New Developments in Antiplatelet Therapies for Patients with Peripheral Artery Disease

Patients with lower extremity peripheral artery disease (PAD) are at heightened risk of major adverse cardiovascular events (MACE), regardless of their symptom status. Progression of lower limb atherosclerosis over time can also lead to functional limitations and amputation.1,2 Antiplatelet therapy (APT) favorably impacts each of these adverse outcomes. APT has been shown to reduce the occurrence of MACE in patients with PAD, particularly atherothrombotic events occurring in the coronary and cerebral vasculature, improve claudication free walking distance, and lower amputation rates.3-5 Despite these potential benefits, patients with PAD have consistently been undertreated with antiplatelet agents despite an overwhelming majority with pre-existing cardiovascular disease.6 This area of unmet need has become the focal point of new developments in drug therapies and clinical evidence base, with some of the key findings outlined in this article.

Current data and guidelines support the use of aspirin or clopidogrel as a single agent in patients with PAD who have symptoms or who have experienced a previous myocardial infarction (MI) or stroke. This recommendation is endorsed by the ACC/AHA guidelines (Table 1) and based on the CAPRIE (A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events) trial which demonstrated a small yet statistically significant reduction in MACE in patients with PAD treated with clopidogrel compared with aspirin (relative risk reduction of 8.7%; 95% CI: 0.3–16.5; p = 0.043).3 Routine use of antiplatelet monotherapy for patients with asymptomatic PAD is currently not supported by published evidence.7

Table 1: Excerpts from antiplatelet and antithrombotic drug guideline recommendations (updated 2011)19

Class I

Antiplatelet therapy is indicated to reduce the risk of MI, stroke, and vascular death in individuals with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or CLI, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia. (Level of Evidence: A)

Aspirin, typically in daily doses of 75 to 325 mg, is recommended as safe and effective antiplatelet therapy to reduce the risk of MI, stroke, or vascular death in individuals with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or CLI, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia. (Level of Evidence: B)

Clopidogrel (75 mg per day) is recommended as a safe and effective alternative antiplatelet therapy to aspirin to reduce the risk of MI, ischemic stroke, or vascular death in individuals with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or CLI, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia. (Level of Evidence: B)

Class IIa

Antiplatelet therapy can be useful to reduce the risk of MI, stroke, or vascular death in asymptomatic individuals with an ABI less than or equal to 0.90. (Level of Evidence: C)

Class IIb

The usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death in asymptomatic individuals with borderline abnormal ABI, defined as 0.91 to 0.99, is not well established. (Level of Evidence: A)

The combination of aspirin and clopidogrel may be considered to reduce the risk of cardiovascular events in patients with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or CLI, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia and who are not at increased risk of bleeding and who are high perceived cardiovascular risk. (Level of Evidence: B)

Class III

In the absence of any other proven indication for warfarin, its addition to antiplatelet therapy to reduce the risk of adverse cardiovascular ischemic events in individuals with atherosclerotic lower extremity PAD is of no benefit and is potentially harmful due to increased risk of major bleeding. (Level of Evidence: B)

Results of the overall MATCH (Aspirin and clopidogrel compared with clopidogrel alone after recent ischemic stroke or transient ischemic attack in high-risk patients) trial and its PAD cohort revealed that adding aspirin to clopidogrel (DAPT) in high-risk patients with recent ischemic stroke or transient ischemic attack was associated with a non-significant reduction in MACE (19.1% for DAPT vs. 24.0% for clopidogrel).8 The results of the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) trial have indicated that among stable patients with prior MI and PAD ticagrelor reduced MACE (large absolute risk reduction of 4%, number needed to treat = 25), and major adverse limb events (MALE, hazard ratio or HR of 0.65; 95% CI: 0.44-0.95; p = 0.026; ).9 There was a large absolute reduction in components of MALE among patients with PAD: peripheral revascularization occurred in 9.2% and ALI in 1.0%, whereas these events occurred in < 1% of patients without known PAD. The absolute excess of TIMI major bleeding was 0.12% (number needed to harm = 834). The EUCLID (Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease) trial is the first large-scale randomized controlled study to compare MACE outcomes with ticagrelor or clopidogrel over a median of 27 months. The trial has completed enrolment and results are expected in late 2017.

Vorapaxar, an antagonist of the primary thrombin receptor expressed on vascular endothelium and smooth muscle (PAR-1), was evaluated in the TRA 2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial. Over 26,000 patients with stable vascular disease (MI, stroke, or PAD) were randomized in a double-blind fashion to vorapaxar sulfate daily or placebo.10 The trial included 3787 patients who were randomized into the PAD cohort and followed for a median of 36 months. In the PAD cohort, 88% received concomitant aspirin, 37% a thienopyridine (primarily clopidogrel) at baseline, and 28% of were prescribed DAPT. Most (75%) patients in the PAD cohort were symptomatic (claudication = 72%, rest pain = 2%, and tissue loss = 1%). MACE (primary endpoint), a composite of cardiovascular death, MI or stroke was similar in both groups (11.3% vs 11.9%, HR 0.94; p = 0.53).11 However, hospitalization for acute limb ischemia (ALI) was significantly lower with vorapaxar (2.3% vs 3.9%, HR 0.58; p = 0.006) as was the need for peripheral artery revascularization (18.4% vs. 22.2%, HR 0.84; p = 0.017). Importantly, patients receiving vorapaxar did have a higher risk of GUSTO moderate or severe bleeding (7.4% vs. 4.5%, HR 1.62; p = 0.001). Addition of vorapaxar to aspirin and/or clopidogrel was associated with a 41% relative risk reduction in the incidence of ALI primarily from a reduction in lower extremity peripheral artery bypass graft thrombosis (3-year event rate of 2.3% vs 3.9%, HR 0.58, 95% CI 0.39–0.86). Additionally, in patients taking vorapaxar, there was a significant reduction in the incidence of peripheral revascularization for claudication (HR 0.84, 95% CI 0.71–0.99; p = 0.04), and a trend towards fewer revascularization procedures for limb ischemia (ALI or CLI) and amputations.12 In May 2014 vorapaxar was approved by the US Food and Drug Administration for patients with established PAD and no history of stroke, transient ischemic attack, or at a high risk for bleeding.

Evidence regarding optimal APT regimen and its duration following revascularization for PAD remains unsettled. Following surgical revascularization, aspirin improves infrainguinal bypass patency and is the primary post-operative antiplatelet agent prescribed. However, in patients with below-knee prosthetic bypasses addition of clopidogrel to aspirin for at least 1 year significantly improves bypass patency (occlusion on DAPT 32% vs. 47% for aspirin alone; p = 0.02) and amputation rates (DAPT = 9.4% vs. 19.2% for aspirin alone; p = 0.03), with no significant increase in the incidence of major hemorrhage.13 APT regimens are less efficacious for autologous vein bypasses. Vitamin K antagonist (VKA) is not routinely indicated because of limited benefit and increased incidence of associated major hemorrhage.13 Aspirin therefore remains the mainstay antiplatelet agent following endovascular lower extremity arterial interventions. More recently, endovascular device trials have required a minimum duration of DAPT use following infrainguinal peripheral artery interventions that have been included in the FDA approved instructions for use. At least 6 months of aspirin and one month of clopidogrel is recommended following peripheral artery drug-coated balloon use; and at least 2 months of DAPT after peripheral artery drug (paclitaxel) coated stent implantation. 14,15

In a propensity weighted observational cohort analysis of 629 patients with claudication or CLI, during 3 years of follow-up DAPT use was associated with a decreased risk of MACE (adjusted HR: 0.65; 95% CI: 0.44-0.96) and overall mortality (adjusted HR: 0.55; 95% CI: 0.35-0.89).16 A large proportion of patients undergoing peripheral artery interventions may have underlying CAD and have pre-existing indication for longer duration of DAPT. These patients suffer significantly higher 12-month MACE despite longer DAPT use (17.6% vs. 9.5%; p = 0.019); MALE rates over the same duration are similar (DAPT ≤ 3 months = 22.3% and DAPT > 3 months = 23.9%, p = 0.541).17 The ongoing ASPIRE (Antiplatelet Strategy for Peripheral Arterial Interventions for Revascularization of Lower Extremities) trial is evaluating minimal clinically indicated duration of DAPT (aspirin and clopidogrel) compared to an additional 12 months following lower extremity arterial interventions in a multicenter randomized clinical trial setting.

Direct oral anticoagulants are currently being tested in prospective clinical trials in patients with PAD. The COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease) trial is randomly assigning 21,400 patients to either 2.5 mg of rivaroxaban twice daily and aspirin (100 mg once daily) or 5 mg of rivaroxaban twice daily and aspirin (100 mg once daily) or placebo twice daily and 100 mg of daily aspirin. The primary outcomes are time from randomization to first occurrence of MI, stroke or cardiovascular death, and time from randomization to the first occurrence of major bleeding. The estimated completion date is February 2018. The multicenter randomized controlled Edoxaban in Peripheral Artery Disease (ePAD) trial evaluating the efficacy of edoxaban (60 mg once daily) and aspirin (100 mg daily) versus clopidogrel (300 mg load, 75 mg daily) and aspirin (100 mg daily) following femoropopliteal endovascular intervention has completed enrollment.18 Primary results are anticipated in 2016. The VOYAGER-PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) randomized controlled trial is assigning approximately 6500 patients over the age of 50 years of age with symptomatic lower extremity PAD following recent (≤ 10 days) successful infrainguinal revascularization to rivaroxaban (2.5 mg twice daily) or placebo in addition to standard background therapy to evaluate both MACE and MALE endpoints. The expected completion date of trial is January 2019. The RIFLE (Pilot Study to Examine the Use of Rivaroxaban After Angioplasty for Critical Limb Ischemia) study is an open label randomized controlled trial that is assigning patients to either rivaroxaban 2.5 mg twice daily for 90 days plus aspirin 81 mg daily or clopidogrel 75 mg daily for 90 days plus aspirin 81 mg daily following successful percutaneous intervention for CLI. The expected completion date of the study remains unknown.

Take Home Message

  1. Patients with PAD are at a significantly increased risk of atherothrombotic events such as MI, stroke, and CLI.
  2. Based on available evidence, it is appropriate to consider antiplatelet monotherapy for patients with established PAD, and dual antiplatelet therapy with aspirin plus clopidogrel or vorapaxar for patients with more advanced disease and after revascularization for limb ischemia.


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Clinical Topics: Anticoagulation Management, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Interventions and Vascular Medicine

Keywords: Adenosine, Amputation, Angioplasty, Anticoagulants, Arteries, Endothelium, Vascular, Ischemic Attack, Transient, Lactones, Myocardial Infarction, Paclitaxel, Peripheral Arterial Disease, Platelet Aggregation Inhibitors, Pyridines, Risk Factors, Secondary Prevention, Thiazoles, Thrombosis, Ticlopidine, Vitamin K, Warfarin

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