Angiotensin Receptor-Neprilysin Inhibition in Patients With STEMI vs NSTEMI.

Background: Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), remain at high risk for heart failure (HF), coronary events, and death. Angiotensin-converting enzyme inhibitors have been shown to significantly decrease the risk for cardiovascular events in both STEMI and NSTEMI patients.
Objectives: The objectives were to determine whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan, compared with ramipril, has impact on reducing cardiovascular events according to the type of AMI.
Methods: The PARADISE-MI (Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) trial enrolled patients with AMI complicated by left ventricular dysfunction and/or pulmonary congestion and at least 1 risk-enhancing factor. Patients were randomized to either sacubitril/valsartan or ramipril. The primary endpoint was death from cardiovascular causes or incident HF. In this prespecified analysis, we stratified patients according to AMI type.
Results: Of 5,661 enrolled patients, 4,291 (75.8%) had STEMI. These patients were younger and had fewer comorbidities and cardiovascular risk factors than NSTEMI patients. After adjustment for potential confounders, the risk for the primary outcome was marginally higher in NSTEMI vs STEMI patients (adjusted HR: 1.19; 95% CI: 1.00-1.41), with borderline statistical significance (P = 0.05). The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan vs ramipril in STEMI (10% vs 12%; HR: 0.87; 95% CI: 0.73-1.04; P = 0.13) and NSTEMI patients (17% vs 17%; HR: 0.97; 95% CI: 0.75-1.25; P = 0.80; P interaction = 0.53).
Conclusions: Compared with ramipril, sacubitril/valsartan did not significantly decrease the risk for cardiovascular death and HF in patients with AMI complicated by left ventricular dysfunction, irrespective of the type of AMI. (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI; NCT02924727).
Competing Interests: Funding Support and Author Disclosures The PARADISE-MI trial was funded by Novartis. Dr Braunwald has received research grants through his institution from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; and has consultancies with Amgen, Bristol Myers Squibb, Boehringer Ingelheim/Lilly, Cardurion, and Verve. Dr Claggert has received consultancy fees from Novartis, Amgen, Boehringer Ingelheim, Cardurion, Corvia, and Myokardia. Dr Granger has received research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Duke Clinical Research Institute, FDA, GlaxoSmithKline, Janssen Pharmaceutical Products, L.P., Medtronic Foundation, Novartis Pharmaceutic Company, and Pfizer; has received consulting fees from Abbvie, Abiomed, Alnylam Pharm, Bayer Corporation US, Boehringer Ingelheim, Boston Scientific Corporation, Bristol Myers Squibb, Cardionomic, CeleCor Therapeutics, HengRui USA, Janssen Pharmaceutica Products, L.P., Medscape, LLC, Medtronic Inc, Merck, NIH, Novo Nordisk, Novartis Pharmaceutic Company, Pfizer, Phillips, and REATA; and owns equity in Tenac.io. Dr Kerkar has received speaker fees from Novartis, AstraZeneca, Bayer Zydus, Boehringer Ingelheim, Cipla, Dr Reddy’s, Emcure, Intas, Johnson and Johnson, Mankind, Pfizer, Torrent, and USV. Dr Kober has received speaker honorarium from Nova, Novartis, AstraZeneca, Bayer, and Boehringer. Dr Lewis has received personal fees from Amgen and Dal-Cor. Dr Maggioni has received personal fees for participation in committees of studies supported by Bayer, Novartis, AstraZeneca, and Fresenius, outside the present work. Dr Mann has received consulting fees from Cardurion, HAYA Therapeutics, Tenaya, and Novo Nordisk. Dr Mehran has received institutional research payments from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Applied Therapeutics, Arena, AstraZeneca, BAIM, Bayer, Beth Israel Deaconess, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CellAegis, CeloNova, CERC, Chiesi, Concept Medical, CSL Behring, Cytosorbents, DSI, Duke University, Element Science, Faraday, Humacyte, Idorsia, Insel Gruppe AG, Magenta, Medtronic, Novartis, OrbusNeich, Philips, RenalPro, Vivasure, and Zoll; has received personal fees from Cine-Med Research and WebMD; has received consulting fees paid to the institution from Abbott, Janssen, Medtronic, and Novartis; has equity <1% in Applied Therapeutics, Elixir Medical, STEL, and CONTROLRAD (spouse); and is on the Scientific Advisory Board for AMA, ACC (BOT Member), SCAI (Women in Innovations Committee Member), and JAMA Associate Editor; and Faculty CRF (no fee). Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; has received personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd., Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma. Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica health, Intas Pharma, J.B. Chemicals & Pharma. Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma., The Corpus, Translation Research Group, and Translational Medicine Academy; and he is a director of Global Clinical Trial Partners Ltd. Dr Nunez has received personal fees from or is on the advisory boards for Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Cytokinetics, Novartis, Novo Nordisk, Rovi, and Vifor Pharma. Dr Pfeffer has received research grant support through his institution from Novartis; has been a consultant to Alnylam, AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, Lexicon, NHLBI CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, and Sanofi; and has equity in DalCor. Dr Rouleau has received consultant fees from Novartis, BMS, Bayer, and AstraZeneca. Dr Sim has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. Dr Steg has received research grants from Amarin, Bayer, Sanofi, and Servier; and has received speaker or consultant fees from Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Kowa, Idorsia, Lexicon, Merck, Novartis, Novo Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, and Servier. Dr Van der Meer has received consultancy fees and/or grants, through the University Medical Center Groningen, from Novartis, Pharmacosmos, Vifor Pharma, AstraZeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi-Sankyo, Boehringer Ingelheim, and Ionis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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