Rivaroxaban in peripheral artery disease after revascularisation

Selected in NEJM by A. N. Calik , P. Xaplanteris

VOYAGER-PAD (presented at the ACC 2020 Scientific Sessions Virtual Event) evaluates whether rivaroxaban plus aspirin is better than aspirin alone in reducing MALE in symptomatic patients undergoing lower limb revascularisation.

Reviewers

Ali Nazmi Calik

@ANazmiCalik

Interventional cardiologist / Cardiologist

Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Center - Istanbul, Türkiye

Panagiotis Xaplanteris

@panosxap

Interventional cardiologist / Cardiologist

CHU Saint-Pierre - Bruxelles, Belgium

Our Comment

Why this study – the rationale/objective?

Despite the increasing incidence of lower-extremity peripheral artery disease (PAD), at present, the use of antithrombotic therapy for reducing cardiovascular and major adverse limb events (MALE) in patients undergoing peripheral interventions is not evidence-based.

VOYAGER-PAD, a multicenter randomised trial, was designed to evaluate whether rivaroxaban plus aspirin is better than aspirin alone in reducing MALE in symptomatic patients undergoing lower limb revascularisation.

How was it executed – the methodology?

Inclusion criteria were an age of >=50 years old and lower extremity PAD including ischemic symptoms (functional limitation, rest pain or ischemic ulceration), anatomical (imaging) and hemodynamic evidence [abnormal ankle-brachial index (ABI)] of occlusion.

Eligible patients were successfully revascularised within 10 days before starting their study treatment.

Clopidogrel usage was allowed for up to 6 months after revascularisation and was left to the discretion of the investigator.

The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or cardiovascular death and the principal safety endpoint was defined as major bleeding based on the Thrombolysis in Myocardial Infarction (TIMI) classification.

What is the main result?

A total of 6,564 PAD patients who had undergone lower-extremity revascularisation were randomly assigned to take rivaroxaban 2.5 mg twice daily plus aspirin (n=3,286) or a placebo and aspirin (n=3,278). While two-thirds of the study population were revascularised by endovascular methods, the remaining one third underwent surgical revascularisation.

The primary efficacy outcome occurred in 508 patients in the rivaroxaban group, compared with 584 patients in the placebo group (HR, 0.85; 95% CI, 0.76-0.96; p =0.009). This corresponded to a 2.6% absolute difference and a 15% risk reduction during a median follow up of 28 months, primarily driven by a reduction in acute limb ischemia.

The principal safety outcome – defined as the rate of TIMI major bleeds – occurred in 62 patients in the rivaroxaban group and 44 in the placebo group (HR, 1.43; 95% CI, 0.97-2.10, p=0.07), and just missed statistical significance. However, secondary safety outcome – defined as International Society on Thrombosis and Haemostasis (ISTH) major bleeding – occurred in 5.9% and 4.1% of the rivaroxaban and placebo groups, respectively (HR, 1.42; 95% CI, 1.10-1.84; p=0.007).

Critical reading and the relevance for clinical practice

VOYAGER-PAD trial provides evidence-based treatment for lower-extremity PAD patients undergoing either endovascular or surgical revascularisation due to a range of severe symptoms, from claudication to critical limb ischemia.

The results of the study also expands the range of patients proven to benefit from rivaroxaban plus aspirin combination from the type of PAD patients included in COMPASS trial. However, higher bleeding rates mitigate the net clinical benefit and should be considered when implementing this combination therapy in daily practice. Even though addition or exclusion of concurrent clopidogrel treatment was outside of the study's design, a prespecified subgroup analysis of VOYAGER-PAD randomly assigned half of the patients (51%) to receive clopidogrel at the time of revascularisation for up to six months.

The efficacy of rivaroxaban and aspirin were consistent regardless of clopidogrel usage, but clopidogrel increased the risk of bleeding.

In a nutshell, rivaroxaban therapy on top of aspirin has favourable effects in this particular patient group at the cost of increased bleeding rates; the addition of clopidogrel should be avoided.

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