Rivaroxaban plus aspirin, lowers CV and major adverse limb events, but increases bleeding in patients with stable CAD and PAD

Treatment with low-dose rivaroxaban plus aspirin resulted in a reduction of major CV events compared to aspirin in patients with stable CAD and reduced major adverse limb events in patients with PAD.

Connolly SJ, Eikelboom JW, Bosch J, et al. The Lancet 2018;391:205-218

Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

Anand SS, Bosch J, Eikelboom JW, et al. The Lancet 2018;391:219-229

Background

Use of anticoagulant therapy, an antiplatelet agent or a combination of these two has given mixed results in the outcomes of patients with stable coronary artery disease (CAD) and peripheral artery disease (PAD). The factor Xa inhibitor apixaban, in combination with antiplatelet therapy, showed no reduction in thrombotic events in ACS patients compared to placebo, whereas fatal and intracranial bleeding were increased [1]. In contrast, in the ATLAS 2 trial, rivaroxaban with aspirin reduced the risk of major ischemic events, the composite outcome of stroke, MI and CV death and overall mortality in ACS patients, although rivaroxaban alone (5 mg twice a day) increased major, intracranial and fatal bleeding [2].

The Cardiovascular Outcomes for People using Anticoagulation Strategies (COMPASS) trial [3,4] was a multicenter, randomized, double-blind, placebo-controlled trial, which enrolled 27395 patients with CAD or PAD and evaluated the effect of a factor Xa inhibitor on top of antiplatelet therapy. Patients with CAD (n=24824, median follow-up: 1.95 years) were required to be ≥65 years with documented atherosclerosis, revascularization or 2 of the following risk factors: smoking, diabetes, eGFR<60 mL/min, HF or non-lacunar stroke. Patients eligible for the PAD cohort (n=7470, median follow-up: 21 months) had PAD of the lower extremities, of the carotid arteries, or CAD with an ankle brachial index of <0.90.

After a run-in period of 30 days, patients were randomized to receive low-dose rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg twice a day) or aspirin alone (100 mg once a day). The primary outcome was a composite consisting of stroke, MI, or CV death. The primary PAD outcome was major adverse limb events including major amputations. There were three secondary outcomes: a composite of coronary heart disease (CHD) death, MI, ischemic stroke, or acute limb ischemia; occurrence of MI, ischemic stroke, CV death, or acute limb ischemia; and overall mortality.

Main results

Patients with stable CAD (Connolly et al.)

• 347 (4%) of 8313 patients had a primary outcome event in the low-dose rivaroxaban plus aspirin group, and 460 (6%) of 8261 patients in the aspirin alone group (HR 0.74, 95% CI 0.65–0.86, P<0·0001). No difference in the primary outcome was observed for rivaroxaban alone compared with aspirin alone.
• Similar results were seen when examining stroke alone as an outcome (low-dose rivaroxaban plus aspirin vs. aspirin alone: HR 0.56, 95% CI 0.42–0.75, P<0.0001).
• There were significant reductions in all three secondary outcomes in the low-dose rivaroxaban plus aspirin group compared with aspirin (composite of MI, ischemic stroke, CHD death, or acute limb ischemia: -28% [P<0.0001], composite of MI, ischemic stroke, CV death, or acute limb ischemia:-27% [P<0.0001] and mortality: -1% (P=0.0012).
• Major bleeding occurred in 263 (3%) of 8313 patients in the low-dose rivaroxaban plus aspirin group and in 158 (2%) of 8261 patients in the aspirin alone group (HR 1.66, 95% CI 1.37–2.03, P<0.0001). Intracranial and fatal bleeding were not significantly different between the rivaroxaban plus aspirin group and the aspirin alone group.
• The most common site of major bleeding in patients receiving rivaroxaban plus aspirin was the gastrointestinal tract. Gastrointestinal major bleeding was increased by rivaroxaban plus aspirin compared with aspirin alone (HR 2.13, 95% CI 1.57–2.88, P<0.0001).

Patients with PAD (Anand et al.)

• The primary outcome of CV death, MI, or stroke occurred in 126 (5%) of 2492 PAD patients with low-dose rivaroxaban plus aspirin and in 174 (7%) of 2504 patients who received aspirin alone (HR 0.72, 95% CI 0.57–0.90, P=0.0047). No difference in the primary outcome was observed for the rivaroxaban alone group vs. the aspirin alone group.
• Major adverse limb events were significantly lower in the low-dose rivaroxaban plus aspirin group compared with the aspirin alone group (30 [1%] of 2492 vs. 56 [2%] of 2504; HR 0.54, 95% CI 0.35–0.84, P=0.0054). Major amputations were less frequent in the low-dose rivaroxaban plus aspirin group when compared with aspirin alone (HR 0.30, 95% CI 0.11–0.80).
• There was an increase in major bleeding in the low-dose rivaroxaban plus aspirin group compared with the aspirin alone group (HR 1.61, 95% CI 1.12–2.31, P=0.0089). No differences in fatal bleeding or non-fatal intracranial hemorrhages or symptomatic bleeding into a critical organ were observed for any of the groups.
• The net clinical benefit outcome that takes major adverse CV events, major adverse limb events including major amputation, and fatal or critical organ bleeding into account, occurred in 169 (7%) rivaroxaban plus aspirin compared to 234 patients (9%) in aspirin alone (HR 0.72, 95% CI 0.59–0.87, P=0.0008). This means that for every 1000 patients treated, 27 major adverse CV events or major adverse limb events would be prevented and one fatal and one critical organ bleed would be caused over a 21-month period.

Conclusion

References

Find Connolly et al online at The Lancet 2018Find Anand et al online at The Lancet 2018