A Cochrane review [Abstract] 1 included 12 studies with a total of 12 168 subjects with intermittent claudication (Fontaine Stage II). Studies which included patients with asymptomatic peripheral arterial disease (PAD), rest pain, ischaemic ulcer or gangrene (Fontaine stages I, III and IV) were excluded. Similarly, patients undergoing planned future vascular surgical intervention (angioplasty, surgery or amputation) were excluded. Six studies incorporated patients with previous reconstructive surgery or amputation. Ten studies compared an antiplatelet agent (ticlopidine 5, indobufen 2, picotamide 2, and triflusal 1) against placebo, and 2 studies compared an antiplatelet agent other than aspirin against aspirin (1 study compared clopidogrel against aspirin, and 1 study compared picotamide against aspirin).
Antiplatelet agents reduced all cause mortality (RR 0.76, 95% CI 0.60 to 0.98; 4 studies, n=3 926). Combined data from trials of ticlopidine, which showed a statistically significant effect in reducing all cause mortality (RR 0.73, 95% CI 0.56 to 0.96; 4 studies, n=1 622), contributed 81.9% of weight to this analysis. Antiplatelet agents reduced cardiovascular mortality (RR 0.54, 95% CI 0.32 to 0.93; 4 studies, n=1 622) compared with placebo; all 4 trials used ticlopidine as the drug of intervention. A reduction in total cardiovascular events was not statistically significant (RR 0.80, 95% CI 0.63 to 1.01; 5 studies, n=3 926).
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; 2 studies, n=7 661) and cardiovascular events (RR 0.81, 95% CI 0.67 to 0.98; 2 studies, n=7 661), but not of cardiovascular mortality (RR 0.74, 95% CI 0.48 to 1.15; 2 studies, n=7 661) with antiplatelets other than aspirin compared with aspirin. For the comparison of clopidogrel versus aspirin (1 study, n=6 452), the results were: all-cause mortality RR 0.78, 95% CI 0.60 to 1.02; cardiovascular mortality RR 0.83, 95% CI 0.51 to 1.35; cardiovascular events RR 0.79, 95% CI 0.64 to 0.97.
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; 9 studies, n=3818) and adverse events leading to cessation of therapy (RR 2.05, 95% CI 1.53 to 2.75; 8 studies, n=4388) compared with placebo; data on major bleeding (RR 1.73, 95% CI 0.51, 5.83; 2 studies, n=838) 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; 5 studies, n=3304).
The majority of evidence was derived from historical trials incorporating ticlopidine, which has since been supplanted by another thienopyridine (clopidogrel) due to the increased risk of neutropaenia and thrombocytopaenic purpura. The review was limited to patients with stage II Fontaine and cannot be extrapolated to patients with stage I, III or IV; 4 large RCTs were excluded as they recruited participants with asymptomatic PAD.
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