Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

Abstract

Objective: To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events.

Design: Collaborative meta-analyses (systematic overviews).

Inclusion criteria: Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen.

Studies reviewed: 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens.

Main outcome measure: "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death.

Results: Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000.

Conclusions: Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.

Figures

Figure 1

Proportional effects of antiplatelet therapy on vascular events (myocardial infarction, stroke, or vascular death) in five main high risk categories. Stratified ratio of odds of an event in treatment groups to that in control groups is plotted for each group of trials (black square) along with its 99% confidence interval (horizontal line). Meta-analysis of results for all trials (and 95% confidence interval) is represented by an open diamond. Adjusted control totals have been calculated after converting any unevenly randomised trials to even ones by counting control groups more than once, but other statistical calculations are based on actual numbers from individual trials

Figure 2

Absolute effects of antiplatelet therapy on vascular events (myocardial infarction, stroke, or vascular death) in five main high risk categories. Adjusted control totals have been calculated after converting any unevenly randomised trials to even ones by counting control groups more than once

Figure 3

Absolute effects of antiplatelet therapy on various outcomes in patients with (a) previous myocardial infarction (12 trials); (b) acute myocardial infarction (15 trials); (c) previous stroke or transient ischaemic attack (21 trials); and (d) acute (presumed ischaemic) stroke (seven trials). Adjusted control totals have been calculated after converting any unevenly randomised trials to even ones by counting control groups more than once. In “any death” columns, non-vascular deaths are represented by lower horizontal lines (and may be calculated by subtracting vascular deaths from any deaths)

Figure 3

Absolute effects of antiplatelet therapy on various outcomes in patients with (a) previous myocardial infarction (12 trials); (b) acute myocardial infarction (15 trials); (c) previous stroke or transient ischaemic attack (21 trials); and (d) acute (presumed ischaemic) stroke (seven trials). Adjusted control totals have been calculated after converting any unevenly randomised trials to even ones by counting control groups more than once. In “any death” columns, non-vascular deaths are represented by lower horizontal lines (and may be calculated by subtracting vascular deaths from any deaths)

Figure 3

Absolute effects of antiplatelet therapy on various outcomes in patients with (a) previous myocardial infarction (12 trials); (b) acute myocardial infarction (15 trials); (c) previous stroke or transient ischaemic attack (21 trials); and (d) acute (presumed ischaemic) stroke (seven trials). Adjusted control totals have been calculated after converting any unevenly randomised trials to even ones by counting control groups more than once. In “any death” columns, non-vascular deaths are represented by lower horizontal lines (and may be calculated by subtracting vascular deaths from any deaths)

Figure 3

Absolute effects of antiplatelet therapy on various outcomes in patients with (a) previous myocardial infarction (12 trials); (b) acute myocardial infarction (15 trials); (c) previous stroke or transient ischaemic attack (21 trials); and (d) acute (presumed ischaemic) stroke (seven trials). Adjusted control totals have been calculated after converting any unevenly randomised trials to even ones by counting control groups more than once. In “any death” columns, non-vascular deaths are represented by lower horizontal lines (and may be calculated by subtracting vascular deaths from any deaths)

Figure 4

Proportional effects of antiplatelet therapy on vascular events in 195 trials in high risk patients subdivided by disease category. Stratified ratio of odds of an event in treatment groups to that in control groups is plotted for each group of trials (black square) along with its 99% confidence interval (horizontal line). Meta-analysis of results for each main category and for all trials (and 95% confidence interval) is represented by an open diamond. Adjusted control totals have been calculated after converting any unevenly randomised trials to even ones by counting control groups more than once, but other statistical calculations are based on actual numbers from individual trials

Figure 5

Direct comparisons of proportional effects of different antiplatelet regimens on vascular events in high risk patients. Only meta-analyses involving a total of 500 or more high risk patients are shown. *Includes one trial comparing 1400 mg/day v 350 mg/day,30 and another (excluding those with acute stroke) comparing 1000 mg/day v 300 mg/day among patients who were also given dipyridamole.31 †Includes two trials comparing 75-325 mg aspirin daily v <75 mg aspirin daily and one trial of 500-1500 mg aspirin daily v <75 mg aspirin daily. ‡Includes cilostazol, sulotroban, trapidil, E5510, eptifibatide, and GR32191B. Stratified ratio of odds of an event in regimen 1 group to that in regimen 2 group is plotted for each group of trials (black square) along with its 99% confidence interval (horizontal line). Meta-analysis of results for all trials for a particular comparison (and 95% confidence interval) is represented by an open diamond

Figure 6

Indirect comparisons of proportional effects of different antiplatelet regimens on vascular events in high risk patients (excluding those with acute stroke). Only meta-analyses involving 500 or more high risk patients are shown. *Some trials contributed to more than one comparison. †Includes indobufen, flurbiprofen, GR32191B, dazoxiben, and trapidil. Stratified ratio of odds of an event in treatment groups to that in control groups is plotted for each group of trials (black square) along with its 99% confidence interval (horizontal line). Meta-analysis of results for each main comparison and for all trials (and 95% confidence interval) is represented by an open diamond. Adjusted control totals have been calculated after converting any unevenly randomised trials to even ones by counting control groups more than once, but statistical calculations are based on actual numbers from individual trials