Systematic Review: Pharmacological Treatment of HFrEF

Abstract and Introduction

Abstract

Objectives: This study sought to estimate and compare the aggregate treatment benefit of pharmacological therapy for heart failure (HF) with reduced ejection fraction.

Background: The estimated treatment effects of various combinations of contemporary HF medical therapies are not well characterized.

Methods: We performed a systematic network meta-analysis, using MEDLINE/EMBASE and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between January 1987 and January 2020. We included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers (BB), mineralocorticoid receptor antagonists (MRAs), digoxin, hydralazine-isosorbide dinitrate, ivabradine, angiotensin receptor–neprilysin inhibitors (ARNi), sodium glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv-mecarbil. The primary outcome was all-cause death. We estimated the life-years gained in 2 HF populations (BIOSTAT-CHF [BIOlogy Study to TAilored Treatment in Chronic Heart Failure] and ASIAN-HF [Asian Sudden Cardiac Death in Heart Failure Registry]).

Results: We identified 75 relevant trials representing 95,444 participants. A combination of ARNi, BB, MRA, and SGLT2i was most effective in reducing all-cause death (HR: 0.39; 95% CI: 0.31–0.49); followed by ARNi, BB, MRA, and vericiguat (HR: 0.41; 95% CI: 0.32–0.53); and ARNi, BB, and MRA (HR: 0.44; 95% CI: 0.36–0.54). Results were similar for the composite outcome of cardiovascular death or first hospitalization for HF (HR: 0.36; 95% CI: 0.29–0.46 for ARNi, BB, MRA, and SGLT2i; HR: 0.44; 95% CI: 0.35–0.56 for ARNi, BB, MRA, and omecamtiv-mecarbil; and HR: 0.43; 95% CI: 0.34–0.55 for ARNi, BB, MRA, and vericiguat). The estimated additional number of life-years gained for a 70-year-old patient on ARNi, BB, MRA, and SGLT2i was 5.0 years (2.5–7.5 years) compared with no treatment in secondary analyses.

Conclusions: In patients with HF with reduced ejection fraction, the estimated aggregate benefit is greatest for a combination of ARNi, BB, MRA, and SGLT2i.

Introduction

Heart failure (HF) remains a major cause of mortality and hospitalization globally, despite advances in pharmacological treatment.^[1] Successes of early clinical trials established angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), beta-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) as the foundation for the pharmacological treatment of HF with reduced ejection fraction (HFrEF).^[2,3] In the last decade, treatment options for HFrEF increased with the addition of sacubitril/valsartan (ARNi) and ivabradine.^[4,5] Results of trials published in the past year showed that treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin^[6] and dapagliflozin,^[7–9] soluble guanylase cyclase stimulator vericiguat,^[10] and cardiac-specific myosin activator omecamtiv-mecarbil^[11] can further improve outcomes in HFrEF.

Continued success in treatment of HFrEF has led to important challenges for clinicians who are left with multiple effective treatment options for their patients.^[12,13] Earlier trials were performed largely sequentially—showing incremental benefit of novel pharmacological therapy on top of existing treatment—but recent trials were performed in parallel.^[6,8,10,11] Results of more recent trials cannot guide sequencing of therapy or determine the most beneficial combination of pharmacotherapy. Network-meta-analyses allow for comparisons between different combinations of therapies to compare differences in the aggregate treatment effects. Information on the optimal cumulative benefit of treatment can help physicians and patients in their shared decision for therapy. An underlying assumption is that therapies have an additive effect. This is plausible for ARNi, SGLT2i, vericiguat, and omecamtiv-mecarbil, because they potentially target different disease pathways. Therefore, we conducted a systematic review and network meta-analysis to estimate and compare the aggregate treatment benefit of pharmacological therapy for HFrEF.

Authors and Disclosures

Jasper Tromp, MD, PHD^a,b,c,*, Wouter Ouwerkerk, PHD^b,d,*, Dirk J. van Veldhuisen, MD, PHD^a, Hans L. Hillege, MD, PHD^a, A. Mark Richards, MBCHB, PHD^e,f,g, Peter van der Meer, MD, PHD^a, Inder S. Anand, MD^h, Carolyn S.P. Lam, MBBS, PHD^a,b,c and Adriaan A. Voors, MD, PHD^a

^aUniversity Medical Centre Groningen, Department of Cardiology, University of Groningen, the Netherlands; ^bSaw Swee Hock School of Public Health and National University of Singapore and National University Health System, Singapore; ^cDuke-NUS Medical School Singapore, Singapore; ^dDepartment of Dermatology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, the Netherlands; ^eCardiovascular Research Institute, Yong Loo-Lin School of Medicine, National University of Singapore, Singapore; ^fNational University Heart Centre, Singapore; ^gChristchurch Heart Institute, University of Otago, Christchurch, New Zealand; and the ^hVeterans Affairs Medical Center, Minneapolis, Minnesota, USA.

Address For Correspondence
Dr Carolyn S.P. Lam, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609. E-mail: Carolyn.lam@duke-nus.edu.sg. OR Dr Adriaan A. Voors, University Medical Centre Groningen, Department of Cardiology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands. E-mail: A.A.Voors@umcg.nl. Twitter: @drjasper01, @AdriaanVoors, @lamcardio.

*Drs Tromp and Ouwerkerk contributed equally to this work and are co-first authors.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

Funding Support and Author Disclosures
Dr Tromp is supported by the National University of Singapore Start-up Grant; and has received consultancy fees from Olink proteomics and Roche Diagnostics; and served as a scientific advisor and shareholder of Us2.ai. Dr Richards has received consultancy/advisory board/speaker fees, research grants, and/or support in kind from Roche Diagnostics, Abbott Laboratories, Thermo Fisher, AstraZeneca, Novartis, Medtronic, and Boston Scientific. Dr van der Meer has received consultancy and/or research grants from Vifor Pharma, AstraZeneca, Servier, Novartis, Pfizer, and Ionis. Dr Anand has received consultancy fees from Amgen, ARCA, AstraZeneca, Boehringer Ingelheim, Boston Scientific, LivaNova, Novartis, Rockwell Medical, and Zensun. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the advisory board/steering committee/executive committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research and Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd, and Corpus; and serves as cofounder and non-executive director of Us2.ai. Dr Voors has received consultancy fees and/or research grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novartis, Novo Nordisk, and Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

A Systematic Review and Network Meta-Analysis of Pharmacological Treatment of Heart Failure With Reduced Ejection Fraction

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A Systematic Review and Network Meta-Analysis of Pharmacological Treatment of Heart Failure With Reduced Ejection Fraction

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