Revascularisation for Symptomatic Peripheral Artery Disease: External Applicability of the VOYAGER PAD Trial

Mette Søgaard,Peter B Nielsen,Flemming Skjøth,Torben B Larsen,Nikolaj Eldrup

doi:10.1016/j.ejvs.2021.10.026

Abstract

In the VOYAGER PAD trial, rivaroxaban 2.5 mg plus aspirin significantly reduced the primary composite efficacy outcome of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death compared with aspirin alone. However, patients enrolled in the trial may not reflect patients encountered in daily clinical practice. This study described the proportion of patients eligible for VOYAGER PAD within the nationwide Danish Vascular Registry (DVR), reasons for ineligibility, and outcomes according to eligibility. In total, 32 911 patients who underwent lower extremity revascularisation for symptomatic peripheral arterial disease (PAD) in the DVR (2000-2016) were identified. Trial inclusion and exclusion criteria were applied, and the three year cumulative incidence of primary and secondary trial outcomes was estimated. Altogether, 27.1% of patients with PAD in the DVR were "VOYAGER eligible". Of those not included, 30.7% had at least one exclusion criterion ("VOYAGER excluded"), and an additional 42.3% did not fulfil the inclusion criteria ("VOYAGER not included"). The main reasons for exclusion were atrial fibrillation (32.3%), poorly regulated hypertension (20.6%), requirement for long term dual antiplatelet therapy (10.9%), cytochrome P450 inhibitors or inducers (9.7%), and renal failure (9.3%). The three year rate of the primary efficacy outcome was 10.08 per 100 person years among the "VOYAGER eligible", 16.32 among "VOYAGER excluded", and 6.98 among the "VOYAGER not included". For the primary safety outcome of thrombolysis in myocardial infarction (TIMI) major bleeding, rates were 2.24, 3.76, and 1.17, respectively. Rates of secondary endpoints were also consistently lower for patients who did not meet the inclusion criteria (predominantly due to central aorto-iliac procedures) and highest for "VOYAGER excluded" patients. "VOYAGER eligible" patients experienced a higher cumulative incidence of most endpoints than patients enrolled in the control arm of the VOYAGER PAD trial. Among patients in routine clinical practice, 27.1% were eligible for the VOYAGER PAD trial. These patients were older, had more severe vascular symptoms, higher bleeding risk, and worse prognosis than trial participants.

Highlights

Guidelines recommend single antiplatelet therapy with either aspirin or clopidogrel to reduce risks of major adverse limb events (MALE) and major CV events in patients with symptomatic Peripheral artery disease (PAD), regardless of whether they receive conservative medical treatment or undergo revascularisation.3e5 peripheral artery revascularisation is associated with an immediate high risk of postprocedural re-thrombosis of the peripheral arteries, and elevated risk of major CV and limb events, which persists long after the intervention, despite antiplatelet and statin therapy.[1,6,7]
In the VOYAGER PAD trial, dual pathway therapy with low dose rivaroxaban added to aspirin, compared with aspirin alone, reduced the composite endpoint of acute limb ischaemia (ALI), major amputation due to vascular aetiology, myocardial infarction (MI), ischaemic stroke, or CV death in patients after a receent peripheral revascularisation for symptomatic PAD.[9]
The VOYAGER PAD trial (ClinicalTrials.gov identifier: NCT02504216) was an international, multicentre phase III randomised controlled trial (RCT) designed to assess the efficacy and safety of 2.5 mg rivaroxaban twice daily added to background therapy of 100 mg aspirin once daily for the prevention of major atherothrombotic vascular events in patients with symptomatic PAD after a recent revascularisation

Summary

Introduction

The choice of intensified antithrombotic therapy is a tradeoff between a favourable effect on major limb and CV outcomes and increased bleeding risk.[8] Patients with symptomatic PAD who undergo revascularisation represent a vulnerable subgroup of multimorbid patients at high risk of complications.[1,10] These factors are known to influence enrolment in trials and raise questions about the external applicability of trial results to patients in daily clinical practice. The principal reasons for ineligibility were assessed, and the clinical characteristics and outcomes compared according to eligibility for enrolment

Methods

Results

Discussion

Conclusion