Pharmacotherapy in Peripheral Artery Disease
Faisal Hasan, MD
Khwaja Yousuf Hasan, MBBS
William L. Bennett, MD, PhD
Sameh Mohareb, MD
Key Points
Treatment of hypertension with ACEI has been shown to have antiatherogenic properties as well as reduced clinical events in patient with peripheral arterial disease (PAD).
Aspirin monotherapy has been shown to be of benefit in treatment of secondary prevention patient with peripheral arterial disease.
Statin therapy is known to improve morbidity and mortality in patients with peripheral arterial disease.
Smoking cessation and supervised walking programs have shown benefit in patients with PAD.
I. Introduction
Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis. It is associated with a reduction in functional capacity and quality of life, but more importantly, presence of PAD is associated with an increased risk of cardiovascular and cerebrovascular morbidity and mortality compared with the general population.1 Treatment of PAD is based on lifestyle modification, relief of symptoms, and aggressive treatment of risk factors of atherosclerosis. This includes aggressive management of hypertension, dyslipidemia, diabetes mellitus, antiplatelet therapy, cessation of smoking, and graded exercise prescription. Guideline-directed medical therapy (GDMT) has been shown to reduce cardiovascular events and improve functional status of patients with PAD. However, these patients are less likely to receive GDMT than patients with other forms of cardiovascular disease such as coronary artery disease.2
Medical management of PAD has a proven role in improving cardiovascular outcomes and functional capacity. Therapy with antiplatelet agents has been shown to improve cardiovascular and lower extremity atherosclerotic disease outcomes among patients with symptomatic or asymptomatic PAD irrespective of revascularization. Treatment of hypertension with ACE inhibitors has been shown to decrease clinical events in patients with PAD. ACE inhibitors have also been shown to have antiatherogenic properties that would have favorable effects in PAD. Statins have been shown to lower the risk of adverse limb outcomes of revascularization and amputation as well as reduce symptoms in PAD.
II. Antithrombotic Therapy
A. Antiplatelet Agents Antiplatelet agents have been studied extensively in cardiovascular diseases. The Antithrombotic Trialists’ Collaboration studies have shown that antiplatelet therapy is associated with a mortality benefit that is driven primarily by a significant reduction in myocardial infarction, stroke, and vascular death among patients with PAD.3 The recently published American Heart Association/American College of Cardiology and European Society of Cardiology guidelines on PAD endorse the long-term use of single antiplatelet agents (aspirin or clopidogrel) in patients with symptomatic
PAD for prevention of major adverse cardiac events.4,5 Their role in asymptomatic patients with PAD (that is ABI <0.9) or with atypical symptoms is uncertain; however, it is still recommended, as aspirin has been shown to reduce the risk of vascular events in this population as well.6
1. Aspirin acts by irreversibly inhibiting cyclooxygenase-2 and prevents formation of thromboxane A2 from arachidonic acid.7 It has been shown to reduce the risk of myocardial infarction, stroke, and death from cardiovascular events in patients with symptomatic and asymptomatic PAD. The use of aspirin for secondary prevention has been well established by the Antithrombotic Trialists’ Collaboration studies. A meta-analysis of 287 studies involving more than 200,000 patients compared different antiplatelet regimens or antiplatelet agents with controls. Antiplatelet therapy resulted in a reduction in outcomes of myocardial infarction by 33%, reduction in stroke by 25% and reduction in vascular death by 17% without any apparent side effects.3 Similarly in a meta-analysis of 60 studies (mostly aspirin alone or in combination with dipyridamole) antiplatelet therapy was associated with a significant reduction in arterial or venous graft occlusion among patients undergoing any form of a vascular procedure.8 The role of aspirin in primary prevention has been less well established. The Aspirin for Asymptomatic Atherosclerosis (AAA) trial examined the role of aspirin in patients with subclinical PAD (ABI [ankle-brachial index] <0.95). The primary endpoint of the study was an initial fatal or nonfatal myocardial infarction, stroke, or need for revascularization. There was no difference in the primary endpoint among patients who received aspirin or placebo over a follow-up of 8.2 years.9 The POPAD trial similarly compared use of aspirin and antioxidants versus placebo among diabetic patients with subclinical PAD. Again, no difference was found in the primary endpoints of nonfatal or fatal cardiovascular events despite the high-risk profile of the patients.10
2. The adenosine diphosphate (ADP) P2Y12 receptor antagonists include the thienopyridines (ticlopidine, clopidogrel, prasugrel) and ticagrelor. Thienopyridines are irreversible antagonists, whereas ticagrelor is a reversible antagonist of the ADP receptor.11,12 Ticlopidine was found to be very effective in prevention of vascular events; however, its use has been discontinued because significant hematologic side effects. Only clopidogrel and ticagrelor have been studied in patients with PAD. The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) was a large multicenter double-blinded randomized controlled trial that compared aspirin with clopidogrel for secondary prevention in patients who had evidence of atherosclerotic disease.13 The PAD cohort included patients who had intermittent claudication with an ABI of <0.85 or those who had intermittent claudication and had undergone a peripheral vascular intervention in the form of surgical or percutaneous revascularization. Generally, the results of the trial favored the use of clopidogrel over aspirin monotherapy for PAD; however, the absolute benefit was small, albeit statistically significant. The PLATO (ticagrelor versus clopidogrel in patients with acute coronary
syndrome) trial established the superiority of ticagrelor over clopidogrel in acute coronary syndrome.14 In light of these findings, it was hypothesized that similar findings could be extrapolated among patients with PAD. The EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial was carried out to test this hypothesis; however, it failed to establish the superiority of ticagrelor over clopidogrel in PAD.15 There were no significant differences in the primary and secondary endpoints among both drugs; however, there was a higher rate of discontinuation of ticagrelor due to side effects (mainly dyspnea and minor bleeding). Both the ACC and ESC guidelines to date recommend the use of clopidogrel or aspirin as single antiplatelet therapy for prevention of major adverse cardiac events in patients with PAD.4,5
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