Rivaroxaban use falls short of the expected level
“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.
“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”
VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.
In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.
Adding clopidogrel adds little except bleeding
Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.
“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.
The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.
But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.
“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.
VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.