Abstract
‘The bottom line is that women considering the use of aspirin to prevent CVD must weigh the balance of benefits and risks in consultation with their physicians before beginning therapy.’
Results from the first large-scale randomized trial of aspirin in the primary prevention of cardiovascular disease (CVD) in women are now available. Although aspirin had been shown to be effective in the treatment of acute myocardial infarction (MI) and in the secondary prevention of CVD among both women and men, there had been few data to inform current guidelines for the use of aspirin in primary prevention in women. Such guidelines have been based largely on results from trials in men, which suggest that aspirin reduces incidence of first MI by approximately a third while having little or no effect on stroke. The new findings suggest a nearly opposite pattern in women.
The Women's Health Study (WHS) was a randomized, double-blind, placebo-controlled trial to evaluate the benefits and risks of low-dose aspirin (100 mg on alternate days) and vitamin E in the primary prevention of CVD and cancer among women [1]. The trial included 39,876 initially healthy female health professionals aged 45 years and older who were followed for an average of 10 years. During follow-up, 477 major cardiovascular events (i.e., MI, stroke, and cardiovascular death) occurred among women assigned to the aspirin group, compared with 522 events among women in the placebo group, a 9% overall reduction that was not statistically significant (relative risk [RR], 0.91; 95% confidence interval [CI], 0.80–1.03; p = 0.13). However, in a pattern different from that found in trials in men, this 9% overall reduction was due almost entirely to statistically significant reductions in stroke events without a reduction in MI rates. Specifically, aspirin lowered the risk of total stroke by 17% (RR, 0.83; 95% CI, 0.69–0.99; p = 0.04) and the risk of ischemic stroke by 24% (RR, 0.76; 95% CI, 0.63–0.93, p = 0.009) but had no effect on the risk of MI (RR, 1.02: 95% CI, 0.84–1.25; p = 0.83) or cardiovascular death (RR, 0.95; 95% CI, 0.74–1.22; p = 0.68). This set of results is intriguing in light of the gender-specific pattern of CVD incidence in the US population – namely, that CVD events in women are more likely to be strokes than MIs, whereas the reverse in true in men. With respect to side effects, aspirin, as expected, increased the risk of bleeding. Gastro-intestinal hemorrhages requiring transfusion were significantly more common in women assigned to aspirin than in those assigned to placebo (RR, 1.40; 95% CI, 1.07–1.83; p = 0.02), and there was also a nonsignificant increase in the risk of hemorrhagic stroke (RR, 1.24; 95% CI, 0.82–1.87; p = 0.31).
The most consistent cardiovascular benefits of aspirin were found among women aged 65 years and older, a group that comprised only 10% of the study population yet suffered a third of all cardiovascular events. Among these women, aspirin use led to a statistically significant 26% reduction in risk of major cardiovascular events (RR, 0.74; 95% CI, 0.59–0.92, p = 0.008), with a benefit on both ischemic stroke (RR, 0.70; 95% CI, 0.49–1.00; p = 0.05) and MI (RR, 0.66; 95% CI, 0.44–0.97; p = 0.04). In contrast, for younger women, aspirin appeared to provide little or no cardiovascular protection.
Contrary to expectation, the association between aspirin and CVD risk was not modified by baseline level of cardiovascular risk as measured by the Framingham Risk Score, although it should be noted that only a small proportion of WHS participants had high Framingham scores. Interestingly, the salutary effects of aspirin were observed only in never and former smokers. Current smokers did not benefit from aspirin therapy but instead experienced a significantly higher incidence of major CVD events (RR, 1.30; 95% CI, 1.03–1.64; p = 0.03) and MI (RR, 1.50; 95% CI, 1.06–2.13; p = 0.02) than their counterparts assigned to placebo. In addition, although women with diabetes were less likely to develop total stroke (RR, 0.46; 95% CI, 0.25–0.85; p = 0.01) or ischemic stroke (RR, 0.42; 95% CI, 0.22–0.82; p = 0.01) if in the aspirin rather than the placebo group, they also experienced an apparent (albeit nonsignificant) elevation in MI risk (RR, 1.48; 95% CI, 0.88–2.49; p = 0.14) associated with aspirin therapy. On the other hand, women with hypertension or hyperlipidemia appeared somewhat more likely than women without these conditions to derive overall cardiovascular protection from aspirin therapy, although statistical tests of interaction were not significant.
From a policy standpoint, the WHS results demonstrate the critical importance of directly studying cardiovascular interventions in both women and men rather than routinely extrapolating the results from one gender to another. From a clinical standpoint, the data provide the beginning of an empirical foundation from women for rational decision-making about the use of aspirin for primary prevention of CVD in women.
How should the WHS findings shape current clinical practice? The WHS results do not address secondary prevention, and previous guidelines for aspirin use in treating women with prior CVD should continue to be followed – i.e., all such women should be treated with aspirin unless contraindicated. Indeed, the Anti-thrombotic Trialists' Collaboration showed that aspirin clearly reduces the risk of cardiovascular events, MI and ischemic stroke in both men and women in secondary prevention settings [2].
For primary prevention, the WHS results indicate that age may be an important determinant of a woman's response to aspirin therapy. The data suggest that most women aged 65 years and older are likely to attain a net benefit from preventive aspirin therapy, regardless of their Framingham Risk Score. Thus, women in this age group should be advised to consult with their personal physicians to determine whether they are good candidates for aspirin therapy – that is, to rule out contraindications to aspirin use, such as a history of gastrointestinal bleeding or allergy to aspirin. Unless there are such contraindications, women aged 65 years and older should be seriously considered for long-term, low-dose aspirin therapy. This recommendation conforms to current clinical knowledge regarding the course of atherosclerotic vascular disease in aging women and men; that is, it is well recognized that the degree of atherosclerosis in a typical 65-year-old woman is similar to that in a typical 50-year-old man. Thus, it is perhaps not surprising that preventive guidelines for women aged 65 years and older should parallel that for men aged 50 years and older.
The clinical implications of the WHS results for women younger than 65 years are less clear. More research is needed to determine whether there are subgroups of younger women that benefit from aspirin therapy and whether a dose higher than that studied in the WHS is required for cardiovascular protection, especially in those with health behaviors and conditions such as smoking and diabetes that are known or suspected to induce aspirin resistance. Guidelines released prior to publication of the WHS results include the American Heart Association's recommendation that physicians consider prescribing aspirin for women at intermediate risk (10-year coronary heart disease [CHD] risk of 10 to 20%) and definitely prescribe aspirin for women at high risk (10-year CHD risk of 20% or higher) unless contraindicated [3]; the US Preventive Services Task Force's recommendation that physicians consider prescribing aspirin for adults with a 10-year CHD risk of 6% or higher [4]; and the American Diabetes Association's recommendation of aspirin for adults with diabetes who are aged 40 or older or who have additional cardiovascular risk factors [5]. While awaiting additional research, we conservatively recommend that women under 65 years do not initiate aspirin therapy unless they are at substantially elevated cardiovascular risk by virtue of a high Framingham Risk Score or the presence of diabetes (10-year CHD risk of 20% or greater).
The bottom line is that women considering the use of aspirin to prevent CVD must weigh the balance of benefits and risks in consultation with their physicians before beginning therapy. For both women and men, adhering to a health-promoting lifestyle – eating healthy foods; engaging in regular physical activity; maintaining a healthy weight; not smoking; and controlling hypertension, dyslipidemia, and diabetes – remains the best choice for long-term CVD prevention.