Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial
BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d3527 (Published 17 June 2011) Cite this as: BMJ 2011;342:d3527- Stefan K James, associate professor1,
- Matthew T Roe, associate professor2,
- Christopher P Cannon, associate professor3,
- Jan H Cornel, cardiologist4,
- Jay Horrow, executive director, global medicines development5,
- Steen Husted, chief of thrombosis unit6,
- Hugo Katus, chief of the department of internal medicine, head of cardiology7,
- Joao Morais, chief of cardiology8,
- Ph Gabriel Steg, professor91011,
- Robert F Storey, professor12,
- Susanna Stevens, senior biostatistician2,
- Lars Wallentin, professor1,
- Robert A Harrington, professor2
- For the PLATO Study Group
- 1Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
- 2Duke Clinical Research Institute, Durham, NC, USA
- 3TIMI Study Group, Brigham and Women’s Hospital, Boston, MA, USA
- 4Medisch Centrum Alkmaar, Alkmaar, Netherlands
- 5AstraZeneca R&D, Wilmington, DE, USA
- 6Department of Cardiology, Århus University Hospital, Århus, Denmark
- 7Medizinische Klinik, Universitätsklinikum Heidelberg, Germany
- 8Santo Andre’s Hospital, Leiria, Portugal
- 9INSERM U-698, Paris, France
- 10Université Paris 7, Paris, France
- 11Hôpital Bichat, AP-HP, Paris, France
- 12Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
- Correspondence to: S James, Uppsala Clinical Research Center, Dag Hammarskjölds väg 50A, MTC-huset, Science Park, Box 6363, 751 85 Uppsala, Sweden Stefan.James{at}ucr.uu.se
- Accepted 21 April 2011
Abstract
Objective To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy.
Design Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial.
Setting 862 centres in 43 countries.
Participants 5216 (28%) of 18 624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management.
Interventions Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615).
Main outcome measurements Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year.
Results 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel.
Conclusions In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy.
Trial registration Clinical trials NCT00391872.
Footnotes
Contributors: SKJ participated in study design; data gathering, analysis, and interpretation; writing the first draft; and all revisions of the report. CPC, JH, SH, HK, PGS, RFS, LW, and RAH were involved in study design; data gathering, analysis, and interpretation; and revision of the report. MTR, JK, and JM participated in data gathering and interpretation and revision of the report. SS was involved in data analysis and revision of the report. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. SKJ is the guarantor.
Funding: This work was supported by AstraZeneca, who funded the PLATO trial. Representatives of the sponsor were involved in study design; data gathering, analysis, and interpretation; and revision of the report. Support for the analysis and interpretation of results and preparation of the manuscript was provided through funds to the Uppsala Clinical Research Center and Duke Clinical Research Institute as part of the clinical study agreement.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available upon request from the corresponding author). SKJ declares research grants and advisory board fees from AstraZeneca and honorariums from AstraZeneca, Bristol-Myers Squibb, Schering-Plough, Merck, and Eli-Lilly. MTR declares research grants from Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, and Merck/Schering-Plough; consulting fees or honorariums from GlaxoSmithKline, Novartis, Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, Merck/Schering-Plough, and AstraZeneca. CPC receives research grants/support from Accumetrics, AstraZeneca, Glaxo-SmithKline, Intekrin Therapeutics, Merck, and Takeda; has served on advisory boards for Bristol-Myers Squibb/Sanofi-Aventis, Novartis, and Alnyam (but donates funds to charity); receives honorariums for development of independent educational symposiums from Pfizer and AstraZeneca; and is a clinical adviser for and holds equity in Automedics Medical Systems. JHC declares consulting fees from Eli Lilly and Pfizer. JH is an employee of AstraZeneca and has equity ownership in AstraZeneca. SH declares research grants from AstraZeneca, Bristol-Myers Squibb, Pfizer, and Bayer and consultant fees from Sanofi-Aventis, Pfizer, and AstraZeneca. HK declares consulting and lecture fees from AstraZeneca., Bayer, Daiichi, Sankoy, and Roche. JM declares research grants from AstraZeneca, Bayer, Daiichi Sankyo, MSD/Schering-Plough, and Eli Lilly. PGS declares research grants from Servier; consultant fees from/advisory board membership for Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi/Sankyo/Eli Lilly alliance, GlaxoSmithKline, Medtronic, Merck, Otsuka Pharmaceutical, Roche, Sanofi-Aventis, Servier, and the Medicines Company; and having equity ownership in Aterovax. RFS declares institutional grants from AstraZeneca, Dynabyte, Eli Lilly/Daiichi Sankyo alliance, Merck/Schering-Plough, and Accumetrics; honorariums from AstraZeneca, Eli Lilly/Daiichi Sankyo alliance, Novartis, Medscape, GlaxoSmithKline, and Merck/Schering-Plough; consultant fees from AstraZeneca, Eli Lilly/Daiichi Sankyo alliance, Merck/Schering-Plough, Novartis, Sanofi-Aventis/Bristol-Myers Squibb, the Medicines Company, and Accumetrics; travel support from AstraZeneca, Eli Lilly/Daiichi Sankyo alliance, and Merck/Schering-Plough. LW reports research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and Schering-Plough; honorariums from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Schering-Plough, and Eli Lilly; consultant fees from Regado Biotechnologies, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, and Eli Lilly; and lecture fees from AstraZeneca, Boehringer Ingelheim, and Eli Lilly. RAH reports advisory board fees from Novartis, Portola Pharmaceutical, and Merck; consulting fees from AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Portola, and Sanofi-Aventis; honorariums/lecture fees from Eli Lilly, Merck, and AstraZeneca; grant support from AstraZeneca, Bristol-Myers Squibb, Portola Pharmaceutical, and Merck; travel support from AstraZeneca, Novartis, and Merck; and potential grant support from the Medicines Company.
Ethical approval: The trial was approved by ethical review boards. All patients gave a written informed consent.
Data sharing: The authors are willing to share the protocol and the statistical analysis plan for this study but will not be able to share the database.
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