Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Low-dose aspirin after transient ischemic attack prevented vascular events as well as medium-dose aspirin and had fewer adverse effects

ACP J Club. 1992 Mar-April;116:40. doi:10.7326/ACPJC-1992-116-2-040

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• Companion Abstract and Commentary: Low-dose aspirin for cerebrovascular ischemic events reduced the risk for stroke or death

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Antiplatelet agents reduce risks for death, stroke, myocardial infarction, deep venous thrombosis, and arterial occlusion


Source Citation

The Dutch TIA Trial Study Group. 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. N Engl J Med. 1991 Oct 31;325:1261-6.


Abstract

Objective

To compare the effectiveness of low-dose (30 mg/d) and medium-dose (283 mg/d) aspirin in preventing vascular events in patients who have had a transient ischemic attack (TIA) or minor ischemic stroke.

Design

Randomized, double-blind trial.

Setting

63 hospital clinics in the Netherlands.

Patients

3131 men and women who had a TIA or minor ischemic stroke within 3 months before entering the study.

Intervention

Study patients received either 30 mg or 283 mg of soluble aspirin dissolved in water and taken daily before breakfast. 1454 of the 3131 patients also participated in a trial of 50 mg of atenolol per day compared with placebo.

Main outcome measures

The primary outcome measure was death from all vascular causes or the first occurrence of nonfatal stroke or myocardial infarction. Secondary outcome events were death from all causes, death from vascular causes, and death from vascular causes or nonfatal stroke. Mean duration of follow-up was 31 months (range 12 to 52 months).

Main results

228 of 1555 patients (15%) in the 30-mg group and 240 of 1576 (15%) in the 283-mg group died of vascular causes or had a nonfatal stroke or myocardial infarction. The age- and sex-adjusted hazard ratio (HR) for the low-dose group was 0.91 (95% CI 0.76 to 1.09). The adjusted HRs for death, death from vascular causes, and death from vascular causes or nonfatal stroke were 1.01 (CI 0.81 to 1.26), 0.93 (CI 0.71 to 1.22), and 0.86 (CI 0.71 to 1.05), respectively. A trend toward fewer major bleeding complications ocurred in the 30-mg group (2.6% vs 3.4%, HR 0.77, CI 0.51 to 1.16). Significantly fewer episodes of minor bleeding ocurred in the 30-mg group (3.2% vs 5.3%, HR 0.58, CI 0.41 to 0.83), and a similar number of episodes of gastric discomfort in both groups (10.5% vs 11.4%, HR 0.92, CI 0.75 to 1.14).

Conclusion

In patients who have had a transient ischemic attack or minor ischemic stroke, 30 mg of aspirin daily was no less effective in the prevention of vascular events than 283 mg daily and had fewer adverse effects.

Sources of funding: The Netherlands Heart Foundation; Praeventiefonds; ICI-Farma; ICI Pharmaceuticals; Dagra-Pharma; University Hospital Utrecht.

Address for article reprint: Dr. J. van Gijn, University Department of Neurology, University Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.


Commentary

Although it is perhaps not as good as getting "more for less," the latest Dutch and Swedish trials of aspirin confirm that lower doses of aspirin are effective in reducing the risk for major fatal and nonfatal vascular events after initial minor cerebrovascular events and that the risk for adverse events is less with the lower doses. In addition, both studies found equal benefits for men and women from treatment with very low doses of aspirin.

The close timing of publication of these two studies was auspicious. The Dutch trial has an important limitation: There was no placebo group and both doses of aspirin were far below the dose level of 1300 mg per day that was originally shown to be effective (1). Thus, one possible interpretation is that neither dose was effective. The Swedish trial, however, does have a placebo control group and documents the effectiveness of 75 mg of aspirin per day after initial treatment with aspirin or anticoagulants.

The Swedish trial provides an interesting ethical twist. A placebo-controlled trial of aspirin for patients with mild qualifying cerebrovascular events could not be conducted today after previous trials showed the efficacy of aspirin (2). However, the Swedish study was in its final phase when the efficacy of aspirin became clearly defined, and the demonstration by this study that lower doses of aspirin than previously tested are also effective will likely lead to many more patients enjoying aspirin's benefits at a lower risk for adverse effects. This is not to say that low-dose aspirin is benign. Both studies show about a 3% risk for severe gastrointestinal bleeding, and the Swedish study provides a comparison risk of 1.3% for severe bleeding among patients receiving placebo (for a relative risk of about 2). It is likely that this complication rate cannot be lowered without losing the effectiveness of aspirin: Presumably both the bleeding and the prevention of ischemic vascular events are the result of the same process—inhibition of platelet cyclo-oxygenase. There may be a small increase in the risk for hemorrhagic stroke, although this is more than offset by the risk reduction for ischemic stroke.

Do the lower doses of aspirin give a benefit comparable to larger doses? The relative risk reduction for vascular events in trials comparing aspirin in the dose range of 900 mg to 1500 mg daily with placebo from the Antiplatelet Trialists' Collaboration meta-analysis was 22% (2), which is consistent with the 18% relative risk reduction seen in the Swedish trial. This is not surprising if the mechanism of aspirin's effect is mediated through cyclo-oxygenase inhibition: Complete inhibition occurs with a daily aspirin dose as low as 30 mg.

Although these studies began well before the demonstration of benefit for carotid endarterectomy for high-grade internal carotid artery stenosis, it is regrettable that little or no information was collected about the effect of aspirin for various degrees and locations of vascular stenosis. It is important that patients with minor vascular events in the anterior circulation of the brain receive further investigation to determine the need for endarterectomy. Despite the use of aspirin by patients with high-grade carotid stenosis, their risk for subsequent events remains unacceptable and can be reduced substantially by surgery.

Finally, judging by the stocks of aspirin in pharmacies, it will be difficult for patients to reduce their aspirin dose without splitting standard aspirin pills into small bits or paying the exorbitant price of children's aspirin. It is high time for pharmaceutical manufacturers to provide low-dose aspirin in economical packaging.

Preston C. Calvert, MD
The Neurology Center, P.A.Falls Church, Virginia, USA
R. Brian Haynes, MD
McMaster UniversityHamilton, Ontario, Canada

Preston C. Calvert, MD
The Neurology Center, P.A.
Falls Church, Virginia, USA

R. Brian Haynes, MD
McMaster University
Hamilton, Ontario, Canada


References

1. The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med. 1978;299:53-9.

2. Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged anti-platelet therapy. BMJ. 1988;296:320-31.