Antiplatelet agents for reducing risks in patients with peripheral arterial disease and cramping pain in legs on walking

Peripheral arterial disease (PAD) refers to the blocking of large arteries. Patients with peripheral arterial disease as a result of narrowing of the arteries in the legs may present with cramping pain in the legs or buttocks on walking; this is also known as intermittent claudication (IC). This group of patients are at high risk of a heart attack, stroke and death. Treatment often involves stopping cigarette smoking and the optimising of other risk factors such as diabetes, high blood pressure and cholesterol. Another treatment often used to reduce the risk of heart attacks and strokes in patients with IC is antiplatelet treatment. Antiplatelets make the blood less sticky and therefore block the formation of blood clots, thereby preventing blockages in arteries which can cause heart attacks and strokes. Antiplatelet treatments include drugs such as aspirin, clopidogrel and dipyridamole, but there is limited evidence to date on the benefits of antiplatelet therapy in patients with IC. Twelve studies with a total of 12,168 patients were included in this review. The analyses show that, in patients with IC, antiplatelet agents reduced the risk of death from all causes, and from heart attack and stroke combined when compared with placebo. When aspirin was compared with other antiplatelet agents, there was some evidence that the alternative antiplatelet had a more beneficial effect in reducing all cause mortality or of suffering a cardiovascular event such as heart attack or stroke. However, this was based on only two trials. Antiplatelet usage, however, does increase the risk of indigestion and may also increase risk of major bleeding events. Despite its widespread use, the evidence for first line use of aspirin in patients with IC is weak and further research is required to determine whether aspirin would be better replaced by a different class of antiplatelet agent which has a greater beneficial effect with fewer side-effects.

Authors' conclusions: 

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.

Read the full abstract...

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.

Search strategy: 

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.

Selection criteria: 

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 collection and analysis: 

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.

Main results: 

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).