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Subgroup analysis VOYAGER PAD

Presented by
Prof. W. Hiatt, University of Colorado, USA
ACC 2020
A prespecified subgroup analysis of VOYAGER PAD demonstrated that background clopidogrel in patients with peripheral artery disease (PAD) receiving rivaroxaban and low-dose aspirin after lower extremity revascularisation does not modify the benefit of rivaroxaban but appears to increase bleeding [1].

The VOYAGER PAD trial was the largest evidence base of patients with revascularised symptomatic PAD, which demonstrated that the combination of twice-daily rivaroxaban and once-daily aspirin was safe and more effective than aspirin alone for reducing future thrombotic and ischaemic events [2]. In the current subgroup analysis of VOYAGER PAD, presented by Prof. William Hiatt (University of Colorado, USA), investigators aimed to evaluate whether efficacy and safety of rivaroxaban were consistent regardless of background clopidogrel use.

The rationale for this particular subgroup analysis was that the dual-antiplatelet therapy (DAPT) in PAD patients who have just undergone endovascular lower-extremity revascularisation usually consists of aspirin and clopidogrel, although this choice is not based on any Class I evidence and instead is "an extrapolation from the coronary artery literature, where it does have some benefit, particularly after percutaneous coronary intervention,‚ÄĚ Prof. Hiatt explained.

Here, half of the 6,564 randomised patients enrolled in VOYAGER PAD also received clopidogrel at the time of their lower extremity revascularisation procedure, which was at the discretion of their treating physician and was allowed for up to 6 months. Patients receiving clopidogrel were more likely to undergo endovascular procedures (90.7%) than undergo surgery (9.3%), consistent with the common use of clopidogrel in endovascular procedures.

Results of this pre-specified subgroup analysis demonstrated that the benefit of rivaroxaban + aspirin versus aspirin alone in patients with symptomatic PAD undergoing revascularisation is consistent, regardless of background clopidogrel. The primary efficacy endpoint had a hazard ratio ~0.85 with rivaroxaban, regardless of clopidogrel with number needed to treat <50 with or without clopidogrel. The safety of rivaroxaban + aspirin versus aspirin alone was also consistent regardless of background clopidogrel overall. The principal safety outcome of Thrombolysis in Myocardial Infarction (TIMI) major bleeding had a hazard ratio of ~1.3 to 1.5 regardless of clopidogrel, with number needed to harm >90 with or without clopidogrel.

In an exploratory analysis of early bleeding, exposure to clopidogrel was associated with higher rates of bleeding while used, particularly with longer durations (e.g. >30 days). Prof. Hiatt concluded: "In the absence of clear benefit, clopidogrel exposure along with aspirin and rivaroxaban should be minimised or avoided to reduce this risk." It should be noted that VOYAGER PAD was not designed to assess whether clopidogrel provides any benefit in this setting, a question that remains unanswered.


    1. Hiatt WR, et al. Abstract 406-13. ACC/WCC 28-30 March 2020.
    2. Bonaca MP, et al. N Engl J Med. 2020. DOI:10.1056/NEJMoa2000052.


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