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Meta-Analysis
. 2021 Jun 16:373:n1332.
doi: 10.1136/bmj.n1332.

P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trials

Marco Valgimigli  1   2   3 , Felice Gragnano  4   3 , Mattia Branca  5 , Anna Franzone  6 , Usman Baber  7 , Yangsoo Jang  8 , Takeshi Kimura  9 , Joo-Yong Hahn  10 , Qiang Zhao  11 , Stephan Windecker  2 , Charles M Gibson  12 , Byeong-Keuk Kim  8 , Hirotoshi Watanabe  9 , Young Bin Song  10 , Yunpeng Zhu  11 , Pascal Vranckx  13 , Shamir Mehta  14   15 , Sung-Jin Hong  8 , Kenji Ando  16 , Hyeon-Cheol Gwon  10 , Patrick W Serruys  17   18 , George D Dangas  7 , Eùgene P McFadden  19   20 , Dominick J Angiolillo  21 , Dik Heg  5 , Peter Jüni  22   3 , Roxana Mehran  7   3
Affiliations
Meta-Analysis

P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trials

Marco Valgimigli et al. BMJ. .

Erratum in

Abstract

Objective: To assess the risks and benefits of P2Y12 inhibitor monotherapy compared with dual antiplatelet therapy (DAPT) and whether these associations are modified by patients' characteristics.

Design: Individual patient level meta-analysis of randomised controlled trials.

Data sources: Searches were conducted in Ovid Medline, Embase, and three websites (www.tctmd.com, www.escardio.org, www.acc.org/cardiosourceplus) from inception to 16 July 2020. The primary authors provided individual participant data.

Eligibility criteria: Randomised controlled trials comparing effects of oral P2Y12 monotherapy and DAPT on centrally adjudicated endpoints after coronary revascularisation in patients without an indication for oral anticoagulation.

Main outcome measures: The primary outcome was a composite of all cause death, myocardial infarction, and stroke, tested for non-inferiority against a margin of 1.15 for the hazard ratio. The key safety endpoint was Bleeding Academic Research Consortium (BARC) type 3 or type 5 bleeding.

Results: The meta-analysis included data from six trials, including 24 096 patients. The primary outcome occurred in 283 (2.95%) patients with P2Y12 inhibitor monotherapy and 315 (3.27%) with DAPT in the per protocol population (hazard ratio 0.93, 95% confidence interval 0.79 to 1.09; P=0.005 for non-inferiority; P=0.38 for superiority; τ2=0.00) and in 303 (2.94%) with P2Y12 inhibitor monotherapy and 338 (3.36%) with DAPT in the intention to treat population (0.90, 0.77 to 1.05; P=0.18 for superiority; τ2=0.00). The treatment effect was consistent across all subgroups, except for sex (P for interaction=0.02), suggesting that P2Y12 inhibitor monotherapy lowers the risk of the primary ischaemic endpoint in women (hazard ratio 0.64, 0.46 to 0.89) but not in men (1.00, 0.83 to 1.19). The risk of bleeding was lower with P2Y12 inhibitor monotherapy than with DAPT (97 (0.89%) v 197 (1.83%); hazard ratio 0.49, 0.39 to 0.63; P<0.001; τ2=0.03), which was consistent across subgroups, except for type of P2Y12 inhibitor (P for interaction=0.02), suggesting greater benefit when a newer P2Y12 inhibitor rather than clopidogrel was part of the DAPT regimen.

Conclusions: P2Y12 inhibitor monotherapy was associated with a similar risk of death, myocardial infarction, or stroke, with evidence that this association may be modified by sex, and a lower bleeding risk compared with DAPT.

Registration: PROSPERO CRD42020176853.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: MV has received personal grants and personal fees from Terumo and personal fees from Astra Zeneca, Alvimedica/CID, Abbott Vascular, Daiichi Sankyo, from Bayer, CoreFLOW, Idorsia Pharmaceuticals, Universität Basel Dept Klinische Forschung, Bristol Myers Squib SA, Medscape, Biotronik, and Novartis, outside the submitted work; MB and DH are affiliated with CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees; however, CTU Bern is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organisations; in particular, pharmaceutical and medical device companies provide direct funding to some of these studies (for an up to date list of CTU Bern’s conflicts of interest see https://www.ctu.unibe.ch/research/declaration_of_interest/index_eng.html; TK has received grants and personal fees from Abbott Medical Japan and grants from Boston Scientific and served on an advisory board for Abbott Medical Japan and Terumo, outside the submitted work; J-YH has received grants from the Ministry of Health and Welfare, grants and personal fees from Abbott Vascular, Biotronik, Boston Scientific, Daiichi Sankyo, and Medtronic, and personal fees from Astra Zeneca and Sanofi-Aventis, outside the submitted work; QZ has received grants and personal fees from AstraZeneca and Chugaipharma, personal fees from Novartis and Sanofi, and personal fees and non-financial support from Johnson & Johnson, and Medtronic, outside the submitted work; SW has received research and educational grants to the institution from Abbott, Amgen, BMS, Bayer, Boston Scientific, Biotronik, Cardinal Health, CardioValve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Johnson & Johnson, Medtronic, Querbet, Polares, Sanofi, Terumo, and Sinomed, serves as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, BMS, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Sinomed, V-Wave, and Xeltis, is a member of the steering/executive committee group of several investigator initiated trials that receive funding by industry without impact on his personal remuneration, and is an unpaid member of the Pfizer Research Award selection committee in Switzerland; CMG has received personal fees from AstraZeneca during the conduct of the study and personal fees from Angel Medical Corporation and Bayer Corp, grants and personal fees from CSL Behring, Janssen Pharmaceuticals, and Johnson & Johnson Corporation, personal fees from the Medicines Company, Boston Clinical Research Institute, Cardiovascular Research Foundation, Eli Lilly and Company, Gilead Sciences Inc, Novo Nordisk, Web MD, UpToDate in Cardiovascular Medicine, Amarin Pharma, Amgen, Boehringer Ingelheim, Merck & Co Inc, PharmaMar, Sanofi, Somahlution, Vereseon Corporation, Boston Scientific, Duke Clinical Research Institute, Impact Bio Ltd, MedImmune, Medtelligence, Microport, PERT Consortium, GE Healthcare, Caladrius Bioscience, CeleCor Therapeutics, Thrombolytic Science, Eidos Therapeutics, Kiniksa Pharmaceuticals, Micodrop LLC, MD Magazine, MJHealth, Samsung, SCAI, Revance Therapeutics, Pfizer, and Gentech, non-financial support from Baim Institute, and grants from SCAD Alliance and has other relationships with Dyad Medical, outside the submitted work; HW has received personal fees from Abbott Medical Japan and Daiichi Sankyo, outside the submitted work; YZ has received grants and personal fees from AstraZeneca, personal fees from Novartis and Sanofi, personal fees and non-financial support from Medtronic, and grants and personal fees from Chugaipharma, outside the submitted work; PWS has received personal fees from Sinomedical, SMT, Philips, Xeltis, Novartis, and Merillife, outside the submitted work; GDD has received grants from AstraZeneca during the conduct of the study and personal fees from Biosensors, grants from Abbott Vascular, Medtronic, Daiichi-Sankyo, and Bayer, and grants and personal fees from Boston Scientific, outside the submitted work; EPMF reports personal fees from Cardialysis BV, Rotterdam, Netherlands, outside the submitted work; DJA has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and the Medicines Company and payments for participation in review activities from CeloNova and St Jude Medical, outside the present work, and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and Scott R MacKenzie Foundation; PV has received consulting fees or honoraria from AstraZeneca, Bayer AG, Daiichi-Sankyo, and the Medicines Company outside the present work, and his institution has received research grants from Daiichi-Sankyo and Medtronic; PJ serves as unpaid member of steering group or executive committee of trials funded by Abbott Vascular, Astra Zeneca, Biotronik, Biosensors, St Jude Medical, Terumo, and the Medicines Company and has received research grants to the institution from Appili Therapeutics, Astra Zeneca, Biotronik, Biosensors International, Eli Lilly, and the Medicines Company and honoraria to the institution for participation in advisory boards and/or consulting from Amgen, Ava, and Fresenius; RM has received grants from Abbott Laboratories, AstraZeneca, Bayer, Beth Israel Deaconess, BMS, CSL Behring, DSI, Medtronic, Novartis Pharmaceuticals, and OrbusNeich and personal fees from Abbott Laboratories, Boston Scientific, Medscape/WebMD, Siemens Medical Solutions, PLx Opco Inc/dba PLx Pharma Inc, Roivant Sciences, Sanofi, Medtelligence, and Janssen Scientific Affairs, has other financial relationships with Abbott Laboratories, Abiomed, the Medicines Company, Regeneron Pharmaceuticals, and Bristol Myers Squibb, and has non-financial support from and other relationships with Spectranetics/Philips/Volcano Corp and Watermark Research Partners, outside the submitted work; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
Hazard ratios for individual trials and for pooled population and Kaplan-Meier estimates for primary endpoint of all cause death, myocardial infarction, or stroke in intention to treat population. Kaplan-Meier curves and hazard ratios from one step, fixed effect meta-analysis (top) and two step, fixed effect meta-analysis (bottom). DAPT=dual antiplatelet therapy; P2Y12i=P2Y12 inhibitor monotherapy
Fig 2
Fig 2
Subgroup analyses for primary endpoint of all cause death, myocardial infarction, or stroke in intention to treat population. High bleeding risk was defined on basis of PRECISE-DAPT score ≥25. *P value obtained by merging within study and across study interactions (owing to design of trials). †European regions pooled together and within study and across study interactions merged owing to trial designs. ACS=acute coronary syndrome; CABG=coronary artery bypass grafting; CAD=coronary artery disease; CKD=chronic kidney disease; DAPT=dual antiplatelet therapy; LAD=left anterior descending artery; P2Y12i=P2Y12 inhibitor monotherapy; PCI=percutaneous coronary intervention
Fig 3
Fig 3
Sex stratified analysis for primary endpoint, all cause death, cardiovascular death, myocardial infarction, or stroke in intention to treat population. DAPT=dual antiplatelet therapy; P2Y12i=P2Y12 inhibitor monotherapy
Fig 4
Fig 4
Primary endpoint or its components and key safety endpoint stratified by use of clopidogrel or newer P2Y12 inhibitors in experimental arm of intention to treat population. BARC=Bleeding Academy Research Consortium; DAPT=dual antiplatelet therapy
Fig 5
Fig 5
Hazard ratios for individual trials and for pooled population and Kaplan-Meier estimates for key safety endpoint of Bleeding Academic Research Consortium (BARC) type 3 or type 5 bleeding in intention to treat population. Kaplan-Meier curves and hazard ratios from one step, fixed effect meta-analysis (top) and two step, fixed effect meta-analysis (bottom). DAPT=dual antiplatelet therapy
See this image and copyright information in PMC

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