From the Brigham and Women's Hospital, Boston, Mass (J.E.B.);
Service de Neurologie, Centre Hospitalier Université Vaudois, Lausanne,
Switzerland (J.B.); and the Stroke Editorial Office, Indiana University,
Indianapolis, Ind (M.L.D.).
Correspondence to Julie E. Buring, ScD, Brigham and Women's Hospital, 900 Commonwealth Ave East, Boston, MA 02215. E-mail jeburing{at}bics.bwh.harvard.edu
In this issue of
Stroke, Kronmal and colleagues report the intriguing finding
that in a cohort of elderly people, self-selection for aspirin use was
associated with increased risks of ischemic stroke in women and
hemorrhagic stroke in men and women. The authors are commendably
cautious in their interpretation of the findings and raise the
possibility of confounding by reasons for aspirin use as an explanation
for the observed association. However, it is useful to view these
findings in the context of the totality of available
evidence.1 2
Despite 100 years of widespread use, the potential for aspirin to
affect risks of stroke has only been recognized relatively recently,
due to the Nobel prize–winning work of Sir John Vane, who demonstrated
that aspirin permanently inhibits
cyclooxygenase-dependent platelet
aggregation.3 Since that time, case-control and
cohort studies conducted largely among middle-aged populations have
suggested that individuals who self-select for aspirin therapy tend to
have small (i.e., 20% to 30%) decreased risks of total and
ischemic stroke.4 If true, such benefits
would be clinically very worthwhile and would have an important public
health impact. Unfortunately, however, the amount of uncontrolled and
uncontrollable confounding in such studies, no matter how well designed
and conducted, is likely to be as large as the effects being sought. In
such circumstances, the most reliable design strategy to answer the
question definitively is a large-scale randomized
trial.5
In a collaborative worldwide overview of all randomized trials of
antiplatelet agents, aspirin was shown to reduce the risk of
nonfatal stroke by 25%.6 This reduction was a
weighted average of a 31% (±5%) highly statistically
significant reduction among high-risk patients with a history of
occlusive disease and a possible but statistically nonsignificant 21%
(±13%) increase among all low-risk patients (ie, primary
prevention). The latter uninformative null result derived primarily
from inadequate numbers of stroke end points in the two completed
primary prevention trials, the US Physicians' Health Study and the
British Doctors' Trial, both of which included only
men.1 With respect to cerebral
hemorrhage, the data from all these randomized trials taken
together are compatible with about a 1 per 1000 excess due to asprin, which is not surprising, as any agent that decreases
clotting may increase bleeding.
In this context then, the findings of Kronmal and colleagues of a
potential increase in hemorrhagic stroke among elderly men and women
seems plausible. However, as the authors state, the conclusion that
aspirin itself increases risk of ischemic stroke in elderly
women is premature and unwarranted. The totality of evidence from basic
research, observational epidemiological studies, and all randomized
trials is in fact most compatible with decreased, not increased, risks
of ischemic stroke due to aspirin among women as well as men,
and at all ages.1 2 Moreover, issues dealing with
the recording of aspirin use limit the interpretability of the
findings by Kronmal et al. Because use of aspirin for only 10 of 14
days was required for a patient to be considered a "frequent user,"
this category included many patients taking aspirin for reasons other
than cardiovascular (cardiovascular
prevention would imply 14 of 14 days' use). In this setting, very high
doses of aspirin (several grams), which may have antiatherogenic and/or
thrombogenic properties, may have been taken by several of these
patients (for pain or arthritis, for example). Indeed, the use of
aspirin immediately before stroke may be more important than
intermittent use over a few days, especially if a very high dose was
taken within a few hours before stroke. Also, as only 10 of 14 days on
aspirin were required for a patient to be considered a frequent user,
this group may include patients who in fact stopped aspirin a few days
before stroke, in the setting of previous regular use. In this case,
because of the short duration of action of aspirin, ischemic
stroke may have been associated with the interruption of regular
aspirin treatment. Moreover, calling 1-day users "nonusers"
may be misleading if that particular day was the one before the stroke
and the dose of aspirin was very high.
Thus, we agree with Kronmal and colleagues that the question of aspirin
for primary prevention of stroke can be settled only by randomized
clinical trials. At this time among women, the only available data on
aspirin and stroke derive from observational studies that tend to
suggest decreases in ischemic but possible increases in
hemorrhagic stroke. To evaluate directly the balance of benefits and
risks of aspirin among apparently healthy women, the ongoing Women's
Health Study7 has randomized approximately
40 000 female health professionals aged 45 years and older. A large
proportion of the strokes in this trial will occur among the
elderly.
There are presently no approved prescription indications for
aspirin in the primary prevention of cardiovascular
disease, and any such formal policy recommendations need to await the
results of the ongoing randomized trials. In the meantime, aspirin
prophylaxis may nonetheless be considered appropriate for some
individuals. The recently updated guidelines from the US Preventive
Services Task Force suggest that the benefit of aspirin may outweigh
the harm in men with risk factors for coronary disease who lack
contraindications to aspirin use.8 The American
Heart Association has made similar
recommendations.2 No guidelines have been issued
for women. However, while awaiting definitive data from the Women's
Health Study, the observational data in women, in conjunction with the
definitive randomized trial data in male physicians, suggest that
aspirin may also be beneficial in primary prevention for women whose
risk of myocardial infarction is sufficiently high to warrant exposure
to risks of long-term administration of this drug.
It is important to view the potential benefits of aspirin in the
context of current knowledge about modification of other
cardiovascular risk factors. For example, a 10%
decrease in blood cholesterol corresponds to a roughly 20%
to 30% reduction in risk of cardiovascular
disease.9 For blood pressure, a 5- to 6-mm
decrease in diastolic pressure among those with
mild-to-moderate hypertension lowers risks of coronary heart
disease by 14% and stroke by 42%.10 Finally,
cessation of cigarette smoking results in an approximately 60%
decrease in coronary heart disease, perhaps even within a
matter of months.11
Thus, aspirin should always be viewed as a possible adjunct, not an
alternative, to control or elimination of other
cardiovascular risk factors. Aspirin therapy should be
initiated only on the recommendation of a physician or other primary
healthcare provider. Such a recommendation should be based on an
individual clinical judgment that considers the
cardiovascular risks of the patient, the adverse
effects of the drug, and the documented benefits on various
manifestations of cardiovascular disease in different
categories of patients.
Kronmal and colleagues have added importantly relevant information to
the question of aspirin and the primary prevention of stroke in the
elderly, and they are to be commended for advising clinicians and the
general public to await the results of ongoing randomized trials before
clear recommendations can be made.
Footnotes
Reviews of this manuscript were directed by Associate Editors Hermes Kontos, MD, and José Biller, MD.
References
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© 1998 American Heart Association, Inc.
Editorial
Aspirin and Stroke
Key Words: aspirin • stroke prevention
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