Clopidogrel versus aspirin for coronary artery disease.

# Clopidogrel versus aspirin for coronary artery disease *The Lancet 2026* Correspondence and industry-funded, yet all were 2 Zeng L, Brignardello-Petersen R, Hultcrantz M, making it difficult to evaluate the judged as having a low risk of bias. et al. GRADE guidance 34: update on rating differential effect of each phenotype.4 imprecision using a minimally contextualized Results appear precise and consistent; approach. J Clin Epidemiol 2022; 150: 216–24. Valgimigli and colleagues also however, we are not convinced they highlight substantial interindividual support clopidogrel replacing aspirin Clopidogrel is a prodrug that needs to variability in the response to aspirin,1 as the preferred long-term strategy. be activated in the liver by CYP2C19, the underlying factors of which are less The absolute effect is small: the and genetic variability affects its understood. The fact that clopidogrel difference in MACCE is 0·38 per clinical efficacy. The UK National is more effective than aspirin cannot 100 patient-years, which we calculated Institute for Health and Care Excellence be used to conclude that no variability to correspond to a number needed recommended in 2024 that patients exists in clopidogrel response. The to treat (NNT) of 263 per year. The with acute transient ischaemic attack main conclusion of the meta-analysis included trials had anticipated relative and stroke should have pretreatment is that, in the population studied, risk reductions from 11% to 40%, far CYP2C19 genotyping.1 Marco the rate of poor response to aspirin greater than the observed reductions. Valgimigli and colleagues, in their is higher than that to clopidogrel. Mortality (hazard ratio 0·99 [95% CI systematic review and meta-analysis on Thus, the role of CYP2C19 genotyping 0·89–1·09]) and major bleeding (0·94 clopidogrel versus aspirin for secondary cannot be discounted when using [95% CI 0·74–1·21]) showed no prevention of coronary artery disease, clopidogrel for secondary prevention. meaningful differences.1 These suggest that CYP2C19 genetic variation Better outcomes might be found by findings are more compatible with might be less important over time than personalising therapy for secondary equivalence than superiority of it is acutely.2 This suggestion is based prevention, with the current standard clopidogrel. Showing true superiority on a study done with 300 patients in of care, aspirin, being used in the would have required prespecified whom platelet reactivity changed from minority of patients who are unable minimally important differences,2 baseline to 1 month, with genotype to adequately metabolise clopidogrel. reasonably exceeding the observed justifying 18% of this result.3 The All authors were partly funded by UK Research and absolute reduction in MACCE. effect of CYP2C19*2 and CYP2C19*17 Innovation and the Economic and Social Research Recommending switching from on platelet reactivity, two variants in Council through the grant The organisation and diffusion of translational research: can aspirin to clopidogrel is difficult to CYP2C19 gene, did not change over cardiovascular medicine learn from oncology? Case justify given the high NNT and no time in this study. Importantly, another studies of pharmacogenomics in the NHS (grant difference in mortality or bleeding. Very loss-of-function variant, CYP2C19*3, number ESRC – ES/W011484/1). MP and CDR received funding from Innovate UK to develop the small differences in benefit and harm, was not tested.3 Centre of Excellence in Regulatory Science and combined with cost-effectiveness In Valgimigli and colleagues’ meta- Innovation in Pharmacogenomics at the University analyses, make supporting clopidogrel analysis, the rate of events (10·7%) of Liverpool. MP also received funding from the MRC Medicines Development Fellowship, the as standard care unlikely. In conclusion, in the clopidogrel group is still National Institute for Health Research, the Medical large numbers can yield statistical significant.2 The effect of CYP2C19 Research Council, the National Health Service significance but not clinical relevance. genetic variation was not adequately Genomics Unit as part of the North West Genomic Medicine Service Alliance, the NHS Race and Health evaluated because of insufficient We declare no competing interests. During the Observatory, Health Data Research UK, and the EU preparation of this work, the authors used data: only one trial included in the Innovative Medicines Initiative; received ChatGPT 4.1 to assist with grammar and meta-analysis, SMART CHOICE 3, institutional royalties for the development of an punctuation. After using this tool, the authors conducted exploratory pharma- HLA genotyping panel with MC Diagnostics; is Chair reviewed and edited the content as needed and take of an advisory board for the Bosch Health full responsibility for the content of the publication. cogenetic analysis on a subgroup of Foundation; is Vice Chair of the Qatar Precision 731 (26·6%) of 2752 patients in the Health Initiative; is Chair of the Commission on *Agostino Colli, Giovanni Casazza, clopidogrel group.4 A comparison Human Medicines; is a Medical Trustee of the British Christian Gluud Heart Foundation; and is a council member of the made between rapid and normal colliagostino@gmail.com Medical Research Council. RR, AA, and DG received versus intermediate and poor funding from The Christie NHS Foundation Trust Copenhagen Trial Unit, Centre for Clinical Intervention metabolisers showed no influence (Christie 2030 research programme). DG also Research, Copenhagen University Hospital - received funding from ERA-LEARN 2023–27 (grant Rigshospitalet, DK-2100 Copenhagen, Denmark of the genotype on the primary number 101102316). (AC, CG); Department of Clinical Sciences and outcome.4 The rate of event in this Community Health, Università degli Studi di Milano, *Cinzia Dello Russo, Luigi Venetucci, subpopulation (~2%)4 is well below Milan, Italy (GC); Department of Regional Health Ronnie Ramlogan, Dimitri Gagliardi, Research, The Faculty of Health Sciences, University of the rate of events of the meta- Abisobe Akintola, Munir Pirmohamed Southern Denmark, Odense, Denmark (CG) analysis, which raises questions cdr@liverpool.ac.uk 1 Valgimigli M, Choi KH, Giacoppo D, et al. of whether this subpopulation is Clopidogrel versus aspirin for secondary representative. The investigators Department of Pharmacology and Therapeutics, prevention of coronary artery disease: a Institute of Systems, Molecular and Integrative systematic review and individual patient data analysed intermediate and poor Biology, University of Liverpool, Liverpool L69 3GL, meta-analysis. Lancet 2025; 406: 1091–102. metabolisers as a single group, UK (CDR, MP); Section of Pharmacology, 852 Correspondence Department of Translational Medicine and Surgery, found for clopidogrel as compared 5 Ferreiro JL, Ueno M, Tomasello SD, et al. Università Cattolica del Sacro Cuore - Fondazione with aspirin in patients taking PPIs Pharmacodynamic evaluation of pantoprazole Policlinico Universitario A Gemelli, IRCCS, Rome, therapy on clopidogrel effects: results of a Italy (CDR); Division of Cardiovascular Sciences, (HR 0·98; 95% CI 0·72–1·33).1 prospective, randomized, crossover study. University of Manchester, Manchester, UK (LV); This divergence, by which PPI Circ Cardiovasc Interv 2011; 4: 273–79. Manchester Institute of Innovation Research, cotherapy can attenuate both efficacy Alliance Manchester Business School, University of and safety advantages, should be Authors’ reply Manchester, Manchester, UK (RR, DG, AA); The Wolfson Centre for Personalised Medicine, Centre interpreted with caution, as subgroup We welcome the interest in our for Drug Safety Science, University of Liverpool, analyses are inherently hypothesis- individual patient data meta-analysis.1 Liverpool, UK (MP) generating. This analysis highlights Agostino Colli and colleagues 1 National Institute for Health and Care that a patient’s concomitant question whether our findings are Excellence. CYP2C19 genotype testing to guide clopidogrel use after ischaemic stroke or medication list is not minor but clinically relevant or rather futile, transient ischaemic attack. July 31, 2024. could be the primary determinant because of “very small differences in https://www.nice.org.uk/guidance/dg59 of net clinical benefit. Therefore, benefit and harm” and “no difference (accessed Feb 5, 2026). 2 Valgimigli M, Choi KH, Giacoppo D, et al. although the clinical significance in mortality or bleeding”. In our meta- Clopidogrel versus aspirin for secondary of the interaction between PPIs analysis, clopidogrel was associated prevention of coronary artery disease: a systematic review and individual patient data and clopidogrel remains a subject with a significant reduction in the meta-analysis. Lancet 2025; 406: 1091–102. of debate, with many large studies composite endpoint of cardiovascular 3 Campo G, Parrinello G, Ferraresi P, et al. showing no significant increase in death, myocardial infarction, or Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated adverse cardiovascular events,3,4 if PPI stroke (adjusted hazard ratio 0·84 with percutaneous coronary intervention cotherapy is required, pantoprazole [95% CI 0·75–0·94]; p=0.0021), driven relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011; should be recommended over other by significant reductions in both 57: 2474–83. PPIs due to its more favourable myocardial infarction and stroke, 4 Choi KH, Park YH, Lee JY, et al. Efficacy and pharmacodynamic profile.5 As data including haemorrhagic events.1 safety of clopidogrel versus aspirin monotherapy in patients at high risk of regarding clopidogrel–PPI interaction The relevance of these findings is subsequent cardiovascular event after specifically in the secondary unquestionable when the proper time percutaneous coronary intervention (SMART- CHOICE 3): a randomised, open-label, prevention phase are scarce, we call horizon of one or even more decades multicentre trial. Lancet 2025; 405: 1252–63. for dedicated studies to definitively is considered, rather than an arbitrary evaluate this clinical relationship. treatment duration of a single year, The meta-analysis by Marco Valgimigli considering the lifelong management We declare no competing interests. and colleagues provides compelling of coronary artery disease. The Ahmed Ibrahim, Laila Shalabi, evidence favouring clopidogrel over absence of a bleeding penalty with *Giuseppe Andò aspirin for secondary prevention clopidogrel reinforces the clinical giuseppe.ando@unime.it in coronary artery disease,1 with a relevance of the treatment rather significant reduction in major adverse Faculty of Medicine, Alexandria University, than undermining it. The absence of Alexandria, Egypt (AI); Faculty of Medicine, Gharyan cardiovascular events that challenges a mortality benefit with clopidogrel University, Gharyan, Libya (LS); Department of Clinical conventional aspirin monotherapy.2 and Experimental Medicine, University of Messina reflects current knowledge about Although overall safety profiles and Azienda Ospedaliera Universitaria Policlinico the long-term use of antithrombotic Gaetano Martino, Messina 98124, Italy (GA) were similar between clopidogrel drugs in coronary artery disease; not 1 Valgimigli M, Choi KH, Giacoppo D, et al. and aspirin, a crucial finding was a single antithrombotic treatment or Clopidogrel versus aspirin for secondary a significant interaction between prevention of coronary artery disease: treatment combination for chronic a systematic review and individual patient clopidogrel and proton pump secondary prevention in coronary data meta-analysis. Lancet 2025; inhibitor (PPI) use on major 406: 1091–102. artery disease—including aspirin— bleeding (p =0·0072).1 Notably, 2 Vrints C, Andreotti F, Koskinas KC, et al, and has shown a clear mortality benefit interaction the ESC Scientific Document Group. 2024 ESC clopidogrel significantly reduced compared with placebo.2 Cost- Guidelines for the management of chronic major bleeding compared with aspirin coronary syndromes. Eur Heart J 2024; effectiveness is inherently dependent 45: 3415–537. in patients not taking PPIs; however, on context, pricing, and health-care 3 Focks JJ, Brouwer MA, van Oijen MGH, Lanas A, this protective effect was not found Bhatt DL, Verheugt FWA. Concomitant use of systems, and should be addressed among concurrent PPI users, with a clopidogrel and proton pump inhibitors: through formal economic modelling impact on platelet function and clinical non-significant increase in bleeding rather than hypothetical assumptions. outcome-a systematic review. Heart 2013; risk found for concurrent PPI users 99: 520–27. The concerns raised by Cinzia Dello (hazard ratio 1·32; 95% CI 0·95–1·83).1 4 Guo H, Ye Z, Huang R. Clinical outcomes of Russo and colleagues regarding concomitant use of proton pump inhibitors Similarly, a non-significant effect in and dual antiplatelet therapy: a systematic clopidogrel resistance should be terms of major adverse cardiovascular review and meta-analysis. Front Pharmacol interpreted within the appropriate 2021; 12: 694698. or cerebrovascular events was clinical context. The relevance of --- [PDF原文](https://sci-net.xyz/storage/7932541/e3dee54dbd9bc502ef40d696a01eb640b9ea047bd9832c9cf823923fecc9243c/Clopidogrel-versus-aspirin-for-coronary-artery-disease.pdf) DOI: 10.1016/S0140-6736(25)02644-3