Rivaroxaban (Xarelto, Bayer/Janssen), in addition to low-dose aspirin, should be considered as an adjunctive therapy after lower extremity revascularisation to reduce first and subsequent adverse outcomes, analysis from VOYAGER PAD, presented during a late-breaking trial session at the American College of Cardiology’s 70th Annual Scientific Session (ACC.21, 15–17 May, virtual), indicates. The findings were simultaneously published online in the Journal of the American College of Cardiology (JACC).
Rupert Bauersachs, director of vascular medicine at the Darmstadt Clinic (Darmstadt, Germany) and lead author of the study told ACC.21 attendees that the use of rivaroxaban significantly reduced the occurrence of total severe events of the heart, limb or brain and issues related to other vascular complications in patients with symptomatic peripheral arterial disease (PAD) who underwent lower extremity revascularisation. The findings underscore the broad benefits of this strategy in this high-risk patient population, he said.
“To our knowledge, this is the first time that the addition of low-dose rivaroxaban to aspirin has been clearly shown to reduce the occurrence of both first and total adverse events in patients with PAD who have undergone lower extremity revascularisation but remain at high risk for a heart attack, stroke or recurrent arterial blockage in a limb,” Bauersachs said. “The benefits we saw in the trial for total events were statistically significant and entirely consistent with those for first events. Rivaroxaban 2.5mg twice daily with aspirin should be considered as adjunctive therapy after revascularisation to reduce first and subsequent adverse outcomes.”
Recent data have shown that, after lower extremity revascularisation, there is a four-fold risk of acute limb ischaemia, Bauersachs told ACC.21 attendees, adding that this is associated with a high incidence of limb-related complications.
“There is a need for greater awareness that PAD is a distinct disease state and that patients with PAD have a high risk for cardiovascular adverse events and are generally a very vulnerable population, especially in the post-revascularisation setting,” Bauersachs said. “Care for these patients is often fragmented because the surgeon or interventionalist who performs the revascularisation may not follow them for complications or recurrences. They deserve to receive optimal treatment to reduce the risk of recurrences.”
The randomised, double blind VOYAGER PAD trial enrolled 6,564 patients in 34 countries who had PAD and had undergone lower extremity revascularisation. The patients’ median age was 67 years and 74% were men.
Patients were randomly assigned to receive either rivaroxaban or a placebo in addition to daily aspirin. The trial’s primary endpoint was timed to the first event of a composite of acute limb ischaemia, major amputation of vascular aetiology, myocardial infarction (MI), ischaemic stroke or cardiovascular death. Another prespecified endpoint was the total number of vascular events, including recurrent primary endpoint events as well as other vascular events. The median follow-up time was 28 months after revascularisation.
The research team reported in a late-breaking clinical trial presented at ACC.20/WCC that VOYAGER PAD met its primary endpoint, with a 15% statistically significant reduction in the risk of a first major adverse limb or cardiovascular event seen in patients who received rivaroxaban compared with those who received the placebo. The current study reports on the total number of vascular events, with over 4,700 occurring in the 6,564 patients randomised over three years.
“There were 342 fewer adverse events in the rivaroxaban group than in the placebo group, which translates to an absolute reduction in risk of 12.5%,” Bauersachs said. “In a high-risk population, that is a big gain in avoiding the need for patients to come back with vascular complications.”
The 6,564 study participants experienced a total of 4,714 vascular events during the study period with 2,301—or about one-third—experiencing at least one vascular event, Bauersachs said.
“So, during approximately three years of follow-up, about two to three out of six patients with PAD had a vascular event in spite of high utilisation of background medical therapy. This overall rate of vascular events is eye-opening and speaks to the high vulnerability of this patient population,” Bauersachs said. “First events are just the tip of the iceberg.”
A limitation of the study is that the trial was designed to assess the occurrence of first adverse events following lower extremity revascularisation, Bauersachs said. Therefore, in a double blinded trial, patients may come off study treatment or go on to other therapies after an event, which can attenuate the observed benefit. Assessment of the total number of adverse events, however, was a prespecified secondary endpoint and despite this limitation, the findings were statistically significant and robust in absolute terms.
VOYAGER PAD was funded by pharmaceutical companies Bayer and Janssen, who in a press release highlighting the presentation of the results, said that the analysis showed a very high burden of subsequent events and a consistent 14% reduction in both primary endpoint events and total vascular events over a median of 2.5 years.
“The VOYAGER PAD trial is the first and only study of antithrombotic therapy in the past 20 years to demonstrate a significant benefit in patients with PAD after lower extremity revascularisation,” James List, global therapeutic area head, Cardiovascular & Metabolism, Janssen Research & Development, was quoted as saying in the release. “With these new data, we now have a full picture of evidence demonstrating the potential of Xarelto in treating patients through various stages of PAD—chronic, symptomatic, those requiring revascularisation and beyond.”
“Even years after revascularisation, patients with PAD continue to have a markedly high risk for future thrombotic events due to excessive thrombin generation and platelet aggregation,” added Marc P Bonaca, Department of Medicine, Division of Cardiovascular Medicine, University of Colorado Anschutz Medical Campus, (Aurora, USA). “This analysis from VOYAGER PAD looked beyond the first event and found subsequent thrombotic event reduction with rivaroxaban plus aspirin, underscoring the importance of long-term prevention in these high-risk patients.”