Aspirin Prophylaxis
-------------------------------------------------------------------------------
Recommendation:
Low-dose aspirin therapy should be considered for men aged
40 and over who are at significantly increased risk for
myocardial infarction and who lack contraindications to the
drug (see Clinical Intervention). Patients should
understand the potential benefits and risks of aspirin
therapy before beginning treatment.
Burden of Suffering
Coronary artery disease is the leading cause of death in
the United States, accounting for about 1.5 million
myocardial infarctions and over 520,000 deaths each
year.1,2 About 400,000 Americans are victims of sudden
death each year, due primarily to underlying
atherosclerotic disease. Myocardial infarction is
associated with significant mortality, morbidity, and
disability. The cost to the United States of medical care
and lost productivity due to cardiovascular diseases was
nearly $80 billion in 1986.2 Myocardial infarction and
sudden death often occur without warning in persons without
a history of angina pectoris or other clinical symptoms.
The principal risk factors for coronary artery disease are
smoking, hypertension, elevated serum cholesterol, obesity,
and family history.
Efficacy of Chemoprophylaxis
The platelet-inhibitory effect of aspirin prevents the
formation of arterial thrombi on atherosclerotic plaques.3
A number of secondary prevention trials have shown that
daily aspirin ingestion can lower the risk of nonfatal
strokes and myocardial infarctions (MI) in persons at
increased risk for atherosclerosis and thrombogenesis
(persons with unstable angina, previous MI, transient
ischemic attacks, and post4,5 Few studies, however, have
examined the efficacy of using aspirin as a primary
prevention tool in asymptomatic persons without such a
history, who are thus at much lower risk of developing
myocardial infarctions. The use of aspirin in preventing
stroke in persons without neurologic symptoms has been
proposed for persons at risk for thromboembolic events
(e.g., those with carotid bruits, valvular heart disease,
atrial fibrillation),6 but convincing data to support its
efficacy even in these populations is lacking.
Two recent randomized controlled trials, in the United
States and Britain, have examined the efficacy of aspirin
in preventing myocardial infarction in healthy men. In the
American trial, over 22,000 asymptomatic male physicians
received either 325 mg of aspirin every other day or
placebo.7 The study was terminated prematurely after 4.5
years when a statistically significant 47% reduction in the
incidence of fatal and nonfatal MI was noted in the group
receiving aspirin. The British trial, with a smaller sample
size (5139 male physicians) and a higher dose (500 mg
daily), found no significant reduction in MI.8 Although the
absence of an apparent reduction in MI may have been due to
lack of efficacy, the British trial may have failed to
demonstrate a significant effect on MI due to its
inadequate sample size and other differences in study
design (e.g., higher dose, no placebo).9 Neither study had
sufficient statistical power to demonstrate a reduction in
overall cardiovascular mortality.9 Both trials observed an
increase in the incidence of stroke among persons taking
aspirin, but in neither study was the difference
statistically significant.7,8 In the preliminary results of
the American trial, a statistically significant increase in
the incidence of moderate and severe hemorrhagic strokes
was reported among men taking aspirin.7 In a more recent
analysis of the final data, however, the investigators
determined that this difference was not statistically
significant.10
Other side effects of aspirin therapy must also be
considered in evaluating its long-term safety. Aspirin can
produce unpleasant gastrointestinal symptoms such as
stomach pain, heartburn, nausea and constipation, as well
as occult gastrointestinal blood loss, hematemesis, and
melena.5 The likelihood of such side effects in otherwise
healthy persons is directly related to the dose of the
drug. In the British trial, in which the dose was 500 mg
daily, 20% of the doctors taking aspirin had to discontinue
the drug due to dyspepsia and constipation, 3.6%
experienced bleeding or bruising, and 2.2% had
gastrointestinal blood loss.8 In the American trial, in
which the dose was 325 mg every other day, there was less
than a 1% difference in gastrointestinal complaints between
the aspirin and placebo groups, and only one case of fatal
gastrointestinal hemorrhage was reported in 4.5 years of
treatment.7,10 Similarly, a large secondary prevention
trial also reported little difference in epigastric
discomfort, decreased hemoglobin concentration, or occult
blood in stool in persons receiving 324 mg per day.11
In addition to reducing the risk of side effects, low-dose
therapy appears to have comparable (if not greater)
platelet-inhibitory action when compared with higher doses.
A review of 25 secondary prevention trials with a total of
29,000 patients found little difference in outcome in
dosages ranging from 300 to 1200 mg per day.4 In one study,
a dose of only 60 mg daily was effective in reducing the
incidence of pregnancy-induced hypertension.12 It is
possible that high-dose therapy may even have less
platelet-inhibitory effect, by inhibiting vessel wall
synthesis of prostacyclin along with platelet production of
thromboxane A2. Doses as low as 30-40 mg daily may be
necessary to achieve an optimal balance.13 The probability
of adverse effects at such low doses is likely to be small,
but further studies of aspirin therapy are needed to
provide definitive evidence regarding both the clinical
efficacy of low-dose regimens and the safety of long-term
administration.
Effectiveness of Counseling
There is little information on whether asymptomatic
patients will comply with physician advice to take aspirin
for an extended period of time. Aspirin is the most
consumed drug in the United States, with an estimated 20-30
billion tablets ingested each year,5 but most users are
suffering from pain, fever, or other forms of discomfort
when they choose to use the drug. It is not known whether
healthy individuals would be able or willing to comply with
a lifelong daily (or alternate day) regimen, especially if
it produces unpleasant side effects. As noted above, over
the course of six years, 20% of the doctors participating
in the British trial were forced to discontinue a daily 500
mg aspirin regimen because of dyspepsia and constipation.8
Recommendations of Others
The American Heart Association has recently advised
physicians to exercise care before starting a patient on
lifelong aspirin therapy; efforts should first be directed
at modifying primary risk factors for heart disease and
stroke, assessing potential contraindications to aspirin,
and counseling patients about potential side effects and
symptoms requiring medical attention.14 Investigators in
the U.S. and British trials have recommended that
physicians prescribing aspirin to asymptomatic persons
first consider the cardiovascular risk profile of the
patient and balance the known hazards of aspirin (e.g.,
gastrointestinal discomfort and bleeding, cerebral
hemorrhage) against the benefit of reducing the risk of a
first myocardial infarction.9
Discussion
Although data from a large trial have provided evidence
that low-dose aspirin therapy can reduce the risk of
myocardial infarction in asymptomatic men,7 it is premature
to recommend routine use of aspirin for this purpose in the
general population. These benefits were demonstrated in a
select population: male doctors between the ages of 40 and
84 in exceptionally good health, who were then prescreened
to eliminate persons unable to tolerate aspirin. In
addition, the study was terminated prematurely; therefore,
it is not known with certainty whether the long-term
complications of aspirin therapy might have ultimately
exceeded its benefits.15 Some patients might judge the
reduced risk of MI inadequate to justify the unpleasant
side effects or increased risk of gastrointestinal
bleeding. Moreover, in both the U.S. and British studies,
strokes may have been more common in men taking aspirin.
Although the differences were not statistically
significant, the consistency of the findings suggests that
further study of the relationship between aspirin therapy
and cerebral hemorrhage is warranted. Hypertensives, a
population at increased risk for both coronary artery and
cerebrovascular disease, may be more likely to experience
hemorrhagic stroke while taking this drug.5,16
Clinical Intervention
Low-dose aspirin therapy (325 mg every other day) should be
considered for primary prevention in men aged 40 and over
who have risk factors for myocardial infarction (e.g.,
hypercholesterolemia, smoking, diabetes mellitus, family
history of early-onset coronary artery disease) and who
lack a history of uncontrolled hypertension, liver or
kidney disease, peptic ulcer disease, a history of
gastrointestinal or other bleeding problems, or other risk
factors for bleeding or cerebral hemorrhage. Patients
should understand the potential benefits and risks
associated with aspirin therapy before beginning treatment,
and they should be encouraged to focus their efforts on
modifying primary risk factors such as smoking (see Chapter
48), elevated cholesterol (Chapters 2 and 50), and
hypertension (Chapter 3).
References
1.
National Center for Health Statistics. Advance report of
final mortality statistics, 1986. Monthly Vital Statistics
Report [Suppl], vol. 37, no. 6. Hyattsville, Md.: Public
Health Service, 1988. (Publication no. DHHS (PHS)
88-1120.)
2.
American Heart Association. 1989 heart facts. Dallas, Tex.:
American Heart Association, 1988.
3.
Fuster V, Adams PC, Badimon JJ, et al. Platelet-inhibitor
drugs' role in coronary artery disease. Prog Cardiovasc Dis
1987; 29:325-46.
4.
Anti-Platelet Trialists Collaboration. Secondary prevention
of vascular disease by prolonged antiplatelet treatment. Br
Med J 1988; 296:320-31.
5.
Fuster V, Cohen M, Chesebro JH. Usefulness of aspirin for
coronary artery disease. Am J Cardiol 1988; 61:637-40.
6.
Foster JW, Hart RG. Antithrombotic therapy for
cerebrovascular disease: prevention and treatment of
stroke. Postgrad Med 1986; 80:199-206.
7.
The Steering Committee of the Physicians' Health Study
Research Group. Preliminary report: findings from the
aspirin component of the ongoing Physicians' Health Study.
N Engl J Med 1988; 318:262-4.
8.
Peto R, Gray R, Collins R, et al. Randomised trial of
prophylactic daily aspirin in British male doctors. Br Med
J 1988; 296:313-6.
9.
Hennekens CH, Peto R, Hutchison GB, et al. An overview of
the British and American aspirin studies. N Engl J Med
1988; 318:923-4.
10.
Hennekens CH. Personal communication, November 1988.
11.
Lewis HD, Davis JW, Archibald DG, et al. Protective effects
of aspirin against acute myocardial infarction and death in
men with unstable angina: results of a Veterans
Administration cooperative study. N Engl J Med 1983;
309:396-403.
12.
Wallenburg HCS, Dekker GA, Makovitz JW, et al. Low-dose
aspirin prevents pregnancy-induced hypertension and
preeclampsia in angiotensin-sensitive primigravidae. Lancet
1986; 1:1-3.
13.
Anonymous. Aspirin: what dose? Lancet 1986; 1:592-3.
14.
American Heart Association. Physicians' Health Study report
on aspirin. Circulation 1988; 77:1447A.
15.
Rimm AA. (letter). N Engl J Med 1988; 318:926.
16.
Shapiro S. The Physicians' Health Study: aspirin for the
primary prevention of myocardial infarction (letter). N
Engl J Med 1988; 318:924.
.