Elsevier

The Lancet

Volume 367, Issue 9523, 20–26 May 2006, Pages 1665-1673
The Lancet

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Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial

https://doi.org/10.1016/S0140-6736(06)68734-5Get rights and content

Summary

Background

Results of trials of aspirin and dipyridamole combined versus aspirin alone for the secondary prevention of vascular events after ischaemic stroke of presumed arterial origin are inconsistent. Our aim was to resolve this uncertainty.

Methods

We did a randomised controlled trial in which we assigned patients to aspirin (30–325 mg daily) with (n=1363) or without (n=1376) dipyridamole (200 mg twice daily) within 6 months of a transient ischaemic attack or minor stroke of presumed arterial origin. Our primary outcome event was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever happened first. Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN73824458) and with ClinicalTrials.gov (NCT00161070).

Findings

Mean follow-up was 3·5 years (SD 2·0). Median aspirin dose was 75 mg in both treatment groups (range 30–325); extended-release dipyridamole was used by 83% (n=1131) of patients on the combination regimen. Primary outcome events arose in 173 (13%) patients on aspirin and dipyridamole and in 216 (16%) on aspirin alone (hazard ratio 0·80, 95% CI 0·66–0·98; absolute risk reduction 1·0% per year, 95% CI 0·1–1·8). Addition of the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or myocardial infarction of 0·82 (95% CI 0·74–0·91). Patients on aspirin and dipyridamole discontinued trial medication more often than those on aspirin alone (470 vs 184), mainly because of headache.

Interpretation

The ESPRIT results, combined with the results of previous trials, provide sufficient evidence to prefer the combination regimen of aspirin plus dipyridamole over aspirin alone as antithrombotic therapy after cerebral ischaemia of arterial origin.

Introduction

Patients with a transient ischaemic attack or non-disabling ischaemic stroke of presumed arterial origin have, without secondary preventive treatment, a yearly risk of a major vascular event of 4–16% in clinical trials1, 2 and of 9% in population-based studies.3 Aspirin 30–300 mg daily prevents only 13–22%1, 2, 4 of these vascular complications. Findings of studies5, 6 indicate no additional benefit of the combination of clopidogrel and aspirin compared with either of these drugs alone. The results of the Second European Stroke Prevention Study (ESPS 2)7, 8, 9 show that the addition of modified-release dipyridamole 200 mg twice daily to aspirin 50 mg daily leads to a relative risk reduction of all major vascular events of 22% (95% CI 9–33) compared with aspirin alone. This finding contrasts with those of four earlier but smaller studies of the same treatment comparison, which showed no such benefit. The pooled analysis of data from the four earlier studies shows a relative risk reduction of dipyridamole and aspirin combined compared with aspirin alone of 3% (95% CI −22 to 22),8, 10, 11, 12, 13 whereas a meta-analysis that included ESPS 2 resulted in a pooled relative risk reduction of vascular events of 16% (95% CI 3–28).8 The uncertainty about the secondary preventive value of combined dipyridamole and aspirin is sustained by a Cochrane review,14 showing that in patients with other types of vascular disease the combination was no more effective than aspirin alone. Because of these conflicting results, the routine use of the combination of dipyridamole and aspirin in the secondary prevention of vascular events after ischaemic stroke of presumed arterial origin is controversial.

Our aim, in the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), is to resolve this uncertainty by comparing dipyridamole and aspirin with aspirin alone in patients with a transient ischaemic attack or a minor ischaemic stroke of presumed arterial origin.15, 16

Section snippets

Participants

Between July 1, 1997, and Dec 31, 2005, we did a randomised controlled trial. All patients who were referred to one of the participating hospitals within 6 months of a transient ischaemic attack (including transient monocular blindness) or minor ischaemic stroke (grade ≤3 on the modified Rankin scale17, 18) of presumed arterial origin were eligible for the trial. Exclusion criteria were a possible cardiac source of embolism (atrial fibrillation on ECG, valvular heart disease, or recent

Results

Figure 1 shows the trial profile. We randomly assigned and analysed 2739 patients; 1363 allocated to aspirin and dipyridamole and 1376 allocated to aspirin alone. Patients originated from 79 hospitals in 14 countries. Mean length of follow-up was 3·5 years (SD 2·0). In retrospect, we inappropriately enrolled 12 patients, of whom four were allocated to aspirin monotherapy; two had a brain tumour, one motor neuron disease, one multiple sclerosis, one syphilis, one peripheral nerve injury, one

Discussion

Our findings show that the combination therapy of aspirin and dipyridamole is more effective than aspirin alone in the prevention of new serious vascular events in patients after non-disabling cerebral ischaemia of presumed arterial origin. These results are consistent with those of ESPS 2,8 which also showed a benefit of the combination therapy over aspirin alone with respect to the occurrence of all vascular events.8 Although four earlier, but smaller studies did not show such a benefit, the

References (30)

  • DL Bhatt et al.

    Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events

    N Engl J Med

    (2006)
  • Efficacy and safety data

    J Neurol Sci

    (1997)
  • A Algra et al.

    Secondary prevention after cerebral ischaemia of presumed arterial origin: is aspirin still the touchstone?

    J Neurol Neurosurg Psychiatry

    (1999)
  • Persantine Aspirin Trial in cerebral ischemia, part II: endpoint results

    Stroke

    (1985)
  • MG Bousser et al.

    “AICLA” controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia

    Stroke

    (1983)
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