Women's Health Study formally published: Discussion continues over results

March 30, 2005

Boston, MA - As the results of the Women's Health Study (WHS), reported earlier this month at the American College of Cardiology (ACC) meeting in Orlando, are formally published in the March 31, 2005 issue of the New England Journal of Medicine, debate continues about why the study yielded such unexpected findings.[1]

As reported by heart wire , the National Institutes of Health (NIH)-sponsored trial looked at the use of aspirin for primary prevention of cardiovascular events in women only and enrolled almost 40 000 participants. The findings were surprising because aspirin did not lower the risk of myocardial infarction or cardiovascular death overall, but it did significantly reduce the risk of stroke. In women aged over 65, however, there was a significant reduction in major cardiovascular events, including myocardial infarction and ischemic stroke.

The study was first published online March 7, 2005, along with an editorial that also appears in print in this week.[2]

Physicians are still pondering why the study failed to show an effect on cardiovascular events in women aged 45 to 65. Some are concerned that the dose of aspirin used was too low (100 mg every other day) or that there were too many young, low-risk women enrolled in the study.

But the authors maintain that aspirin was just not effective against myocardial infarction or cardiovascular death in this age group. The study, they say, simply illustrates a difference between men and women in the rates of myocardial infarction and stroke and in their responses to aspirin and emphasizes the importance of carrying out research specifically in women.

Were the women too young?

Among those who believe the women in the study were too young is Dr Cindy Grines (William Beaumont Hospital, Royal Oaks, MI).

She told heart wire : "I am not at all surprised by these findings. This was an extremely low-risk population (no prior cardiovascular history whatsoever, 90% of women were below aged 65, and the estimated 10-year cardiovascular risk was only 4%). In fact, these patients had a less than 1% risk of having an MI over the 10-year periodwhat therapy can improve on that?

No one expects cardiovascular disease in women until they are 10 years postmenopausal, so what's the point of this study? It definitely enrolled patients who were too young.

"Furthermore, no one expects cardiovascular disease in women until they are 10 years postmenopausal, so what's the point of this study? It definitely enrolled patients who were too young and very unlikely to have a cardiovascular event. This is the biggest reason that aspirin was not effective in young women."

And Dr Noel Bairey-Merz (Women's Health Resource Center, Cedars Sinai Hospital, Los Angeles) says: "What we saw was relatively young, relatively low-risk women producing results consistent with what we know about risk. But it's reassuring that we did see a benefit in older women.

"Also, I am personally encouraged by the fact that we saw a benefit in stroke, because women suffer disproportionately from stroke," she adds. "Stroke was significantly reduced for the entire population, and that's an effect you can count on. I think the stroke thing is kind of exciting. I'm so glad it wasn't a totally negative trial.

"As the smoke clears, people are disappointed by the results, but we have to swing around and try to make the most of it."

But lead author of the WHS, Dr Paul Ridker (Brigham and Women's Hospital, Boston), counters that there were, in fact, a substantial number of events in women in the 45-to-65 age group, so they were not "too young" to show an effect.

"There were a total of 693 cardiovascular events among women under age 65 and thus the study was well powered to show a difference between aspirin and placebo if in fact one was present. However, in this age group, there were 346 events among those on aspirin and 347 among those on placebo, no difference whatsoever," he told heart wire .

Both Grines and Bairey-Merz say they would not recommend aspirin for primary prevention of cardiovascular events in women under 65 based on the results of WHSsimilar sentiments to those expressed by Ridker and others at the ACC meeting when the results were first reported.

This advice could change, however, for younger women with multiple risk factors, Grines says.

"If the younger woman were at high risk (diabetes, family history, hypertension, hyperlipidemia, etc) I would recommend aspirin, as does the [American Heart Association (AHA)]," she commented. But "this study did not enroll enough high-risk [young] patients to determine the risk/benefit ratio."

Bairey-Merz says, "Some young women are at high risk, although historically this is not a big group." Nevertheless, she notes, women in this age group have routine Pap smears and mammographies, "but their risk of breast and cervical cancer is much lower than their risk of heart disease and stroke."

We observed no evidence that aspirin was more beneficial among younger women with greater numbers of risk factors or higher global risk scores.

But again, Ridker begs to differ and says that the study data are simply not consistent with these conclusions. "We observed no evidence that aspirin was more beneficial among younger women with greater numbers of risk factors or higher global risk scores. Specifically, regardless of age, aspirin was not more beneficial among those with diabetes, family history, hyperlipidemia, higher Framingham scores, or metabolic syndrome. Moreover, among smokers, we saw, if anything, an excess of events among those allocated to aspirin, an interesting finding that will undoubtedly lead to discussions about aspirin resistance."

He also points out that in WHS, the total number of cancers was actually greater than the total number of cardiovascular events, contrary to the statement made by Bairey-Merz. "In the WHS as a whole, there were nearly 2800 incident cancers during follow-up as compared with 1000 incident cardiovascular events."

Was the aspirin dose too low?

Another complaint about the WHS study muttered in the corridors of the ACC meeting was that the dose of aspirin used100 mg every other daywas too low to be of benefit.

Dr Roger Blumenthal (Johns Hopkins Ciccarone Center for the Prevention of Heart Disease) told heart wire : "One reason we may not have seen a benefit in myocardial infarction was that the effective dose of aspirin was only 50 mg a day. Perhaps 81 mg a day would have been more effective. Nevertheless, the rate of GI bleeding was higher than many of us would have anticipated."

Ridker and colleagues say they can't rule out the possibility that the dose of aspirin or the alternate-day regimen was insufficient to show a benefit. But they do not believe this to be the case for several reasons, including the fact that it has been shown that aspirin every other day reduces thromboxane levels by 93% and prostacyclin levels by 85%. Further, Ridker points out, the dose of aspirin used was sufficient to reduce the risk of thromboembolic stroke and significantly increase the risk of hemorrhagic complications in these women.

Bairey-Merz also believes the aspirin dose used was sufficient. "We were all concerned about the relatively low dose," she told heart wire , "but we did see an effect on stroke and we did see a cardiovascular effect in those aged over 65."

"We are testing the lowest doses," she admits, "But these results are consistent with observational data that show, for example, that even women who take aspirin once a week for a headache gain benefit."

And aspirin has a long half-life, she points out. "Platelets are blocked for seven days after one dose."

Results should not be a surprise: They are down to gender differences

In the editorial, Dr Richard I Levin (Leon H Charney Division of Cardiology, New York University School of Medicine, NY) says the unexpected differences seen in the study are simply down to gender disparities. Coinvestigator Dr Julie Buring (Brigham and Women's Hospital, Boston, MA) also made this point at the ACC meeting, stressing that it has not been widely appreciated that women are more likely to suffer strokes than MIs, but for men it is the other way around.

"The cardiovascular systems of women and men are not the same, differing expression of disease follows, and the disquieting results of the current study should not be a complete surprise," writes Levin.

Levin contrasts the findings of WHS with those of the Physicians' Health Study, and although he acknowledges that they can't be directly compared because they were carried out 20 years apart, he says the investigators of both trials "have produced two landmark studies on the use of aspirin in asymptomatic persons, the results of which segregate according to sex."

The decision to prescribe aspirin for the primary prevention of stroke and other vascular events should be left to the patient and her physician.

He writes, "On the basis of the Women's Health Study, for now it would appear reasonable to avoid prescribing 'low-dose' aspirin, defined as a daily dose of 75 to 100 mg or so, as a preventive measure for coronary disease in women under the age of 65 unless the global risk score is very high."

However, he wonders, "What about the prevention of stroke? Ridker and colleagues conclude, correctly, that the decision to prescribe aspirin for the primary prevention of stroke and other vascular events should be left to the patient and her physician."

He concludes: "The aspirin saga needs additional chapters, and clinical research, as the current authors and so many other authorities have concluded, needs always to account for the evolutionary biology of sex."

Confusion for the public?

Some of the doctors contacted by heart wire say they are very concerned that media reports of this study may confuse the public.

"I have seen headlines that say, 'Aspirin not effective for heart-disease prevention in women,' " says Bairey-Merz.

Both she and Grines stressed the importance of aspirin for secondary prevention of cardiovascular events, and they are worried that this study may prevent some of these patients from taking aspirin. "I think the average patient has no idea of the difference between primary and secondary prevention," says Grines. "I am concerned that patients with established disease would stop their aspirin."

Both Ridker and Buring fully agree: "Aspirin is well documented in prior studies to be a highly effective and life-saving agent in secondary prevention and during acute coronary ischemia for both men and women. The new data apply only to primary prevention," Ridker clarified.

The AHA is also concerned that women may be confused by media reports. AHA president Dr Alice Jacobs said in a media advisory at the time that the WHS was reported that it is well established that aspirin therapy is beneficial in reducing heart attacks as well as strokes in women with known cardiovascular disease. "We want to be sure that these women realized that this study does not apply to them," she commented.

Grines also believes that healthy women over 65 should be on aspirin for primary prevention, while Bairey-Merz says the risk/benefit profile must be weighed individually for each patient in this population, because of the risk of gastrointestinal bleeding. "But," she points out, "aspirin can be a lifesaver in this group. Not taking it can be akin to driving with your seat belt off the day you have a bad accident."

"The clinical trial take-home message is for women over 65 to talk with their physicians about aspirin to prevent heart-disease risk," Ridker concludes.

Bairey-Merz has acted as a consultant for Bayer.


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