Appropriate Antiplatelet Therapy for Peripheral Arterial Disease

Patients with lower extremity peripheral artery disease (PAD) are at increased risk for major adverse cardiovascular events (MACE), regardless of symptoms. Progression of lower limb atherosclerosis over time can also lead to functional limitations and amputation. Fortunately, antiplatelet therapy favorably impacts each of these adverse outcomes.

Antiplatelet therapy has been shown to reduce MACE occurrence in PAD patients, improve claudication distance, and reduce amputation rates. Nevertheless, PAD patients have consistently been undertreated with antiplatelets, despite an overwhelming majority having pre-existing cardiovascular disease. This area of unmet need affords pharmacists a key opportunity to improve the care of PAD patients.

The American College of Cardiology/American Heart Association have published guidelines for antiplatelet therapy in PAD¹:

• Antiplatelets are indicated to reduce the risk of myocardial infarction (MI), stroke, and vascular death in individuals with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or chronic limb ischemia, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia. (Class I, 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 the aforementioned individuals. (Class I, Level of Evidence: B)
• Clopidogrel (75 mg/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 the aforementioned individuals. (Class I, Level of Evidence: B)
• Combination aspirin and clopidogrel may be considered to reduce the risk of cardiovascular events in the aforementioned individuals who aren’t at increased risk of bleeding and have high perceived cardiovascular risk. (Class IIb, Level of Evidence: B)
• Antiplatelet therapy can be useful to reduce the risk of MI, stroke, or vascular death in asymptomatic individuals with an ankle-brachial index ≤ 0.90. (Class IIa, Level of Evidence: C)
• 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 potentially harmful due to increased risk of major bleeding. (Class III, Level of Evidence: B)

In addition to those guidelines, several newer agents either have been or are being studied in PAD patients:

• PEGASUS-TIMI 54 results indicate that among stable patients with prior MI and PAD, ticagrelor reduced MACE and major adverse limb events (MALE).²
• In the TRA 2P-TIMI 50 trial, which included patients with stable vascular disease (MI, stroke, or PAD), hospitalization for acute limb ischemia was significantly lower with addition of vorapaxar to aspirin and/or clopidogrel, as was the need for peripheral artery revascularization. Importantly, patients receiving vorapaxar had a higher risk of GUSTO moderate or severe bleeding.³ In May 2014, vorapaxar was approved for patients with established PAD and no history of stroke, transient ischemic attack, or high risk for bleeding.
• Novel oral anticoagulants are currently being tested in prospective clinical trials in PAD patients. The COMPASS trial is randomly assigning 21,400 patients to rivaroxaban 2.5 mg twice-daily and aspirin 100 mg once-daily, rivaroxaban 5 mg twice-daily and aspirin 100 mg once-daily, or placebo twice-daily and aspirin 100 mg once-daily. Estimated completion date is February 2018.
• The ePAD trial is 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 completed enrollment. Primary results are anticipated later this year.
• The VOYAGER-PAD trial is assigning approximately 6500 patients older than 50 years with symptomatic lower extremity PAD following recent (≤10 days) successful infrainguinal revascularization to rivaroxaban (2.5 mg twice-daily) or placebo plus standard background therapy to evaluate both MACE and MALE endpoints. Expected completion date is January 2019.

Key Takeaways

• Most patients with PAD should receive antiplatelet therapy.
• Aspirin is the preferred first-line agent, but clopidogrel monotherapy can be considered in those with contraindication to aspirin.
• Aspirin and clopidogrel dual therapy can be considered for those with elevated ischemic risk and acceptable bleeding risk.
• Triple therapy with aspirin, clopidogrel, and vorapaxar increases bleeding risk and should be reserved for those with the highest risk of ischemic limb complications.

References

• Rooke TW, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. JACC. 2013;61:1555-1570.
• Bonaca MP, et al. Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease. JACC. 2016;67:2719-2728.