Risks Exceed CV, Cancer Gains from Primary-Prevention ASA: WHS

Marlene Busko

December 11, 2014

UTRECHT, THE NETHERLANDS — A new analysis based on a randomized trial suggests that all healthy middle-aged and older women should not be taking low-dose aspirin for primary prevention of CVD or colorectal cancer, since the risk of major gastrointestinal (GI) bleeding outweighs the prevention benefits[1].

However, prophylactic therapy with low-dose aspirin might be warranted for women over age 65 with a low risk of GI bleeding. Thirty-two such women over age 65 would need to take low-dose aspirin (100 mg every second day) for 15 years to prevent one event—nonfatal MI, nonfatal stroke, death from CVD causes, or invasive colorectal cancer.

The study, based on an analysis of data from the Women's Health Study, was published online December 4, 2014 in Heart.

Based on these results, "we would advise that individual women discuss the pros and cons of aspirin therapy with their own doctors," lead author Dr Rob CM van Kruijsdijk (University Medical Centre Utrecht, the Netherlands) told heartwire in an email. "Women with an increased risk of GI bleeding, such as those with a history of peptic ulcer or a previous episode of GI bleeding, were not included in the Women's Health Study, and we would advise against aspirin for primary prevention in this group."

Aspirin's Controversial Role in Primary Prevention

The CV potential benefits from aspirin prophylaxis are controversial, as recently reported by heartwire , and the US Food and Drug Administration recently published a consumer update that discourages this use[2], Kruijsdijk and colleagues write.

However, there has been renewed interest in aspirin based on its effect on preventing colorectal cancer. "Recent findings that both daily and alternate-day aspirin can reduce cancer risk, particularly for colorectal cancer, have reignited the debate on aspirin in primary prevention," the researchers note. Potentially, because "aspirin only modestly lowers cardiovascular risk, while increasing the risk of major GI bleeding, the benefits for cancer could tip the balance in favor of aspirin in primary prevention."

To investigate this, they used data from 27 939 healthy women who were age 45 and older and participated in the Women's Health Study. At baseline, the women had a mean age of 54.7 and about one in 10 women was 65 or older. The women were randomized to receive placebo or 100-mg aspirin, taken every other day.

The researchers developed four models to predict the effect of 15 years of aspirin prophylaxis on four outcomes: CVD, colorectal cancer, other cancers (excluding colorectal and nonmelanoma skin cancer), and major GI bleeding.

They aimed to determine the optimal treatment strategy: treat all, treat none, treat only women of 65 years and older, or treat based on predicted risk.

During a median follow-up of 10.1 years, there were 604 cases of CVD, 168 cases of colorectal cancer, 1832 cases of other cancers, and 302 cases of major GI bleeds. During a further posttrial follow-up of 7.2 years, another 107 cases of colorectal cancer and 1388 cases of other cancers were diagnosed.

The model predicted that during 15 years the women had an 11.4% risk for an adverse outcome: 1.5% for CVD, 0.5% for colorectal cancer, 8.7% for other cancers, and 0.8% for major GI bleeding.

Compared with taking placebo, regular low-dose aspirin use was associated with a modestly lower risk of heart disease, stroke, and colorectal cancer, but 1.1% of the women taking the nonsteroidal anti-inflammatory drug had a major GI bleed.

15-Year Adjusted Risk Reduction (ARR) Associated With Primary-Prevention Aspirin, Overall and by Baseline Age, in the Women's Health Study

End points All, ARR (95% CI) <65 y, ARR (95% CI) > 65 y, ARR (95% CI)
Major cardiovascular event 0.27 (0.06 to 0.86) −0.06 (−0.39 to 0.26) 3.11 (1.67 to 5.27)
Colorectal cancer 0.14 (0.02 to 0.59 0.17 (0.04 to 0.55) −0.11 (−1.15 to 0.93)
Noncolorectal cancer −0.08 (−0.80 to 0.64) −0.32 (−1.06 to 0.42) 2.05 (0.43 to 6.28)
Major GI bleeding −0.75 (−0.50 to −1.00) −0.64 (−0.40 to −0.87) −1.66 (−0.50 to −2.82)
Total −0.42 (−1.29 to 0.45) −0.85 (−1.72 to 0.03) 3.39 (0.98 to 8.42)

However, with increasing age, the protective effect of aspirin on CVD increased—as seen was seen in men in the Physicians Health Study, the researchers note.

In many women age 65 and older, the protective effect of aspirin on the risk of cancer and CVD outweighed the increased bleeding risk, especially if bleeding was deemed to be less important

In this subgroup of older women, the number needed to treat (NNT) for 15 years to prevent one adverse event was 29. The number willing to treat (NWT) for 15 years to prevent one adverse event—which also takes into account less serious side effects such as minor bleeding and peptic ulcer and the burden of taking medication every other day—was 32.

Treat 32 Older Women for 15 Years to Prevent One Event?

In an accompanying editorial[3], Drs Marco M Ferrario and Giovanni Veronesi (University of Insubria, Varese, Italy) agree that the study does not support giving aspirin to all healthy middle-aged women.

"When balancing combined long-period aspirin benefits on CVD and cancer with its harmful effects, taking into account the individual risk profile for each investigated outcome, these Women's Health Study results support no treatment indications with alternate-day low-dose aspirin in healthy women," they write.

In women age 65 and older, "the question becomes whether it is meaningful to treat more than 32 healthy subjects for 15 years at least in order to prevent one combined event during the same time span."

According to Ferrario and Veronesi, more research is needed to clarify the benefits of aspirin for women with diabetes or metabolic syndrome, who have a higher risk of CVD. They also suggest that "another path of future research is to improve risk estimation through new biomarkers that could help identify men and women at high risk more accurately."

The Women's Health Study was supported by the National Heart, Lung, and Blood Institute and the National Cancer Institute. The current study was financially supported by a grant from the Netherlands Organization for Health Research and Development. van Kruijsdijk has reported he has no relevant financial relationships; disclosures for the coauthors are listed in the article. The editorialists have reported they have no relevant financial relationships.

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