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Timing of Statistical Benefit of Mineralocorticoid Receptor Antagonists Among Patients With Heart Failure and Post-Myocardial Infarction

2022; Lippincott Williams & Wilkins; Volume: 15; Issue: 10 Linguagem: Francês

10.1161/circheartfailure.121.009295

1941-3297

Wassim Bedrouni, Abhinav Sharma, Bertram Pitt, Carolyn S.P. Lam, Jiayi Ni, João Pedro Ferreira, John J.V. McMurray, Nadia Giannetti, Nicolas Girerd, Patrick Rossignol, Scott D. Solomon, Brian Claggett, Stuart J. Pocock, Thao Huynh, Faı̈ez Zannad,

Cardiovascular, Neuropeptides, and Oxidative Stress Research

HomeCirculation: Heart FailureVol. 15, No. 10Timing of Statistical Benefit of Mineralocorticoid Receptor Antagonists Among Patients With Heart Failure and Post-Myocardial Infarction Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBTiming of Statistical Benefit of Mineralocorticoid Receptor Antagonists Among Patients With Heart Failure and Post-Myocardial Infarction Wassim Bedrouni, Abhinav Sharma, Bertram Pitt, Carolyn S.P. Lam, Jiayi Ni, João Pedro Ferreira, John McMurray, Nadia Giannetti, Nicolas Girerd, Patrick Rossignol, Scott D. Solomon, Brian Claggett, Stuart Pocock, Thao Huynh and Faiez Zannad Wassim BedrouniWassim Bedrouni Department of Medicine (W.B.), McGill University Health Centre, Montreal, Quebec, Canada. , Abhinav SharmaAbhinav Sharma Correspondence to: Abhinav Sharma, MD, PhD, McGill University Health Centre, 1001 Decarie Blvd, Montreal, Quebec H4A 3J1, Canada. Email E-mail Address: [email protected] https://orcid.org/0000-0002-2346-8330 Division of Cardiology (A.S., J.N., N.G., T.H.), McGill University Health Centre, Montreal, Quebec, Canada. , Bertram PittBertram Pitt Department of Medicine, University of Michigan School of Medicine, Ann Arbor (B.P.). , Carolyn S.P. LamCarolyn S.P. Lam https://orcid.org/0000-0003-1903-0018 Department of Cardiology, National Heart Center Singapore (C.S.P.L.). Duke-National University of Singapore (C.S.P.L.). , Jiayi NiJiayi Ni https://orcid.org/0000-0002-1941-8170 Division of Cardiology (A.S., J.N., N.G., T.H.), McGill University Health Centre, Montreal, Quebec, Canada. , João Pedro FerreiraJoão Pedro Ferreira https://orcid.org/0000-0002-2304-6138 Université de Lorraine, Centre d'Investigations Cliniques Plurithématique 1433 and Inserm U1116, CHRU Nancy, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., N.G., P.R., F.Z.). , John McMurrayJohn McMurray https://orcid.org/0000-0002-6317-3975 BHF Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.M.). , Nadia GiannettiNadia Giannetti https://orcid.org/0000-0001-7173-8051 Université de Lorraine, Centre d'Investigations Cliniques Plurithématique 1433 and Inserm U1116, CHRU Nancy, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., N.G., P.R., F.Z.). Division of Cardiology (A.S., J.N., N.G., T.H.), McGill University Health Centre, Montreal, Quebec, Canada. , Nicolas GirerdNicolas Girerd Université de Lorraine, Centre d'Investigations Cliniques Plurithématique 1433 and Inserm U1116, CHRU Nancy, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., N.G., P.R., F.Z.). , Patrick RossignolPatrick Rossignol https://orcid.org/0000-0001-8009-3873 Université de Lorraine, Centre d'Investigations Cliniques Plurithématique 1433 and Inserm U1116, CHRU Nancy, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., N.G., P.R., F.Z.). , Scott D. SolomonScott D. Solomon https://orcid.org/0000-0003-3698-9597 Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C.). , Brian ClaggettBrian Claggett https://orcid.org/0000-0002-4215-9218 Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C.). , Stuart PocockStuart Pocock Department of Medical Statistics, London School of Hygiene & Tropical Medicine, United Kingdom (S.P.). , Thao HuynhThao Huynh Division of Cardiology (A.S., J.N., N.G., T.H.), McGill University Health Centre, Montreal, Quebec, Canada. and Faiez ZannadFaiez Zannad https://orcid.org/0000-0001-7456-1570 Université de Lorraine, Centre d'Investigations Cliniques Plurithématique 1433 and Inserm U1116, CHRU Nancy, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., N.G., P.R., F.Z.). Originally published4 Aug 2022https://doi.org/10.1161/CIRCHEARTFAILURE.121.009295Circulation: Heart Failure. 2022;15Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 4, 2022: Ahead of Print Heart failure (HF) with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF), and myocardial infarction (MI) complicated with systolic dysfunction have a poor prognosis. Mineralocorticoid-receptor antagonists (MRAs) reduce morbidity or mortality in these syndromes, but MRAs remain underutilized. Understanding the timing of benefit may help clinicians better understand the treatment effect and motivate them to prescribe MRAs. Therefore, we investigated the treatment effect of MRAs over time by conducting a post hoc analysis of 4 trials in 3 clinical scenarios: (1) HFrEF: pooled cohort of RALES (Randomized Aldactone Evaluation Study)1 and EMPHASIS-HF (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms),2 (2) HFpEF: TOPCAT (Spironolactone for Heart Failure With Preserved Ejection Fraction)-Americas,3 and (3) post-MI complicated by LV dysfunction: EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study).4The clinical characteristics of these trials were as follows: RALES (n=1663; spironolactone versus placebo; New York Heart Association class III–IV with left ventricular ejection fraction [LVEF] ≤35%); EMPHASIS-HF (n=2737; eplerenone versus placebo; New York Heart Association class II with LVEF ≤35%); TOPCAT-Americas (n=3445; spironolactone versus placebo; HF signs and symptoms with LVEF ≥45%); and EPHESUS (n=6632; eplerenone versus placebo; 3–14 days post-MI with diabetes or complicated by HF signs/symptoms or LVEF≤40%). While RALES and EMPHASIS-HF enrolled patients with more and less severe HF symptoms (respectively), they were pooled together as they both enrolled patients with HFrEF. Hazard ratios were calculated on each day following randomization until the last observation of the last patient using the Cox proportional hazards model. All events until the respective day were considered. Patients without any events were censored at the respective day. We assessed the treatment effect of MRAs over time from initiation and assessed when the hazard ratio and the 95% CI for the treatment effect of MRA versus placebo first crossed unity and reached and maintained statistical significance based on a P value of <0.05. Our primary outcome was the composite of cardiovascular death or HF hospitalization (HHF). We also evaluated time to statistically significant benefit for HHF and all-cause death. Data supporting this study will not be available from the corresponding author. Trial conduct was approved by local institutional review committee and subject enrolled provided informed consent.The pooled cohort of RALES and EMPHASIS-HF included a total of 2186 participants in the MRA arms and 2214 participants in the placebo arms. TOPCAT-Americas included 886 participants in the MRA arm and 881 in the placebo arm. EPHESUS included 3319 in the MRA arm and 3313 in the placebo arm. The median age of the pooled cohort of patients with HFrEF was 68 (interquartile, 12), 24.0% were female, and the median LVEF was 27%. In TOPCAT-Americas, the median age was 72 (interquartile, 15), 49.9% were female, and the median LVEF was 58%. In EPHESUS, the median age was 65.0 (18.0) and 28.9% were female, and the median LVEF was 33%.For the pooled HFrEF cohort, significant statistical reduction in cardiovascular death or hospitalization was observed after 19 days (Figure). The timing of significant statistical reduction for HHF was 11 days, 122 days for all-cause death, and 332 for CV death. In TOPCAT-Americas, statistical reduction was observed later: on day 208 for the primary outcome and day 224 for HHF. For EPHESUS, the timing of statistical reduction for the primary outcome was seen on day 7, 84 days for HHF, 10 days for all-cause death, and 9 days for CV death (Figure).Download figureDownload PowerPointFigure. Timing of statistical demonstration of benefit of mineralocorticoid receptor antagonist vs placebo for cardiovascular (CV) mortality or hospitalization for heart failure. A, Pooled cohort of RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms). B, TOPCAT (Spironolactone for Heart Failure With Preserved Ejection Fraction-Americas). C, EPHESUS trial (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). The primary outcome for this analysis was CV death or heart failure hospitalization (HHF). In the pooled cohort, the benefit was seen by day 19. In TOPCAT-Americas, the benefit for CV death or HHF was seen on day 208. In the EPHESUS trial, the benefit was seen by day 7. Follow-up truncated at day 50 for the pooled cohort (RALES and EMPHASIS-HF) and EPHESUS. MRA indicates mineralocorticoid receptor antagonist.This study is one of the first to determine the timing of significant reduction in mortality and hospitalizations after MRA initiation in HFrEF and HFpEF. A Pitt et al5 study on timing to benefit in EPHESUS found a 13% reduction within 30 days after randomization. These differences are due to contrasting approaches to the study question; Pitt et al adopted a prespecified analysis studying the effect at the 30-day mark, whereas we analyzed the treatment effect until the point of statistical significance.We present evidence of early significant benefit of MRA initiation in patients with HFrEF and those who are post-MI complicated by systolic dysfunction, heart failure, or diabetes. Our analysis suggests a longer time horizon of statistical significance in the HFpEF population compared with HFrEF. While this may reflect differences in pathophysiology between HFrEF and HFpEF, this more likely reflects differences in event rates seen across trials.Our study has a few limitations to consider, namely those inherent to post hoc analyses. With the available sample size and event rates, the TOPCAT-Americas cohort is likely underpowered, thereby showing a more delayed achievement of statistical significance. Our analysis is also not powered to determine time interactions with response to therapy over time and we did not adjust for multiple comparisons.Understanding when treatment benefits become statistically significant may motivate clinicians to introduce MRAs in the treatment course of people (both in the in- and out-patient setting) with HFrEF, HFpEF, and those who are post-MI with systolic dysfunction, HF, or diabetes.Article InformationSources of FundingDr Sharma received support from the Canada Institute for Health Research—175095 and the McGill Lucien Award.Nonstandard Abbreviations and AcronymsEPHESUSEplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival StudyHFheart failureHFpEFheart failure with preserved ejection fractionHFrEFheart failure with reduced ejection fractionHHFheart failure hospitalizationLVEFleft ventricular ejection fractionMImyocardial infarctionMRAmineralocorticoid receptor antagonistRALESRandomized Aldactone Evaluation StudyDisclosures Dr Sharma has received funding from the FRSQ-Junior 1 scholars program, the Bayer-Canadian Cardiovascular Society, Alberta Innovates Health Solution, Roche Diagnostics, Novartis, Takeda, Boehringer Ingelheim, AstraZeneca, and Akcea. Dr Pitt has received consultant fees for Bayer, AstraZeneca, Sanofi/Lexicon, scPharmaceuticals, SQ Innovation, G3 Pharmaceuticals, Sarfez, Phasebio, Vifor/Relypsa, Cereno Scientific, Ardelyx, KBP Biosciences, Boehringer Ingelheim, Brainstorm Medical, and Tricida. He has stock options for Ardelyx, KBP Biosciences, SQ Innovation, Sarfez, scPharmaceuticals, Cereno Scientific, G3 Pharmaceuticals, Vifor/Relypsa, Brainstorm Medical, and Tricida, and he also holds a patent for site-specific delivery of eplerenone to the myocardium (US patent 9931412) and a provisional patent for histone-acetylation–modulating agents for the treatment and prevention of organ injury (provisional patent US 63/045,784). Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Abbott, Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and non-executive director of Us2.ai. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius and personal fees from Boehringer Ingelheim. Dr McMurray has received nonfinancial support and other from AstraZeneca; other from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and personal fees from Abbott, Hickma, Sun Pharmaceuticals, and from Servier outside the submitted work. Dr Ferreira has received consulting fees from Boehringer Ingelheim. Dr Giannetti has received personal fees from AstraZeneca, Bristol Myers Squibb/Pfizer, Medtronic, Novartis, Pfizer, Servier, Abbott, Boehringer Ingelheim, Amgen, V-wave, Merck, and Sanofi and research grants from AstraZeneca, Medtronic, Novartis, and Servier. Dr Girerd receives honoraria from Novartis and Boehringer. Dr Rossignol has received grants and personal fees from AstraZeneca, Bayer, CinCor, CVRx, Fresenius, and Novartis and personal fees from Grunenthal, Servier, Stealth Peptides, Vifor Fresenius Medical Care Renal Pharma, Idorsia, NovoNordisk, Ablative Solutions, G3P, Corvidia and Relypsa. He is CardioRenal cofounder. Dr Solomon has received grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead Sciences, GlaxoSmithKline, Ionis Pharmaceuticals, LoneStar Heart, Mesoblast, MyoKardia, NeuroTronik, the National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos, as well as personal fees from Abbott, Actelion, Akros, Alnylam Pharmaceuticals, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior Pharmaceuticals, Cardurion Pharmaceuticals, Corvia Medical, Cytokinetics, Daiichi Sankyo, Gilead Sciences, GlaxoSmithKline, Ironwood Pharmaceuticals, Eli Lilly, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion Pharmaceuticals, AOBiome, Janssen, Cardiac Dimensions, Sanofi Pasteur, Tenaya, DiNAQOR, Tremeau Pharmaceuticals, CellProthera, and Moderna. Dr Pocock is a consultant for Boehringer Ingelheim and has received personal fees from Boehringer Ingelheim. Dr Huynh has received research grants and honoraria from Boehringer Ingelheim, Bayer, Sanofi and AstraZeneca. The other authors report no conflicts.FootnotesThis manuscript was sent to Dr Gregg C. Fonarow, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 990.*W. Bedrouni and A. Sharma contributed equally.Correspondence to: Abhinav Sharma, MD, PhD, McGill University Health Centre, 1001 Decarie Blvd, Montreal, Quebec H4A 3J1, Canada. Email abhinav.[email protected]caReferences1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.N Engl J Med. 1999; 341:709–717. doi: 10.1056/NEJM199909023411001CrossrefMedlineGoogle Scholar2. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms.N Engl J Med. 2011; 364:11–21. doi: 10.1056/NEJMoa1009492CrossrefMedlineGoogle Scholar3. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, et al; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction.N Engl J Med. 2014; 370:1383–1392. doi: 10.1056/NEJMoa1313731CrossrefMedlineGoogle Scholar4. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.N Engl J Med. 2003; 348:1309–1321. doi: 10.1056/NEJMoa030207CrossrefMedlineGoogle Scholar5. Pitt B, White H, Nicolau J, Martinez F, Gheorghiade M, Aschermann M, van Veldhuisen DJ, Zannad F, Krum H, Mukherjee R, et al; EPHESUS Investigators. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure.J Am Coll Cardiol. 2005; 46:425–431. doi: 10.1016/j.jacc.2005.04.038CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Mebazaa A, Davison B, Chioncel O, Cohen-Solal A, Diaz R, Filippatos G, Metra M, Ponikowski P, Sliwa K, Voors A, Edwards C, Novosadova M, Takagi K, Damasceno A, Saidu H, Gayat E, Pang P, Celutkiene J and Cotter G (2022) Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial, The Lancet, 10.1016/S0140-6736(22)02076-1, 400:10367, (1938-1952), Online publication date: 1-Dec-2022. October 2022Vol 15, Issue 10 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.121.009295PMID: 35924555 Originally publishedAugust 4, 2022 Keywordsmorbiditymyocardial infarctioneplerenoneprognosisspironolactonePDF download Advertisement SubjectsHeart Failure