Combination of DOAC with aspirin effective for prevention of stroke in patients with CAD or PAD
Stroke Outcomes in the Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) TrialLiterature - Sharma M, Hart RG, Connolly SJ et al. - Circulation 2019; Online published ahead of print
Introduction and methods
Although treatment with aspirin is recommended for CV prevention in individuals with atherosclerosis, aspirin reduces risk for major vascular events (myocardial infarction, stroke, or vascular death) by only 12% in primary prevention and 19% in secondary prevention . A more effective antithrombotic strategy is therefore needed for prevention of major vascular events in patients with atherosclerosis. The Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) trial (n=27.395) therefore investigated the effect of rivaroxaban and aspirin vs. aspirin alone or rivaroxaban alone on stroke for prevention of vascular events in patients with stable coronary artery (CAD) or peripheral artery disease (PAD). This subanalysis investigated the effect on different stroke types, independent predictors of stroke, and effects in different key subgroups.
COMPASS was a double-blind, double-dummy trial including patients with stable CAD or PAD (including asymptomatic carotid artery stenosis ≥50% or previous carotid revascularization) who were randomized 1:1:1 to receive low-dose rivaroxaban (2.5 mg) twice daily plus aspirin 100 mg once daily (n=9.152), rivaroxaban 5 mg twice daily (n=9.117), or aspirin 100 mg once daily (n=9.126) for prevention of CV death, myocardial infarction, or stroke. The mean follow-up was 23 months.
Outcome was stroke, defined as the presence of acute focal neurological deficit thought to be of vascular origin with signs and symptoms lasting ≥24 hours or to time of death. Strokes were classified as: ischemic stroke, hemorrhagic stroke, or uncertain type of stroke. Abilities were evaluated by the modified Rankin Scale (mRS) and Standard Assessment of Global activities in the Elderly (SAGE) assessment.
Treatment effects on stroke incidence and severity
- The occurrence of stroke was reduced in patients treated with rivaroxaban plus aspirin, compared to those treated with aspirin alone (HR: 0.58, 95%CI: 0.44-0.76, P<0.0001), while no significant differences were observed between the rivaroxaban alone group compared with aspirin monotherapy (HR: 0.82, 95%CI: 0.65-1.05, P=0.12).
- Ischemic/uncertain strokes were reduced by nearly half in the rivaroxaban plus aspirin group, compared with aspirin alone (HR: 0.51, 95%CI: 0.38-0.68, P<0.0001). The treatment effect of rivaroxaban alone on ischemic/uncertain strokes was similarly substantial, compared to aspirin (HR: 0.69, 95%CI: 0.53-0.90, P=0.006).
- Significantly increased incidence of hemorrhagic stroke was seen with rivaroxaban alone (HR: 2.70, 95%CI: 1.31-5.58. P=0.005), but not by rivaroxaban plus aspirin (HR: 1.49, 95%CI: 0.67-3.31, P=0.33), compared with aspirin monotherapy.
- The mRs scores at day 7 or hospital discharge were similarly distributed for patients treated with aspirin monotherapy and those treated with rivaroxaban plus aspirin. Mean SAGE scores in those experiencing a stroke were not significantly different between treatment groups.
Baseline predictors of stroke and treatment effect in subgroups
- Independent predictors for stroke were age, systolic blood pressure at baseline, history of hypertension, prior stroke, and Asian ethnicity, of which prior stroke was the strongest predictor (HR: 3.63, 95%CI: 2.65-4.97, P<0.0001).
- Consistent treatment effects were seen on the outcome of stroke across all relevant subgroups identified as predictors of stroke occurrence during the trial, with no significant treatment interactions.
Treatment effects in secondary prevention of stroke
- Treatment with rivaroxaban plus aspirin reduced the rate for ischemic/unknown stroke by 67% (HR: 0.33, 95%CI: 0.14-0.77, P=0.01), compared to aspirin monotherapy, whereas no significant reduction was found with rivaroxaban alone. The absolute stroke reduction was 2.3% per year with rivaroxaban plus aspirin (NNT= 43 for one year).
- The annualized rate of the composite outcome of CV mortality, stroke or MI was 6.5% in participants with aspirin monotherapy and reduced to 3.7% in the rivaroxaban plus aspirin group (HR: 0.57, 95%CI: 0.34-0.96, P=0.04, NNT=36 for one year), whereas no significant reduction was found with rivaroxaban alone.
- Those with a prior stroke showed a higher annualized rate of hemorrhagic stroke of 0.3% with combination therapy than 0.08% for participants without prior stroke (HR: 3.12, 95%CI: 1.22-7.98, P=0.02). However, in the population with previous stroke, the total number of hemorrhagic strokes was small.
- Major bleeding was not significantly increased with combination therapy in those with prior stroke, occurring at an annualized rate of 1.5% as compared to 1.4% in those without a history of previous stroke (HR: 1.06, 95%CI: 0.72-1.56, P=0.76).
Treatment effects in prevention of first stroke in high-risk patients
- Combination therapy was associated with a 53% reduction in the annualized rate of ischemic/unknown strokes in high-risk patients (absolute reduction of 0.6% per year, NNT= 142 for one year) (HR: 0.51, 95%CI: 0.34-0.76, P=0.001, P=0.001), compared with aspirin monotherapy, whereas no effect was seen on the risk of hemorrhagic stroke.
- In high-risk patients treated with the combination therapy there was no increased risk of hemorrhagic stroke, whereas with rivaroxaban alone, a reduction was observed in the occurrence of ischemic/uncertain stroke (HR: 0.51, 95%CI: 0.34-0.77, P=0.001) and an increase in hemorrhagic stroke (HR: 3.08, 95%CI: 1.12-8.47, P=0.03), compared with aspirin monotherapy.
This subanalysis of the COMPASS trial showed that combination therapy with low-dose rivaroxaban plus aspirin reduced stroke in general and the subtype ischemic/uncertain stroke in patients with CAD or PAD without increased risk for hemorrhagic stroke. Treatment effects were similar across different key subgroups and prior stroke was the strongest predictor of stroke. This combination therapy is an important new option for efficacious antithrombotic therapy for primary and especially secondary prevention of stroke in patients with CAD or PAD.