Stroke: low-dose aspirin for secondary prevention. (28 October 1999, updated 29 January 2000).

Formulated question:

5 Articles Selected:

1) Arch Intern Med 1999 (Jun 14); 159: 1248-53
A metaregression analysis of the dose-response effect of aspirin on stroke.
Johnson ES, Lanes SF, Wentworth CE 3d, et al. For correspondence: Mr. E.S. Johnson, Epidemiology Resources Inc., 1 Newton Executive Park, Newton Lower Falls,USA.

Abstract done by Robert Hart, MD, University of Texas Health Sciences Center for ACP Journal Club, January/February 2000 number.
QUESTION: In patients with a previous transient ischemic attack (TIA) or stroke, does a dose-response relation exist for aspirin use and the risk for stroke?.
DATA SOURCES: Studies were identified by searching MEDLINE (to April 1996) and by scanning reference lists of relevant articles.
STUDY SELECTON: Studies were selected if they were randomized, placebo-controlled, secondary prevention trials that included a comparison of aspirin alone and reported stroke as an outcome.
DATA EXTRACTION: 2 reviewers extracted published data on demographics, inclusion and exclusion criteria, treatment regimen, duration of follow-up, and all strokes (ischemic and hemorrhagic). Another reviewer independently extracted data on outcomes, inclusion and exclusion criteria, and health status at entry.
MAIN RESULTS: 11 randomized controlled trials met the selection criteria (9629 patients [5228 allocated to aspirin and 4401 to placebo], mean age 63 y, 63% men, mean follow-up 32 mo). 1391 strokes occurred. Aspirin doses ranged from 50 to 1500 mg/d. The combined results for all doses showed a benefit for aspirin in stroke (relative risk reduction 15%, 95% CI 6% to 23%). Results were similar after adjustment for study and length of follow-up. A linear regression model showed that no linear dose-response relation (P > 0.2) or quadratic dose-response relation (P > 0.2) existed for aspirin dose and the risk for stroke.
CONCLUSIONS: In patients with a previous transient ischemic attack or stroke, aspirin reduces the risk for stroke. No dose-response relation exists for aspirin doses between 50 and 1500 mg/d and the risk for stroke.
SOURCE OF FUNDING: Boehringer Ingelheim.
COMMENTARY: The optimal dose of aspirin for prevention of stroke has been a long-standing controversy. Some neurologists believe that the most effective dose of aspirin to prevent stroke is higher than that for prevention of myocardial infarction. Although debated ad nauseum in recent years, the issue has risen again with the results of the European Stroke Prevention Study II, which showed that high-dose dipyridamole enhanced the protective effect of low-dose aspirin (i.e., 25 mg twice daily). This combination was recently approved by the U.S. Food and Drug Administration (FDA) for secondary prevention of stroke and will be marketed soon by Boehringer Ingelheim (who sponsored this metaregression analysis by Johnson and colleagues). Whether the combination of high-dose dipyridamole and low-dose aspirin is considered superior to aspirin alone depends in large part on whether it is accepted that the dose of aspirin has no important effect on stroke prevention.
Johnson and colleagues report a sophisticated biostatistical analysis based on indirect comparison of the results of 11 randomized clinical trials, including the European Stroke Prevention Study II, and conclude that the protective effect of aspirin on stroke is uniform across aspirin doses from 50 to 1500 mg/d. More convincing to me is the similar conclusion reached from considering the randomized clinical trials that directly compared ranging aspirin doses from 50 to 1200 mg/d and, most recently, the Aspirin and Carotid Endarterectomy trial (81 vs 325 vs 650 vs 1300 mg/d). Although some have disputed the generalizability of the results of these direct randomized comparisons, no persuasive evidence exists that higher doses of aspirin offer additional protection. In 1998, the FDA recommended aspirin doses between 50 and 325 mg/d for secondary prevention of stroke.
For prevention of stroke in patients with TIA and previous ischemic stroke, consensus on aspirin doses 325 mg/d is emerging. Is aspirin alone the best available antiplatelet prophylaxis? Clopidogrel (congener of ticlopidine without its toxicity) and high-dose dipyridamole have also been shown to be efficacious (see the critical, balanced, recent reviews by Gorelick and colleagues and Wilterdink and Easton). Aspirin remains the mainstay, but the era of combined antiplatelet therapies using aspirin with such agents as clopidogrel or dipyridamole for secondary prevention of stroke is on the near horizon, pending confirmatory evidence from ongoing clinical trials.
Meta-analysis

2) J Neurol Sci 1996; 143 (1-2): 1-13
European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.
Diener HC; Cunha L; Forbes C; Sivenius J; Smets P; Lowenthal A.

(Methods) In 1988, we undertook a randomized, placebo-controlled, double-blind trial to investigate the safety and efficacy of low-dose acetylsalicylic acid (ASA), modified-release dipyridamole, and the two agents in combination for secondary prevention of ischemic stroke. Patients with prior stroke or transient ischemic attack (TIA) were randomized to treatment with ASA alone (50 mg daily), modified-release dipyridamole alone (400 mg daily), the two agents in a combined formulation, or placebo. Primary endpoints were stroke, death, and stroke or death together. TIA and other vascular events were secondary endpoints. Patients were followed on treatment for two years.
(Results) Data from 6,602 patients were analysed. Factorial analysis demonstrated a highly significant effect for ASA and for dipyridamole in reducing the risk of stroke (p < or = 0.001) and stroke or death combined (p < 0.01). In pairwise comparisons, stroke risk in comparison to placebo was reduced by 18% with ASA alone (p = 0.013); 16% with dipyridamole alone (p = 0.039); and 37% with combination therapy (p < 0.001). Risk of stroke or death was reduced by 13% with ASA alone (p = 0.016); 15% with dipyridamole alone (p = 0.015); and 24% with the combination (p < 0.001). The treatment had no statistically significant effect on the death rate alone. Factorial analysis also demonstrated a highly significant effect of ASA (p < 0.001) and dipyridamole (p < 0.01) for preventing TIA. The risk reduction for the combination was 36% (p < 0.001) in comparison with placebo. Headache was the most common adverse event, occurring more frequently in dipyridamole-treated patients. All-site bleeding and gastrointestinal bleeding were significantly more common in patients who received ASA in comparison to placebo or dipyridamole.
(Conclusions) We conclude that (1) ASA 25 mg twice daily and dipyridamole, in a modified-release form, at a dose of 200 mg twice daily have each been shown to be equally effective for the secondary prevention of ischemic stroke and TIA; (2) when co-prescribed the protective effects are additive, the combination being significantly more effective than either agent prescribed singly; (3) low-dose ASA does not eliminate the propensity for induced bleeding.
Randomized controlled trial
MEDLINE 97135755 EMBASE 96367631

3) N Engl J Med 1991; 325 (18): 1261-6
A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke.
The Dutch TIA Trial Study Group.

BACKGROUND. Aspirin is known to improve the outcome of patients who have had a cerebral transient ischemic attack, but the optimal dose of aspirin remains uncertain. Experimental evidence indicates that 30 mg of aspirin daily alters platelet aggregation more favorably than the 300-mg dose currently used in patients after transient ischemic attack or minor ischemic stroke.
METHODS. We assessed the effects of two doses of a water-soluble preparation of acetylsalicylic acid, or aspirin (30 mg vs. 283 mg a day), on the occurrence of death from all vascular causes, nonfatal stroke, or nonfatal myocardial infarction in a double-blind, randomized, controlled clinical trial in patients who had had a transient ischemic attack or minor stroke. A total of 3131 patients participated in the study. The mean follow-up was 2.6 years.
RESULTS. In the group assigned to receive 30 mg of aspirin, the frequency of death from vascular causes, nonfatal stroke, or nonfatal myocardial infarction was 228 of 1555 (14.7 percent), as compared with 240 of 1576 (15.2 percent) in the group assigned to receive 283 mg. The age- and sex-adjusted hazard ratio for the group receiving the lower dose was 0.91 (95 percent confidence interval, 0.76 to 1.09). There were slightly fewer major bleeding complications in the 30-mg group than in the 283-mg group (40 vs. 53), and significantly fewer reports of minor bleeding (49 vs. 84). Fewer patients receiving 30 mg of aspirin reported gastrointestinal symptoms (164 vs. 179) and other adverse effects (73 vs. 90).
CONCLUSIONS. Our data indicate that 30 mg of aspirin daily is no less effective in the prevention of vascular events than a 283-mg dose in patients with a transient ischemic attack or minor stroke, and has fewer adverse effects.
Randomized controlled trial
MEDLINE 92018050

4) Lancet 1991; 338 (8779): 1345-9
Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
The SALT Collaborative Group.

(Background) The efficacy of aspirin in daily doses of 300 mg and more as secondary prophylaxis after cerebrovascular events is well established. Since much lower doses of aspirin can inhibit platelet function, and carry a lower risk of adverse effects, the Swedish Aspirin Low-dose Trial (SALT) was set up to study the efficacy of 75 mg aspirin daily in prevention of stroke and death after transient ischaemic attack (TIA) or minor stroke.
(Methods) 1360 patients entered the study 1-4 months after the qualifying event: 676 were randomly assigned to aspirin treatment and 684 to placebo treatment. The median duration of follow-up was 32 months.
(Results) Compared with the placebo group, the aspirin group showed a reduction of 18% in the risk of primary outcome events (stroke or death; relative risk 0.82, 95% confidence interval 0.67-0.99; log-rank analysis p = 0.02), and reductions of 16-20% in the risks of secondary outcome events (stroke; stroke or two or more TIAs within a week of each other necessitating a change of treatment; or myocardial infarction). Adverse drug effects were reported by 147 aspirin-treated and 123 placebo-treated patients Gastrointestinal side-effects were only slightly more common in the aspirin-treated patients, but that group had a significant excess of bleeding episodes (p = 0.04).
(Conclusions) Thus, we have found that a low dose (75 mg/day) of aspirin significantly reduces the risk of stroke or death in patients with cerebrovascular ischaemic events.
Randomized controlled trial
MEDLINE 92048022

5) Br Med J Clin Res Ed 1988; 296 (6618): 316-20
United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results.
UK-TIA Study Group.

(Methods) From 1979 to 1985, 2435 patients thought to have had a transient ischaemic attack or minor ischaemic stroke were allocated at random to receive long term blind treatment with either aspirin 600 mg twice daily (n = 815), aspirin 300 mg once daily (806), or placebo (814). Treatment continued with about 85% compliance until September 1986 (mean four years).
(Results) The odds of suffering one or more of four categories of event (namely, non-fatal myocardial infarction, non-fatal major stroke, vascular death, or non-vascular death) were 18% less in the two groups allocated to receive aspirin than in the group allocated to receive placebo (2p = 0.01). The more relevant but less frequent composite event of disabling stroke or vascular death was reduced by only 7%; this reduction was not significantly different from zero, but nor was it significantly different from a 25% reduction.
(Conclusions) There was no definite difference between responses to the 300 mg and 1200 mg daily doses, except that the lower dose was significantly less gastrotoxic.
Randomized controlled trial
MEDLINE 88150403

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