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In the Women’s Health Study (WHS) reported in 2005 (N Eng J Med, 2005, 352(13): 1293-304), approximately 40,000 healthy women, 45 years of age or older, were randomly assigned to receive either 100 mg aspirin on alternate days or placebo. Both groups were monitored for 10 years for a first major cardiovascular event. The results showed 522 major cardiovascular events in the placebo group and 477 major cardiovascular events in the aspirin group.
This was interpreted as a 9% reduction in risk in the aspirin group and not a significant difference from the placebo group. Evaluation of primary endpoints, however, showed a 17% reduction in the risk of stroke in the aspirin group, which was significantly different from the placebo group. Subgroup analysis of the women 65 years of age or older showed a significant reduction by 26% in the risk of major cardiovascular events, including heart attack and stroke, in the aspirin group.
In a more recent Nurses Health Study (NHS), published in 2007 (Arch Intern Med, 2007, 167:562-572), it was reported that use of low-to-moderate doses of aspirin in women was associated with a significant reduction in not only cardiovascular events but also in a reduction in all-cause mortality.
In the NHS study, a total of 79,439 patients, who had neither cardiovascular disease nor cancer, were enrolled in 1980 and followed through 2004. The subjects completed questionnaires that determined risk factors, identified newly diagnosed conditions, and assessed aspirin use over the years. The reasons for aspirin use included headache, arthritis, musculoskeletal pain, cardiovascular disease prevention, back pain, or other reasons. Those patients who died during the study period were considered the case patients and were matched with control patients. The primary end point was the number of deaths from all biological causes (all-cause mortality). The secondary end points were cardiovascular-related deaths and cancer-related deaths.
During the 24-year study period, there were a total of 9,477 deaths. Of that total, there were 1,991 deaths from cardiovascular disease and 4,469 deaths from cancer. The other deaths were from other causes. Cardiovascular-related deaths were broken down into 889 caused by coronary heart disease, 502 caused by stroke and 600 caused by other cardiovascular conditions.
Cancer-related deaths were broken down into 979 cases of lung cancer, 864 cases of breast cancer, 433 cases of colorectal cancer, and 2,193 deaths caused by all other forms of cancer.
The results of the NHS were as follows:
1.
There was a significant reduction by 25% in all-cause mortality among subjects who reported current use of aspirin compared with non-users of aspirin. The relative risk (RR) was 0.75; 95% Cl, 0.71-0.81.
2.
The greatest risk reduction of 38% was observed for cardiovascular mortality (RR=0.62; 95% Cl, 0.55-0.71). This risk reduction was realized within the first 5 years of taking aspirin.
3.
For deaths associated with all cancers, the risk reduction was 22% (RR=0.88; 95% Cl, 0.81-0.96) and significantly different from non-aspirin users. This risk reduction was not observed until after 10 years of aspirin use.
4.
The lower risk of cancer death among current aspirin users was statistically significant for death from colorectal cancer (RR=0.72; 95% Cl, 0.56-0.92).
5.
Current aspirin use did not seem to confer an overall significant benefit in death from breast or lung cancer, and women who used aspirin for longer than 20 years seemed to have only a modest reduction in the risk of death from either of these cancers.
6.
The benefits associated with current aspirin use seemed greater with increasing age for total mortality death from cardiovascular diseases and death from cancer.
7.
Smoking did not modify the association of aspirin with death from all causes or death due to cardiovascular disease.
8.
The study confirmed that aspirin use was not significantly associated with death from accidents, for which aspirin does not have a biologically plausible role.
The NHS also tracked the effects of aspirin in the study subjects according to the doses of aspirin taken. These data showed the following:
1.
Compared with women who never used aspirin on a daily basis, current users of low to moderate doses of aspirin (1-2 standard 325 mg aspirin tablets per week) had a substantially lower risk of death. This lower risk of death also was observed in users of 3-5 standard 325 mg aspirin tablets per week.
2.
Contrary to the above, the use of aspirin at the highest doses of >14 standard 325 mg aspirin tablets per week was not associated with any reduction in the risk of death. Thus, at these higher doses, the benefits of aspirin seen at low doses were lost.
3.
The study also examined the effect of aspirin dose on the risk of death from hemorrhagic stroke. Among women who used more than 14 standard 325 mg tablets per week, the study found a nonsignificant increased risk of death from hemorrhagic stroke compared with women who never used aspirin.
The explanation of the loss of benefit of death risk reduction of high dose aspirin was as follows. According to the authors of the NHS, aspirin therapy may reduce the risk of death from cardiovascular disease and cancers through its effect on common pathogenic pathways “such as inflammation, insulin resistance, oxidative stress and cyclo-oxygenase activity.” Aspirin inhibits the prothrombotic cyclo-oxygenase type 1 (COX-1) enzyme in platelets and the tumorigenic cyclo-oxygenase type 2 (COX-2) enzyme in epithelial cells. Thrombosis and platelet aggregation are acute events - events consistent with the observed benefit of aspirin therapy on vascular disease within 5 years of use.
According to the authors, the finding of a modest benefit against death from cancer only after prolonged use "is consistent with the understanding of the slower, stepwise progression of carcinogenesis."
The loss of benefit in death risk reduction with higher doses of aspirin could be explained by the fact that higher aspirin doses inhibit the COX-2 enzyme which synthesizes antithrombotic prostacyclins. The loss of the antithrombotic prostacyclins would shift a balance to more of a risk of a prothrombotic state.
Comparing the results of the WHS report to the NHS report:
The WHS did not detect any statistically significant reduction in the risk of death from all cardiovascular causes with 100 mg aspirin every other day. However, the study showed that aspirin users older than 65 years of age experienced significant benefits across all cardiovascular endpoints. The effects in the over 65 years of age group were consistent with the findings in the NHS which showed progressively greater reduction in mortality with increasing age.
The authors of the NHS remind us that their study was observational and the results should be interpreted cautiously and are insufficient evidence to alter current clinical recommendations of aspirin use in women. A related editorial (Arch Intern Med, 2007,167:535-6) suggested that the difference between the NHS results and the aggregated data from the WHS and other trials is still very large. Although the common finding of enhanced effects in older women leaves room for the hypothesis that aspirin reduces cardiovascular mortality in those patients, a large reduction in cardiovascular mortality in middle-aged women still seems unlikely.
It would seem prudent, however, that adherence to aspirin use (as suggested by the latest recommended guidelines on aspirin published in February of this year by the American Heart Association and accessed at http://www.americanheart.org/presenter.jhtml?identifier=3045524) would certainly be of benefit. These guidelines are as follows:
1.
Routine low-dose aspirin therapy may be considered in women age 65 or older, regardless of cardiovascular disease risk status, if benefits are likely to outweigh the risks. (Previous guidelines did not recommend aspirin in lower risk or healthy women.)
2.
The upper dosage of aspirin for high-risk women increases to 325 mg per day from 162 mg per day. This brings the women’s guidelines up to date with other recently published guidelines.
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