Aristeidis H. Katsanos, MD, PhD
The Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) is a double-blind randomized clinical trial, which assigned a total of 27,395 participants with stable coronary artery or peripheral artery disease to receive either aspirin 100 mg once daily or rivaroxaban 5 mg twice daily or rivaroxaban 2.5 mg twice daily plus aspirin. Stroke occurrence during a mean follow-up of 23 months was reduced to 0.5% in the rivaroxaban 2.5 mg BID plus aspirin group (HR=0.58, 95%CI: 0.44-0.76, p<0.0001), while no significant difference was noted in the occurrence of stroke in the rivaroxaban 5 mg BID group (HR=0.82, 95%CI: 0.65-1.05) compared to aspirin monotherapy. Interestingly, the incidence of hemorrhagic stroke was significantly increased in the rivaroxaban 5mg BID group compared to the aspirin alone group (HR=2.70, 95%CI: 1.31-5.58, p=0.005), but no increase in the risk of hemorrhagic stroke was found for the combination of rivaroxaban 2.5 mg BID with aspirin group (HR=1.49, 95%CI: 0.67-3.31, p=0.33). The annualized rate of disabling or fatal stroke (modified Rankin Scale scores 3-6) was also found to be reduced in the rivaroxaban 2.5 mg BID plus aspirin group (HR=0.58, 95%CI: 0.37-0.89, p=0.01).
In predefined subgroup analysis, the authors found that the preventive effect of rivaroxaban 2.5 mg BID with aspirin combination was consistent for all cardiovascular risk strata, while it was found to be particularly marked for patients with history of previous stroke. In multivariable analysis, previous stroke history was highlighted as the strongest predictor of incident stroke during follow-up (HR=3.63, 95%CI: 2.65-4.97, p<0.0001), with those participants receiving aspirin monotherapy having an almost 5-fold higher annualized stroke risk compared to those having no history of stroke. Compared to aspirin monotherapy, the rate of ischemic/unknown stroke was reduced by 67% with the combination of rivaroxaban 2.5mg BID plus aspirin (HR 0.33, 95% CI 0.14-0.77, p=0.01), while no significant reduction was observed for patients assigned to rivaroxaban 5mg BID alone (HR 0.79, 95% CI: 0.41-1.52, p=0.47). Although the total number of hemorrhagic strokes was small in the population of patients with prior stroke (5 total events in 1032 total participants with prior stroke), the risk of hemorrhagic stroke was found to be generally higher in patients with prior stroke compared to patients without prior stroke (HR 3.12, 95% CI 1.22-7.98, p=0.02).
The combination of rivaroxaban 2.5mg BID with aspirin 100 mg was found to prevent stroke and disabling stroke better than both aspirin and rivaroxaban 5mg BID monotherapies, without increasing the risk of hemorrhagic stroke — at least in primary stroke prevention. This amelioration of atherothrombotic embolism into the cerebral vasculature could be attributed to the concurrent inhibition of factor Xa (by anticoagulation) and cyclo-oxygenase (by antiplatelets). Further research on the patient subgroups that were excluded from the COMPASS trial (patients requiring anticoagulation, patients with stroke within 1 month or with previous lacunar stroke or intracerebral hemorrhage) and in the subgroup of patients with significant carotid stenosis ≥50% or previous carotid intervention (present in 7% of the COMPASS trial population) is needed to shed further light on the potential utility of combination treatment in these high-risk patient populations.