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How would you treat the following patient?
Marie has stenoses in the distal superficial femoral artery
The next morning, Marie’s surgeon initiates dual antiplatelet therapy (DAPT) with clopidogrel for 4 weeks.
Are you aware that Marie has a high risk of limb ischaemia and major cardiovascular (CV) events even after a successful revascularization?
Despite having undergone lower-extremity revascularization, patients like Marie remain at high risk of ischaemic cardiac and limb events.1,2 Given the serious, ongoing risk that patients like Marie face, they require further protection. Current guidelines recommend that these patients can be treated with a period of DAPT with clopidogrel and aspirin, which Marie has been prescribed; however, this recommendation reflects a lack of robust evidence to support clinical decision-making.3-6
Despite the lack of compelling evidence, patients like Marie are commonly treated with DAPT following peripheral revascularization.7
A study of more than 85,000 US patients undergoing peripheral vascular intervention found that approximately one-third of patients were receiving a P2Y12 inhibitor prior to their revascularization and continued to receive it after the procedure. A further third started on a P2Y12 inhibitor after their procedure and most of these patients received it for more than 30 days.8
Use of P2Y12 inhibitors in US patients undergoing peripheral revascularization between 2010 and 2012 (N=85,830)8
P2Y12 inhibitors included clopidogrel, ticagrelor or prasugrel.
Can patients receiving clopidogrel benefit from dual pathway inhibition (DPI) with rivaroxaban?
The VOYAGER PAD trial evaluated the efficacy and safety of DPI with rivaroxaban vascular dose 2.5 mg twice daily (bid) plus aspirin 100 mg once daily (od) versus aspirin 100 mg od, to reduce the risk of thrombotic vascular events in 6564 high-risk patients with symptomatic peripheral artery disease (PAD) undergoing peripheral revascularization.9 Patients were stratified according to procedure type and clopidogrel use.9
Concomitant clopidogrel was allowed for ≤6 months post-procedure at the discretion of the treating physician. It was used in approximately half of the patients enrolled in VOYAGER PAD for a median duration of 29 days in both treatment arms.9,10
Marie could be considered typical of the patients receiving clopidogrel in the VOYAGER PAD trial. Female patients and those at an increased risk of CV events were more likely to receive clopidogrel in combination with aspirin 100 mg od than aspirin 100 mg od. Patients receiving DAPT had a higher prevalence of CV risk factors, including CAD, prior coronary intervention, diabetes and hyperlipidaemia, than those receiving aspirin 100 mg od.10
Additionally, 91% of patients receiving clopidogrel plus aspirin underwent endovascular revascularization compared with 42% of patients not receiving clopidogrel. Only 9% of patients underwent surgical revascularization and received DAPT compared with 58% of patients receiving aspirin 100 mg od.10
Half of the patients enrolled in the VOYAGER PAD trial received concomitant clopidogrel, most of whom underwent endovascular revascularization10
The primary efficacy outcome of the VOYAGER PAD trial was a composite of acute limb ischaemia (ALI), major amputation of vascular aetiology, myocardial infarction, ischaemic stroke or CV death.11 Rivaroxaban vascular dose 2.5 mg bid in combination with aspirin 100 mg od significantly lowered the risk of limb ischaemia and major CV events by 15% in patients with symptomatic PAD post revascularization compared with aspirin 100 mg od, regardless of concomitant clopidogrel use.10
Patients receiving DPI were not at a significantly increased risk of the primary safety outcome, Thrombolysis In Myocardial Infarction (TIMI) major bleeding, regardless of concomitant clopidogrel use.10,11 However, a trend towards increased International Society on Thrombosis and Haemostasis (ISTH) bleeding was observed with long-term clopidogrel exposure, particularly for durations >30 days.10
Although the clopidogrel subgroup analysis was prespecified, it is important to note that clopidogrel use was not randomized. Patients receiving clopidogrel were more likely to be women, have concomitant CAD and have a greater prevalence of CV risk factors. Clopidogrel use for more than 30 days was more common in female patients, patients from Western Europe and North America, and patients with diabetes, CAD, prior coronary intervention or hyperlipidaemia.10
Primary efficacy and safety outcomes of the VOYAGER PAD trial according to clopidogrel use10
What do these results mean for Marie, who has just undergone a revascularization?
Patients like Marie can be protected beyond revascularization using rivaroxaban vascular dose 2.5 mg bid in combination with aspirin 100 mg od to significantly reduce the risk of ALI and major CV events, regardless of whether they are receiving concomitant clopidogrel. Clinical characteristics, region and practice patterns were major determinants of clopidogrel use rather than characteristics specific to PAD. A short course of clopidogrel did not alter the efficacy of DPI therapy, including the reduction in ALI. Importantly, the use of DPI was not associated with a significant increase in TIMI major bleeding; however, concomitant clopidogrel use, particularly with exposure >30 days, was associated with a numerically increased risk of ISTH major bleeding. The data, therefore, support a primary treatment approach of DPI with rivaroxaban vascular dose 2.5 mg bid in combination with aspirin 100 mg od for patients with symptomatic PAD following peripheral revascularization, regardless of the addition of concomitant clopidogrel. Clopidogrel may be administered, if desired, to reduce short-term procedural complications; however, it is generally recommended to limit exposure to <30 days post procedure.
These new, high-quality data provide robust evidence to support a new treatment option that could benefit patients such as Marie and could prolong the impact of your intervention.
VOYAGER PAD results and implications for clinical practice.
Prof. S. Debus presents a vascular surgeon’s perspective
Approval code PP-XAR-ALL-1783-1
Watch this short video summarizing the VOYAGER PAD trial
Watch Professor Marc Bonaca present the main results of the VOYAGER PAD trial
How can atherothrombotic risk be reduced in patients undergoing lower-extremity revascularization?