PERIPHERAL ARTERIAL DISEASE OBJECTIVE: To assist in the selection and dosing of antithrombotic agents for patients with peripheral artery disease, considering the risk of vascular events and bleeding. BACKGROUND: Antiplatelet agents, mainly acetyl salicylic acid (ASA), are a cornerstone of peripheral artery disease (PAD) management. In PAD, these agents prevent mostly cardiac events and, to a lesser extent, stroke and peripheral ischemic complications. Antiplatelet agents inhibit platelet aggregation, with no significant effect on hemodynamic processes such as claudication. Antiplatelet drugs are a key part of the comprehensive management of PAD, which also includes aggressive control of risk factors such as dyslipidemia, hypertension, and diabetes, as well as smoking cessation and regular exercise. INDICATIONS FOR ANTITHROMBOTIC THERAPY IN PAD: Symptomatic PAD Patients with symptomatic PAD, manifested by intermittent claudication with objective evidence of limb atherosclerosis, or a previous vascular intervention (including prior bypass surgery or peripheral angioplasty or prior vascular amputation of the lower extremity), benefit from antiplatelet therapy (ASA, clopidogrel). ASA or clopidogrel lowers the risk for major adverse cardiovascular events (MACE), largely driven by a relative risk reduction in myocardial infarction of ~25%. In most studies, the dose of ASA varies between 80 and 160 mg. For patients allergic or intolerant to ASA, the use of clopidogrel is recommended. The CAPRIE study suggests that clopidogrel may be marginally better than ASA in reducing cardiovascular events in the PAD subgroup. In the CHARISMA study, the combination of clopidogrel 75 mg and ASA 75-162 mg led to a lower rate of myocardial infarction but with no effect on other vascular or limb events, at the cost of an increased risk of bleeding. Other dual antiplatelet combinations, including ASA and ticagrelor, may be considered as an alternative to clopidogrel and ASA in patients with PAD and acute coronary syndrome or who are post-coronary percutaneous intervention. However, there is no significant benefit of ticagrelor over clopidogrel when used as mono antiplatelet therapy in symptomatic PAD patients. The addition of Voraxapar, a platelet receptor antagonist, to a second antiplatelet therapy (primarily ASA) resulted in a reduced rate of acute limb revascularization and amputations in patients with PAD. However, there was no difference in the rates of cardiovascular death, stroke and myocardial infarction. Further, this combination was associated with an increased risk of severe bleeding events and intracranial hemorrhages. In the recently published COMPASS trial, the combination of low dose rivaroxaban (2.5 mg BID) plus ASA therapy in patients with symptomatic PAD (defined as prior history of lower extremity vascular © 2017 Thrombosis Canada Page 1 of 5 surgery, intermittent claudication supported by objective criteria of peripheral artery disease, coronary artery disease with an ankle-brachial index (ABI) <0.90, or carotid artery disease) reduced cardiovascular death, stroke and myocardial infarction by a relative 28% compared to ASA monotherapy after an average of 21 months of follow-up. Additionally, a 46% relative risk reduction in major adverse limb events including severe limb ischemia leading to an intervention (including major limb amputations) was demonstrated with rivaroxaban and ASA versus ASA alone. While a significant increase in major bleeding was observed (mostly gastrointestinal or GI), there was no increase in fatal or symptomatic bleeding into a critical organ (e.g. intracranial hemorrhage). Of note, patients with a high risk of bleeding, stroke within 1 month, a history of hemorrhagic stroke, or estimated glomerular filtration rate of less than 15 mL/min were excluded from this study. Rivaroxaban is not currently licensed for this indication in Canada and, at this time, there is no tablet formulation available in Canada suitable for administering 2.5 mg. In patients with chronic stable PAD, the WAVE trial showed that the addition of warfarin (INR 2-3) to antiplatelet therapy does not reduce major adverse cardiovascular events or severe limb ischemia and is associated with a 3.4-fold increase in life threatening bleeding. There have been no trials evaluating the MACE, major adverse limb event and major bleeding outcomes with full dose direct oral anticoagulants (DOACS or NOACS) in patients with chronic stable PAD. In patients with PAD who are on oral anticoagulant therapy with warfarin or a newer full dose oral anticoagulant (e.g. apixaban, dabigatran, edoxaban, rivaroxaban) for another indication (i.e. atrial fibrillation), the addition of a platelet inhibitor might provide some additional protection (i.e. myocardial infarction, stroke, cardiovascular death) but with an unacceptable increased bleeding risk. Therefore, we caution against the use of platelet inhibitors in fully anticoagulated patients with PAD unless it is short term, or there is a specific other indication for this combination (i.e. recent stent placement). Asymptomatic PAD: There is no evidence that supports the use of ASA alone in patients with asymptomatic PAD or a reduced ABI without symptoms. This absence of a beneficial effect is akin to the role of ASA in primary prevention where the reduced risk of cardiovascular events is counterbalanced by an increased risk of bleeding. As the COMPASS trial did show a consistent reduction in MACE (in patients with CAD and an ABI < 0.90), the combination of ASA and low dose rivaroxaban [2.5 mg bid] could be considered in select patients with asymptomatic PAD who have concomitant CAD once Health Canada approval is obtained and an appropriate tablet formulation is available. Peripheral limb procedures: Patients who undergo endovascular interventions of the peripheral arteries, without stenting, should receive single antiplatelet therapy or ASA plus rivaroxaban 2.5 mg BID long-term (once Health Canada approval and an appropriate tablet formulation are available), started once hemostasis is obtained and the patient is deemed to be low risk for bleeding. For patients who undergo endovascular interventions where a bare metal stent or a drug eluting stent is placed, guidelines suggest dual antiplatelet therapy (DAPT) with clopidogrel and ASA for 1 to 3 months. Benefits of therapy beyond this time are unclear. The risk-benefit profile of direct oral anticoagulants used © 2017 Thrombosis Canada Page 2 of 5 immediately post endovascular intervention is still unknown; however, a large randomized trial (Voyager) is underway. Until then, consideration could be given to transitioning patients from DAPT after 1 to 3 months of therapy to low dose rivaroxaban and aspirin therapy based on the results of the COMPASS trial, once Health Canada approval and an appropriate tablet formulation are available. Among patients who are surgically-treated with peripheral artery bypass grafts with native or synthetic grafts, a single antiplatelet agent is the standard of care. The DUTCH BOA trial demonstrated that adding warfarin (target INR 3-4.5) to aspirin is associated with an excess of life threatening bleeding when used long-term. Addition of clopidogrel or ticagrelor to ASA has not shown clear benefit in optimizing limb patency, but studies addressing dual antiplatelet therapy in this setting are small. It is not clear whether complicated distal bypasses might benefit from temporary dual antiplatelet therapy. Once stable post operatively and if deemed to be low risk for bleeding, such patients could be considered candidates for low dose rivaroxaban and aspirin as per the COMPASS trial, with the caveats noted above. DOSING: • The standard daily dose of ASA is 81 mg and the standard dose of clopidogrel is 75 mg. • The standard dose of ticagrelor is 60 mg bid. • Rivaroxaban dosing is 2.5 mg BID used together with low dose aspirin (still pending Health Canada approval). ADVERSE EFFECTS: The main adverse effect of ASA, seen more at higher doses, is bleeding (mainly GI) but there is also increased risk of intracranial bleeding. The risk-benefit ratio is generally acceptable in patients with symptomatic PAD. The main adverse effect of clopidogrel is also bleeding but the rate of GI bleeding is less than with ASA. The combination of ASA and low dose rivaroxaban increased the risk of major bleeding (mostly GI), however there was no difference in the risk of intracranial or fatal bleeds when compared to ASA alone. PERI-PROCEDURAL MANAGEMENT: There is little data on the thrombotic risk in patients with PAD who have antiplatelet therapy interrupted for a surgical or other invasive procedure. It is reasonable to continue ASA if the procedure is associated with a low risk of bleeding and to stop ASA before the procedure if the bleeding risk of the procedure is anticipated to be high. For patients on clopidogrel for PAD, clopidogrel should be discontinued 5 – 7 days before an invasive procedure. After the procedure, the highest risk of major life-threatening bleeding is 2 days post procedure, with a significant reduction by day 8 and resumption of antiplatelet therapy at this time minimizes major bleeding risks. However, in high risk patients, physicians may elect to resume antiplatelet therapy before day 8 after weighing the risks of a thrombotic event versus major bleeding. OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES: • Acetyl Salicylic Acid (ASA) © 2017 Thrombosis Canada Page 3 of 5 • Clopidogrel (Plavix®) • Ticargrelor (Brilinta®) • Rivaroxaban