According to the results of a large controlled trial (PRoFESS), early initiation of treatment after stroke with clopidogrel or low-dose plus aspirin plus dipyridamole both give similar rates of recurrent stroke and other major cardiovascular outcomes, although the combination therapy may be associated with a slightly higher rate of serious bleeding events.
Aspirin (low-dose), clopidogrel, and aspirin plus dipyridamole have all been shown to reduce the risk of recurrent stroke. Aspirin plus dipyridamole and clopidogrel are both superior to aspirin alone (by around 20-23% and 8% respectively), however there has been no direct comparison between them. This study aimed to compare the relative efficacy of the two approaches. It also had another treatment arm that compared telmisartan with placebo (reported separately).
Participants were aged 55 and over, had had a stroke within 90 days of randomisation, and were stable. In this arm of the study, they were randomised to treatment with the fixed combination of low-dose aspirin (25 mg) and extended-release dipyridamole (200 mg) given twice daily as compared with clopidogrel (75 mg) given once daily. Participants were evaluated on hospital discharge or after 1 week, then at 1, 3 and 6 months, then at 6 months intervals. Planned study duration was 4 years, and the primary outcome was recurrent stroke. Secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes.
Two major protocol amendments took place: the initial comparison was between aspirin/dipyridamole and aspirin plus clopidogrel, however other trial results suggested an unacceptable rate of bleeding with aspirin plus clopidogrel so this was amended to clopidogrel only. Also, recruitment criteria were amended to allow younger patients (age 50 to 54) and a longer gap after stroke (to 120 days), providing at least two other risk factors were present.
The planned initial sample size was 15,500: because stroke rates were lower than expected, this was increased to over 20,000 and the study was prolonged by six months. A total of 20,332 patients was randomised, of whom 10,181 received aspirin plus dipyridamole and 10,151 clopidogrel. Median interval from stroke to treatment initiation was 15 days, and mean duration of follow-up was 2.5 years.
Over this time, 1,814 patients had confirmed recurrent stroke, 916 (9.0%) in the aspirin plus dipyridamole group and 898 (8.8%) in the clopidogrel group (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). The composite secondary outcome occurred in 1,333 patients in each group (13.1% each, HR for aspirin/dipyridamole, 0.99; 95% CI, 0.92 to 1.07). There were numerically more major bleeding events in the aspirin / dipyridamole group, although this was of borderline statistical significance (4.1% vs. 3.6%; HR, 1.15; 95% CI, 1.00 to 1.32). Net risk of recurrent stroke or major bleeding was similar for the two groups (11.7% vs. 11.4%; HR, 1.03; 95% CI, 0.95 to 1.11).
The authors conclude that their results show neither treatment to be superior for prevention of recurrent stroke. There was also no clinically significant difference between the two treatments for the composite secondary outcome, and both primary and secondary outcomes were consistent across subgroups with different baseline risk factors. While there were numerically more major bleeding events in the combination group, the net risk of recurrent stroke or bleeding was similar in the two groups.
New Engl J Med, published early online 27 Aug 2008; doi: 10.1056/NEJMoa0805002 (link to abstract)
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