Antiplatelet agents for intermittent claudication

Peripheral arterial disease (PAD) is common and is a marker of systemic atherosclerosis. Patients with symptoms of intermittent claudication (IC) are at increased risk of cardiovascular events (myocardial infarction (MI) and stroke) and of both cardiovascular and all cause mortality.

To determine the effectiveness of antiplatelet agents in reducing mortality (all cause and cardiovascular) and cardiovascular events in patients with intermittent claudication.

The Cochrane Peripheral Vascular Diseases group searched their Specialised Register (last searched April 2011) and CENTRAL (2011, Issue 2) for publications on antiplatelet agents and IC. In addition reference lists of relevant articles were also searched.

Double-blind randomised controlled trials comparing oral antiplatelet agents versus placebo, or versus other antiplatelet agents in patients with stable intermittent claudication were included. Patients with asymptomatic PAD (stage I Fontaine), stage III and IV Fontaine PAD, and those undergoing or awaiting endovascular or surgical intervention were excluded.

Data on methodological quality, participants, interventions and outcomes including all cause mortality, cardiovascular mortality, cardiovascular events, adverse events, pain free walking distance, need for revascularisation, limb amputation and ankle brachial pressure indices were collected. For each outcome, the pooled risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) was calculated.

A total of 12 studies with a combined total of 12,168 patients were included in this review. Antiplatelet agents reduced all cause (RR 0.76, 95% CI 0.60 to 0.98) and cardiovascular mortality (RR 0.54, 95% CI 0.32 to 0.93) in patients with IC compared with placebo. A reduction in total cardiovascular events was not statistically significant (RR 0.80, 95% CI 0.63 to 1.01). Data from two trials (which tested clopidogrel and picotamide respectively against aspirin) showed a significantly lower risk of all cause mortality (RR 0.73, 95% CI 0.58 to 0.93) and cardiovascular events (RR 0.81, 95% CI 0.67 to 0.98) with antiplatelets other than aspirin compared with aspirin. Antiplatelet therapy was associated with a higher risk of adverse events, including gastrointestinal symptoms (dyspepsia) (RR 2.11, 95% CI 1.23 to 3.61) and adverse events leading to cessation of therapy (RR 2.05, 95% CI 1.53 to 2.75) compared with placebo; data on major bleeding (RR 1.73, 95% CI 0.51, 5.83) and on adverse events in trials of aspirin versus alternative antiplatelet were limited. Risk of limb deterioration leading to revascularisation was significantly reduced by antiplatelet treatment compared with placebo (RR 0.65, 95% CI 0.43 to 0.97).

Antiplatelet agents have a beneficial effect in reducing all cause mortality and fatal cardiovascular events in patients with IC. Treatment with antiplatelet agents in this patient group however is associated with an increase in adverse effects, including GI symptoms, and healthcare professionals and patients need to be aware of the potential harm as well as the benefit of therapy; more data are required on the effect of antiplatelets on major bleeding. Evidence on the effectiveness of aspirin versus either placebo or an alternative antiplatelet agent is lacking. Evidence for thienopyridine antiplatelet agents was particularly compelling and there is an urgent need for multicentre trials to compare the effects of aspirin against thienopyridines.