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Antithrombotic protection after lower-extremity revascularization: Can clopidogrel be used alongside DPI?

Patient case: Evidence-based management after revascularization

How would you treat the following patient?

  • Marie is a 71-year-old retired accountant who has a keen interest in gardening and suffers from hypertension and hypercholesterolaemia
  • Four years ago, Marie underwent a percutaneous coronary intervention (PCI) to treat her coronary artery disease (CAD), but because of dissection during the procedure, an emergency coronary artery bypass graft was performed a year later
  • She has suffered with pain in her left leg for more than a year, but Marie has noticed that the pain has worsened over the last 2 months and that she can no longer walk further than 100 metres
  • Magnetic resonance angiography reveals that Marie has multiple stenoses in the distal superficial femoral artery, which are subsequently treated with a balloon angioplasty and stent placement
Marie has stenoses in the distal superficial femoral artery

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?


Patients with peripheral artery disease are often treated with clopidogrel

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

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.

Use of clopidogrel in the VOYAGER PAD trial

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 revascularization

Half of the patients enrolled in the VOYAGER PAD trial received concomitant clopidogrel, most of whom underwent endovascular revascularization10

Rivaroxaban provides protection against limb ischaemia and major CV events regardless of background clopidogrel

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 use

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.

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VOYAGER PAD results and implications for clinical practice.
Prof. S. Debus presents a vascular surgeon’s perspective
Approval code PP-XAR-ALL-1783-1

External links

  • Jones WS, Baumgartner I, Hiatt WR et al. Ticagrelor compared with clopidogrel in patients with prior lower extremity revascularization for peripheral artery disease. Circulation 2017;135:241–250. Return to content
  • Bonaca MP, Gutierrez JA, Creager MA et al. Acute limb ischemia and outcomes with vorapaxar in patients with peripheral artery disease: results from the trial to assess the effects of vorapaxar in preventing heart attack and stroke in patients with atherosclerosis-thrombolysis in myocardial infarction 50 (TRA2°P-TIMI 50). Circulation 2016;133:997–1005. Return to content
  • Aboyans V, Ricco JB, Bartelink MEL et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Eur Heart J 2018;39:763–816. Return to content
  • Gerhard-Herman MD, Gornik HL, Barrett C et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2017;69:e726–e779. Return to content
  • Conte MS, Bradbury AW, Kolh P et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg 2019;69:3S–125S.e140. Return to content
  • Frank U, Nikol S, Belch J et al. ESVM guideline on peripheral arterial disease. Vasa 2019;48:1–79. Return to content
  • Hess CN, Norgren L, Ansel GM et al. A structured review of antithrombotic therapy in peripheral artery disease with a focus on revascularization: a TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) initiative. Circulation 2017;135:2534–2555. Return to content
  • Jones WS, Mi X, Qualls LG et al. Significant variation in P2Y12 inhibitor use after peripheral vascular intervention in Medicare beneficiaries. Am Heart J 2016;179:10–18. Return to content
  • Capell WH, Bonaca MP, Nehler MR et al. Rationale and design for the Vascular Outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD). Am Heart J 2018;199:83–91. Return to content
  • Hiatt WR, Bonaca MP, Patel MR et al. Rivaroxaban and aspirin in peripheral artery disease lower extremity revascularization: Impact of concomitant clopidogrel on efficacy and safety. Circulation 2020: doi:10.1161/CIRCULATIONAHA.120.050465. Return to content
  • Bonaca MP, Bauersachs RM, Anand SS et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020;382:1994–2004. Return to content

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