Rivaroxaban and aspirin effective and safe for PAD patients

Results from the VOYAGER PAD trial showed that rivaroxaban 5 mg (2.5 mg twice daily) + aspirin significantly reduced the risk of acute limb ischaemia and cardiovascular events in patients with symptomatic peripheral artery disease (PAD) after peripheral artery revascularisation [1]. Although there was a numerical increase in thrombolysis in myocardial infarction (TIMI) major bleeding and significantly increased International Society on Thrombosis and Haemostasis (ISTH) major bleeding, no excess was observed in intracranial or fatal bleeding.

The multicentre, randomised, double-blind VOYAGER PAD trial was presented by Prof. Marc Bonaca (University of Colorado, USA), and simultaneously published in the New England Journal of Medicine [2]. The purpose of this trial was to investigate whether the benefits of a treatment strategy of rivaroxaban added to background antiplatelet therapy, which has been shown to reduce ischaemic risk in patients following recent acute coronary syndromes, could extend to patients with symptomatic PAD who had recently undergone lower limb revascularisation.

The trial enrolled 6,564 participants from 34 countries with moderate-to-severe symptomatic PAD in the lower extremities. Of these participants, 65% underwent endovascular revascularisation within 10 days before starting study treatment. The remaining 35% had undergone surgical revascularisation. Patients received either rivaroxaban 2.5 mg twice daily added to low-dose aspirin (n=3,286) or placebo + aspirin (n=3,278). The primary endpoint was a composite of acute myocardial infarction, ischaemic stroke, cardiovascular death, acute limb ischaemia, or major amputation. Median follow-up was 28 months.

The primary endpoint occurred in 508 patients in the rivaroxaban group, compared with 584 patients in the placebo group. The Kaplan-Meier estimates of incidence at 3 years were 17.3% of patients who received rivaroxaban + aspirin and 19.9% of those on placebo + aspirin (HR 0.85; 95% CI 0.76-0.96; P=0.0085; see Figure), translating to a 15% relative risk reduction in the rivaroxaban arm. The absolute risk reduction was 1.5% at 6 months, 2.0% at 1 year, and 2.6% at 3 years. This endpoint was primarily driven by a reduction in acute limb ischaemia.

Figure: Cumulative incidence of the primary endpoint versus time [1]


 

 

 

 

 

 

 

 

 

ARR, absolute risk reduction; CI, confidence interval; HR, hazard ratio; NNT, number needed to treat. Figure kindly provided by Prof. Bonaca.

Regarding safety, the rate of TIMI major bleeds was 2.7% for patients treated with rivaroxaban versus 1.9% for patients on placebo (HR 1.43; 95% CI 0.97-2.10; P=0.07). Although this result did not reach statistical significance, it did demonstrate a small but important increased risk for bleeding events of this combined regimen, which was underscored by the secondary safety outcome, ISTH major bleeding score, occurring 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). Despite bleeding events being more common in the patients receiving rivaroxaban, the rate of ischaemic events prevented by rivaroxaban + aspirin exceeded the excess bleeding rate by 3- to 6-fold (depending on the definition of the bleeding episodes).

In conclusion, PAD patients who have undergone lower-extremity revascularisation and take rivaroxaban plus aspirin have a lower incidence of major adverse limb and cardiovascular events than patients who take aspirin alone in this population and setting. In addition, the benefit of rivaroxaban was apparent early in treatment and was consistent over time across all major subgroups, including patients with critical limb-threatening ischaemia, and reduced the need for unplanned index limb revascularisation.

 

1. Bonaca MP, et al. Abstract 402-10. ACC/WCC 28-30 March 2020.
2. Bonaca MP, et al. N Engl J Med. 2020; DOI: 10.1056/NEJMoa2000052.

 



Posted on 7 September 202022 February 2024