Please note: In 2003, the CTF updated its Grades of Recommendations to include an "I Recommendation" for situations where insufficient evidence exists to allow a recommendation to be made.  (Formerly, these situations were captured under a "C Recommendation".)  This change is not retroactive, and all "C Recommendations" made prior to 2003 have not been reevaluated in light of the new "I" recommendation grade.  For a discussion of these recommendation grades, please link to the 2003 article in the Canadian Medical Association Journal here.

Acetylsalicylic Acid and the Primary Prevention of Cardiovascular Disease

Overview
A series of clinical trials has provided convincing evidence that acetylsalicylic acid (ASA) can significantly reduce the incidence of vascular events and related deaths in patients with a history of symptomatic vascular disease, including previous myocardial infarction, unstable angina, stroke and transient ischemic attack.< 1,2> The drug’s beneficial effects in preventing premature illness and death in symptomatic patients have led to interest in the possible benefits of preventing vascular disease in people without previous symptoms. Case-control and cohort studies have raised the possibility that ASA reduces the risk of cardiovascular disease by about 20%.<3> This chapter reviews the results of recent studies and makes recommendations regarding the appropriate use of ASA in asymptomatic patients.

Burden of Suffering
In 1989 an estimated 80,858 deaths from circulatory disease occurred in Canada; this resulted in 362,235 potential life-years lost. An estimated 49,148 deaths were due to coronary artery disease and 14,232 to stroke. Coronary artery disease was the leading cause of death among men 40 years of age or more and among women 60 years or more. In 1987 there were 77,790 deaths due to circulatory disease, for a death rate of 324 per 100,000 among men and 283 per 100,000 among women. The rate of death from cardiovascular disease begins to increase about 10 years earlier among men than among women, but eventually nearly as many women as men die from such disease (36,794 vs. 40,977 in 1987).

The overall rate of death from cardiovascular disease has shown a relatively stable decrease since the 1950s. The rates among men and women 35 to 90 years of age are expected to decrease from 780 and 415 per 100,000 respectively (1982-86 data) to 655 and 310 per 100,000 respectively by the year 2000. The age-standardized rates of death from stroke among Canadians over 65 years of age decreased by more than 60% among women and 50% among men between 1951 and 1986, but hospital morbidity rates from 1971 to 1984 did not reflect the same rate of decline. Each year in Canada about 50,500 patients are admitted to hospital for treatment of acute myocardial infarction. In 1987-88 there were 8.9 million hospital patient-days for diseases of the circulatory system. In addition, circulatory disease accounts for 25% of all disability pensions paid by the Canada Pension Plan before age 65.

Over 40% of deaths from coronary artery disease are sudden, and half of the sudden deaths occur in people without a history of overt disease. Reduction of the incidence of sudden death in asymptomatic people will require the use of effective primary prevention strategies.

Effectiveness of Prevention
The results of two large randomized clinical trials of the effects of ASA in males without symptomatic cardiovascular disease have been published<4-7> and the results of a large prospective cohort study of ASA use in women was published recently.<8>

The British Aspirin Trial
This trial was undertaken in Britain from 1978 to 1984.<4> The study subjects were recruited in two stages. All male physicians residing in Britain in 1951 were contacted and asked to participate. The total sample was 5,139 out of about 20,000 physicians contacted. The authors stated that most of those contacted but not recruited were willing to participate but were ineligible because they had a history of symptomatic vascular disease or were unable to take ASA. All physicians over 79 years of age were excluded. About 50% of the subjects were less than 60 years old, and about 15% were between 70 and 79.

Two-thirds (3,429) of the subjects were randomly allocated to the experimental group and were asked to take 500 mg of ASA daily. The remaining 1,710 physicians constituted the control group and were asked to avoid the use of ASA. The two groups were similar in terms of several risk factors for cardiovascular disease, although the control group had a mean systolic blood pressure (BP) that was on average 1 mmHg lower than the mean pressure in the experimental group (p=0.05).

Follow-up was excellent, 99% of the surviving physicians completed the final questionnaire. The study provided some 30,000 man-years of observation. The results were analyzed according to which study group the physicians were assigned to and not their actual use of ASA. After 1 year 19% of the physicians in the experimental group had stopped taking ASA, and by the end of the 6-year trial compliance with the treatment regimen had decreased to 55%. In the control group about 10% of the physicians were taking ASA regularly by the end of the trial.

The main outcomes of the trial are presented in Table 1. There were no statistically significant differences in the rates of fatal or non-fatal myocardial infarction between the two groups. However, given the small number of poor outcomes the confidence interval (CI) for the estimated differences is wide. The experimental group had a significantly lower rate of transient ischemic attacks than the control group, but there was no significant difference in either the total rate of strokes or of deaths from stroke. Further analysis indicated a significantly higher rate of disabling strokes in the experimental group than in the control group. Differences in the rates of vascular and nonvascular events and total deaths were not significant. Detailed subgroup analysis indicated the rate of death from endocardial disease and acute respiratory disease was significantly lower in the experimental group. The experimental group also had a significantly lower rate of migraines and musculoskeletal disorders but a higher rate of peptic ulcers.

The U.S. Aspirin Trial
This study began in 1982 and ended in early 1988.<5-7> Recruitment letters were sent to all 261,248 male physicians in the U.S. aged 40 to 84 years; 112,528 responded, and 59,285 agreed to participate. Physicians were excluded if they reported a history of myocardial infarction, stroke, transient ischemic attack, important health problems, current routine use of ASA or contraindications to the use of ASA. This left 33,223 eligible physicians. After an 18-week pretrial compliance study 22,071 physicians were found to be compliant and were randomly assigned to an experimental group (11,037) or a control group (11,034). The participants were blinded to their allocation: those in the experimental group were asked to take a pill containing 325 mg of ASA every second day, and those in the control group were asked to take a placebo pill every second day. About 75% of the participants were less than 60 years of age, and only 7% were 70 or older.

At the end of the trial the vital status of all the participants was known, and 99.7% of the surviving physicians had completed the final questionnaire. The study provided slightly more than 110,000 man-years of observations.

The results were analyzed according to the group to which the physicians had been allocated. At the end of the trial 86% of those in the experimental group and 14% in the control group were taking ASA or another platelet-active drug.

The main results of this trial<6> are summarized in Table 2. There was a significant decrease in the rates of fatal and nonfatal myocardial infarction in the experimental group. ASA had no significant effect on the rates of fatal and nonfatal stroke, although the rates were higher in the experimental group. Further analysis of the stroke data indicated a relative risk (RR) of 2.14 for confirmed hemorrhagic stroke in the experimental group; however, this difference failed to reach conventional levels of significance (95% CI: 0.96 to 4.77, p=0.06). ASA had no significant effect on the overall cardiovascular death rate or the all-cause death rate. A separate analysis involving the 21,738 physicians who did not have angina pectoris at the beginning of the trial revealed no significant effect of ASA on the incidence of angina pectoris (RR 1.10 in the experimental group; 95% CI: 0.84 to 1.36).<7>

Compared with the control group, the experimental group had a higher rate of bleeding problems such as bruising, hematemesis and melena (RR 1.32; 95% CI: 1.25 to 1.40, p<0.0001). The experimental group also had a higher incidence of transfusion (RR 1.75; 95% CI: 1.09 to 2.69, p=0.02).

Subgroup analysis indicated that the beneficial effect of ASA on the incidence of myocardial infarction was greater among the subjects who were 50 years of age or older and those with lower cholesterol levels than among the others.

The Nurses’ Health Study
The Nurses’ Health Study<8> established a cohort of 121,700 female nurses aged 30 to 55 years in 1976. The analyses included 6 years of follow-up for the cohort with a total of 475,265 persons-years of data for fatal outcomes and 459,696 person-years of data for nonfatal outcomes. The follow-up rate for nonfatal outcomes was 96.7%. The authors estimated that the follow-up for fatal events was more than 98%. The cohort was divided into 4 exposure groups based on survey responses: 1) 0 aspirin per week; 2) 1-6 aspirin per week; 3) 7-14 aspirin per week; and 4) 15 or more aspirin per week. Relative risks were computed as the rate of events in each exposure category divided by the rate in the reference category (no aspirin per week). All relative risks were age-adjusted and controlled for the effects’ cardiovascular risk factors.

The main results of the trial are summarized in Table 3. There was a statistically significant reduction in relative risk for nonfatal MI and coronary artery deaths combined in the group taking 1 to 6 aspirin per week compared to the no aspirin group. Women aged 50 years and more and women with coronary risk factors had the largest risk reductions. The relative risk for nonfatal MI alone was 0.68 (95% CI: 0.49-0.93) in this exposure group. The relative risk for strokes, cardiovascular deaths and total deaths were each less than 1.0 for the group exposed to 1 to 6 aspirin per week, but none of these lower relative risks was statistically significant.

Overview
The two randomized controlled ASA trials were conducted in populations of male physicians. Although the inclusion of physicians may have improved the quality of self-reported information the generalizability of the results to other populations has to be questioned. On one hand, physicians may be more compliant with long-term therapy than members of the general public. On the other hand, the subjects in the two studies may have been "healthier" than asymptomatic men in other populations. In the U.S. study the overall rate of death from cardiovascular disease was 15% of that expected in a general population of white men with the same age distribution.

The U.S. trial did show a significant decrease in the incidence of both fatal and nonfatal myocardial infarction. The decrease in the incidence of fatal myocardial infarction did not translate into a decrease in the overall rate of death from cardiovascular disease; this was because of death from other causes, most notably stroke and "sudden death". As Sempos and Cooper<9> pointed out, the rate of sudden death noted in the U.S. study was much higher than that found in the general population, and if diagnosed cases of sudden death are included in the category of myocardial infarction, then there is no longer a significant decrease in the incidence of fatal myocardial infarction in the experimental group.

The British trial showed a statistically significant decrease in the incidence of transient ischemic attacks in the experimental group. This did not translate into a significant decrease in the incidence of either fatal or nonfatal stroke. The U.S. study did not report on the impact of ASA therapy on transient ischemic attacks.

When assessing the benefits of long-term therapy in previously asymptomatic patients it is important to consider carefully the impact of side effects. The two studies showed a higher incidence of adverse effects, including peptic ulcer and bleeding disorders, in the experimental groups than in the control groups. They also indicated that ASA therapy may be related to an increased incidence of hemorrhagic stroke. The routine use of ASA may have some unexpected beneficial effects, such as a decreased incidence of migraines and musculoskeletal disorders.

Although the two studies differed with regard to the age distribution of the physicians, dosage of ASA, compliance rate and some of the details of causes of death, it has been suggested that it would be useful to combine the results. Analysis of the combined data<10> indicated a significant reduction of 33% in the incidence of nonfatal myocardial infarction among those taking ASA (p<0.0001). There was no significant change in the incidence of nonfatal stroke or death from stroke or myocardial infarction; however, there was a significant increase in the incidence of disabling stroke among those taking ASA (p=0.016).

A recent overview of antiplatelet therapy concluded that there was no clear evidence on the balance of risks and benefits of antiplatelet therapy in primary prevention among low risk subjects.<11> To try to balance the effects on myocardial infarction and stroke Jonas<12> analyzed the U.S. trial data that applied quality-of-life values to the main outcomes (i.e., death, nonfatal myocardial infarction and major or minor stroke). This analysis indicated that the lost quality of life over the 5-year follow-up was not significantly different in the experimental group from that in the control group. Although these results are based on specific assumptions regarding the quality of various health states they do indicate the importance of balancing benefits against risks.

The prospective cohort study in women indicated a lower rate of fatal and nonfatal MI in those who reported using 1 to 6 aspirin per week compared to those who reported no aspirin use. There was no statistically significant association between aspirin use and cardiovascular deaths or total deaths.

Recommendations of Others
The recommendation of the U.S. Preventive Services Task Force on low-dose aspirin therapy is currently under review.

Conclusions and Recommendations
Given the available information there is no clear evidence that routine use of ASA in asymptomatic men leads to a reduction in the rates of death from all causes, from cardiovascular disease or from myocardial infarction (when sudden deaths are taken into account). The benefit of ASA therapy observed in the decreased incidence of myocardial infarction needs to be balanced against the potential adverse effects, particularly disabling stroke, that may be related to hemorrhagic properties of ASA.

There is no evidence from the U.S. Aspirin trial to indicate that ASA therapy is particularly effective in reducing the incidence of myocardial infarction among asymptomatic people who may have risk factors for ischemic heart disease (i.e., smoking, hypertension or a family history of myocardial infarction).

The evidence is not strong enough to support a recommendation that routine ASA therapy be used or not be used for the primary prevention of cardiovascular disease in asymptomatic men (C Recommendation). The Nurses’ Health Study is a large cohort study that suggests that regular use of 1 to 6 aspirin a week may be associated with lower rates of MI in women. The study did not reveal a significant association of aspirin use with a lower risk of death. This evidence is not strong enough to support a recommendation of routine ASA therapy to prevent heart disease in women (C Recommendation). The decision on whether to prescribe ASA should be made on an individual basis after the benefits of decreased risk of ischemic cardiovascular events have been balanced against the potential risks associated with prolonged ASA use.

Evidence
The evidence was identified using a MEDLINE search for the period 1991 to March 1993 with the MESH headings: aspirin and cardiovascular diseases.

This review was initiated in March 1993 and updates a report with a full reference list (except for the Nurses’ Health study) that was published in 1991.<13> Recommendations were finalized by the Task Force in March 1994.

Full Citation
Anderson G. Acetylsalicylic acid and the primary prevention of cardiovascular disease. In: Canadian Task Force on the Periodic Health Examination. Canadian Guide to Clinical Preventive Health Care. Ottawa: Health Canada, 1994; 680-90.