Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease
Courtney Murphy, Pharm.D., Essentia Health 

Background: Aspirin therapy lowers risk of cardiovascular (CV) events and death and is widely used as a secondary prevention therapy. Yet each year, 5-10% of patients with CV disease have a recurrent event.  Treatment with anticoagulants such as warfarin increases risk of bleeding and is not recommended in this setting.  Rivaroxaban, a selective direct factor Xa inhibitor used for stroke prevention in atrial fibrillation and treatment or prevention of venous thromboembolism, is another potential therapy for secondary CV prevention.

Purpose: The purpose of this study was to determine whether rivaroxaban alone or rivaroxaban plus aspirin would be more effective than aspirin alone for secondary prevention of cardiovascular events.

Study Design: This was one of two randomized comparisons in the COMPASS trial, which was double-blind and double-dummy. In a double-dummy design, two treatment arms cannot be made identical so two placebos are utilized.  In this case, the trial had a rivaroxaban placebo with the aspirin alone group and an aspirin placebo with the rivaroxaban alone group.  Patients included in the study had a history of stable atherosclerotic vascular disease, specifically coronary artery disease, peripheral arterial disease, or both.  Patients were excluded if they had a high bleed risk, recent stroke or previous hemorrhagic or lacunar stroke, severe heart failure, advanced stable kidney disease, used dual antiplatelet therapy, or non-CV conditions associated with poor prognosis.

Participants were given rivaroxaban matched placebo twice daily and aspirin 100 mg once daily during a run-in period to determine if they would be suitable for randomization.  Individuals 4 to 14 days post CABG were not required to participate in the run-in period since thrombotic graft occlusion is more common shortly after surgery.  After the run-in period, participants were randomly assigned in a 1:1:1 ratio to the following groups: rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg once daily.  Follow up occurred at one month and six months, and then every six months thereafter.

The primary efficacy outcome was composite CV death, stroke, or myocardial infarction.  The primary safety outcome was fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, or bleeding that led to hospitalization (with or without overnight stay).

Results: After a mean follow up of 23 months, the study was terminated early because a consistent difference was seen in the primary efficacy outcome favoring rivaroxaban plus aspirin.  The primary outcome occurred in 4.1% of patients in the rivaroxaban plus aspirin group, 4.9% of the rivaroxaban alone group, and 5.4% of the aspirin alone group.  The primary outcome occurred less with rivaroxaban plus aspirin versus aspirin alone (HR 0.76 [95% CI, 0.66 to 0.86; P<0.001]).  There was no significant difference in the primary outcome between rivaroxaban alone versus aspirin alone (HR 0.9 [95% CI 0.79 to 1.03], P=0.12).  Major bleeding occurred at a higher rate in the rivaroxaban plus aspirin group (HR 1.7 [95% CI 1.4 to 2.05], P<0.001).  The difference was largely seen in bleeding that led to presentation at an acute care facility or hospitalization and origin was most commonly in the gastrointestinal tract.  Comparing rivaroxaban alone to aspirin alone, more major bleeding occurred in the rivaroxaban group (HR 1.51 [95% CI 1.25 to 1.84], P<0.001).

The risk of composite net clinical benefit outcome (CV death, stroke, MI, fatal bleeding, or symptomatic bleeding into a critical organ) was lower in the rivaroxaban plus aspirin group than the aspirin alone group (HR 0.8 [95% CI 0.7 to 0.91], P<0.001).

Conclusions: In patients with stable atherosclerotic vascular disease, risk of major adverse CV events was significantly lower with rivaroxaban plus aspirin, although the risk of major bleeding was higher.

Key Point: In patients with stable atherosclerotic vascular disease, risk of major adverse cardiovascular events was significantly lower with rivaroxaban plus aspirin. However, the risk of major bleeding was higher which may warrant a risk versus. benefit analysis on an individual patient basis.

References:
Eikelboom JW, Connolly SJ, Bosch J, er al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017; 377:1319-1330.