Clopidogrel versus aspirin for secondary prevention of coronary artery disease: a systematic review and individual patient data meta-analysis
- PMID: 40902613
- DOI: 10.1016/S0140-6736(25)01562-4
Clopidogrel versus aspirin for secondary prevention of coronary artery disease: a systematic review and individual patient data meta-analysis
Abstract
Background: Aspirin monotherapy is recommended indefinitely for patients with established coronary artery disease (CAD). The aim of this individual patient level meta-analysis was to provide a comprehensive evaluation of the comparative efficacy and safety of clopidogrel versus aspirin monotherapy in patients with established CAD, most of whom had undergone percutaneous coronary intervention or had acute coronary syndrome.
Methods: We conducted a systematic search in PubMed, Scopus, Web of Science, and Embase to identify randomised trials published from database inception to April 12, 2025, comparing clopidogrel monotherapy with aspirin monotherapy in patients with established CAD who had discontinued or never started dual antiplatelet therapy. Randomised trials featuring an initial phase of dual antiplatelet therapy were eligible for inclusion in this individual patient data meta-analysis. In the main analysis, we used semi-parametric shared log-normal frailty models (one-stage analysis), including a random intercept to account for differences in the baseline hazard across trials, and a random slope to account for between-trial differences in treatment effects. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular or cerebrovascular events [MACCE]); the primary safety endpoint was major bleeding. This study is registered with PROSPERO (CRD42025645594).
Findings: Seven randomised trials including 28 982 patients (14 507 assigned to clopidogrel; 14 475 assigned to aspirin) with a median follow-up of 2·3 years (IQR 1·1-4·0) were eligible and included. At 5·5 years, MACCE was less common in patients assigned to clopidogrel than in patients assigned to aspirin (929 events [2·61 per 100 patient-years] vs 1062 events [2·99 per 100 patient-years]; hazard ratio 0·86 [95% CI 0·77-0·96]; p=0·0082). Mortality and major bleeding (256 events [0·71 per 100 patient-years] with clopidogrel vs 279 events [0·77 per 100 patient-years] with aspirin; 0·94 [0·74-1·21]; p=0·64) did not differ.
Interpretation: These findings add to the evidence that clopidogrel monotherapy is superior to aspirin monotherapy for MACCE prevention with no increase in the risk of bleeding, and support the preferential use of clopidogrel over aspirin for secondary prevention in patients with established CAD.
Funding: Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Switzerland.
Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Conflict of interest statement
Declaration of interests MV reports personal fees from Astra Zeneca, Alvimedica–CID, Abbott Vascular, Daiichi Sankyo, Bayer, CoreFLOW, Idorsia Pharmaceuticals, Universität Basel Depart Klinische Forschung, Bristol Myers Squibb, Medscape, Biotronik, and Novartis; and grants and personal fees from Terumo. KHC reports funding from the Korean Society of Cardiology and Abbott Vascular. FG reports personal fees from Sanofi for participation on an advisory board. TK reports research grants from Abbott and Boston Scientific. MW is a consultant for Freeline and has, in the past 12 months, been a consultant to Amgen. DLB is on advisory boards for Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; is on the board of directors for American Heart Association New York City; holds stock options at Angiowave and DRS.LINQ; holds stock at Bristol Myers Squibb and High Enroll; is a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; and is on the data monitoring committees of Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, and Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo). DLB is funded by Concept Medical (for the ABILITY-DM trial), by Alleviant Medical, Novartis, and Population Health Research Institute (for ALLAY-HF), and by Rutgers University (for the NIxnded MINT Trial). DLB reports honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi–Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim, AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor and Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence–ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee). DLB is a deputy editor for Clinical Cardiology; and is named on a patent for sotagliflozin assigned to Brigham and Women's Hospital, who subsequently assigned it to Lexicon; neither DLB nor the Brigham and Women's Hospital receive any income from this patent. DLB reports research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio. DLB reports receiving royalties from Elsevier (Editor, Braunwald's Heart Disease); is a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a trustee for the American College of Cardiology; and reports unfunded research for FlowCo. DJA reports consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and the Scott R MacKenzie Foundation, all paid to institution. RM reports grants or contracts from Abbott, Affluent Medical, Alleviant Medical, Amgen, AstraZeneca, BAIM, Beth Israel Deaconess Medical Center, Boston Scientific, Bristol Myers Squibb, CardiaWave, CERC, Chiesi, Concept Medical, Daiichi Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Pi-Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi, and Zoll (paid to their institution); consulting fees from Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, Daiichi Sankyo, Esperion Science–Innovative Biopharma, Gaffney Events, Educational Trust, Global Clinical Trial Partners, IQVIA, Medscape–WebMD Global, Novo Nordisk, PeerView Institute for Medical Education, TERUMO Europe NV, and Radcliffe (personal fees); honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the American College of Cardiology Board of trustees, Steering Committee Member, and American Medical Association (for being an Associate Editor at JAMA); leadership or a fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, from the American Medical Association (Scientific Advisory Board, and as Associate Editor for JAMA Cardiology), American College of Cardiology (Board of Trustees Member and Steering Committee Member of the Clinical Trial Research Program), and the Society for Cardiovascular Angiography & Interventions (Women in Innovations committee member); stock or stock options for Elixir Medical, Stel, and ControlRad; and was a faculty member but receives no fees from the Cardiovascular Research Foundation. YBS reports funding from the Korean Society of Cardiology and Microport. J-YH reports funding from the South Korean National Evidence-based Healthcare Collaborating Agency, the South Korean Ministry of Health & Welfare, Abbott Vascular, Biosensors, Biotronik, Boston Scientific, Daiichi Sankyo, Dong-A ST, Hanmi Pharmaceutical, and Medtronic. All other authors declare no competing interests.
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