy. Methods: We conducted an observational cohort study of 1794 adults with stable chronic heart failure and reduced left ventricular ejection fraction, recruited from cardiology outpatient departments of four UK hospitals. Data from an 11-year maximum (5-year median) follow-up period (999 deaths) were used to define how heart failure and its major comorbidities impact on survival, relative to an age-sex matched control UK population, using a relative survival framework. Results: After 10 years, mortality in the reference control population was 29%. In people with heart failure, this increased by an additional 37% (95% CI 34% to 40%), equating to an additional 2.2 years of lost life or a 2.4-fold (2.2-2.5) excess loss of life. This excess was greater in men than women (2.4 years (2.2-2.7) vs 1.6 years (1.2-2.0); p<0.001). In patients without major comorbidity, men still experienced excess loss of life, while women experienced less and were non-significantly different from the reference population (1 year (0.6-1.5) vs 0.4 years (-0.3 to 1); p<0.001). Accrual of comorbidity was associated with substantial increases in excess lost life, particularly for diabetes, chronic kidney and lung disease. Conclusions: Comorbidity accounts for the majority of lost life expectancy in people with heart failure. Women, but not men, without comorbidity experience survival close to reference controls. Keywords: heart failure; heart failure with reduced ejection fraction.

Effect of disease-modifying agents and their association with mortality in multi-morbid patients with heart failure with reduced ejection fraction

Article

Full-text available

Sep 2020

Aims An increasing proportion of patients with heart failure with reduced ejection fraction (HFrEF) have co‐morbidities. The effect of these co‐morbidities on modes of death and the effect of disease‐modifying agents in multi‐morbid patients is unknown. Methods and results We performed a prospective cohort study of ambulatory patients with HFrEF to assess predictors of outcomes. We identified four key co‐morbidities—ischaemic aetiology of heart failure, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and chronic kidney disease (CKD)—that were highly prevalent and associated with an increased risk of all‐cause mortality. We used these data to explore modes of death and the utilization of disease‐modifying agents in patients with and without these co‐morbidities. The cohort included 1789 consecutively recruited patients who had an average age of 69.6 ± 12.5 years, and 1307 (73%) were male. Ischaemic aetiology of heart failure was the most common co‐morbidity, occurring in 1061 (59%) patients; 503 (28%) patients had diabetes mellitus, 283 (16%) had COPD, and 140 (8%) had CKD stage IV/V. During mean follow‐up of 3.8 ± 1.6 years, 737 (41.5%) patients died, classified as progressive heart failure (n = 227, 32%), sudden (n = 112, 16%), and non‐cardiovascular deaths (n = 314, 44%). Multi‐morbid patients were older (P < 0.001), more likely to be male (P < 0.001), and had higher New York Heart Association class (P < 0.001), despite having higher left ventricular (LV) ejection fraction (P = 0.001) and lower LV end‐diastolic diameter (P = 0.001). Multi‐morbid patients were prescribed lower doses of disease‐modifying agents, especially patients with COPD who received lower doses of beta‐adrenoceptor antagonists (2.7 ± 3.0 vs. 4.1 ± 3.4 mg, P < 0.001) and were less likely to be implanted with internal cardioverter defibrillators (7% vs. 13%, P < 0.001). In multivariate analysis, COPD and diabetes mellitus conferred a >2.5‐fold and 1.5‐fold increased risk of sudden death, whilst higher doses of beta‐adrenoceptor antagonists were protective (hazard ratio per milligram 0.92, 95% confidence interval 0.86–0.98, P = 0.009). Each milligram of bisoprolol‐equivalent beta‐adrenoceptor antagonist was associated with 9% (P = 0.001) and 11% (P = 0.023) reduction of sudden deaths in patients with <2 and ≥2 co‐morbidities, respectively. Conclusions Higher doses of beta‐adrenoceptor antagonist are associated with greater protection from sudden death, most evident in multi‐morbid patients. Patients with COPD who appear to be at the highest risk of sudden death are prescribed the lowest doses and less likely to be implanted with implantable cardioverter defibrillators, which might represent a missed opportunity to optimize safe and proven therapies for these patients.

Prioritizing symptom management in the treatment of chronic heart failure

Article

Full-text available

Aug 2020

Chronic heart failure (CHF) is a chronic, progressive disease that has detrimental consequences on a patient's quality of life (QoL). In part due to requirements for market access and licensing, the assessment of current and future treatments focuses on reducing mortality and hospitalizations. Few drugs are available principally for their symptomatic effect despite the fact that most patients' symptoms persist or worsen over time and an acceptance that the survival gains of modern therapies are mitigated by poorly controlled symptoms. Additional contributors to the failure to focus on symptoms could be the result of under‐reporting of symptoms by patients and carers and a reliance on insensitive symptomatic categories in which patients frequently remain despite additional therapies. Hence, formal symptom assessment tools, such as questionnaires, can be useful prompts to encourage more fidelity and reproducibility in the assessment of symptoms. This scoping review explores for the first time the assessment options and management of common symptoms in CHF with a focus on patient‐reported outcome tools. The integration of patient‐reported outcomes for symptom assessment into the routine of a CHF clinic could improve the monitoring of disease progression and QoL, especially following changes in treatment or intervention with a targeted symptom approach expected to improve QoL and patient outcomes.

Clinical and echocardiographic benefit of Sacubitril/Valsartan in a real-world population with HF with reduced ejection fraction

Article

Full-text available

Apr 2020

The aim of this study was to evaluate the effects of Sacubitril/Valsartan (S/V) on clinical, laboratory and echocardiographic parameters and outcomes in a real-world population with heart failure with reduced ejection fraction (HFrEF). This was a prospective observational study enrolling patients with HFrEF undergoing treatment with S/V. The primary outcome was the composite of cardiac death and HF rehospitalization at 12 months follow-up; secondary outcomes were all-cause death, cardiac death and the occurrence of rehospitalization for worsening HF. The clinical outcome was compared with a retrospective cohort of 90 HFrEF patients treated with standard medical therapy. The study included 90 patients (66.1 ± 11.7 years) treated with S/V. The adjusted regression analysis showed a significantly lower risk for the primary outcome (HR:0.31; 95%CI, 0.11–0.83; p = 0.019) and for HF rehospitalization (HR:0.27; 95%CI, 0.08–0.94; p = 0.039) in S/V patients as compared to the control group. A significant improvement in NYHA class, left ventricular ejection fraction, left ventricular end systolic volume and systolic pulmonary arterial pressure was observed up to 6 months. S/V did not affect negatively renal function and was associated with a significantly lower dose of furosemide dose prescribed at 6- and 12-month follow-up. In this study, S/V reduced the risk of HF rehospitalization and cardiac death at 1 year in patients with HFrEF. S/V improved NYHA class, echocardiographic parameters and need of furosemide, and preserved renal function.

How Should We Sequence the Treatments for Heart Failure and a Reduced Ejection Fraction? A Redefinition of Evidence-Based Medicine

Article

Dec 2020

Revisiting heart failure assessment based on objective measures in NYHA functional classes I and II

Article

Dec 2020

Objective New York Heart Association (NYHA) functional class plays a central role in heart failure (HF) assessment but might be unreliable in mild presentations. We compared objective measures of HF functional evaluation between patients classified as NYHA I and II in the Re de B rasileira de Estudos em I nsuficiência C ardíaca (ReBIC)-1 Trial. Methods The ReBIC-1 Trial included outpatients with stable HF with reduced ejection fraction. All patients had simultaneous protocol-defined assessment of NYHA class, 6 min walk test (6MWT), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and patient’s self-perception of dyspnoea using a Visual Analogue Scale (VAS, range 0–100). Results Of 188 included patients with HF, 122 (65%) were classified as NYHA I and 66 (35%) as NYHA II at baseline. Although NYHA class I patients had lower dyspnoea VAS Scores (median 16 (IQR, 4–30) for class I vs 27.5 (11–49) for class II, p=0.001), overlap between classes was substantial (density overlap=60%). A similar profile was observed for NT-proBNP levels (620 pg/mL (248–1333) vs 778 (421–1737), p=0.015; overlap=78%) and for 6MWT distance (400 m (330–466) vs 351 m (286–408), p=0.028; overlap=64%). Among NYHA class I patients, 19%–34% had one marker of HF severity (VAS Score >30 points, 6MWT <300 m or NT-proBNP levels >1000 pg/mL) and 6%–10% had two of them. Temporal change in functional class was not accompanied by variation on dyspnoea VAS (p=0.14). Conclusions Most patients classified as NYHA classes I and II had similar self-perception of their limitation, objective physical capabilities and levels of natriuretic peptides. These results suggest the NYHA classification poorly discriminates patients with mild HF.

Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure

Article

Nov 2020

Background Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown. Methods We performed a multicenter, double-blind trial in which patients with type 2 diabetes mellitus who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin or placebo. The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). The trial ended early because of loss of funding from the sponsor. Results A total of 1222 patients underwent randomization (608 to the sotagliflozin group and 614 to the placebo group) and were followed for a median of 9.0 months; the first dose of sotagliflozin or placebo was administered before discharge in 48.8% and a median of 2 days after discharge in 51.2%. Among these patients, 600 primary end-point events occurred (245 in the sotagliflozin group and 355 in the placebo group). The rate (the number of events per 100 patient-years) of primary end-point events was lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3; hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). The rate of death from cardiovascular causes was 10.6 in the sotagliflozin group and 12.5 in the placebo group (hazard ratio, 0.84; 95% CI, 0.58 to 1.22); the rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (hazard ratio, 0.82; 95% CI, 0.59 to 1.14). Diarrhea was more common with sotagliflozin than with placebo (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively). The benefits of sotagliflozin were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose. Conclusions In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo. (Funded by Sanofi and Lexicon Pharmaceuticals; SOLOIST-WHF ClinicalTrials.gov number, NCT03521934.)

Association of heart failure and its comorbidities with loss of life expectancy

Article

Oct 2020

Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure

Article

Aug 2020

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. Methods: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. Results: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. Conclusions: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).

Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials

Article

May 2020

Background Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor–neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF. Methods In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker). Findings The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30–0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37–0·67]), hospital admission for heart failure alone (0·32 [0·24–0·43]), and all-cause mortality (0·53 [0·40–0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy. Interpretation Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard. Funding None.

Four pillars of heart failure: contemporary pharmacological therapy for heart failure with reduced ejection fraction

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