Although rivaroxaban patients had more bleeding, the events were not severe and none were intracranial or fatal.
Among PAD patients who have undergone revascularization, a combination of rivaroxaban (Xarelto; Bayer/Janssen) and low-dose aspirin is superior to aspirin alone for the prevention of acute limb ischemia, amputation, CV events, and stroke. The results of the VOYAGER PAD study bolster the findings of the COMPASS trial by showing the combination therapy’s long-term benefit in a large PAD-only population.
“Even long after intervention, PAD patients that have had revascularization are at fourfold increased risk of acute limb ischemia versus those that have never had revascularization, and they never return to the risk profile of a stable PAD patient,” noted Marc P. Bonaca, MD (University of Colorado School of Medicine, Aurora), during a presentation at the American College of Cardiology 2020 Scientific Session.
As VOYAGER PAD showed, twice-daily rivaroxaban plus aspirin resulted in fewer cases of acute limb ischemia compared with aspirin alone, a difference that was apparent as early as 3 months after randomization. Additionally, there was an approximate sixfold increase in the number of ischemic events prevented relative to bleeds caused.
Commenting on the results following Bonaca’s presentation, Joshua A. Beckman, MD (Vanderbilt University Medical Center, Nashville, TN), said they enhance understanding of rivaroxaban’s value in PAD patients and expand “the concentric circles” of patients who are now likely to gain benefit from the drug.
“If we take a look at the COMPASS study, and even in the PAD-specific patients of the COMPASS study, this was primarily a polyvascular disease patient population,” he observed. “We now know that in a PAD population without significant evidence of polyvascular disease, rivaroxaban also provides a significant benefit.” Beckman said the findings also clarify the point that immediately after endovascular or surgical limb revascularization is an appropriate time to begin rivaroxaban and aspirin in this population, since patients who begin medication regimens while in the hospital are more likely to still be taking them long-term.
Bonaca concurred, noting that the difficulties and uncertainties of stacking therapies in the outpatient setting for secondary prevention probably explain some of the low penetrance of rivaroxaban in PAD patients. By tying a medical therapy to an intervention that patients have just undergone, “we often get greater penetrance because we understand when to start and for whom to start,” he added.
Higher ISTH Bleeding, but Not TIMI Major
For VOYAGER PAD, Bonaca and colleagues enrolled 6,564 PAD patients from 34 countries who were symptomatic and had undergone a limb revascularization in the previous 10 days. Patients were randomly assigned to receive rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily or to receive placebo plus aspirin 100 mg daily.
Despite significant comorbidities such as diabetes and hypertension, and a large cohort of active smokers, fewer than one-third of patients had known CAD and only 11% percent had ever had an MI or plaque rupture. The majority of patients underwent limb revascularization for claudication and leg pain, with only about one quarter of all patients having critical limb ischemia (CLI). Stents and balloons were used in about two-thirds of procedures, while the remaining one-third required open surgery. Clopidogrel was used at the discretion of the treating physician and amounted to 51% of the population treated.
At a median follow-up of 28 months, the incidence of the composite primary endpoint (acute limb ischemia, major amputation for vascular cause, heart attack, ischemic stroke or cardiovascular death) was 17.3% in the rivaroxaban plus aspirin group and 19.9% in the aspirin and placebo group (HR 0.85; 95% CI 0.76-0.96). To put the relative risk reduction into context, at 6 months there was a 1.5% absolute risk reduction and a number-needed-to-treat (NNT) of 65. At 12 months, there was a 2% risk reduction and an NNT of 50, and at 3 years, there was a 2.6% risk reduction and an NNT of 39.
Among the individual components on the primary endpoint, Bonaca showed that there was a pattern of consistency where rivaroxaban patients had statistically significant lower rates of all events except CV death. There also was a consistent benefit of rivaroxaban across key subgroups, including those with CLI.
The rate of TIMI major bleeding did not significantly differ at 2.65% with rivaroxaban and 1.87% with aspirin (HR 1.43; 95% CI 0.97-2.12). There was, however, a greater incidence of the secondary safety outcome of ISTH major bleeding. At 3 years, ISTH major bleeding occurred in 5.9% of the rivaroxaban group versus 4.1% of the aspirin-only group (HR 1.42; 95% CI 1.10-1.84), representing an absolute risk increase of 0.60% per year.
According to Bonaca, for every 10,000 patients with PAD requiring revascularization, treatment for 1 year with rivaroxaban 2.5 mg twice daily plus aspirin would result in the prevention of 181 first ischemic events at a cost of 29 TIMI major bleeds, with no increased risk of intracranial hemorrhage or fatal bleeding.
A Severe Event ‘to Be Feared and Avoided’
Beckman also commented on the consequences of acute limb ischemia borne out in those on the aspirin-only regimen, noting that they should drive the point home to cardiologists that “this is a severe event that comes with a significant amount of morbidity and mortality, and it's something to be feared and avoided as much as possible.”
Also speaking after the presentation, Patrick T. O’Gara, MD (Brigham and Women’s Hospital, Boston, MA), was struck by the low prevalence of CAD in the population, pointing out that it seemed somewhat at odds with the typical phenotype of PAD patients seen in clinical practice.
Bonaca said while many patients with PAD do have coronary disease, the population in VOYAGER PAD is consistent with similar studies such as EUCLID, where only 30% of the population had CAD and 10% had a prior MI.
“I think the issue from a trialist perspective is the majority of data we have in PAD is subgroups of coronary trials where coronary disease is, of course, very common because that's the reason they're in the trial,” he added. “We have very few dedicated PAD trials. I think for the vascular practitioner doing intervention, they're seeing a lot of patients with symptomatic PAD that don't have known coronary disease. This probably reflects that population in a very distinct fashion.”
· Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med. 2020;Epub ahead of print.
- The study was funded by Bayer and Janssen Pharmaceuticals.
- Bonaca reports no relevant conflicts of interest.