VOYAGER PAD Shows Rivaroxaban Reduces First and Total Ischemic Events in Patients With PAD

May 16, 2021—Findings from the VOYAGER PAD trial demonstrated that rivaroxaban, in addition to low-dose aspirin, 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 artery disease (PAD) who underwent lower extremity revascularization.

“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 revascularization but remain at high risk for a heart attack, stroke, or recurrent arterial blockage in a limb,” commented the study’s lead author Rupert Bauersachs, MD, in a press release from the American College of Cardiology (ACC).

Dr. Bauersachs, who presented the study’s findings virtually at ACC.21, the ACC’s 70th annual scientific sessions, continued, “The benefits we saw in the trial for first events were statistically significant and entirely consistent with those for total events. Rivaroxaban 2.5 mg twice daily with aspirin should be considered as adjunctive therapy after revascularization to reduce first and subsequent adverse outcomes.” The findings expand on earlier data and underscore the broad absolute benefits of this strategy in this high-risk patient population, noted the investigators in the ACC announcement.

This study was simultaneously published online by Dr. Bauersachs et al in the Journal of the American College of Cardiology. VOYAGER PAD was funded by Bayer AG and the Janssen Pharmaceutical Companies of Johnson & Johnson, which market rivaroxaban as Xarelto.

As summarized in the ACC announcement, the randomized, double-blinded VOYAGER PAD trial enrolled 6,564 patients in 34 countries who had PAD and had undergone lower extremity revascularization. The patients’ median age was 67 years, and 74% were men. Patients were randomly assigned to receive 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 ischemia, leg amputation caused by blood vessel disease, heart attack, stroke, or death due to cardiovascular causes. Another prespecified endpoint was the total number of vascular events, including recurrent primary endpoint events as well as other vascular events like blood clots in the leg veins or lungs or the need for repeat vascular procedures. The median follow-up time was 28 months after patients underwent revascularization.

At ACC.20/WCC—the ACC’s annual scientific session together with World Congress of Cardiology held in March 2020, the VOYAGER PAD investigators reported that the trial 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. Marc P. Bonaca, MD, et al published those findings in The New England Journal of Medicine (2020;382:1994-2004).

The current findings presented at ACC.21 report on the total number of vascular events, which totaled 4,714 in the 6,564 study participants during the 3-year study period, with 2,301 patients (approximately one-third) experiencing at least one vascular event, stated Dr. Bauersachs.

In the ACC announcement, Dr. Bauersachs commented, “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%. In a high-risk population, that is a big gain in avoiding the need for patients to come back with vascular complications.”

He continued, “So, during approximately 3 years of follow-up, about 2 to 3 out of 6 patients with PAD had a vascular event in spite of high utilization of background medical therapy. This overall rate of vascular events is eye-opening and speaks to the high vulnerability of this patient population. First events are just the tip of the iceberg.”

Dr. Bauersachs advised that a limitation of the study is that the trial was designed to assess the occurrence of first adverse events after lower extremity revascularization. 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. However, assessment of the total number of adverse events was a prespecified secondary endpoint, and despite this limitation, the findings were statistically significant and robust in absolute terms.

“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 postrevascularization setting. Care for these patients is often fragmented because the surgeon who performs the revascularization may not follow them for complications or recurrences. They deserve to receive optimal treatment to reduce the risk of recurrences,” concluded Dr. Bauersachs in the ACC announcement.