Aspirin does not prevent MI, CV death in primary-prevention study in women

March 07, 2005

Boston, MA - In a surprise finding, the use of aspirin for primary prevention did not lower the risk of myocardial infarction or cardiovascular death in almost 40 000 women in the Women's Health Study. It did, however, reduce the risk of stroke.

The results appear online in the New England Journal of Medicine today[1] and are being presented later this morning at the American College of Cardiology (ACC) 2005 Scientific Sessions in Orlando, FL by lead investigator Dr Paul M Ridker (Brigham and Women's Hospital, Boston, MA).

Aspirin reduced the risk of stroke by 17% in the women in the study, and it also lowered the risk of major cardiovascular events, ischemic stroke, and MI among a subgroup of patientswomen aged 65 or older.

"Any decision about the use of aspirin in primary prevention among women must be ultimately made after a woman consults her physician or healthcare provider, so that the absolute net benefits and risks for the individual patient can be ascertained," Ridker and colleagues say in their paper.

Use of aspirin in primary prevention remains controversial

They explain that although aspirin is effective in the treatment of acute MI and in the secondary prevention of cardiovascular disease among both men and women, "its use in primary prevention remains controversial."

To date, five randomized trials involving just over 55 000 participants have evaluated aspirin in the primary prevention of CV disease and, on aggregate, aspirin was associated with a 32% reduction in the risk of MI compared with placebo, but the data on risk of stroke and death from CV disease remain inconclusive, they note. More important, three of these trials examined men exclusively and fewer than 180 of the 2402 vascular events occurred in women.

"Thus, at this time, the current recommendations for the use of aspirin in primary prevention in women [US Preventive Services Task Force and American Heart Association guidelines] are based on limited direct data from women," they observe.

They decided to address the issue in the Women's Health Study, in which 39 876 initially healthy women 45 years of age or older were randomized to 100 mg of aspirin on alternate days or placebo and then monitored for 10 years for a first major CV event (nonfatal MI, nonfatal stroke, or death from CV causes).

During the follow-up, there were 477 major CV events in the aspirin group, compared with 522 in the placebo patients, for a nonsignificant reduction in risk with aspirin of 9% (relative risk 0.91).

Incidence and relative risk of confirmed cardiovascular end points

End point Events (n), aspirin (n=19 934) Events (n), placebo (n=19 942) Relative risk p
Major CV event 477 522 0.91 0.13
Stroke 221 266 0.83 0.04
 -Ischemic 170 221 0.76 0.009
-Hemorrhagic 51 41 1.24 0.31
-Fatal 23 22 1.04 0.90
-Nonfatal 198 244 0.81 0.02
MI 198 193 1.02 0.83
-Fatal 14 12 1.16 0.70
-Nonfatal 184 181 1.01 0.90
Death from CV causes 120 126 0.95 0.68
Transient ischemic attack 186 238 0.78 0.01
Coronary revascularization 389 374 1.04 0.61
Death from any cause 609 642 0.95 0.32

There were consistent benefits in women over 65, who made up only 10% of the study population (n=4097) but who had almost one third of the cardiovascular events. The relative risk of a major cardiovascular event was 0.74 among those taking aspirin compared with placebo in this subgroup (p=0.008), relative risk of ischemic stroke was 0.70 (p=0.05), and that of MI 0.66 (p=0.04). There was no evidence that menopausal status, use or nonuse of hormone-replacement therapy after menopause, or global cardiovascular risk status modified the effects of aspirin.

In this group overall, use of aspirin as compared with placebo resulted in 44 fewer MIs, strokes, or deaths from cardiovascular causes (p=0.008) but in 16 more gastrointestinal hemorrhages requiring transfusion (p=0.05). This emphasizes the importance of balancing risks and benefits, the researchers stress, and they add that this age-based difference "requires further investigation."

Results must be interpreted carefully; sex differences evident

The researchers caution that their results overall "must be interpreted in the context of those other completed randomized trials of aspirin in the primary and secondary prevention of cardiovascular disease." They performed a random-effects meta-analysis that included the current data from the Women's Health Study as well as the data from the five prior trials involving 55 580 participants with no history of heart disease. Overall, as compared with placebo, aspirin significantly reduced the risk of MI (relative risk 0.76; p=0.01) but had no significant effect on the risk of stroke (relative risk 0.97; p=0.69).

 
The reasons for any sex-based differences in the efficacy of aspirin for primary prevention are unclear and require further exploration.
 

But when they combined data on women alone from the current study, the HOT study, and the Primary Prevention Project, aspirin therapy was associated with a significant 19% reduction in the risk of stroke (p=0.81), with no reduction in the risk of MI (relative risk 0.99; p=0.95).

In contrast, the aggregate data on men from all the primary-prevention studies show that aspirin was associated with a 32% reduction in the risk of MI and a nonsignificant increase in the risk of stroke.

"The differences between men and women were significant at the p=0.01 level for MI and at the p=0.05 level for stroke," they say. "The reasons for any sex-based differences in the efficacy of aspirin for primary prevention are unclear and require further exploration," they add.

They also note that they cannot rule out the possibility that the null finding for the risk of MI in women in the Women's Health Study is due to an insufficient dose of aspirin or to the alternate-day regimen; however, they do not believe this to be the case for several reasons. First, it has been shown that aspirin every other day reduces thromboxane levels by 93% and prostacyclin levels by 85%. Second, in the HOT study, a 75-mg daily dose of aspirin significantly lowered the risk of MI overall, but the reduction in risk in women was far smaller and nonsignificant compared with the risk in men; and finally, the dose and alternate-day regimen in the current study were adequate to lower the risk of stroke, they point out.

Reduction in stroke important

Ridker and colleagues stress the importance of the reduction in stroke seen in the study, "since as compared with men, women have a relatively greater proportion of strokes than MIs." The study also reinforces how vital it is to study women as well as men in major cardiovascular trials, they observe.

Further discussion and comment on this study will appear on heart wire later today, following the presentation of the findings at the ACC meeting in Orlando.

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