Abstract
Background: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease. Methods: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. Findings: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65–0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78–1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37–2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23–1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65–0·90, p=0·0012). Interpretation: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide. Funding: Bayer AG.
| Original language | English |
|---|---|
| Pages (from-to) | 205-218 |
| Number of pages | 14 |
| Journal | The Lancet |
| Volume | 391 |
| Issue number | 10117 |
| DOIs | |
| State | Published - 20 Jan 2018 |
Bibliographical note
Publisher Copyright:© 2018 Elsevier Ltd
Funding
SJC reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo, during the conduct of the study, and grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Portola, and Sanofi Aventis outside the submitted work. JWE reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo during the conduct of the study, and grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Sanofi Aventis outside the submitted work. FL reports grants and personal fees from Bayer during the conduct of the study; personal fees from Pfizer; and grants and personal fees from Merck, Sharp & Dohme, Sanofi-Aventis, and Boehringer Ingelheim outside the submitted work. MO'D reports that his institution received grants from Population Health Research Institute/Bayer, during the conduct of the study. ALD reports grants, personal fees, and non-financial support from the Population Health Research Institute during the conduct of the study, and personal fees from Pfizer and Boehringer Ingelheim outside the submitted work. J-WH reports grants from the Population Health Research Institute during the conduct of the study. ANP reports grants and personal fees from Pfizer, Bayer, Janssen, AstraZeneca, Sanofi-Aventis, and Merck, Sharp & Dohme outside the submitted work. AAA reports consultancy fees from Boehringer Ingelheim outside the submitted work. EL reports personal fees from Bayer outside the submitted work. LL reports grants from the Population Health Research Institute during the conduct of the study. CT-P reports grants and personal fees from Bayer during the conduct of the study, and grants from Biotronic outside the submitted work. APM reports personal fees from Novartis, Bayer, Cardiorentis, and Fresenius outside the submitted work. CF reports personal fees from the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada during the conduct of the study. TJG reports personal fees from the Public Health Reasearch Institute during the conduct of the study, and personal fees from Sanofi Aventis outside the submitted work. DLB reports personal fees from the Population Health Research Institute during the conduct of the study, grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Eli Lilly, Chiesi, Ironwood, and The Medicines Company; personal fees from the Mayo Clinic, the Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, HMP Communications, Harvard Clinical Research Institute, Journal of the American College of Cardiology, Cleveland Clinic, Mount Sinai School of Medicine, Duke Clinical Research Institute; personal fees and non-financial support from the American College of Cardiology and the Society of Cardiovascular Patient Care; non-financial support from the American Heart Association; and non-financial relationships with Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Veterans Administration, Merck, Clinical Cardiology, St Jude Medical, Biotronik, Cardax, American College of Cardiology, Boston Scientific, FlowCo, PLx Pharma, and Takeda, outside the submitted work. KRHB reports grants from Bayer during the conduct of the study; and advisory board fees from Janssen outside the submitted work. NCB reports employment by Bayer during the conduct of the study. SDB reports employment by Bayer during the conduct of the study. SSA reports personal fees from Bayer and Novartis outside the submitted work. JDV reports personal fees from Novartis outside the submitted work. KAAF reports grants and personal fees from Bayer/Janssen during the conduct of the study, and grants and personal fees from AstraZeneca, personal fees from Sanofi/Regeneron and Eli Lilly outside the submitted work. SY reports grants and personal fees from Bayer during the conduct of the study. All other authors declare no competing interests.
| Funders | Funder number |
|---|---|
| Forest Laboratories/AstraZeneca | |
| Population Health Research Institute | |
| Society of Cardiovascular Patient Care | |
| U.S. Department of Veterans Affairs | |
| Mayo Clinic | |
| American Heart Association | |
| Eli Lilly and Company | |
| Pfizer | |
| Merck | |
| Roche | |
| American College of Cardiology Foundation | |
| Duke Clinical Research Institute | |
| Icahn School of Medicine at Mount Sinai | |
| Cleveland Clinic | |
| Boston VA Research Institute |