Neprilysin

This large meta-analysis confirms the substantial life extension conferred by aggressive, four drug treatment of CHF with reduced EF. James W. Mold, MD, MPH

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Background: In 2022, a network meta-analysis showed that a combination of β-blockers, angiotensin receptor-neprilysin inhibitors (ARNi), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2i) was most effective in reducing all-cause mortality in heart failure with reduced ejection fraction (HFrEF). This study updates the treatment benefit by including additional large randomized controlled trials (RCTs) since 2022, including the VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial.

Objectives: The goal of this study was to evaluate and compare regimens of pharmacotherapy in patients with HFrEF.

Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases were searched for RCTs in patients with HFrEF through April 2025. Using frequentist network meta-analysis, HRs for all-cause mortality (primary outcome), cardiovascular death, and the composite of cardiovascular death or heart failure hospitalization (secondary outcomes) were estimated. Absolute benefits were quantified as life-years gained by using BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) and ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) cohort data.

Results: The analysis included 103,754 patients across 89 randomized controlled trials. Relative to placebo, quintuple therapy with ARNi, β-blockers, MRAs, SGLT2i, and vericiguat most effectively reduced all-cause mortality (HR: 0.35; 95% CI: 0.27-0.45), followed by quadruple therapy with ARNi, β-blockers, MRAs, and SGLT2i (HR: 0.39; 95% CI: 0.32-0.49). For a representative 70-year-old patient, quadruple therapy (ARNi/β-blockers/MRAs/SGLT2i) provided 5.3 additional life-years (95% CI: 2.8-7.7) vs no treatment, while quintuple therapy (ARNi/β-blockers/MRA/SGLT2i/vericiguat) provided 6.0 additional life-years (95% CI: 3.7-8.4).

Conclusions: This analysis reinforces the substantial mortality and morbidity benefit associated with the currently recommended quadruple therapy regimen (ARNi, β-blockers, MRAs, and SGLT2i) in patients with HFrEF. The addition of vericiguat may provide an incremental survival gain of approximately 0.7 year beyond that achieved with quadruple therapy. However, these results should be regarded as exploratory, as they are derived from a secondary endpoint of a single trial.

Keywords: HFrEF; drug therapy; pharmacotherapy.

Author/s:

Bart J. van Essen, Daan C.H. Ceelen, Wouter Ouwerkerk, Tiew-Hwa K. Teng, Ganash N. Tharshana, Fook Ming Hew, Javed Butler, Faiez Zannad, Carolyn S. Lam, Justin Ezekowitz, Adriaan A. Voors, Jasper Tromp

Milestones in Heart Failure: How Far We Have Come and How Far We Have Left to Go

Saige Blanchard — Mon, 03 Jan 2022 06:00:00 +0000

Date Added:

January 3, 2022

Journal/Publication:

Cureus Journal of Medical Science

Publication Date:

December 12, 2021

URL:

Milestones in Heart Failure: How Far We Have Come and How Far We Have Left to Go

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.7759/cureus.20359

Keywords

MeSH

Angiotensin Receptor Antagonists

heart failure

Disease Progression

A nice summary of what we currently know about the pharmacologic treatment of congestive heart failure. James W. Mold, MD, MPH

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Heart failure is a clinically complex syndrome that results due to the failure of the ventricles to function as pump and oxygenate end organs. The repercussions of inadequate perfusion are seen in the form of sympathetic overactivation and third spacing, leading to clinical signs of increased blood pressure, dyspnea, fatigue, palpitations, etc. This article provided a brief overview of the clinical syndrome of heart failure; its epidemiology, risk factors, symptoms, and staging; and the mechanisms involved in disease progression. This article also described several landmark trials in heart failure that tested the efficacy of first-line drugs such as beta-blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and the latest drugs in the field of heart failure: angiotensin receptor neprilysin inhibitors. Most studies described in this article were guideline-setting trials that revolutionized the practice of medicine and cardiology.

Author/s:

H., Kela, I., Kakarlala, C., Hassan, M., Belavadi, R., Gudigopuram, S. V. R., Raguthu, C., Modi, S., Sange, I.

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

John Bayhi — Tue, 26 May 2020 20:29:33 +0000

Date Added:

May 26, 2020

Journal/Publication:

Lancet

Publisher:

Elsevier Ltd

Publication Date:

May 21, 2020

Volume:

Online ahead of print

URL:

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

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1016/S0140-6736(20)30748-0

Keywords

CHF patients

heart failure

pharmacologic management

PMID (1):

32446323

MeSH

Humans

Angiotensin Receptor Antagonists

Mineralocorticoid Receptor Antagonists

Angiotensin-Converting Enzyme Inhibitors

Sodium-Glucose Transporter 2 Inhibitors

Peptidyl-Dipeptidase A

Neprilysin

heart failure

SLC5A2 protein, human

sodium-glucose transporter 2

Stroke Volume

Control Groups

Receptors, Drug

Progression-Free Survival

Receptors, Angiotensin

NR3C2 protein, human

For those of you who still initiate and manage CHF with reduced LV ejection fraction, this meta-analysis appears to support using combinations of the following five agents: 1) an ACEI or ARB, 2) a beta-blocker, 3) a mineralocorticoid receptor antagonist [MRA], 4) an angiotensin receptor–neprilysin inhibitor [ARNI], and 5) a sodium/glucose cotransporter 2 [SGLT2] inhibitor. They estimate that combined therapy could increase life expectancy for an 80-year-old 1.4 years and for a 55-year-old 6.3 years. If we are going to continue to manage these patients, it looks like we are going to have to develop specific CHF visits and protocols like those used in CHF clinics run by cardiology teams. James W. Mold, MD, MPH

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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.

Author/s:

Vaduganathan, M., Claggett, BL, Jhund, PS, Cunningham, JW, Ferreira, JP, Zannad, F, Packer, M, Fonarow, GC, McMurray, JJV, Solomon, S.D.

Meta-Analysis Evaluating the Effects of Renin-Angiotensin-Aldosterone System Blockade on Outcomes of Heart Failure With Preserved Ejection Fraction

John Bayhi — Sat, 14 Mar 2020 20:03:18 +0000

Date Added:

March 14, 2020

Journal/Publication:

The American Journal of Cardiology

Publisher:

Elsevier Inc.

Publication Date:

January 30, 2020

URL:

Meta-Analysis Evaluating the Effects of Renin-Angiotensin-Aldosterone System Blockade on Outcomes of Heart Failure With Preserved Ejection Fraction

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1016/j.amjcard.2020.01.009

Keywords

RAAS Anatgonists

heart failure

PMID (1):

32081366

ACEIs, ARBs, and spironolactone do not appear to reduce mortality or CHF hospitalizations in patients with CHF with preserved LV function. However, the combination of sacubitril (a neprilysin inhibitor) and valsartan may reduce CHF hospitalizations in those patients. James W. Mold, MD, MPH

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Clinical trials of renin-angiotensin-aldosterone system (RAAS) antagonists in heart failure with preserved ejection fraction (HFpEF) have suggested neutral results and treatment is focused on associated symptoms and comorbidities. MEDLINE and EMBASE were searched through October 2019 for randomized controlled studies investigating the effects of different RAAS antagonists in patients with HFpEF. The main outcomes were all-cause mortality, trial defined cardiovascular mortality, and heart failure (HF) hospitalizations. To compare different RAAS antagonists, a random-effects restricted-maximum-likelihood network meta-analysis based on a frequentist framework for indirect and mixed comparisons was used. We used p scores to rank best treatments per outcome. Our search identified 5 eligible clinical trials (PEP-CHF, perindopril; CHARM-preserved, candesartan; I-PRESERVE, irbesartan; TOPCAT, spironolactone; PARAGON-HF, sacubitril-valsartan and valsartan) enrolling a total 10,523 on RAAS antagonists and 6,259 controls. We did not identify any statistical difference in all-cause and cardiovascular mortality among RAAS antagonists and placebo. The combination of sacubitril-valsartan was associated with significantly decreased HF hospitalization risk compared with controls (odds ratio 0.73, 95% confidence interval 0.61 to 0.87) and angiotensin II receptor blockers (odds ratio 0.80, 95% confidence interval 0.71 to 0.91), without heterogeneity among studies (I2 = 0). Angiotensin receptor neprilysin inhibitor (ARNI) ranked better than other RAAS antagonists for HF hospitalizations (p value 0.9). In conclusion, RAAS antagonists do not affect mortality but the combination of sacubitril-valsartan is associated with lower HF hospitalizations in HFpEF patients.

Author/s:

Kuno, T, Ueyama, H, Fujisaki, T, Briasouli, A, Takagi, H, Briasoulis, A

Primary Prevention of Sudden Cardiac Death

Brian Desmarais — Wed, 19 Jun 2019 00:11:44 +0000

Date Added:

June 18, 2019

Journal/Publication:

Journal of the American Medical Association

Publisher:

Journal of the American Medical Association

Publication Date:

June 13, 2019

URL:

Primary Prevention of Sudden Cardiac Death

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2019.7662

Keywords

MeSH

Angiotensin-Converting Enzyme Inhibitors

Mineralocorticoid Receptor Antagonists

myocardial infarction

Receptors, Angiotensin

Death, Sudden, Cardiac

Angiotensin Receptor Antagonists

This is the most recent AHA/ACC guideline regarding how to reduce the risk of sudden cardiac death in those at risk.

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In patients with heart failure with reduced ejection fraction (<40%), guideline-directed medical therapy (GDMT) is recommended to reduce sudden cardiac death and all-cause mortality; GDMT includes β-blockers; mineralocorticoid receptor antagonists; and angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor–neprilysin inhibitors (class I, level A recommendation).
In patients with left ventricular ejection fraction (LVEF) of 35% or less due to ischemic heart disease at least 40 days after myocardial infarction, at least 90 days after revascularization, and with New York Heart Association (NYHA) class II or III heart failure despite GDMT, an ICD is recommended if expected survival is greater than 1 year (class I, level A recommendation).
In patients with LVEF of 30% or less due to ischemic heart disease at least 40 days after myocardial infarction, at least 90 days after revascularization, and with NYHA class I heart failure symptoms despite GDMT, an ICD is recommended if expected survival is greater than 1 year (class I, level A recommendation).
In patients with nonischemic cardiomyopathy, NYHA class II to III symptoms, and LVEF of 35% or less despite GDMT, an ICD is recommended if expected survival is greater than 1 year (class I, level A recommendation).

Author/s:

Beaser, A.D., Cifu, A.S.