A substudy from the VOYAGER PAD trial shows that low-dose rivaroxaban is safe and effective in patients with peripheral arterial disease (PAD) undergoing revascularization, irrespective of clopidogrel use, according to late-breaking trial results presented Sunday at the American College of Cardiology (ACC) Scientific Sessions 2020 virtual conference.
William R. Hiatt, MD, of the University of Colorado School of Medicine, presented the study.
The primary VOYAGER PAD study, which was presented as a late-breaking trial Saturday at ACC.20, shows that low-dose rivaroxaban, 2.5 mg twice daily, is effective in lowering the primary efficacy endpoint in patients with PAD undergoing revascularization (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.76-0.96; p=0.008). At 3 years, the absolute risk reduction (ARR) with rivaroxaban was 2.6%, with a number needed to treat of 39. The primary efficacy endpoint was a composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke or cardiovascular death.
In this study, clopidogrel was used at the investigator’s discretion, and the substudy was performed to evaluate whether the safety and efficacy of rivaroxaban would remain with the background use of clopidogrel.
A total of 3,313 patients were on clopidogrel, and 3,234 were not. The mean age of the patients in the clopidogrel group was 67.1±8.6 years, 28% were women, and about 80% were Caucasian. The clopidogrel group had significantly more women, Caucasians, patients with diabetes mellitus, hyperlipidemia, coronary artery disease, prior coronary artery bypass grafting, heart failure and prior coronary intervention. Also, there was a higher percentage of prior limb revascularization in the clopidogrel group; however, there was a higher percentage of patients with a history of critical limb ischemia in the group with no clopidogrel. Almost 91% of patients in the clopidogrel group underwent revascularization via an endovascular approach. In the no-clopidogrel group, only 42% underwent revascularization via an endovascular approach, and 58% underwent revascularization surgically. At the time of randomization, 50.5% of patients were using clopidogrel in both groups.
At 3 years, rivaroxaban was effective in lowering the primary efficacy endpoint, both with clopidogrel (HR, 0.85; 95% CI, 0.71-1.01; ARR 2.3%) and without clopidogrel (HR, 0.86; 95% CI, 0.73-1.01; ARR, 2.8%). Similar results were seen through 180 days (rivaroxaban 4.1% vs. placebo 5.7% with clopidogrel; rivaroxaban 5.5% vs. placebo 7% without clopidogrel). The primary endpoint results were driven primarily by lower rates of acute limb ischemia in both groups with rivaroxaban. The secondary endpoints of myocardial infarction, stroke, and hospitalization for coronary or peripheral event showed lower rates with the rivaroxaban group, irrespective of clopidogrel use.
In terms of the safety endpoint, Thrombolysis in Myocardial Infarction (TIMI) major bleeding, fatal bleeding, intracranial hemorrhage or International Society on Thrombosis and Haemostasis (ISTH) major bleeding did not differ between both groups, irrespective of clopidogrel, although numerically higher rates of ISTH or TIMI major bleeding were seen in patients taking rivaroxaban and clopidogrel. In the first 6 months, which is referred to as the period when clopidogrel triple therapy was allowed, the absolute risk increase (ARI) was 1.2% with clopidogrel vs. 0.4% without clopidogrel. After 6 months, there was only a 0.2% ARI with clopidogrel and 0.3% without clopidogrel.
Hiatt concluded that in patients with lower-extremity PAD undergoing revascularization, the benefit and safety of 2.5 mg of rivaroxaban twice daily with aspirin vs. aspirin alone was not affected by clopidogrel use. He also questioned the benefit of clopidogrel, as all the clinical trials showed no benefit. He added that there is more bleeding with background clopidogrel, and therefore, clopidogrel should be minimized or avoided.
The VOYAGER PAD trial was co-sponsored by Bayer AG (Leverkusen, Germany) and Janssen Pharmaceuticals (Beerse, Belgium).