Janssen Announces Positive Phase 3 VOYAGER PAD Results: XARELTO® Plus Aspirin Shows Significant Benefit in Symptomatic Peripheral Artery Disease Patients Post Lower-Extremity Revascularization

Compiled by Keke

Competitors have intensified their R&D and marketing efforts, prescription trends have stabilized, and Johnson & Johnson and Bayer’s rivaroxaban faced significant marketing challenges in 2019. However, recent positive outcomes demonstrated by rivaroxaban in a refractory arterial disease have restored confidence, prompting a strategic comeback.

Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, recently announced the evaluation of Xarelto^®The VOYAGER PAD study, evaluating rivaroxaban plus aspirin in patients with symptomatic peripheral artery disease (PAD) after lower-extremity revascularization, met its primary efficacy and primary safety endpoints: compared with aspirin alone, the combination therapy reduced the risk of major adverse limb and cardiovascular (CV) events by 15%, with similar rates of TIMI major bleeding. These results were presented as a late-breaking update at the 69th Annual Scientific Session of the American College of Cardiology and the World Congress of Cardiology (ACC.20/WCC) and were simultaneously published in the New England Journal of Medicine.

VOYAGER PAD is the only study in this patient population to demonstrate significant benefit from dual-pathway inhibition (anticoagulant plus aspirin). This global, randomized, double-blind Phase 3 trial enrolled 6,564 patients from 542 study sites across 34 countries/regions. Eligible patients were at least 50 years of age and had documented symptomatic lower-extremity peripheral artery disease (PAD). Patients had symptomatic PAD within 10 days after successful revascularization. Sixty-five percent of patients underwent endovascular intervention, and 35% underwent surgical intervention. Patients were excluded if they were clinically unstable, had an increased risk of bleeding, or required prohibited concomitant medications (including long-term clopidogrel use).

Patients were randomly assigned in a 1:1 ratio to receive either rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily) (n = 3,286) or aspirin alone (100 mg once daily) (n = 3,278). The median follow-up duration was 28 months. The primary endpoint was a composite of major adverse limb and cardiovascular (CV) events, including acute limb ischemia, major amputation due to vascular causes, myocardial infarction, ischemic stroke, or CV death. The primary safety endpoint was major bleeding, as defined by the Thrombolysis in Myocardial Infarction (TIMI) classification.

The results showed that, with respect to the primary efficacy endpoint, rivaroxaban combined with aspirin significantly reduced the risk of major adverse limb and cardiovascular events compared with aspirin alone. The researchers observed that nearly one in five patients receiving aspirin monotherapy experienced major adverse limb or cardiovascular events, whereas the addition of rivaroxaban reduced the risk of these serious adverse events by 15%. Compared with aspirin alone, the three-year Kaplan–Meier (KM) estimated incidence rates for rivaroxaban/aspirin were 17.3% and 19.9%, respectively (HR=0.85; p=0.009).

Regarding the primary safety endpoint, there was no significant increase in TIMI major bleeding in the rivaroxaban plus aspirin group compared with aspirin alone; the 3-year Kaplan–Meier estimated incidence rates were 2.65% and 1.87%, respectively (HR=1.43; p=0.07). Notably, the rivaroxaban/aspirin group had fewer intracranial hemorrhage events (0.60% vs. 0.90%; HR=0.78) and no increase in fatal bleeding (0.21% vs. 0.21%; HR=1.02).

The results of the VOYAGER PAD trial complement those of the Phase 3 COMPASS clinical study. COMPASS is the largest clinical trial conducted to date on rivaroxaban, enrolling a total of 27,395 patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD). The study met its primary efficacy endpoint and was terminated approximately one year early due to significant efficacy. The COMPASS study also indicated that, compared with aspirin monotherapy, combination therapy significantly reduces the risk of major cardiovascular and limb events in patients with chronic PAD and/or CAD.

“Although the COMPASS trial established the efficacy of rivaroxaban plus aspirin in patients with stable peripheral artery disease (PAD) and coronary artery disease (CAD), important unanswered questions remain regarding the optimal strategy for symptomatic PAD patients following lower-extremity revascularization, including those without CAD,” said Dr. Marc Bonaca, Professor of Medicine and Chief of the Division of Cardiovascular Medicine at the University of Colorado Anschutz Medical Campus. “The VOYAGER PAD trial demonstrated the potential clinical utility of rivaroxaban plus aspirin in preventing the most critical thrombotic complications, adverse limb events, and cardiovascular outcomes during the post-revascularization period, when PAD patients are at highest risk for these serious events.”

James List, Global Therapeutic Area Head for Cardiovascular and Metabolism at Janssen Pharmaceuticals, stated: “The EXPLORER program continues to provide evidence demonstrating the pivotal role of XARELTO in transforming clinical practice and cardiovascular care. Based on findings from the COMPASS and VOYAGER PAD studies, we believe that the dual-pathway regimen of Xarelto combined with aspirin has the potential to change the management of peripheral artery disease (PAD). We look forward to discussing these data with the U.S. FDA and submitting an application for a new clinical indication.”

Dr. Mathai Mammen, Global Head of Janssen Pharmaceuticals, believes that Xarelto is poised to become the first anticoagulant in 20 years to benefit patients with peripheral artery disease (PAD) following lower-extremity revascularization.

Peripheral artery disease (PAD) is a common circulatory disorder that primarily occurs when vascular stenosis reduces blood flow to the extremities, typically the legs. PAD affects more than 200 million people worldwide and approximately 8 million individuals in the United States. This condition is a leading cause of amputation and is associated with a high incidence of both fatal and non-fatal cardiovascular (CV) events. PAD is often asymptomatic at onset and may progress to a chronic symptomatic form, with severe cases requiring revascularization. Current PAD guidelines recommend antiplatelet monotherapy, such as aspirin or clopidogrel, to help prevent CV events following revascularization. However, no specific pharmacologic agents have been identified to prevent amputation or acute limb ischemia in these patients.

Rivaroxaban is a highly selective direct Factor Xa inhibitor with rapid onset of action. It simultaneously inhibits both free and prothrombinase complex-bound Factor Xa. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathways of the coagulation cascade, thereby suppressing thrombin generation and thrombus formation. However, rivaroxaban does not inhibit thrombin directly and has not been demonstrated to affect platelets.

Rivaroxaban, developed by Bayer, was approved for marketing in the United States in 2011, with Janssen Pharmaceuticals holding the U.S. distribution rights. In October 2018, the FDA approved rivaroxaban to reduce the risk of cardiovascular (CV) events in patients with peripheral artery disease (PAD). Currently, Xarelto has received FDA approval for eight indications, six of which are specifically targeted at preventing blood clots. These include the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery; the treatment of deep vein thrombosis and pulmonary embolism; and the reduction of stroke and systemic embolism risk in adult patients with non-valvular atrial fibrillation, among others.

In 2019, total U.S. sales of Xarelto amounted to $2.3 billion, representing a 6.6% decline from the previous year. In April this year, Johnson & Johnson stated that the continued decline in the drug’s sales was attributable to stagnant domestic prescription drug sales, intensifying competition, and Medicare Part D coverage regulations.

Another Factor Xa inhibitor, Eliquis (apixaban), developed by Pfizer and Bristol-Myers Squibb, has taken an early lead in the blood thinner market. It first surpassed other warfarin alternatives in the U.S. market share and then exceeded warfarin itself, achieving global sales of $6.2 billion in 2019. Facing competition from high-performance blood thinners like Eliquis, Xarelto has struggled to maintain its position. Positive evidence from new studies is hoped to provide some momentum for Xarelto to expand its market share.

References:

1、Landmark Phase 3 VOYAGER PAD Study of XARELTO® (rivaroxaban) Plus Aspirin Shows Significant Benefit in Patients with Symptomatic Peripheral Artery Disease (PAD) after Lower-Extremity Revascularization

2、Landmark Phase 3 VOYAGER PAD Study of XARELTO® (rivaroxaban) Plus Aspirin Shows Significant Benefit in Patients with Symptomatic Peripheral Artery Disease (PAD) after Lower-Extremity Revascularization

3、ACC: J&J, Bayer's blood thinner Xarelto scores in artery disease post-surgery

Original Title:Significant Benefits for Peripheral Artery Disease! Janssen Releases Phase 3 Clinical Results of Xarelto Plus Aspirin