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Research

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

BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1332 (Published 16 June 2021) Cite this as: BMJ 2021;373:n1332

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  1. Marco Valgimigli, professor of cardiology1 2*,
  2. Felice Gragnano, research associate and doctoral student3*,
  3. Mattia Branca, senior statistician4,
  4. Anna Franzone, associate professor5,
  5. Usman Baber, assistant professor6,
  6. Yangsoo Jang, professor of cardiology7,
  7. Takeshi Kimura, professor of cardiology8,
  8. Joo-Yong Hahn, associate professor of cardiology9,
  9. Qiang Zhao, professor of cardiac surgery10,
  10. Stephan Windecker, professor of cardiology2,
  11. Charles M Gibson, professor of medicine11,
  12. Byeong-Keuk Kim, professor of cardiology7,
  13. Hirotoshi Watanabe, senior interventional cardiologist8,
  14. Young Bin Song, associate professor of cardiology9,
  15. Yunpeng Zhu, researcher in thoracic and cardiac surgery10,
  16. Pascal Vranckx, professor of cardiology12,
  17. Shamir Mehta, professor of medicine13 14,
  18. Sung-Jin Hong, assistant professor of medicine7,
  19. Kenji Ando, professor of cardiology15,
  20. Hyeon-Cheol Gwon, professor of cardiology9,
  21. Patrick W Serruys, professor of cardiology16 17,
  22. George D Dangas, professor of medicine6,
  23. Eùgene P McFadden, senior interventional cardiologist18 19,
  24. Dominick J Angiolillo, professor of medicine20,
  25. Dik Heg, head of cardiovascular health4,
  26. Peter Jüni, professor of medicine and epidemiology21*,
  27. Roxana Mehran, professor of medicine6*
  1. 1Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland
  2. 2Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland
  3. 3Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Caserta, Italy
  4. 4Clinical Trials Unit, Bern, Switzerland
  5. 5Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
  6. 6Icahn School of Medicine at Mount Sinai, New York, NY, USA
  7. 7Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
  8. 8Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  9. 9Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  10. 10Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  11. 11Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
  12. 12Department of Cardiology and Critical Care Medicine, Hartcentrum Hasselt, Jessa Ziekenhuis, Belgium
  13. 13Department of Medicine, McMaster University, Hamilton, ON, Canada
  14. 14Hamilton Health Sciences, Hamilton, ON, Canada
  15. 15Kokura Memorial Hospital, Department of Cardiology, Kitakyushu, Japan
  16. 16Department of Cardiology, National University of Ireland Galway, Galway, Ireland
  17. 17National Heart and Lung Institute, Imperial College London, London, UK
  18. 18Cardialysis Core Laboratories and Clinical Trial Management, Rotterdam, Netherlands
  19. 19Department of Cardiology, Cork University Hospital, Cork, Ireland
  20. 20Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
  21. 21Applied Health Research Centre of the Li Ka Shing Knowledge Institute, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, ON, Canada
  22. *Contributed equally
  1. Correspondence to: M Valgimigl marco.valgimigli{at}cardiocentro.org (or @vlgmrc on Twitter)
  • Accepted 21 May 2021

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.

Footnotes

  • Contributors: MV and FG contributed equally to this work and are joint first authors. PJ and RM contributed equally to this work and are joint last authors. MV and RM conceived and designed the study. MV, FG, MB, AF, UB, YJ, TK, J-YH, QZ, SW, MG, B-KK, HW, Y-BS, YZ, PV, SM, S-JH, KA, H-CG, PWS, GDD, EPM, DJA, DH, PJ, and RM collected, analysed, and interpreted data. MV, FG, PJ, and RM drafted the manuscript. MV, FG, MB, AF, UB, YJ, TK, J-YH, QZ, SW, MG, B-KK, HW, Y-BS, YZ, PV, SM, S-JH, KA, H-CG, PWS, GDD, EPM, DJA, DH, PJ, and RM critically revised the manuscript for important intellectual content. MB, DH, and PJ did the statistical analysis. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. MV and RM are the guarantors.

  • Funding: This study was funded by institutional support of the Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, which had no role in the data analysis, interpretation, or writing of the report. There was no industry involvement in the design, analysis, or funding of this study.

  • 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.

  • The manuscript’s guarantor affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: The authors will disseminate the study results through their social media outlets, including Twitter, Facebook, and LinkedIn. They will run dedicated #hashtag campaigns (#SIDNEY2, #MonoP2Y12, #monoTx) to promote the main findings. The results will be also disseminated through scientific meetings and webinars. Press releases will be prepared for public engagement via general medicine and cardiology blogs and websites on request.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

Requests for data sharing should be sent to the corresponding author at marco.valgimigli@cardiocentro.org.

http://creativecommons.org/licenses/by-nc/4.0/

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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