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Relative Efficacy of Spironolactone, Eplerenone, and cAnRenone in patients with Chronic Heart failure (RESEARCH): a systematic review and network meta-analysis of randomized controlled trials

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Abstract

This study aims to assess the comparative benefit and risk profile of treatment with mineralocorticoid receptor antagonists (MRAs) with regard to all-cause mortality (primary endpoint), cardiovascular mortality, or heart failure (HF)–related hospitalization (secondary endpoints) and the safety endpoints hyperkalemia, acute renal failure, and gynecomastia in patients with chronic HF. We conducted a systematic review and network meta-analysis following PRISMA-P and PRISMA-NMA guidelines. From 16 different sources, 14 randomized controlled trials totaling 12,213 patients testing an active treatment of either spironolactone, eplerenone, or canrenone/potassium-canreonate in adults with symptomatic HF due to systolic dysfunction reporting any of the above endpoints were retained. Efficacy in comparison to placebo/standard medical care with respect to all-cause mortality was confirmed for spironolactone and eplerenone while no conclusion could be drawn for canrenone (HR 0.69 (0.62; 0.77), 0.82 (0.75; 0.91), and 0.50 (0.17; 1.45), respectively). Indirect comparisons hint a potential (non-significant) preference of spironolactone over eplerenone (HR 0.84 (0.68; 1.03)). The overall risk of bias was low to intermediate. Results for secondary endpoints as well as sensitivity analyses essentially mirrored these findings. The beta-blocker adjusted meta-analysis for the primary endpoint showed the same tendency as the unadjusted one (HR 0.39 (0.07; 2.03)). Results need to be interpreted with caution, though, as the resultant mix of patient- and study-level covariates produced unstable statistical modeling. We found no significant and systematic superiority of either MRA regarding efficacy toward all endpoints considered in both direct and indirect comparisons.

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All authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Authors and Affiliations

  1. Department of Cardiology, Angiology and Pulmology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Lutz Frankenstein, Tobias Täger, Hanna Fröhlich, Mirjam Seiz & Hugo A. Katus

  2. Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany

    Svenja Seide, Katrin Jensen & Lorenz Uhlmann

  3. Hull York Medical School at Castle Hill Hospital, Hull, UK

    Andrew L. Clark

  4. Marketing Group, Gamida-Cell, Cambridge, MA, USA

    Paul Nee

  5. Department of Health Policy, London School of Economics and Political Science, London, UK

    Huseyin Naci

  6. Department of Cardiology, Oslo University Hospital, Ulleval and Institute of Clinical Sciences, University of Oslo, Oslo, Norway

    Dan Atar

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Contributions

L.F., T.T., H.F.: conception and design of the work, and acquisition and interpretation of data; drafting and revising of the manuscript; final approval of the manuscript submitted. S.S., K.J., L.U.: design of the work and analysis and interpretation of data; revising of the manuscript; final approval of the manuscript submitted. A.C., M.S., H.K., P.N., H.N., D.A.: design of the work and interpretation of data; revising of the manuscript; final approval of the manuscript submitted.

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Frankenstein, L., Seide, S., Täger, T. et al. Relative Efficacy of Spironolactone, Eplerenone, and cAnRenone in patients with Chronic Heart failure (RESEARCH): a systematic review and network meta-analysis of randomized controlled trials. Heart Fail Rev 25, 161–171 (2020). https://doi.org/10.1007/s10741-019-09832-y

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