Skip to main content
Log in

Comparative efficacy and safety of mineralocorticoid receptor antagonists in heart failure: a network meta-analysis of randomized controlled trials

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

The efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure (HF) are controversial. To explore the role of MRAs in HF patients with an ejection fraction of no more than 45%, we conducted a network meta-analysis of randomized controlled trials (RCTs). We systematically searched PubMed, Embase, the Cochrane Library, and Clinicaltrials. RCTs involving the efficacy and/or safety of the use of MRAs in patients with HF were included. Outputs are presented as the surface under the cumulative ranking area (SUCRA) probabilities. Thirteen RCTs involving a total of 13,597 participants were included. Finerenone 10 mg was associated with the lowest probability of achieving at cardiovascular mortality (SUCRA, 5.0%), followed by finerenone 7.5 mg (SUCRA, 31.6%). In reducing N-terminal pro-B-type natriuretic peptide, finerenone 15 mg and finerenone 7.5 mg ranked the best and second best (SUCRA 68.1% and 63.8%, respectively), followed by finerenone 10 mg (SUCRA 59.2%). Spironolactone and canrenone have a higher risk of hyperkalemia and renal deterioration. Regarding the prevention of worsening renal function, finerenone 7.5 mg (SUCRA 14.3%) was the best treatment, followed by finerenone 2.5 mg (SUCRA 16.3%) and finerenone 10 mg (SUCRA 25.6%). Compared with spironolactone and eplerenone, finerenone 10 mg was associated with low risk in the occurrence of cardiovascular mortality, hospitalization, and adverse events (P < 0.01). This network meta-analysis is the first to find that finerenone 7.5–10 mg has the highest probability of being the optimal alternative among MRAs in the treatment of HF patients with an ejection fraction of no more than 45%.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O’Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee (2018) Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 137:e67–e492

    Article  Google Scholar 

  2. Mosterd A, Hoes AW (2007) Clinical epidemiology of heart failure. Heart 93:1137–1146

    Article  Google Scholar 

  3. Funder JW (2002) New biology of aldosterone, and experimental studies on the selective aldosterone blocker eplerenone. Am Heart J 144:S8–S11

    Article  CAS  Google Scholar 

  4. Brown NJ (2003) Eplerenone: cardiovascular protection. Circulation 107:2512–2518

    Article  CAS  Google Scholar 

  5. Schrier RW (2010) Aldosterone ‘escape’ vs ‘breakthrough’. Nat Rev Nephrol 6:61

    Article  Google Scholar 

  6. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B (2011) Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 364:11–21

    Article  CAS  Google Scholar 

  7. Pitt B, Williams G, Remme W, Martinez F, Lopez-Sendon J, Zannad F, Neaton J, Roniker B, Hurley S, Burns D, Bittman R, Kleiman J (2001) The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther 15:79–87

    Article  CAS  Google Scholar 

  8. Pitt B (2004) Effect of aldosterone blockade in patients with systolic left ventricular dysfunction: implications of the RALES and EPHESUS studies. Mol Cell Endocrinol 217:53–58

    Article  CAS  Google Scholar 

  9. Pitt D (1995) ACE inhibitor co-therapy in patients with heart failure: rationale for the Randomized Aldactone Evaluation Study (RALES). Eur Heart J 16:107–110

    Article  CAS  Google Scholar 

  10. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force Members, Document Reviewers (2016) Document reviewers. 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 J Heart Fail 18:891–975

    Article  Google Scholar 

  11. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C (2017) 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. J Card Fail 23:628–651

    Article  Google Scholar 

  12. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA (2004) Rates of hyperkalemia after publication of the randomized Aldactone Evaluation Study. N Engl J Med 351:543–551

    Article  CAS  Google Scholar 

  13. Eschalier R, McMurray JJ, Swedberg K, van Veldhuisen DJ, Krum H, Pocock SJ, Shi H, Vincent J, Rossignol P, Zannad F, Pitt B (2013) Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). J Am Coll Cardiol 62:1585–1593

    Article  CAS  Google Scholar 

  14. Albert NM, Yancy CW, Liang L, Zhao X, Hernandez AF, Peterson ED, Cannon CP, Fonarow GC (2009) Use of aldosterone antagonists in heart failure. JAMA 302:1658–1665

    Article  CAS  Google Scholar 

  15. Bärfacker L, Kuhl A, Hillisch A, Grosser R, Figueroa-Pérez S, Heckroth H, Nitsche A, Ergüden JK, Gielen-Haertwig H, Schlemmer KH, Mittendorf J, Paulsen H, Platzek J, Kolkhof P (2012) Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. ChemMedChem 7:1385–1403

    Article  Google Scholar 

  16. Kolkhof P, Delbeck M, Kretschmer A, Steinke W, Hartmann E, Bärfacker L, Eitner F, Albrecht-Küpper B, Schäfer S (2014) Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J Cardiovasc Pharmacol 64:69–78

    Article  CAS  Google Scholar 

  17. Kolkhof P, Borden SA (2012) Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics. Mol Cell Endocrinol 350:310–317

    Article  CAS  Google Scholar 

  18. Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H, Nowack C, Kolkhof P, Kim SY, Zannad F (2013) Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J 34:2453–2463

    Article  CAS  Google Scholar 

  19. Filippatos G, Anker SD, Böhm M, Gheorghiade M, Køber L, Krum H, Maggioni AP, Ponikowski P, Voors AA, Zannad F, Kim SY, Nowack C, Palombo G, Kolkhof P, Kimmeskamp-Kirschbaum N, Pieper A, Pitt B (2016) A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J 37:2105–2114

    Article  CAS  Google Scholar 

  20. Ruilope LM, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, Remuzzi G, Rossing P, Schmieder RE, Nowack C, Ferreira AC, Pieper A, Kimmeskamp-Kirschbaum N, Bakris GL (2014) Rationale, design, and baseline characteristics of ARTS-DN: a randomized study to assess the safety and efficacy of finerenone in patients with type 2 diabetes mellitus and a clinical diagnosis of diabetic nephropathy. Am J Nephrol 40:572–581

    Article  CAS  Google Scholar 

  21. Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, Remuzzi G, Rossing P, Schmieder RE, Nowack C, Kolkhof P, Joseph A, Pieper A, Kimmeskamp-Kirschbaum N, Ruilope LM (2015) Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA 314:884–894

    Article  CAS  Google Scholar 

  22. Lu G, Ades AE (2004) Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 23:3105–3124

    Article  CAS  Google Scholar 

  23. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 151:W65–W94

    Article  Google Scholar 

  24. Brooks SP, Gelman A (1998) General methods for monitoring convergence of iterative simulations. J Comput Graph Stat 7:434–455

    Google Scholar 

  25. Salanti G, Ades AE, Ioannidis JP (2011) Graphical methods and numerical summaries for presenting results from multipletreatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64:163–171

    Article  Google Scholar 

  26. Spiegelhalter DJ, Best NG, Carlin BP, Angelika VDL (2002) Bayesian measures of model complexity and fit. J R Stat Soc 64:583–639

    Article  Google Scholar 

  27. Vardeny O, Wu DH, Desai A, Rossignol P, Zannad F, Pitt B, Solomon SD (2012) Influence of baseline and worsening renal function on efficacy of spironolactone in patients with severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study). J Am Coll Cardiol 60:2082–2089

    Article  CAS  Google Scholar 

  28. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M (2003) Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348:1309–1321

    Article  CAS  Google Scholar 

  29. Boccanelli A, Mureddu GF, Cacciatore G, Clemenza F, Di Lenarda A, Gavazzi A, Porcu M, Latini R, Lucci D, Maggioni AP, Masson S, Vanasia M, de Simone G (2009) Anti-remodelling effect of canrenone in patients with mild chronic heart failure (AREA IN-CHF study): final results. Eur J Heart Fail 11:68–76

    Article  CAS  Google Scholar 

  30. Berry C, McMurray JJV (2001) Serious adverse events experienced by patients with chronic heart failure taking spironolactone. Heart 85:8–9

    Article  Google Scholar 

  31. Masoudi FA, Gross CP (2010) Adoption of spironolactone therapy for older patients with heart failure and left ventricular systolic dysfunction in the United States. Circulation 104:527–549

    Google Scholar 

  32. Stockand JD (2002) New ideas about aldosterone signaling in epithelia. Am J Physiol Renal Physiol 282:F559–F576

    Article  Google Scholar 

  33. Connell JM, Davies E (2005) The new biology of aldosterone. J Endocrinol 186:1–20

    Article  CAS  Google Scholar 

  34. Delbeck M, Kretschmer A, Kast R, Ba¨rfacker L, Hartmann E, Schaefer S, Kolkhof P (2012) Cardiorenal protection by BAY 94-8862, a novel non-steroidal mineralocorticoid receptor antagonist in a preclinical model of hypertension and diastolic heart failure. Eur Heart J 33:772–773

    Google Scholar 

  35. Kolkhof P, Kretschmer A, Baerfacker L, Hartmann E, Schaefer S (2012) Improved survival and nephroprotection in hypertensive rats by BAY 94-8862, a novel non-steroidal mineralocorticoid receptor antagonist. Eur Heart J 33:978–979

    Google Scholar 

  36. Albrecht-Ku¨pper B, Kretschmer A, Kast R, Baerfacker L, Schaefer S, Kolkhof P (2012) Pronounced cardiac protection by BAY 94-8862, a novel non-steroidal mineralocorticoid receptor antagonist in a preclinical rat model of heart failure. Eur Heart J 33:7

    Google Scholar 

  37. Sato N, Ajioka M, Yamada T, Kato M, Myoishi M, Yamada T, Kim SY, Nowack C, Kolkhof P, Shiga T (2016) A randomized controlled study of finerenone vs. eplerenone in Japanese patients with worsening chronic heart failure and diabetes and/or chronic kidney disease. Circ J 80:1113–1122

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Provincial Plans—Social Development Areas—Major Projects of Jiangxi Province (No. 20161ACG70012) and the “5511” Innovative Drivers for Talent Teams of Jiangxi Province (No. 20165BCB18018).

Author information

Authors and Affiliations

Authors

Contributions

Y-PP and S-W performed the meta-analysis; C-X, ZH-D, and X-XX were responsible for the statistical analysis; W-T and X-GS provided editing assistance; and W-QH prepared the manuscript. All authors have reviewed and agreed to this information before submission.

Corresponding author

Correspondence to Qinghua Wu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not required.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOC 11335 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, P., Shen, W., Chen, X. et al. Comparative efficacy and safety of mineralocorticoid receptor antagonists in heart failure: a network meta-analysis of randomized controlled trials. Heart Fail Rev 24, 637–646 (2019). https://doi.org/10.1007/s10741-019-09790-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-019-09790-5

Keywords

Navigation