The Centers for Disease Control and Prevention estimates that approximately 8 million Americans have peripheral arterial disease (PAD).¹ Although a number of disease processes can cause PAD, the most common etiology is atherosclerosis. An increased atherosclerotic burden predisposes the PAD population to increased risk for major adverse cardiac events (MACE) – myocardial infarction (MI), stroke, and death.² Secondary prevention strategies for patients with PAD have focused on reducing MACE through the use antiplatelet therapies. Studies have demonstrated that aspirin monotherapy is not adequate to mitigate MACE in patients with PAD.³ The addition of P2Y12 inhibitors (e.g., clopidogrel) adds incremental benefit to aspirin. Unfortunately, augmenting aspirin with a P2Y12 inhibitor increases a patient's risk of bleeding.² For this reason, guideline-recommended use of P2Y12 inhibitors is limited to a small subgroup of high risk PAD patients.³ The recent emergence of novel anticoagulants has rekindled interest regarding the use of anticoagulants for secondary prevention in the PAD population.

The associated reduction of MACE in PAD patients treated with antiplatelet therapy led to the hypothesis that an intensified antithrombotic regimen of aspirin plus warfarin, a vitamin K antagonist, would be more beneficial. Subsequently the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial randomized 2,161 patients with PAD to either antiplatelet therapy (aspirin, ticlopidine, or clopidogrel) plus warfarin (INR 2.0-3.0) versus antiplatelet therapy alone. Dual antiplatelet therapy was not permitted unless patients suffered an MI or underwent coronary stent placement during follow-up. No significant differences in the primary outcome components of MI [5.0% vs. 6.1%, relative risk (RR) 0.82; 95% confidence interval (CI) 0.57 – 1.18, P = 0.28], stroke (3.5% vs. 3.5%, RR 1.01; 95% CI 0.65 – 1.59, P = 0.96), or severe lower extremity ischemia (3.9% vs. 4.1%, RR 0.96; 95% CI 0.63 – 1.47, P = 0.86) were observed among patients receiving warfarin plus antiplatelet therapy compared to antiplatelet therapy alone, respectively. In addition to the overall lack of benefit, a significant increased risk of life-threatening bleeding was observed in the warfarin plus antiplatelet combination therapy cohort compared to antiplatelet therapy alone, (4.0% vs. 1.2%, RR 3.41; 95% CI 1.84 – 6.35, P < 0.001) (Figure 1).⁴ The findings in the WAVE trial and the lack of further evidence to support any benefit of the addition of warfarin to antiplatelet therapy in the reduction of thrombotic events in patients with PAD is highlighted in current guidelines as a Class IIIb (no benefit) recommendation.³

The use of anticoagulants in the PAD population has also been evaluated following surgical revascularization to maintain graft patency. The use of warfarin (INR 2.0-3.0) plus aspirin (325 mg) compared to aspirin monotherapy was initially evaluated in a pilot study of 54 patients with high-risk vein grafts (defined as having poor run off, suboptimal vein conduit, or need for repeat interventions). The three-year primary graft patency rates were (non-significantly) higher in the anticoagulant therapy cohort compared with the aspirin monotherapy group (75% vs. 51%, P = 0.4). There were no observed anticoagulation therapy related bleeding complications (gastrointestinal, intracranial, and genitourinary hemorrhage).⁵ In a larger follow-up study, the Dutch Bypass Oral Anticoagulants or Aspirin (BOA) trial evaluated anticoagulation with warfarin (INR goal 3.0-4.5) vs. aspirin 80 mg daily in 2,690 patients undergoing infrainguinal bypass surgery. There was no observed difference in the patency rates with warfarin compared to aspirin, respectively [hazard ratio (HR) 0.95; 95% CI 0.82 – 1.11). Subgroup analysis revealed that patients with vein grafts benefited from lower rates of graft occlusion (HR 0.69; 95% CI 0.54 – 0.88) with warfarin monotherapy. Patients with prosthetic grafts experienced higher rates of graft occlusion on warfarin monotherapy (HR 1.26; 95% CI 0.82 – 1.11). As with previous studies, patients treated with warfarin experienced an increased number of major bleeding episodes compared to aspirin (HR 1.96; 95% CI 1.42 – 2.71).⁶ The BOA trial again reiterated that only selected patients with PAD stand to benefit from chronic warfarin therapy – particularly patients undergoing lower extremity bypass with vein grafts.

The recent introduction of novel anticoagulants (specifically dabigatran, rivaroxaban, and apixaban) for prevention of nonvalvular atrial fibrillation (AF) and venous thromboembolism (VTE) has rekindled the idea of anticoagulant use for secondary prevention in patients with atherosclerotic disease. An advantage of novel anticoagulants over warfarin is the lack of need for chronic laboratory monitoring due to more predictable pharmacodynamics.⁷ Currently there are two phase III prospective clinical trials investigating the use of novel anticoagulants, rivaroxaban and edoxaban, in the PAD population. The potential benefits observed with low-dose rivaroxaban in combination with antiplatelet therapy in patients with acute coronary syndrome (ACS) in ATLAS ACS-TIMI 51 is being now explored in patients with PAD. In the Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS), approximately 20,000 patients with documented atherosclerosis (coronary and/or peripheral) will be randomized to either 2.5 mg of rivaroxaban twice-daily plus antiplatelet therapy, 5 mg rivaroxaban twice-daily monotherapy, or antiplatelet therapy alone.⁹ In a similar trial, edoxaban, a once-daily factor Xa inhibitor is being evaluated in a randomized multicenter study in patients with PAD to assess the efficacy of its addition to aspirin compared to a clopidogrel plus aspirin regimen in preventing stenosis or occlusion in patients undergoing femoropoplitieal endovascular intervention.¹⁰

In summary, patients with PAD are at increased risk of MACE – MI, stroke, and death. Previous studies have demonstrated limited benefit of adding warfarin to antiplatelet regimens for secondary prevention of MACE in patients with PAD that was outweighed by a disproportionate increased risk of major or severe bleeding (Figure 2). For this reason, contemporary guidelines support the use of anticoagulants in only select PAD populations – patients undergoing vein graft bypass.^2,3 Studies are currently underway to evaluate the potential role of novel oral anticoagulants for thrombotic prevention in patients with PAD.

References

1. National Center for Chronic Disease Prevention and Health Promotion, Division for Heart Disease and Stroke Prevention. Peripheral Arterial Disease (PAD) Fact Sheet (Centers for Disease Control and Prevention website). Available at: http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_pad.htm. Accessed: 08/07/14.
2. Brogneaux C, Sprynger M, Magnée M,, et al. 2011 ESC guidelines on the diagnosis and treatment of peripheral artery diseases. Rev Med Liege 2012;67:560-5.
3. Rooke TW, Hirsch AT, Misra S, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;58:2020-45.
4. WAVE Investigators. The effects of oral anticoagulants in patients with peripheral arterial disease: rationale, design, and baseline characteristics of the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, including a meta-analysis of trials. Am Heart J 2006;151:1-9.
5. Sarac TP, Huber TS, Back MR, et al. Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk for failure. J Vasc Surg 1998;28:446-57.
6. Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomised trial. Lancet 2000;355:346-51.
7. Eikelboom JW, Weitz JI. Update on antithrombotic therapy: new anticoagulants. Circulation 2010;121:1523-32.
8. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19.
9. U.S. National Institutes of Health. Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) (ClinicalTrials.gov website). Available at: https://clinicaltrials.gov/ct2/show/NCT01776424. Accessed: 08/07/14.
10. U.S. National Institutes of Health. Edoxaban in Peripheral Arterial Disease (ePAD) (ClinicalTrials.gov website). Available from: https://clinicaltrials.gov/ct2/show/NCT01802775. Accessed: 08/07/14.

Keywords: Anticoagulants, Aspirin, Atherosclerosis, Centers for Disease Control and Prevention, U.S., Cost of Illness, Myocardial Infarction, Peripheral Arterial Disease, Secondary Prevention, Stroke, Ticlopidine

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