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Cited by 238Heart Failure Treatment and ManagementHeart rate and cardiovascular healthCardiovascular Function and Risk Factors

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

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Burnett, Heather, Earley, Amy, Voors, Adriaan A., Senni, Michele, McMurray, John J.V., Deschaseaux, Celine, Cope, Shannon·2017·Circulation Heart Failure
DOI 10.1161/circheartfailure.116.003529PMC PMC5265698
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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.

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Crossref · 10.1161/circheartfailure.116.003529

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Figures

Figure 1. Flow diagram. RCT indicates randomized controlled trials.
Figure 1. Flow diagram. RCT indicates randomized controlled trials.CC BY-NC-ND · PubMed Central
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.7,21–77
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.7,21–77CC BY-NC-ND · PubMed Central
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.7,21–45
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.7,21–45CC BY-NC-ND · PubMed Central
Figure 4. Distribution of potential treatment effect modifiers: A, Duration of follow-up7,21–77; B, NYHA class at baseline7,21–77; C, LVEF at baseline.7,21–77 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 4. Distribution of potential treatment effect modifiers: A, Duration of follow-up7,21–77; B, NYHA class at baseline7,21–77; C, LVEF at baseline.7,21–77 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.CC BY-NC-ND · PubMed Central
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.
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.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Burnett, H., Earley, A., Voors, A. A., Senni, M., McMurray, J. J. V., Deschaseaux, C., & Cope, S.
Affiliations
Novartis (Switzerland) (CH)
Corresponding author
Burnett, Heather
ORCID
Venue
Circulation Heart Failure
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2017-01
Volume
10
Issue
1
ISSN
  • 1941-3289 (ISSN-L)
  • 1941-3297
DOI
10.1161/circheartfailure.116.003529
PMC
PMC5265698
OpenAlex
W2577614303
Cited by
238
References
100
Citations by year
2026: 4 · 2025: 19 · 2024: 20 · 2023: 18 · 2022: 45 · 2021: 42 · 2020: 33 · 2019: 33 · 2018: 15 · 2017: 9
FWCI
19.05
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Circulation Heart Failure (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-nd)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart rate and cardiovascular health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
heart failure with reduced ejection fraction, all-cause mortality, ACE inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, combination therapy, treatment efficacy comparison
MeSH terms
Network Meta-Analysis, Chronic Disease, Heart Failure, Humans, Stroke Volume, Randomized Controlled Trials as Topic, Treatment Outcome, Ventricular Dysfunction, Left

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