Abstract
13 min readHomeCirculationVol. 145, No. 1Impact of Sacubitril/Valsartan Versus Ramipril on Total Heart Failure Events in the PARADISE-MI Trial Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBImpact of Sacubitril/Valsartan Versus Ramipril on Total Heart Failure Events in the PARADISE-MI Trial Marc A. Pfeffer, MD, PhD, Brian Claggett, PhD, Eldrin F. Lewis, MD, MPH, Christopher B. Granger, MD, Lars Køber, MD, Aldo P. Maggioni, MD, Douglas L. Mann, MD, John J.V. McMurray, MD, Jean-Lucien Rouleau, MD, Scott D. Solomon, MD, Philippe Gabriel Steg, MD, Otavio Berwanger, MD, PhD, Maja Cikes, MD, PhD, Carmine G. De Pasquale, BMBS, PhD, Alberto Fernandez, MD, Gerasimos Filippatos, MD, Karola Jering, MD, Ulf Landmesser, MD, Venugopal Menon, MD, Béla Merkely, MD, PhD, Mark C. Petrie, MD, Ivo Petrov, MD, PhD, Morten Schou, MD, PhD, Michele Senni, MD, David Sim, MBBS, M Med, Peter van der Meer, MD, PhD, Martin Lefkowitz, MD, Yinong Zhou, MD, Yi Wang, PhD and Eugene Braunwald, MD Marc A. PfefferMarc A. Pfeffer Correspondence to: Marc A. Pfeffer, MD, PhD, Cardiovascular Division, Brigham & Women's Hospital, 75 Francis St, Boston, MA, 02115. Email E-mail Address: [email protected] Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School Boston, MA (M.A.P., B.C., S.D.S., K.J.). , Brian ClaggettBrian Claggett Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School Boston, MA (M.A.P., B.C., S.D.S., K.J.). , Eldrin F. LewisEldrin F. Lewis Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Palo Alto, CA (E.F.L.). , Christopher B. GrangerChristopher B. Granger Duke University Medical Center, Durham, NC (C.B.G.). , Lars KøberLars Køber Rigshospitalet, Blegdamsvej, University of Copenhagen, Denmark (L.K.). , Aldo P. MaggioniAldo P. Maggioni ANMCO Research Center, Florence, Italy (A.P.M.). , Douglas L. MannDouglas L. Mann https://orcid.org/0000-0002-2516-0145 Washington University School of Medicine, St. Louis, MO (D.L.M.). , John J.V. McMurrayJohn J.V. McMurray British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Scotland (J.J.V.M., M.C.P.). , Jean-Lucien RouleauJean-Lucien Rouleau Montréal Heart Institute, University of Montréal, Quebec, Canada (J.-L.R.). , Scott D. SolomonScott D. Solomon Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School Boston, MA (M.A.P., B.C., S.D.S., K.J.). , Philippe Gabriel StegPhilippe Gabriel Steg Université de Paris, AP-HP (Assistance Publique-Hôpitaux de Paris), FACT (French Alliance for Cardiovascular Trials) and INSERM U-1148, France (P.G.S.). , Otavio BerwangerOtavio Berwanger Academic Research Organization – Hospital Israelita Albert Einstein, São Paulo-SP, Brazil (O.B.). , Maja CikesMaja Cikes https://orcid.org/0000-0002-4772-5549 Department of Cardiovascular Diseases, University of Zagreb School of Medicine and University Hospital Centre Zagreb, Croatia (M.C.). , Carmine G. De PasqualeCarmine G. De Pasquale https://orcid.org/0000-0001-5025-6117 Department of Cardiovascular Medicine, Flinders Medical Centre, Adelaide, Australia (C.G.D.P.). , Alberto FernandezAlberto Fernandez Cardiology Service, Sanatorio Modelo Quilmes, Argentina (A.F.). , Gerasimos FilippatosGerasimos Filippatos HF Unit at the Attikon University Hospital, Athens, Greece (G.F.). , Karola JeringKarola Jering Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School Boston, MA (M.A.P., B.C., S.D.S., K.J.). , Ulf LandmesserUlf Landmesser Department of Cardiology, Charité University Medicine Berlin, German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin Institute of Health, Germany (U.L.). , Venugopal MenonVenugopal Menon https://orcid.org/0000-0003-4410-2677 Cardiovascular Medicine, Cleveland Clinic, OH (V.M.). , Béla MerkelyBéla Merkely Semmelweis University, Heart and Vascular Center, Budapest, Hungary (B.M.). , Mark C. PetrieMark C. Petrie Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School Boston, MA (M.A.P., B.C., S.D.S., K.J.). , Ivo PetrovIvo Petrov https://orcid.org/0000-0002-9989-0730 Acibadem City Clinic Cardiovascular Center, Sofia, Bulgaria (I.P.). , Morten SchouMorten Schou Department of Cardiology, Herlev-Gentofte University Hospital, Copenhagen, Denmark (M. Schou). , Michele SenniMichele Senni Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M. Senni). , David SimDavid Sim National Heart Centre Singapore (D.S.). , Peter van der MeerPeter van der Meer Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (P.v.d.M.). , Martin LefkowitzMartin Lefkowitz Novartis Pharmaceutical Corporation, East Hanover, NJ (M.L., Y.Z., Y.W.). , Yinong ZhouYinong Zhou Novartis Pharmaceutical Corporation, East Hanover, NJ (M.L., Y.Z., Y.W.). , Yi WangYi Wang Novartis Pharmaceutical Corporation, East Hanover, NJ (M.L., Y.Z., Y.W.). and Eugene BraunwaldEugene Braunwald TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA (E.B.). Originally published19 Nov 2021https://doi.org/10.1161/CIRCULATIONAHA.121.057429Circulation. 2022;145:87–89Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 19, 2021: Ahead of Print The hypothesis that sacubitril/valsartan is superior to ramipril in reducing time-to-first cardiovascular death or the development of heart failure (hospitalization or outpatient) in patients with acute myocardial infarction was tested in PARADISE-MI (Prospective ARNI versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after MI).1 The risk of this primary composite outcome using the prespecified time-to-first event analysis of the clinical end point committee (CEC)–adjudicated events was not significantly reduced in the sacubitril/valsartan group.2 As such, all secondary analyses are considered exploratory.Because the comparator arm renin-angiotensin system inhibitor has previously proven effective in reducing mortality in this population, exploring additional prespecified end points could offer relevant information regarding the effects of angiotensin receptor neprilysin inhibition in high-risk patients after myocardial infarction. This research letter provides analyses regarding more expansive evaluations of clinical outcomes focusing on total (first and recurrent) CEC-adjudicated, and investigator-reported events, as well.MethodsThe design, baseline characteristics, and primary results of this institutional review board–approved trial are published.1,2 In brief, PARADISE-MI was a double-blind, active-controlled randomized, clinical trial that compared sacubitril/valsartan with ramipril in 5661 patients with written informed consent, an acute myocardial infarction (within 0.5–7 days of presentation) with either left ventricular ejection fraction ≤40% or transient pulmonary congestion. Previous heart failure or clinical instability (requiring intravenous diuretics, inotropes, or blood pressure support within the 24 hours before randomization) were major exclusions, and all patients provided written informed consent.Time-to-first event data were analyzed using Cox models, whereas timing and occurrence of recurrent events (hospitalizations for heart failure, outpatient heart failure, or cardiovascular death) were analyzed using a negative binominal regression model with a Weibull baseline intensity function with treatment, type of myocardial infarction, percutaneous coronary intervention, and region as factors.2 Analyses are exploratory and P values were not adjusted for multiplicity. Data are available on request from the authors.ResultsIn the previously reported time-to-first analysis of CEC-adjudicated primary events, there were 338 patients (11.9%) with a first event among the 2830 randomly assigned to sacubitril/valsartan and 373 patients (13.2%) with a first event among the 2831 randomly assigned to ramipril (hazard ratio, 0.90 [95% CI, 0.78–1.04], P=0.17).2 Comparisons between the components of the end points were previously reported.2Investigator-Reported Time-to-First EventAmong the patients randomly assigned to sacubitril/valsartan, there were 443 patients (15.7%) with a first investigator-reported cardiovascular death, hospitalization for heart failure, or outpatient heart failure, and among the patients randomly assigned to ramipril there were 516 patients (18.2%) with one of these events (hazard ratio, 0.85 [95% CI, 0.75–0.96], P=0.01; Figure [A]).Download figureDownload PowerPointFigure. Clinical outcomes. Shown are Kaplan-Meier curves for the investigator-reported primary composite outcome, analyzed as time to first event (A), and Nelson-Aalen event curves for total (first and recurrent) clinical end point committee (CEC)–adjudicated (B) and investigator-reported (C) primary events of total hospitalizations for heart failure, total outpatient episodes of symptomatic heart failure, and cardiovascular death. A, Investigator-reported time-to-first event: 443 patients (15.7%) in the sacubitril/valsartan group (cardiovascular death, 115; hospitalization, 231; and outpatient, 97) and 516 patients (18.2%) in the ramipril group (cardiovascular death, 111; hospitalization, 264; and outpatient, 141). B, CEC adjudicated total primary events: 452 primary events in the sacubitril/valsartan group (240 hospitalizations, 44 outpatient episodes, and 168 cardiovascular deaths) and 539 events in the ramipril group (286 hospitalizations, 62 outpatient episodes, and 191 cardiovascular deaths). C, Investigator-reported total primary events: 672 primary events in the sacubitril/valsartan group (395 hospitalizations, 122 outpatient episodes, and 155 cardiovascular deaths) and 802 events in the ramipril group (447 hospitalizations, 176 outpatient episodes, and 179 cardiovascular deaths).CEC-Adjudicated Total (First and Recurrent) EventsIn the sacubitril/valsartan group, there were a total of 452 CEC-adjudicated primary events among 338 patients with at least one of these events, whereas there were 539 total events among 373 patients in the ramipril group (rate ratio, 0.79 [95% CI, 0.65–0.97], P=0.02; Figure [B]). The use of open label sacubitril/valsartan after a CEC-confirmed heart failure event (hospitalization or outpatient episode) was 17 of 199 (8.5%) in the sacubitril/valsartan group and 16 of 234 (6.8%) in the ramipril group.Investigator-Reported Total (First and Recurrent) EventsIn the sacubitril/valsartan group, there were 672 investigator-reported total events among 443 patients with at least one of these events, whereas in the ramipril group, there were 802 total events among 516 patients (rate ratio, 0.79 [95% CI, 0.67–0.93], P=0.004; Figure [C]). The use of open label sacubitril/valsartan following an investigator report of heart failure was 23 of 327 (7.0%) in the sacubitril/valsartan group and 28 of 400 (7.0%) in the ramipril group.DiscussionWhen the results of a major randomized trial fail to achieve the level of significance to declare a difference for its primary objective, additional analyses may provide useful information. Questions have been proposed to better understand, although not to change, the neutral result.3 With adequate statistical power and no major deficiencies in trial design or conduct, this retrospective probing of PARADISE-MI focused on choice of the primary outcome. Although recurrent event analyses capture a more complete assessment of the adverse patient and economic impact of heart failure, time-to-first event analysis was chosen because once a patient in PARADISE-MI developed heart failure, open label sacubitril/valsartan use was anticipated to confound the recurrent event analysis. In retrospect, with the minimal use of open label sacubitril/valsartan (<10%) in patients developing symptomatic heart failure during the conduct of our trial, adopting the more expansive outcome of total events would have been a more appropriate primary end point to assess the influence of sacubitril/valsartan relative to ramipril on the full burden of heart failure.Although these exploratory analyses do not alter the primary neutral findings for use after acute myocardial infarction, the consistent findings of reductions in recurrent heart failure events using both CEC adjudications and investigator reports provides more supportive information for the already indicated replacement of an angiotensin-converting enzyme inhibitor with sacubitril/valsartan once the clinical transition to symptomatic heart failure has occurred.4,5Article InformationSources of FundingPARADISE-MI (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) was sponsored by Novartis.Disclosures Dr Pfeffer reports research grant support through Brigham and Women's Hospital from Novartis; and consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, National Heart, Lung, and Blood Institute (NHLBI) CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, and Sanofi; and has equity in DalCor. Dr Claggett reports consultancy fees from Amgen Inc, Beren Therapeutics, Myokardia, Novartis, and Peerbridge Health. Dr Lewis reports research grant support from Novartis; consulting fees from Amgen, Dal-Cor, and Merck. Dr Granger reports consultancy fees and/or research support from Novartis, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Correvio, Daiichi Sankyo Co., Janssen Global Services, and Pfizer Inc. Dr Køber reports consultancy fees from Boehringer Ingelheim. Dr Maggioni reports consultancy fees from Novartis. Dr Mann reports consultancy fees from Bristol-Myers Squibb, Cardurion, LivaNova USA Inc, Novartis, Novo Nordisk, and Renovacor. Dr McMurray reports research grant support through his employer, Glasgow University, from Novartis. Dr Rouleau reports consultancy fees from Novartis Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb and Sanofi-Aventis US, LLC. Dr Solomon reports research grant support through Brigham and Women's Hospital from Actelion Pharmaceuticals, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer, Bellepheron, Bristol-Myers Squibb, Celladon Corporation, Cytokinetics, Eidos, Eli Lilly and Company, GlaxoSmithKline, Ionis, Mesoblast, Myokardia, Neurotronik, Novartis, Novo Nordisk, Respicardia Inc, Sanofi Pasteur Inc, and Theracos; consulting fees from Abbott Vascular, Action Medical Research, Akros, Alnylam Pharmaceuticals, American Regent, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb Eli Lilly and Company, Cardiac Dimensions, Cardior, Cardurion, CellProThera, Cytokinetics, Daiichi Sankyo Company, Genomics, GlaxoSmithKline, Johnson and Johnson, Merck, Moderna, Myokardia, Novartis, Quantum, Roche Diagnostics Corporation, Sanofi Pasteur Inc, Sarepta Therapeutics Inc, Tenaya, Theracos, Tremeau and has equity in Dinaqor; other: Corvia Medical. Dr Steg reports research grant support from Bayer; consulting fees from Amarin Pharma Inc, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen Pharmaceuticals, Novartis, Novo Nordisk, Regeneron Pharmaceuticals, Sanofi US Services Inc, and Servier. Dr Berwanger reports consultancy fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis Pharma, and Pfizer. Dr Cikes reports research support from Abbott and Novartis; and Institutional, Organizational, or Other Financial Benefit from: Abbott, GE Healthcare, Pfizer, and Teva Pharmaceutical Industries. Dr De Pasquale reports consultancy fees from Novartis and Institutional, Organizational, or Other Financial Benefit from Novartis. Dr Landmesser reports research support from Amgen, Bayer, and Novartis; consultancy fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo Company, Novartis, Pfizer, and Sanofi Pasteur Inc. Dr Petrie reports research support from AstraZeneca, Boehringer Ingelheim, Novartis, and SQ Innovation; consulting fees from AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, SQ Innovation, and Vifor Pharma. Dr Senni reports consulting fees from Abbott Fund, Bayer, Bayer Healthcare, Novartis, Merck, and Vifor Pharma. Dr van d reports research support from AstraZeneca, Pfizer, and Vifor Pharma. Drs Lefkowitz, Zhou, and Wang are full-time employees of Novartis. Dr Braunwald reports research grant support through Brigham and Women's Hospital from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; consulting for Amgen, Boehringer-Ingelheim/Lilly, Cardurion, MyoKardia, NovoNordisk, and Verve. The other authors report no conflicts.FootnotesThis manuscript was sent to Faiez Zannad, Guest Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 89.Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02924727.Correspondence to: Marc A. Pfeffer, MD, PhD, Cardiovascular Division, Brigham & Women's Hospital, 75 Francis St, Boston, MA, 02115. Email [email protected]bwh.harvard.eduReferences1. Jering KS, Claggett B, Pfeffer MA, Granger C, Køber L, Lewis EF, Maggioni AP, Mann D, McMurray JJV, Rouleau JL, et al.. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI): design and baseline characteristics.Eur J Heart Fail. 2021; 23:1040–1048. doi: 10.1002/ejhf.2191CrossrefMedlineGoogle Scholar2. 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Frantz S, Hundertmark M, Schulz-Menger J, Bengel F and Bauersachs J (2022) Left ventricular remodelling post-myocardial infarction: pathophysiology, imaging, and novel therapies, European Heart Journal, 10.1093/eurheartj/ehac223 January 4, 2022Vol 145, Issue 1Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.057429PMID: 34797725 Originally publishedNovember 19, 2021 Keywordssacubitril/valsartanramiprilmyocardial infarctionheart failurePDF download Advertisement SubjectsMyocardial Infarction
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