ASPIRIN PRIMARY PREVENTION DATA SHOW SMALL BUT SIGNIFICANT EFFECT: FURTHER TRIALS

ASPIRIN PRIMARY PREVENTION DATA SHOW SMALL BUT SIGNIFICANT EFFECT: FURTHER TRIALS, however, are needed before daily aspirin use by healthy individuals can be recommended for prevention of primary vascular events, Richard Peto, Oxford University, et al., suggested in a large-scale, meta-analysis of data from 257 aspirin studies published in the Jan. 7 issue of the British Medical Journal. The study evaluates antiplatelet therapy, primarily aspirin, for three distinct groups: primary prevention; treatment for acute myocardial infarction and unstable angina; and for secondary prevention of myocardial infarction, angina, stroke, transient ischemic attack, arterial bypass surgery or angioplasty.

The researchers found "a small but highly significant reduction" of five nonfatal myocardial infarction events per 1,000 subjects "among the 28,000 low-risk 'primary prevention' subjects studied."

However, the study found that the "reduction in vascular events was slightly smaller and less clearly significant" within this low-risk group. In addition, "in contrast with the highly significant reduction in nonfatal strokes among high-risk subjects, there was no evidence of any decrease in nonfatal strokes among those low-risk subjects -- rather the reverse" (two per 1,000 increase), Peto et al. said.

The researchers discovered that when the etiology of all strokes (fatal and nonfatal) was observed in low-risk subjects, there was "not only a small, marginally significant excess" of hemorrhagic strokes in that population but also a "non-significant excess of 'other' strokes."

Peto et al. suggested that the increase in strokes in the low- risk group may have been due to the classification of some hemorrhagic strokes caused by antiplatelet therapy in the "other" strokes category and to the effect of "chance." Because hemorrhagic strokes are more likely to be fatal, the researchers suggested that the "small excess...among the primary prevention subjects may account, at least in part, for the lack of any significant difference in vascular mortality."

"There is, as yet, no clear evidence that antiplatelet therapy is indicated for routine use in 'primary prevention' subjects at low risk of occlusive vascular events," the researchers concluded.

Commenting on the risk-to-benefit ratio of this type of treatment for healthy patients and for patients with a "particularly high risk of a major hemorrhagic event," Peto et al. observed that "even a small increase in hemorrhagic events might outweigh the expected decrease in ischemic events."

The researchers decided that "because of this uncertainty and because the numbers to whom this could be relevant are so large, more directly randomized evidence is needed on whether long-term prophylactic antiplatelet therapy produces any worthwhile net benefit in 'primary' prevention." The researchers said they expect to receive this information from the Women's Health Study ("The Tan Sheet" Sept. 27, 1993, p. 6) and from the British Hypertension Society Study.

The meta-analysis marks the largest collaborative overview of disease treatment ever reported, the researchers said. The analysis includes data from 257 randomized trials and nearly 119,000 test subjects. Medium-dose aspirin (75-325 mg/day) was the most widely tested antiplatelet regimen and "no other regimen appeared significantly more effective at preventing myocardial infarction, stroke or death," the researchers found.

In contrast to the findings for healthy subjects, the researchers recommended that the risk-to-benefit ratio strongly favors aspirin therapy for patients with acute myocardial infarction and for patients who have experienced a prior vascular event. The researchers strongly urged FDA to authorize the expansion of professional indications for patients in these two groups.

Two U.S. collaborators, Julie Buring, PhD, and Charles Hennekens, MD, both affiliated with Harvard Medical School, said the study shows a "clear and striking benefit" on the risk of mortality among patients who are treated with aspirin within 24 hours of onset of symptoms of a heart attack. The study found a 23% reduction in mortality in acute heart attack patients receiving aspirin.

Aspirin is not currently indicated in professional labeling for use in patients experiencing acute MI. The researchers suggested that aspirin therapy "should be considered for virtually everyone with suspected acute myocardial infarction [and] unstable angina." Buring noted during a Jan. 6 press briefing on the study that FDA is currently considering this indication.

In relation to other therapies, Hennekens observed that aspirin has the best risk-to-benefit ratio. "By comparison, clot- busters given 12 hours after onset of symptoms" reduces the death rate by 20% (as compared to 23% with aspirin) but "in fact, every 10 lives you save, there is one cerebral hemorrhage caused" and aspirin given during acute MI does not increase the risk of acute MI, Hennekens said.

Cost-to-benefit also favors aspirin therapy, Hennekens contended. The cost measured in terms of each life saved would be about $264,000 if every person with acute MI were to receive angioplasty, according to Hennekens. He estimated that treatment with tissue plasminogen activator costs approximately $88,000 per life saved; treatment with anistreplase costs about $68,000 per life saved; and streptokinase costs about $12,000 per life saved. Aspirin, he noted, would cost approximately $13 for each life saved.

Professional labeling for aspirin currently includes indications for secondary prevention of heart attack and for transient ischemic attack for men only. Given the study findings that deaths were reduced by about 40 per 1,000 treated individuals with a prior heart attack or stroke, and by 20 per 1,000 patients experiencing other vascular diseases, the researchers recommended that professional labeling be revised to include any disease that is a manifestation of occlusive vascular disease without reference to gender.

In addition, Buring suggested that professional labeling be expanded because physicians tend to hesitate to recommend aspirin to women, the elderly and people with a history of hypertension or diabetes who are trying to ward off a subsequent vascular event. "The data indicates clear substantial benefit" to these subgroups, Buring said.