Mortality benefit to adding rivaroxaban to aspirin in coronary artery disease — COMPASS trial

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Combining rivaroxaban with aspirin may help certain patients with coronary artery disease (CAD) or peripheral artery disease (PAD) live longer than they would with aspirin alone, a secondary analysis of the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial suggests.

"For patients with chronic atherosclerosis, adding a small dose of rivaroxaban to aspirin not only reduces the risk of major adverse cardiovascular events, it saves lives," said lead study author Dr John W Eikelboom of Hamilton General Hospital in Hamilton, Canada.

The multinational COMPASS trial enrolled more than 27,000 patients with chronic CAD or PAD, reports MedicalBrief. Eligible participants were 65 years of age or younger with clinically stable atherosclerosis involving at least two vascular beds, or who were at risk due to smoking, diabetes, chronic kidney disease, mild or moderate heart failure, or recent nonlacunar ischemic stroke.

The COMPASS study, published in the Journal of the American College of Cardiology, showed that combining 2.5mg rivaroxaban twice daily with 100mg aspirin once daily prevented cardiovascular death, stroke, or myocardial infarction more effectively than either 100mg aspirin per day alone or 5mg rivaroxaban twice daily. Because the combined therapy was more effective than aspirin, the trial was stopped early, and the combination is now approved for use in this setting in many countries.

In the new analysis, Eikelboom and colleagues compared findings from 9,152 COMPASS participants who received rivaroxaban plus aspirin, with those from 9,126 who received aspirin alone.

After a median follow-up of 23 months, 313 (3.4%) of patients receiving combined treatment vs. 378 (4.1%) getting aspirin alone died (hazard ratio, 0.82; P=0.01), the team reported.

Combined treatment also reduced cardiovascular death, with 160 (1.7%) versus 203 (2.2%) such deaths, respectively; hazard ratio: 0.78; P=0.02). However, combined treatment did not reduce non-cardiovascular death.

Patients with higher baseline risk saw greater absolute mortality benefit. As the researchers report, those "with 0, 1, 2, and 3 or 4 high-risk features at baseline had 4.2, 4.8, 25.0, and 53.9 fewer deaths, respectively, per 1000 patients treated for 30 months".

"These results should prompt clinicians to consider routine use of low- dose rivaroxaban for long-term management of patients with atherosclerosis who are at high risk of further events," Eikelboom said.

He noted that the study included few patients with a history of stroke and lacked patients with end-stage kidney disease. "Both these populations are at very high risk and urgently require further study," he said.

"This is a well-done secondary analysis of the influential COMPASS trial," said Dr Michael J. Blaha, a professor of medicine and the director of clinical research at the Ciccarone Center for the Prevention of Heart Disease at Johns Hopkins University in Maryland. "The most important part of this study is that the highest-risk patients received the most mortality benefit. This points to the importance of risk stratification, even in secondary prevention."

Blaha, who was not involved in the study, said: "For my practice, I try to focus intensive therapy on the high-risk subsets who received the most benefit in this study -polyvascular disease, mild or moderate heart failure, chronic kidney disease, and diabetes."

Dr Jonathan L. Halperin and colleagues from the Cardiovascular Institute of Mount Sinai Medical Center, in New York City, said the authors "provide important new information that helps to identify the patients most likely to benefit from dual pathway inhibitor therapy”.

"The immediate challenge is to identify patients who are likely to gain survival advantage from the specific dual pathway regimen they validated," they add. "That regimen is not appropriate for every patient with atherosclerosis, but for many of those with diabetes, involvement of more than one vascular bed, or ischemic heart disease underlying clinical heart failure, such treatment can begin today."

The authors recommend investigating possible survival benefits of combining the rivaroxaban with another blood thinner, ticagrelor.

Study details

Mortality Benefit of Rivaroxaban Plus Aspirin in Patients With Chronic Coronary or Peripheral Artery Disease

John W. Eikelboom, Deepak L. Bhatt, Keith A.A. Fox, Jacqueline Bosch, Stuart J. Connolly, Sonia S. Anand, Alvaro Avezum, Scott D. Berkowitz, Kelley R.H. Branch, Gilles R. Dagenais, Camilo Félix, Tomasz J. Guzik, Robert G. Hart, Aldo P. Maggioni, Eva Muehlhofer, Mukul Sharma, Olga Shestakovska, Salim Yusuf

Published in JACC Journals (American College of Cardiology), July 2021


Patients with recent coronary artery bypass graft (CABG) surgery are at risk for early graft failure, which is associated with a risk of myocardial infarction and death. In the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial, rivaroxaban 2.5mg twice daily plus aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced the primary major adverse cardiovascular events (MACE) outcome of cardiovascular death, stroke, or myocardial infarction. Rivaroxaban 5mg twice daily alone did not significantly reduce MACE.

This pre-planned substudy sought to determine whether the COMPASS treatments are more effective than aspirin alone for preventing graft failure and MACE after CABG surgery.

The substudy randomized 1,448 COMPASS trial patients 4 to 14 days after CABG surgery to receive the combination of rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone. The primary outcome was graft failure, diagnosed by computed tomography angiogram one year after surgery.

The combination of rivaroxaban and aspirin and the regimen of rivaroxaban alone did not reduce the graft failure rates compared with aspirin alone (combination vs. aspirin: 113 [9.1%] vs. 91 [8.0%] failed grafts; odds ratio [OR]: 1.13; 95% confidence interval [CI]: 0.82 to 1.57; p = 0.45; rivaroxaban alone vs. aspirin: 92 [7.8%] vs. 92 [8.0%] failed grafts; OR: 0.95; 95% CI: 0.67 to 1.33; p = 0.75). Compared with aspirin, the combination was associated with fewer MACE (12 [2.4%] vs. 16 [3.5%]; hazard ratio [HR]: 0.69; 95% CI: 0.33 to 1.47; p = 0.34), whereas rivaroxaban alone was not (16 [3.3%] vs. 16 [3.5%]; HR: 0.99, CI: 0.50 to 1.99; p = 0.98). There was no fatal bleeding or tamponade within 30 days of randomization.

The combination of rivaroxaban 2.5mg twice daily plus aspirin or rivaroxaban 5mg twice daily alone compared with aspirin alone did not reduce graft failure in patients with recent CABG surgery, but the combination of rivaroxaban 2.5mg twice daily plus aspirin was associated with similar reductions in MACE, as observed in the larger COMPASS trial. 


Journal of the American College of Cardiology article – Mortality Benefit of Rivaroxaban Plus Aspirin in Patients With Chronic Coronary or Peripheral Artery Disease


See more from MedicalBrief archives:


Concerns raised about anti-clotting drug trial


Thrombus formation varies according to the type of drug


Alternative approach to thrombosis


Little potential benefit from taking aspirin to treat atherosclerosis


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