Thirty Years of Evidence on the Efficacy of Drug Treatments for Chronic Heart Failure With Reduced Ejection Fraction: A Network Meta-Analysis

Abstract

Background: Treatments that reduce mortality and morbidity in patients with heart failure with reduced ejection fraction, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), β-blockers (BB), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor-neprilysin inhibitors (ARNI), have not been studied in a head-to-head fashion. This network meta-analysis aimed to compare the efficacy of these drugs and their combinations regarding all-cause mortality in patients with heart failure with reduced ejection fraction.

Methods and results: A systematic literature review identified 57 randomized controlled trials published between 1987 and 2015, which were compared in terms of study and patient characteristics, baseline risk, outcome definitions, and the observed treatment effects. Despite differences identified in terms of study duration, New York Heart Association class, ejection fraction, and use of background digoxin, a network meta-analysis was considered feasible and all trials were analyzed simultaneously. The random-effects network meta-analysis suggested that the combination of ACEI+BB+MRA was associated with a 56% reduction in mortality versus placebo (hazard ratio 0.44, 95% credible interval 0.26-0.66); ARNI+BB+MRA was associated with the greatest reduction in all-cause mortality versus placebo (hazard ratio 0.37, 95% credible interval 0.19-0.65). A sensitivity analysis that did not account for background therapy suggested that ARNI monotherapy is more efficacious than ACEI or ARB monotherapy.

Conclusions: The network meta-analysis showed that treatment with ACEI, ARB, BB, MRA, and ARNI and their combinations were better than the treatment with placebo in reducing all-cause mortality, with the exception of ARB monotherapy and ARB plus ACEI. The combination of ARNI+BB+MRA resulted in the greatest mortality reduction.

Keywords: drug combinations; drug therapy; heart failure; mortality; network meta-analysis.

Figure 1.

Flow diagram. RCT indicates randomized controlled trials.

Figure 2.

Network diagram of treatment classes and combinations reporting all-cause mortality. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin-II receptor blocker; AREA-IN CHF, Anti-Remodelling Effect of Canrenone in Patients With Mild Chronic Heart Failure; ARNI, angiotensin receptor-neprilysin inhibitor; BB, beta blocker; BEST, Beta-Blocker Evaluation of Survival Trial; CARMEN, The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure Evaluation Trial; CASSIS, Czech and Slovak Spirapril Intervention Study; CHARM-added, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity–Added; CHARM-alternative, Candesartan in Heart Failure–Assessment of Mortality and Morbidity Alternative; CIBIS, Cardiac Insufficiency Bisoprolol Study; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival; ELITE, Evaluation of Losartan in the Elderly Study; EMPHASIS-HF, Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; ENECA, Efficacy of Nebivolol in the Treatment of Elderly Patients With Chronic Heart Failure as Add-On Therapy to ACE Inhibitors or Angiotensin II Receptor Blockers, Diuretics, and/or Digitalis; FEST, Fosinopril Efficacy/Safety Trial; HEAVEN, Heart Failure Valsartan Exercise Capacity Evaluation; MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure; MHFT, Munich Mild Heart Failure Trial; MIC, Metoprolol in Patients With Mild to Moderate Heart Failure: Effects on Ventricular Function and Cardiopulmonary Exercise Testing; MOCHA, Multicenter Oral Carvedilol Heart Failure Assessment; MRA, mineralocorticoid receptor antagonist; PARADIGM-HF, Prospective Comparison of ARNI (Angiotensin Receptor–Neprilysin Inhibitor) With ACEI (Angiotensin–Converting–Enzyme Inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure; PLBO, placebo; PRECISE, Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise; RALES, Randomized Aldactone Evaluation Study; REPLACE, Replacement of Angiotensin Converting Enzyme Inhibition; RESOLVD, Randomized Evaluation of Strategies for Left Ventricular Dysfunction; SOLVD-prevent, Studies of Left Ventricular Dysfunction–Prevention Trial; SOLVD-treat, Studies of Left Ventricular Dysfunction–Treatment Trial; SPICE, Study of Patients Intolerant of Converting Enzyme Inhibitors; STRETCH, Symptom, Tolerability, Response to Exercise Trial of Candesartan Cilexetil in Heart Failure; SYMPOXYDEX, Sympathetic and Oxydative Stress Kredex Study; and Val-HeFT, Valsartan Heart Failure Trial.^,–

Figure 3.

Sensitivity analysis evidence network of ARNI, ACEI, ARB and placebo for all-cause mortality ignoring background treatments. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin-II receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; CASSIS, Czech and Slovak Spirapril Intervention Study; CHARM-alternative, Candesartan in Heart Failure–Assessment of Mortality and Morbidity Alternative; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; ELITE, Evaluation of Losartan in the Elderly Study; FEST, Fosinopril Efficacy/Safety Trial; HEAVEN, Heart Failure Valsartan Exercise Capacity Evaluation; MHFT, Munich Mild Heart Failure Trial; PARADIGM-HF, Prospective Comparison of ARNI (Angiotensin Receptor–Neprilysin Inhibitor) With ACEI (Angiotensin–Converting–Enzyme Inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure; PLBO, placebo; REPLACE, Replacement of Angiotensin Converting Enzyme Inhibition; RESOLVD, Randomized Evaluation of Strategies for Left Ventricular Dysfunction; SOLVD-prevent, Studies of Left Ventricular Dysfunction–Prevention Trial; SOLVD-treat, Studies of Left Ventricular Dysfunction–Treatment Trial; SPICE, Study of Patients Intolerant of Converting Enzyme Inhibitors; and STRETCH, Symptom, Tolerability, Response to Exercise Trial of Candesartan Cilexetil in Heart Failure.^,–

Figure 4.

Distribution of potential treatment effect modifiers: A, Duration of follow-up^,–; B, NYHA class at baseline^,–; C, LVEF at baseline.^,– AREA-IN CHF indicates Anti-Remodelling Effect of Canrenone in Patients With Mild Chronic Heart Failure; BEST, Beta-Blocker Evaluation of Survival Trial; CARMEN, The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure Evaluation Trial; CASSIS, Czech and Slovak Spirapril Intervention Study; CHARM-added, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity–Added; CHARM-alternative, Candesartan in Heart Failure–Assessment of Mortality and Morbidity Alternative; CIBIS, Cardiac Insufficiency Bisoprolol Study; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival; ELITE, Evaluation of Losartan in the Elderly Study; EMPHASIS-HF, Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; ENECA, Efficacy of Nebivolol in the Treatment of Elderly Patients With Chronic Heart Failure as Add-On Therapy to ACE Inhibitors or Angiotensin II Receptor Blockers, Diuretics, and/or Digitalis; FEST, Fosinopril Efficacy/Safety Trial; HEAVEN, Heart Failure Valsartan Exercise Capacity Evaluation; LVEF, left ventricular ejection fraction; MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure; MHFT, Munich Mild Heart Failure Trial; MIC, Metoprolol in Patients With Mild to Moderate Heart Failure: Effects on Ventricular Function and Cardiopulmonary Exercise Testing; MOCHA, Multicenter Oral Carvedilol Heart Failure Assessment; NR, not reported; NYHA, New York Heart Association; PARADIGM-HF, Prospective Comparison of ARNI (Angiotensin Receptor–Neprilysin Inhibitor) With ACEI (Angiotensin–Converting–Enzyme Inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure; PRECISE, Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise; RALES, Randomized Aldactone Evaluation Study; REPLACE, Replacement of Angiotensin Converting Enzyme Inhibition; RESOLVD, Randomized Evaluation of Strategies for Left Ventricular Dysfunction; SOLVD-prevent, Studies of Left Ventricular Dysfunction–Prevention Trial; SOLVD-treat, Studies of Left Ventricular Dysfunction–Treatment Trial; SPICE, Study of Patients Intolerant of Converting Enzyme Inhibitors; STRETCH, Symptom, Tolerability, Response to Exercise Trial of Candesartan Cilexetil in Heart Failure; SYMPOXYDEX, Sympathetic and Oxydative Stress Kredex Study; and Val-HeFT, Valsartan Heart Failure Trial.

Figure 5.

Results of random effect network meta-analysis for all-cause mortality: hazard ratios for intervention versus placebo for all-cause mortality and 95% credible intervals. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin-II receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BB, beta blocker; and MRA, mineralocorticoid receptor antagonist.