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Study Summary

The VOYAGER-PAD study is a randomized, multicenter trial that investigated the use of low-dose rivaroxaban (2.5 mg twice daily) or placebo on a background of aspirin 100 mg daily in 6,564 patients with symptomatic peripheral artery disease (PAD) undergoing surgical or endovascular revascularization ( Rivaroxaban reduced the first primary efficacy outcome event (cardiovascular death, acute limb ischemia, major amputation, myocardial infarction, or stroke) by ~15% (NNT=39 at 3 years) at a cost of increased International Society on Thrombosis and Haemostasis (ISTH) major bleeding (5.94% and 4.06%, HR 1.42; 95%CI 1.10-1.84, P = 0.007). A pre-specified analysis investigated the number of first and total events (primary efficacy outcome, as well as peripheral revascularization and venous thromboembolism) in PAD patients undergoing revascularization. Rivaroxaban significantly reduced the total primary end point by 14% (745 versus 869; P = 0.02) and total vascular events by 14% (2186 versus 2528; P = 0.003), which translates to the prevention of 4.4 primary and 12.5 vascular events per 100 patients over 3 years (see accompanying Hurst’s Central Illustration). The type of revascularization procedure and baseline clopidogrel status did not significantly affect the outcome.


Study Strengths: This was a well-designed, pre-specified analysis of the VOYAGER-PAD trial investigating the impact of rivaroxaban in addition to aspirin therapy on the rate of total events, rather than first events alone. This analysis highlights the increased thrombotic risk in patients with symptomatic PAD when total events are considered and demonstrates that rivaroxaban is a durable therapy to reduce vascular events at a cost of increased bleeding.

Study Limitations: The primary efficacy outcome for the VOYAGER-PAD trial was assessed according to the first occurrence of any component of the outcome. Therefore, the current pre-specified total events analysis is primarily hypothesis generating. The discontinuation rate differed between placebo and study drug (more patients discontinued rivaroxaban as compared to placebo), which may have underestimated the effect (41% (903/2186) of events in the rivaroxaban group occurred after patient’s last dose). Furthermore, while able to assign multiple outcomes to the same study participant, the statistical analysis did not assign weights to individual outcomes (cardiovascular death and acute limb ischemia were weighted the same as nonfatal myocardial infarction, etc). Lastly, out of the 4714 total first and subsequent events, only 1614 were primary end point events; the additional 3100 events were classified as other vascular events (defined as peripheral revascularization and venous thromboembolism). Therefore, most events in the analysis were not the primary composite end point.

Next Steps/Clinical Perspective: This pre-specified analysis of VOYAGER-PAD demonstrated that the combination of rivaroxaban with aspirin, in comparison to aspirin alone, reduced first and total vascular events, especially recurrent ischemic limb events requiring revascularization. Notable risk factors for development of primary and subsequent events included history of previous revascularization, amputation and lesion length ≥15cm. Otherwise, well-known risk factors for cardiovascular disease (coronary artery disease, hypertension, hyperlipidemia, diabetes, kidney disease with reduced GFR), were also associated with increased risk of primary and subsequent events. Lastly, the combination of rivaroxaban and aspirin came at a cost of increased major bleeding. Further investigation is needed to improve identification of patients at higher thrombotic risk, who would better balance the increased risk of bleeding with rivaroxaban.

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