To assist in the selection and dosing of antithrombotic agents for patients with peripheral artery disease (PAD), considering the risk of vascular events and bleeding.Symptomatic patients with peripheral artery disease often have widespread atherosclerosis and are at risk of both major cardiovascular events (cardiac related deaths, myocardial infarction  and stroke) and limb events (acute limb ischemia and amputation). Antithrombotic therapy (see summary table) for the prevention and treatment of atherothrombotic complications in patients with PAD is a key component of their management, in addition to aggressive control of risk factors such as dyslipidemia, hypertension, and diabetes, and through the promotion of smoking cessation and regular exercise. While atherosclerosis is an integral part of the pathophysiology of lower extremity PAD, a large proportion of severe vascular occlusions are now known to be caused by thrombotic occlusive disease in the absence of significant atherosclerotic plaque. PAD is therefore considered a disease of 'atheroembolism', and often requires antiplatelet therapy, with or without anticoagulant, for optimal treatment.# INDICATIONS FOR ANTITHROMBOTIC THERAPY IN PAD:
Symptomatic chronic PAD Symptomatic patients with chronic PAD, as manifested by intermittent claudication with objective evidence of limb atherosclerosis or a previous vascular intervention (including prior bypass surgery, peripheral angioplasty or prior vascular amputation of the lower extremity), benefit from antithrombotic therapy. Single antiplatelet therapy (ASA or clopidogrel) lowers the risk for major adverse cardiovascular events (MACE) and has long been the standard of care of patients with PAD. 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 subgroup of patients with PAD. Ticagrelor has no benefit over clopidogrel in preventing MACE or major adverse limb events (MALE), such as hospitalization for acute limb ischemia, and is discontinued at a higher frequency due to higher rates of side effects.
In the CHARISMA study, adding clopidogrel 75 mg to ASA 75-162 mg did not result in a significant difference in MACE or major bleeding compared to the use of ASA alone in those at high risk of or with established atherosclerosis. While the combination of ASA and clopidogrel led to a 37% lower rate of myocardial infarction in the subgroup with established PAD, there was no significant effect on the risk of other vascular or limb events or of major bleeding. More recently, a subanalysis of the PEGASUS trial reported that the combination of ticagrelor with ASA decreased both MACE and MALE compared with ASA alone in post-MI patients with concomitant PAD, albeit at the cost of excess bleeding; results specific to PAD patients are not definitive due to relatively small patient numbers. In the TRA 2P-TIMI trial, the addition of Vorapaxar, a platelet thrombin receptor antagonist, to a second antiplatelet therapy (primarily ASA) resulted in a reduced rate of acute limb revascularization and amputations in the subgroup of patients with PAD. However, there was no difference in the rates of cardiovascular death, stroke and myocardial infarction, and this combination was associated with an increased risk of severe bleeding events and intracranial hemorrhages. Overall, while dual antiplatelet therapy (DAPT) suggests benefit over single antiplatelet therapy in reducing MACE and MALE, the benefit is marginal and is associated with increased bleeding complications. Therefore, while DAPT can be considered in PAD patients with acute coronary syndrome or post-coronary percutaneous interventions, it is uncommonly utilized in PAD patients in the absence of recent coronary events or peripheral revascularization.
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 patients in with chronic PAD and is associated with a 3.4-fold increase in life-threatening bleeding, including increased fatal and intracranial bleeding. Full dose anticoagulation should therefore not be added to antiplatelet therapy for the purpose of decreasing arterial ischemic events. There have been no trials evaluating MACE, MALE, or major bleeding outcomes with the combination of full dose direct oral anticoagulants (DOACs) and ASA in patients with chronic PAD. In patients with PAD who are on oral anticoagulant therapy with warfarin or a full dose DOAC for another indication (i.e. atrial fibrillation), the addition of an antiplatelet agent is usually not required. While not specifically evaluated in the PAD literature, robust evidence for patients with stable coronary artery disease requiring full dose anticoagulation shows demonstrable harm with the addition of single antiplatelet therapy. Therefore, we caution against the addition of an antiplatelet agent in fully anticoagulated patients with PAD unless it is short term or there has been a recent (<1 year) coronary or peripheral event (with or without revascularization).
In the COMPASS Trial, the combination of low dose rivaroxaban (2.5 mg bid) and ASA as compared to ASA alone reduced both MACE and MALE in patients with chronic stable PAD, conferring a 28% relative risk reduction in cardiovascular death, stroke and myocardial infarction as well as a 46% relative risk reduction in severe limb ischemia leading to an intervention (including major limb amputations). While a significant increase in major bleeding was observed, there was no increase in fatal or symptomatic bleeding into a critical organ (e.g. intracranial hemorrhage). Most major bleeding events were gastrointestinal. Of note, patients with a high risk of bleeding, recent stroke within 1 month, a history of hemorrhagic stroke, or estimated glomerular filtration rate of less than 15 mL/min, and severe heart failure (NYHA III/IV or EF<30%) were excluded from this study. While rivaroxaban alone at 5 mg bid outperformed ASA alone in preventing MALE, it did not reduce MACE and was similarly associated with increased major bleeding, including intracranial hemorrhage.
Patients at particularly high risk of ischemic vascular events derive the greatest benefit with combination low-dose rivaroxaban and aspirin. PAD patients with a high-risk limb presentation (HRLP), such as previous revascularization, previous amputation, or Fontaine III/IV status, as well as patients with high-risk comorbidities (HRCM), such as polyvascular disease, diabetes, renal insufficiency (eGFR <60) or heart failure, seem to have the highest risk of vascular events when followed over time. Treatment with rivaroxaban 2.5mg BID in addition to aspirin, as compared to aspirin alone, yields an absolute risk reduction in MACE or MALE including major amputation of 4.6% for patients with HRLP, 4.4% for patients with HRCM, and 5.2% for patients with both HRLP and HRCM. This is in contrast to a 1.0% absolute risk reduction for patients with neither HRLP or HRCM. Absolute risk increase of major bleeding was <1.0% for all groups. Therefore patients with these HRLP or HRCM should be considered for rivaroxaban 2.5mg BID in addition to aspirin.