ORIGINAL CONTRIBUTION. Aspirin for the Primary Prevention of Stroke and Other Major Vascular Events

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1 Aspirin for the Primary Prevention of Stroke and Other Major Vascular Events Meta-analysis and Hypotheses ORIGINAL CONTRIBUTION Robert G. Hart, MD; Jonathan L. Halperin, MD; Ruth McBride, BS; Oscar Benavente, MD; Malcolm Man-Son-Hing, MD; Richard A. Kronmal, PhD Background: Aspirin therapy reduces stroke by about 25% for persons with atherosclerotic vascular disease, but the effect in those without clinically apparent vascular disease is distinctly different. Objective: To define the effect of aspirin use on stroke and other major vascular events when given for primary prevention to persons without clinically recognized vascular disease. Data Sources and Extraction: Systematic review of randomized clinical trials and large prospective observational cohort studies examining the relation between aspirin use and stroke in persons at low intrinsic risk. Studies were identified by a computerized search of the English-language literature. Data Synthesis: Five randomized trials of primary prevention included participants randomized to aspirin doses ranging from 75 to 650 mg/d; the mean overall stroke rate was 0.3% per year during an average follow-up of 4.6 years. Meta-analysis revealed no significant effect on stroke (relative risk = 1.08; 95% confidence interval, ) contrasting with a decrease in myocardial infarction (relative risk = 0.74; 95% confidence interval, ). The lack of reduction of stroke by aspirin for primary prevention was incompatible with its protective effect against stroke in patients with manifest vascular disease (P =.001). Intracranial hemorrhage was increased by the regular use of aspirin (relative risk = 1.35; P =.03), similarly for both primary and secondary prevention. In 4 large observational studies, self-selected use of aspirin was consistently associated with higher rates of stroke. Conclusions: The effect of aspirin therapy on stroke differs between individuals based on the presence or absence of overt vascular disease, in contrast with the consistent reduction in myocardial infarction by aspirin therapy observed in all populations. We hypothesize that the effect of aspirin therapy on stroke for persons with major risk factors for vascular disease may be intermediate between a substantial decrease for those with manifest vascular disease and a possible small increase for healthy persons due to accentuated intracranial hemorrhage. When aspirin is given for primary prevention of vascular events, available data support using 75 to 81 mg/d. Arch Neurol. 2000;57: From the Department of Medicine (Neurology), University of Texas Health Science Center, San Antonio (Drs Hart and Benavente); The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (Dr Halperin); Statistics Epidemiology Research Corporation, Seattle, Wash (Ms McBride); Division of Geriatric Medicine, University of Ottawa, Ottawa, Ontario (Dr Man-Son-Hing); and the Department of Biostatistics, University of Washington, Seattle (Dr Kronmal). ONE HUNDRED years after its introduction, aspirin is the world s most commonly used drug. About pounds of aspirin (about 100 million tablets) are consumed each day in the United States alone. 1 Among Americans older than 65 years, about 20% use aspirin regularly, mostly for the relief of pain. 2-7 For editorial comment see page 306 The regular use of aspirin reduces the risks of myocardial infarction (MI), stroke, and vascular death for patients with clinically manifest vascular disease (ie, those at high risk). An influential metaanalysis of over 100 randomized clinical trials involving more than participants showed that aspirin therapy reduces stroke by about 25% in most highrisk patients. 8 Paradoxically, aspirin use was associated with small increases in the incidences of stroke in 2 large clinical trials of primary prevention included in this meta-analysis although these results were not statistically significant An estimated 8 million elderly Americans without apparent vascular disease consume aspirin regularly, 11 and its effect on stroke in such persons is important to characterize. With the recent publication of 4 studies addressing the effect of aspirin use on stroke in low-risk persons, we undertook a critical review of this issue. Our objectives were to determine the effect of the regular use of aspirin on stroke for persons without clini- 326

2 MATERIALS AND METHODS We sought to identify all published randomized clinical trials assessing the effect of aspirin in any dose vs placebo for primary prevention of stroke and other major vascular events in persons without clinically manifest vascular disease. Vascular diseases included MI; stroke; transient ischemic attack; angina pectoris; intermittent claudication; atrial fibrillation; or revascularization of carotid, coronary, or peripheral arteries for atherosclerosis. Clinical trials in which all participants had major atherosclerotic risk factors (ie, advanced age, hypertension, or diabetes mellitus) were included, butconsideredseparatelyinsecondaryanalyses. Clinical trials in which more than 20% of the participantshadclinicallydiagnosedvasculardisease, those who did not report stroke outcomes, and those withoutobservedstrokeswerenotanalyzed. Wheneverpossible from published results, subgroups of participants in primary prevention trials who had vascular disease were removed for secondary analyses. 15 Clinical trials in which aspirin was combined with another antiplatelet agent were excluded. Computerized medical databases were searched for the years 1980 through 1998 using the following key words: clinical trial, aspirin, and stroke. In addition, the Cochrane Collaboration Registry and published lists of the Antiplatelet Trialists Collaboration were reviewed seeking randomized clinical trials meeting these specifications. Of 6 clinical trials identified, 5 were included in the main analyses, 9,10,13,14,16 as the remaining small pilot trial did not report strokes according to treatment assignment. 17 The large, rigorously conducted Antiplatelet Trialists Collaboration meta-analysis was used to assess the effect of aspirin therapy in patients with established vascular disease. 8 In addition to randomized clinical trials, large, prospective observational studies were analyzed separately to assess the effect of the regular use of aspirin on stroke in a broader spectrum of persons taking widely different aspirin doses (although distinguishing association from causeeffect is impossible with confidence in these nonrandomized studies). A computerized literature search using the following key words: aspirin, stroke, population-based, and epidemiological was done, the reference lists of recent review articles were also screened, and 4 studies were identified. 5,11,12,18 Results of the randomized clinical trials were combined using a stratified Mantel-Haenszel estimate of the odds ratio and 95% confidence intervals (CIs). 19 The effect of aspirin therapy vs placebo was compared using a stratified Mantel-Haenszel-Cochran statistic. Homogeneity of the combined results was evaluated by the Breslow-Day test, 20 and confirmed using a random effects model for both rate differences and odds ratio since event rates were low. Computations were performed using SAS (SAS Institute, Cary, NC). cally manifest atherosclerotic vascular disease (ie, primary prevention) as well as its effect on other major vascular events in this population. RESULTS ASPIRIN THERAPY AND STROKE IN RANDOMIZED PRIMARY PREVENTION TRIALS Five randomized clinical trials included participants with a mean age of 57 years who were followed up for about patient-years observation (mean followup = 4.6 years per patient, Table 1). Three clinical trials excluded women 9,10,14 ; women constituted 20% of the participants, contributing 17% of total exposure. Recruits varied widely between clinical trials, from healthy male physicians to patients with diabetes mellitus or hypertension or men with coronary risk factors (Table 1). Mortality rates ranged from 0.4% to 3.0% per year, averaging 1% per year. In comparison, US mortality rates for men and women aged 55 to 59 years, average 0.7% and 0.4% per year, respectively. Although considered primary prevention trials, about 5% of the participants (range, 1%-20%) had clinically manifest vascular disease. Aspirin doses were 75 mg/d ( participants), 325 mg every other day ( participants), and 500 to 650 mg/d (8850 participants; Table 1). The stroke rate in pooled analysis of the 5 clinical trials averaged 0.3% per year (range, 0.2%-0.8% per year, Table 2). Aspirin therapy was associated with modest increases in the rate of stroke in 3 clinical trials 9,10,16 a decrease in 1 small study, 14 no appreciable effect in the large remaining clinical trial, 13 but was not statistically significant in any individual clinical trial or their pooled results (relative risk [RR] = 1.08; 95% CI, , Figure 1). This contrasted with a highly significant reduction in MI in these clinical trials, with an overall RR reduction in MI of 26% (RR, 0.74; 95% CI, ; P.001; Table 2). Secondary analyses of the Physicians Health Study restricted to highly adherent participants widened the contrasting effects of aspirin therapy on stroke (a 29% increase P =.14) vs MI (a 51% decrease, P.001). 21 Pooled analysis of all 5 clinical trials revealed a RR of 0.93% (95% CI for RR, ) for deaths categorized as vascular and of 0.94 (95% CI, ) for allcause mortality, with both trends fairly consistent across the clinical trials although not statistically significant in any individual clinical trial or when pooled. Three 13,14,16 of these 5 clinical trials recruited only participants with vascular risk factors. Participants in these 3 clinical trials had a mean age of 59 years, 42% were women, and rates of death and stroke averaged 1.5% per year and 0.5% per year, respectively. In contrast, the 2 remaining clinical trials 9,10 recruited healthy male physicians of whom only a minority harbored vascular risk factors. In these 2 clinical trials, the mean age averaged 55 years with about half the rates of death and stroke (0.6% per year and 0.2% per year, respectively) compared with clinical trials that included participants with risk factors. No net effect of aspirin therapy on stroke was noted in the clinical trials of participants with vascular risk factors (RR = 1.02; 95% CI, ) compared with a possible small increase (RR = 1.20; 95% CI, ) in 2 clinical trials of men without risk factors although of borderline statistical significance and not statistically significant in either clinical trial individually (Figure 2). 327

3 Table 1. Randomized Clinical Trials of Aspirin Therapy for Primary Prevention* Source, y Total Sample Size Population Category Mean Age, y Aspirin Dose, mg/d Women, % Participants With Hypertension, % Mortality Rate, %/y USPHS, Healthy male physicians mg qod British male physicians, Male physicians ETDRS, Patients with diabetes mellitus MRC-TPT, Patients with coronary risk factors NR 1.3 HOT, Patients with hypertension All Clinical Trials *USPHS indicates US Physicians Health Study; ETDRS, Early Treatment of Diabetic Retinopathy Study; MRC-TPT, Medical Research Council s Thrombosis Prevention Trial; HOT, Hypertension Optimal Treatment; qod, every other day; NR, not reported; and ellipses, not applicable. Exact patient-years of follow-up was not published, estimated to be years for each treatment arm for these analyses. Table 2. Aspirin Effect on All Stroke and Myocardial Infarction (MI) Incidences in Randomized Clinical Trials of Primary Prevention* MI Stroke Source Placebo Rate, %/y % Change Placebo Rate, %/y % Change Healthy male physicians USPHS ( ) (+) 21 British physicians ( ) (+) 16 Vascular risk factors ETDRS 16 (patients with diabetes mellitus) 2.8 ( ) (+) 18 MRC-TPT 14 (patients with coronary risk factors) 1.2 ( ) ( ) 31 HOT 13 (patients with hypertension) 0.4 ( ) ( ) 1 All Clinical Trials 0.7 ( ) (+) 8 *See the asterisk footnote in Table 1 for the explanation of the abbreviations for the clinical trials. Includes both ischemic and hemorrhagic stroke, of which 10% to 15% were hemorrhagic. The change in the incidences of stroke was not statistically significant for any individual clinical trial. All P.05. The MRC-TPT was a factorial design that included additional randomization to warfarin sodium (mean international normalized ratio for anticoagulant monitoring equals 1.5) vs not. Results in the table excludes those who received warfarin with aspirin therapy or placebo. Inclusion of those receiving warfarin therapy, which assumes no interaction between these agents, yields 47 per 2545 strokes for those participants who received aspirin vs 48 per 2540 strokes for those participants who received placebo. Calculated using Peto fixed effects model; see the Aspirin Therapy and Stroke in Randomized Primary Prevention Trials subsection of the Results section for 95% confidence intervals. Source, y British Male Physicians, Participants Who Received Aspirin Therapy 91/3429 Placebo 39/1710 RR (95% CI) Category Primary Prevention No. of Clinical Trials Aspirin- Treated Participants Control Subjects RR (95% CI) USPHS, ETDRS, MRC-TPT, HOT, / / / / / / / /9391 Male Physicians Vascular Risk Factors / / / / All Clinical Trials 466/ RR, 1.08 (95% CI: 0.95, 1.24) 389/ Better Worse Aspirin Therapy Vascular Disease 124 Antiplatelet- Treated Participants 1005/ Control Subjects 1386/ Better Worse Aspirin Therapy Figure 1. Effect of aspirin therapy on the incidence of stroke in 5 randomized clinical trials of primary prevention. Herein stroke includes hemorrhagic, ischemic, and uncertain. RR indicates relative risk; 95% CI, 95% confidence interval; numerator/denominator values, number with stroke/total sample size; USPHS, US Physicians Health Study; ETDRS, Early Treatment of Diabetic Retinopathy Study; MRC-TPT, Medical Research Council s Thrombosis Prevention Trial; and HOT, Hypertension Optimal Treatment. Figure 2. Effect of aspirin therapy and stroke according to the presence of vascular risk factors and clinically manifest vascular disease. Herein stroke includes hemorrhagic, ischemic, and uncertain. Adapted from the Antiplatelet Trialists Collaboration 8 (see their table) excluding the Early Treatment of Diabetic Retinopathy Study (ETDRS) 16 (which is included with vascular risk factors) and with the addition of the recently published European Stroke Prevention Study 2 (206 strokes per 1649 participants for aspirin therapy vs 250 strokes per 1649 participants for placebo). 22 The Antiplatelet Trialists Collaboration 8 analyzed all antiplatelet agents, with aspirin alone accounting for most of the exposure. RR indicates relative risk; 95% CI, 95% confidence interval; numerator/denominator values, subsample size/total sample size. 328

4 Pooled experience in participants with manifest vascular disease (ie, high risk) by the Antiplatelet Trialists Collaboration yielded a 27% RR reduction (RR, 0.73; 95% CI, ) in stroke by antiplatelet therapy (Figure 2). 8,22 This effect was incompatible with the effect of aspirin therapy in the 5 clinical trials of primary prevention (P =.001). In contrast, the effect of aspirin therapy for prevention of MI is similar for those with vs without vascular disease (about 25%) and for participants with vs without vascular risk factors in the 5 primary prevention clinical trials (23% vs 26% reductions, respectively). The influence of aspirin therapy on stroke in randomized clinical trials of participants who had low rates of stroke ( 1% per year) despite manifest vascular disease is difficult to estimate. These clinical trials usually involved young patients with coronary syndromes during an era when stroke was often undetected or underreported (based on high ratios of fatal to nonfatal strokes), with notable exception. 26 Pooled analysis of 4 such clinical trials show stroke rates averaging 0.7% per year, and aspirin treatment associated with a 35% reduction in the incidence of stroke (95% CI for RR, ) OBSERVATIONAL STUDIES OF ASPIRIN THERAPY AND STROKE IN LOW-RISK PERSONS Four large, prospective, observational studies assessed the relation between self-selected regular use of aspirin and stroke in low-risk participants. 5,11,12,18 In each, aspirin use was associated with increases in the incidence of stroke, statistically significant in 2 studies after adjustment for other stroke risk factors. 11,12 In 1 study, the association of the regular use of aspirin with increased incidence of ischemic stroke was observed in women but not men. 11 ASPIRIN THERAPY AND HEMORRHAGIC STROKE Long-term use of aspirin therapy increased the incidence of hemorrhagic stroke (RR = 1.35, P =.03 from pooled analysis of all randomized clinical trials) both for those with and without manifest vascular disease (Table 3). No apparent relation was noted between aspirin dose and the incidence of hemorrhagic stroke based on indirect comparisons from randomized clinical trials (Table 3), and incidence based on direct comparisons are limited by the lack of hemorrhagic events. 29,30 In 1 casecontrol study, aspirin in doses of 1225 mg/wk or more was associated with a 3-fold increased rate of intracerebral hemorrhage (P =.05), while no increase was observed with lower doses. 31 In clinical studies of occidental cohorts, 10% to 15% of all strokes are hemorrhagic. Hence, a 35% increase in the rate of hemorrhagic stroke by aspirin therapy (Table 3) would raise the overall stroke rate of aspirin users by about 3% to 5% accounting theoretically for the small trends in excess stroke observed among those assigned aspirin in the pooled analysis of primary prevention trials (Table 2), assuming no reduction in the incidence of ischemic strokes occurred in those given aspirin therapy. Table 3. Aspirin Therapy and Hemorrhagic Stroke: Randomized Clinical Trials for Primary Prevention* Source Total Sample Size Intracranial Hemorrhage, No. of Participants % Change Primary prevention USPHS 10 Aspirin (+) 92 Placebo British male physicians 9 Aspirin (+) 8 Placebo MRC-TPT 14 Aspirin Placebo HOT 13 Aspirin ( ) 7 Placebo Aggregate Primary Prevention Aspirin (+) 36 Placebo High risk Antiplatelet Trialists Collaboration 8 Aspirin (+) 35 Placebo *See the asterisk footnote in Table 1 for the explanation of the abbreviations for the clinical trials. The ETDRS 16 did not report stroke subtypes. A recent meta-analysis reported a larger increased risk of hemorrhagic stroke (relative risk = 1.84, P.001) associated with aspirin use, 28 but did not include 3 large recent clinical trials considered here. 13,14,27 Excludes primary subarachnoid hemorrhage and hemorrhagic transformation of ischemic strokes whenever possible. Including those randomized to warfarin sodium (international normalized ratio for anticoagulant monitoring equals 1.5) in the factorial design, 9 hemorrhagic strokes occurred with aspirin therapy vs 1 stroke with placebo). The 95% confidence interval was 0.88 to 2.1. A recent large clinical trial of secondary prevention of stroke (European Stroke Prevention Study 2) 27 excluded from this overview reported hemorrhagic stroke in 12 participants receiving aspirin therapy vs 9 in those not receiving aspirin therapy (relative risk, 1.3). The 95% confidence interval was 0.91 to ASPIRIN THERAPY AND ISCHEMIC STROKE It is unclear whether aspirin therapy can paradoxically increase the risk of ischemic stroke in certain individuals at low intrinsic risk. This was initially suggested by the findings of 2 large primary prevention trials involving male physicians (Table 4). 9,10 In the US Physicians Health Study, 32 most strokes were categorized as ischemic or hemorrhagic based on neuroimaging or autopsy. There was a small excess of ischemic strokes in this randomized clinical trial (91 strokes among those assigned aspirin vs 82 among those assigned placebo). In the British Doctors Study, 9 lack of neuroimaging makes data regarding ischemic stroke weaker. Together, a small increase in the incidence of ischemic stroke associated with aspirin therapy was seen, but the overall 14% increase does not reach statistical significance (Table 4). In contrast, 2 clinical trials of patients with vascular risk factors taking an aspirin dose of 75 mg/d showed no increase in the incidence of ischemic stroke although the frequency of neuroimaging was not reported (Table 4). 13,14 Considering pooled data from all 4 randomized primary 329

5 Table 4. Aspirin Therapy and Ischemic Stroke: Randomized Clinical Trials for Primary Prevention* Stroke Type Source Total Sample Size Ischemic Unknown Both % Change Primary prevention male physicians USPHS 10 Aspirin (+) 12 Placebo British male physicians 9 Aspirin (+) 18 Placebo Aggregate Male Physicians Aspirin (+) 14 Placebo Primary prevention vascular risk factors MRC-TPT 14 Aspirin ( ) 37 Placebo HOT 13 Aspirin ( ) 1 Placebo Aggregate Vascular Risk Factors Aspirin ( ) 6 Placebo Aggregate All Primary Prevention Aspirin (+) 3 Placebo High risk Antiplatelet Trialists Collaboration 8 Aspirin ( ) 27 Placebo *See the asterisk footnote in Table 1 for the explanation of the abbreviations for the clinical trials. The ETDRS 16 did not report stroke subtypes. Percentage of change was not statistically significant for any individual clinical trials. Ellipses indicate data were not reported. The 95% confidence interval was 0.87 to The 95% confidence interval was 0.65 to prevention trials that separated ischemic and hemorrhagic stroke, there was no effect on the incidence of ischemic stroke by aspirin therapy (Table 4). This finding contrasts significantly with the effect of aspirin therapy to reduce the incidence of ischemic stroke for those with vascular disease (P =.001). COMMENT Pooled analysis of 5 randomized clinical trials involving over participants testing aspirin therapy for primary prevention shows no overall effect on stroke, a result incompatible (P =.001) with the unequivocal effect of aspirin therapy to reduce stroke by about 25% for those with vascular disease. If the effect of aspirin therapy on stroke differs based on the presence of clinically recognized vascular disease, then there could logically exist an intermediate group of patients with vascular risk factors in whom disease is not manifest. While available data are potentially confounded by differences in aspirin doses and sex distribution, they support the hypothesis that in those persons with major vascular risk factors, the effect of aspirin therapy on stroke may be intermediate between those with recognized vascular disease and those with neither manifestations of nor major risk factors for vascular disease (Figure 2). In the 4 observational studies, the consistent association between the regular use of aspirin and increases in stroke risk in both women and men is notable. Aspirin use in these studies was largely self-selected and confounding by uneven distribution of other stroke precipitants cannot be discounted, even after statistical adjustment for recognized differences. 33 Considered in the context of the randomized comparisons, however, these observational studies raise hypothetical concerns about higher doses of aspirin used for analgesia and accentuation of stroke in elderly persons and in women without manifest vascular disease, underrepresented in randomized clinical trials to date. 34 It is remarkable that the expected decrease in the incidence of ischemic stroke was not observed in randomized clinical trials of primary prevention. Aside from inhibition of platelet thromboxane synthesis underlying aspirin s antithrombotic effect, other competing actions of aspirin could be relevant. Aspirin therapy has been reported to increase systemic blood pressure (especially if measured while the patient is supine) and to antagonize the effect of some antihypertensive drugs. 35 Hypertension is a strong, prevalent risk factor for both hemorrhagic and ischemic stroke. Thrombogenic effects of aspirin possibly related to inhibition of endothelial prostacyclin synthesis have been demonstrated experimentally, particularly at high doses In patients without symptomatic atherosclerotic vascular disease, inhibition of prostacyclin synthesis may predispose to thrombosis (the aspirin dilemma ), 39,40 but the clinical rel- 330

6 Table 5. Aspirin Therapy for Primary Prevention: Estimated Effects in Major Vascular Events* No. of Events per 1000 Given Aspirin per Year No. of Major Population Stroke MI Death Extracranial Bleeds Middle-aged persons No vascular risk factors 0.5 (?) Vascular risk factors Healthy elderly persons 1 (?) *See the asterisk footnote in Table 1 for the explanation of the abbreviations for the clinical trials. Based on the effects and rates defined in the randomized clinical trials (Table 2) and the Cardiovascular Health Study 11 for the healthy elderly persons. Major extracranial bleeding rates based on use of low-dose aspirin therapy (ie, 325 mg/d) and assume an estimated rate of 0.3% per year in middle-aged persons without vascular disease and double that for the healthy elderly subjects. MI indicates myocardial infarction; parenthetical question mark, nonsignificant trends; upward arrow, increased; downward arrow, decreased. evance of this effect of aspirin therapy on prostacyclin is unknown. 34 Given the consistent effect of aspirin therapy to reduce MI by about 25% and the strong trend for reduction of all-cause mortality, is the regular use of aspirin beneficial for healthy elderly persons? Among healthy elderly persons (without recognized vascular disease), the incidence of stroke equals or exceeds that of MI, 5,11 in contrast with younger cohorts in whom the reverse holds. 9,10,14,16 It is clear that aspirin therapy increases major extracranial bleeding, with an average RR of 1.5 in clinical trials testing doses between 75 mg/d and 325 mg every other day. 10,13,14 Rates of major extracranial hemorrhage in placebo-assigned patients vary between primary prevention clinical trials involving middle-aged persons (0.15%-0.5% per year), in part due to differing criteria. The risk of major extracranial hemorrhage during aspirin use is likely age related. 41 For those without manifest vascular disease, the riskbenefit analysis of aspirin therapy is complex and must balance a reduction in MI and possibly death against small increases in major extracranial and intracranial bleeding (Table 5). In our view, the benefits of the regular use of aspirin for primary prevention of vascular events in healthy elderly persons have not been sufficiently established to warrant a general recommendation for widespread use. Available data most clearly favor aspirin use for middle-aged persons at special risk for MI. Individual values and preferences may bear importantly on the risk-benefit equation. Several limitations of these analyses warrant comment. Some fraction of participants in the 5 key primary prevention trials at the core of these analyses had recognized vascular disease (Table 1), and it is unclear how they influenced our estimates of the effect of aspirin therapy in those without vascular disease. Evaluation of the importance of vascular risk factors was confounded by segregation on the basis of aspirin dose and sex; this may be clarified when the results of the Women s Health Study 42 become available. Other potential limitations are those common to meta-analysis: Pooling results of several studies to yield a statistically significant result when no individual clinical trial showed statistical significance is problematic; such a result should be considered hypothesis-generating and not hard evidence. We attempted to identify all relevant clinical trials but, although it seems unlikely that large clinical trials were overlooked, omission of studies could introduce bias. CONCLUSIONS The effect of aspirin therapy on stroke may differ for individuals based on the presence or absence of atherosclerotic vascular disease. The overall effect of the regular use of aspirin for primary prevention of major vascular events in elderly persons is unknown since randomized clinical trials to date have included mostly middle-aged persons who are more likely to suffer MI than stroke. Long-term aspirin use increases the incidence of hemorrhagic stroke, but the magnitude of increase is small (about 1/2000 aspirin users per year for elderly persons). Because of an unequivocal effect to reduce MI in a wide range of doses, aspirin use for primary prevention would benefit most those at special risk for MI (such as patients with diabetes mellitus). 13 Current evidence favors low-dose aspirin (75-81 mg/d) when given for primary prevention. The influence of aspirin therapy on stroke is complex, differing in different patient populations, and further understanding of the mechanisms underlying those differences would allow refinement of therapy with this most widely-used medication. Accepted for publication June 11, Corresponding author: Robert G. Hart, MD, Department of Medicine (Neurology), University of Texas Health Science Center, 7703 Floyd Curl Dr, San Antonio, TX ( hartr@uthscsa.edu). REFERENCES 1. Mann J. Murder, Magic, and Medicine. 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