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Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin
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. The aim of the ESPRIT investigators was to resolve this uncertainty.
Methods
STUDY DESIGN
- Open, randomised, blinded treatment
- N=4,500; average follow-up 3.5 years
- Patients assigned to aspirin (30-325 mg daily) with (n=1,363) or without (n=1,376) dipyridamole (200 mg twice daily) within 6 months of a transient ischaemic attack or minor stroke of presumed arterial origin
- The primary outcome event was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication
- Split randomisation:
- AC vs. ASA+DP vs. ASA
- ASA+DP vs. ASA
- AC vs. ASA
ASA + DP = combination therapy of ASA and dipyridamole; ASA = aspirin; AC = oral anticoagulation.
Trial Profile
TIA = transient ischaemic attack. MI = myocardial infarction.
*10 patients lost to follow-up before first follow-up:
7 untraceable, 1 withdrawn consent, 1 inappropriately included, 1 emigrated.
†5 patients lost to follow-up before
first follow-up: 3 untraceable, 1 withdrawn consent, 1 inappropriately included.
‡Incomplete follow-up because of
close-out at date that all follow-up data were complete (four hospitals).
Results
FIRST OUTCOME EVENTS
During the trial, 389 patients had at least one primary outcome event: 173 assigned to combination therapy (12.8%) vs. 216 assigned to monotherapy (16%). The absolute risk reduction of 1.0% per year (95% CI 0.1-1.8) corresponds with a number of patients needed to treat with the combination regimen instead of with monotherapy to prevent death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication of 104 (95% CI 55-1006) per year. Ischaemic events were less frequent in the combination group than in the monotherapy group. The HR for death from all causes was 0.88. There was no indication that there were differential effects according to cerebral or cardiac outcome event.
Major bleeding complications arose in 35 patients allocated to ASA + DP vs. 53 patients allocated to ASA alone, whereas minor bleeding was reported in 171 patients allocated to the combination regimen vs. 168 patients allocated to ASA (risk ratio 1.03; 95% CI 0.84-1.25).
Patients on ASA + DP discontinued trial medication more often than those on ASA alone (470 vs. 184), mainly because of headache.
Occurrence of First Outcome Events According to Treatment
Time-to-Event Curves
The following figure shows the time-to-event curves for the primary outcome event and for ischaemic events. In the on-treatment analysis, the HR for the primary outcome event was 0.82.
Time-to-Event Curves for Primary Outcome Event and all Ischaemic Events
Subgroup Analysis
The following figure shows the results of the planned and post hoc defined subgroup analyses for the primary outcome event. The investigators noted no major differences between subgroups (smallest p value for interaction 0.18). Because all patients from non-Asian countries (with the exception of 3 patients from hospitals in Portugal, where extended-release dipyridamole is not available) used slow-release dipyridamole, the group did no additional analysis for this type of preparation.
Subgroup Analysis for Primary Outcome Event
Meta-analysis
A meta-analysis in patients with cerebral ischaemia of presumed arterial origin for the composite outcome of vascular death, nonfatal stroke, or non-fatal myocardial infarction was done. The meta-analysis is based on the data of 6 trials, including 3,888 patients allocated to ASA + DP and 3,907 to ASA alone; the total number of outcome events is 1,158.
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).
Discussion
The ESPRIT results, combined with the results of previous trials, provide sufficient evidence to prefer the combination regimen of ASA + DP over ASA alone as antithrombotic therapy after cerebral ischaemia of arterial origin.
The overall risk ratio for ASA + DP vs. ASA was 0.82 (95% CI 0.74-0.91) and the number needed to treat (NNT)/year was 104 (55-1006).
References:
ESPRIT Study Group. Lancet 2006; 367 (9523): 1665-1673.
Dipyridamole in stroke prevention - effect of dipyridamole on blood pressure
Background and purpose
Trial data suggest that dipyridamole, with or without aspirin, is more efficacious in the secondary prevention of stroke than of coronary events. This selective effect might be attributed to blood pressure lowering by dipyridamole. Therefore, we aimed to assess the effect on blood pressure in the setting of a randomised clinical trial in patients with cerebral ischaemia of presumed arterial origin.
Methods
In this study, 591 patients with recent cerebral ischaemia of arterial origin were randomly allocated to treatment with aspirin 30 to 325 mg/d or with the combination of aspirin and dipyridamole 400 mg/d in the European/Australian Stroke Prevention in Reversible Ischaemia Trial. In an on-treatment analysis, the change in blood pressure measurements from baseline to values after at least 6 months of follow up was assessed with linear regression analysis.
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Aspirin Plus
Diprydamole |
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Aspirin |
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Allocated, n |
273 |
318 |
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Male sex % |
69 |
65 |
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Age,* y |
62 ± 10 |
62 ± 9 |
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Time from qualifying event to randomization, %
<1 wk |
18 |
14 |
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1 wk-1 mo |
19 |
22 |
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1-6 mo |
63 |
65 |
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Medical history, %
Stroke |
14 |
10 |
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Angina pectoris |
18 |
11 |
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Myocardial infarction |
7 |
7 |
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Intermittent claudication |
6 |
4 |
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Diabetes mellitus |
20 |
20 |
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Vascular intervention |
5 |
8 |
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Current cigarette smoking |
37 |
38 |
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Hypertension |
57 |
55 |
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Blood pressure,* mm Hg
Systolic |
152 ± 24 |
154 ± 25 |
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Diastolic |
86 ± 12 |
87 ± 13 |
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| *Mean ± SD |
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Results
After an average period of 15 months, systolic blood pressure dropped 6.2 mm Hg in the aspirin plus dipyridamole group (n=273) and 6.2 mm Hg in the aspirin group (n=318), for a difference of 0.0 mm Hg (95% confidence interval, -3.8 to 3.7). Diastolic blood pressure dropped 3.6 mm Hg in the aspirin plus dipyridamole group compared with 2.7 mm Hg in the aspirin group, for a difference of 0.9 mm Hg (95% confidence interval, -1.0 to 2.9).
Flow Chart
Difference between baseline and follow-up for systolic and diastolic blood pressures (with 95% Cls)
Conclusions
It is unlikely that dipyridamole leads to a permanent reduction in blood pressure and that this would explain why this drug might prevent strokes rather than coronary events.
Disclaimer
- ESPRIT is an independent investigator initiated study
- ESPRIT describes the use in a composite endpoint which is not part of the Aggrenox ® (Asasantin ®) label
- The dose range of ASA in ESPRIT was 30-325mg/day; on average less than 75mg/day
- 83% of the patients received dipyridamole; 8% the fixed-dose combination ER-dipyridamole + ASA 200/25mg twice daily, marketed as Aggrenox ® and Asasantin ® retard
References:
De Schryver EL; ESPRIT Study Group. Stroke 2003; 34 (10): 2339-2342.
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