The meta-analysis included 287 trials involving more than 200000 patients that compared an antiplatelet drug with a control, or compared different antiplatelet drugs in high-risk patients with acute or previous vascular disease or some other predisposing condition from which results were available before September 1997. The main outcome measure was "serious vascular event" - a nonfatal MI, nonfatal stroke or vascular death. The researchers note that previous meta-analyses they have conducted, which included trials available in 1990 "left some important clinical questions unanswered." Hence the decision to update these to include new studies.

Overall, among these high-risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious adverse vascular event by about one quarter. Nonfatal MI was reduced by one third, nonfatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). "In each of these high-risk categories the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding," they say.

Absolute reductions in the risk of having a serious vascular event were 36 per 1000 patients treated for 2 years among patients with previous MI; 38 per 1000 among those treated for 1 month with acute MI; 36 per 1000 treated for 2 years with previous stroke or TIA; 9 per 1000 treated for 3 weeks among those with acute stroke and 22 per 1000 treated for 2 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 (AF) (p=0.001).

Reprinted with permission from BMJ 2002;324:71-86.

In conclusion, aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an AMI or ischemic stroke, unstable or stable angina, previous MI, stroke or cerebral ischemia, peripheral arterial disease, or AF. "This analysis extends the direct evidence of benefit from antiplatelet therapy to a much wider range of patients at high risk of occlusive vascular disease," the authors say in their discussion. In addition, they suggest that the protective effects of antiplatelet therapy should be expected to apply to an even wider range of high-risk patients than those categories for which the present meta-analysis provides direct evidence of benefit.

For example, although antiplatelet therapy was associated with only a nonsignificant proportional reduction in serious vascular events among patients with diabetes mellitus (but no history of MI or stroke) "these results do not provide reliable evidence of a lack of worthwhile benefit in such patients...[particularly as] there is now good evidence that antiplatelet therapy is not associated with any special risks (such as bleeding in the eye) in patients with diabetes," the authors say. In fact, "taken as a whole they indicate the converse, although direct evidence from further randomized trials...would still be helpful."

With regard to acute stroke, the randomized evidence from 40000 patients shows that "there is now good reason to consider starting antiplatelet therapy as soon as possible after a suspected acute ischemic stroke," the researchers note, adding that this complements the previous evidence that continuing antiplatelet therapy for some years after the acute phase of ischemic stroke produces substantial further reductions in risk.

Aspirin was the most widely studied antiplatelet drug. The new data allow three main questions about treatment regimens to be examined, say Baigent et al: which range of aspirin doses seem to be most promising; is some other antiplatelet drug better than aspirin; and does any other antiplatelet drug add to the net benefit of aspirin?

The analyses indicate that high doses (500 to 1500 mg) daily of aspirin are no more effective than medium doses (160-325 mg) or low doses (75-150 mg), although the authors note that "in acute settings an initial loading dose of at least 150 mg may be required."

With regard to the differences between antiplatelet drugs, these are likely to be smaller than the differences between antiplatelet therapy and no antiplatelet therapy, "so reliable comparisons between different drugs may require direct randomization of many thousands, or even tens of thousands, of high-risk patients." Such evidence exists "only for clopidogrel versus aspirin," the researchers say, with the indication that clopidogrel may be slightly more effective than aspirin (clopidogrel reduced serious vascular events by 10% compared with aspirin's 4% reduction rate).

There is now good reason to consider starting antiplatelet therapy as soon as possible after a suspected acute ischemic stroke.

In terms of adding other antiplatelet drugs to aspirin, the authors note that the CURE trial, in which clopidogrel was added to aspirin in patients with acute coronary syndromes (ACS), recently reported promising results, and that the second Chinese cardiac study is assessing this question among patients with acute MI. They note that long-term studies of the effects of adding clopidogrel to aspirin might also be useful "among other types of patients at high risk of occlusive vascular disease." Such studies could also examine the "important question" of whether adding clopidogrel to aspirin is effective in patients who were taking aspirin when the event occurred (so-called aspirin failures). They add that in patients who have a definite contraindication to aspirin, "clopidogrel might be an appropriate alternative."

The addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. And, in the high-risk setting of percutaneous coronary intervention or among high-risk patients with ACS, "intensification of antiplatelet therapy by adding an IV GP IIb/IIIa antagonist...may be appropriate." Thus adding a second antiplatelet drug to aspirin "may produce additional benefits in some clinical circumstances," Baigent et al say, "but more research into this strategy is needed."

Although audits have shown that the use of antiplatelet therapy has increased during the past few years, "a substantial proportion of high-risk patients still do not receive it", the researchers note. For example, only about half of all patients with a history of MI, angina or peripheral arterial disease are currently receiving antiplatelet therapy. Use of aspirin among patients with diabetes is "even more limited," and only about one third of patients with AF receive oral anticoagulants, the most effective treatment for the prevention of strokes in this condition.

"Unless some definite contraindication exists, antiplatelet therapy should be considered routinely for all patients whose medical history implies a significant risk of occlusive vascular disease over the next few months or years, and it should generally be continued for as long as the risk remains high." Aspirin therapy should be considered routinely in all such patients "irrespective of whether they have already had a major vascular event", Baigent et al conclude.

In the accompanying editorial, Drs Muredach Reilly and Garret A FitzGerald (University of Pennsylvania) say the efficacy of aspirin in the secondary prevention of MI and stroke "is widely accepted." The development of a combined Antithrombotic Trialists' Collaboration endpoint and the visual display of data in a manner that reflects the size of the drug effect and the size of the dataset "helps to spread the word," the note, adding that aspirin "remarkably...continues to be underused in conditions where it's efficacy has been well established."

Although the review shows that patients with peripheral vascular disease and those at risk of embolic events may also benefit from aspirin, the editorialists say, "whether such data alone preclude placebo controlled evaluation of antiplatelet drugs in such populations is arguable". However, they hope that this new overview "will lay...to rest" the issue of the "cultural lag...which persists in some quarters" favoring the use of high doses of aspirin in preventing stroke.

Although such overviews are by their very nature "reductionist, blunt instruments," this one "has distilled often copious, complex, and apparently conflicting data for the end user, the medical practitioner." Despite being "imprecise and potentially misleading...when combined with information from other sources, it is likely to lead to conviction."

The paper and editorial are accompanied by a third "For debate" paper, in which Dr John Cleland (University of Hull, UK) - who is well known for his controversial opinions on aspirin - says that "among large long term trials after myocardial infarction, there is no evidence that aspirin saves lives." Cleland goes on to suggest that aspirin may in fact conceal, rather than prevent, vascular events. He says the meta-analysis is subject to bias, and that aspirin is neither safe nor cheap. Furthermore, "the greatest potential detriment of aspirin on healthcare...is that it diverts attention away from treatments that are of unequivocal benefit to many groups of patients, such as ACE inhibitors, -blockers and statins."3

Peto told heartwire that Cleland's piece was rejected as an editorial, but that the BMJ took the decision to run it as a "For debate" piece, with the Oxford team only finding out about this on January 5. Peto commented simply: "There isn't a single serious argument in there." He added that he and his team are preparing a response to Cleland for publication in next week's BMJ.