OBJECTIVE: To assess the effectiveness and safety of dual agent antiplatelet therapy combining clopidogrel and aspirin to prevent recurrent thrombotic and bleeding events compared with aspirin alone in patients with acute minor ischaemic stroke or transient ischaemic attack (TIA).
DESIGN: Systematic review and meta-analysis of randomised, placebo controlled trials.
DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Library, ClinicalTrials.gov, WHO website, PsycINFO, and grey literature up to 4 July 2018.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES AND METHODS: Two reviewers independently screened potentially eligible studies according to predefined selection criteria and assessed the risk of bias using a modified version of the Cochrane risk of bias tool. A third team member reviewed all final decisions, and the team resolved disagreements through discussion. When reports omitted data that were considered important, clarification and additional information was sought from the authors. The analysis was conducted in RevMan 5.3 and MAGICapp based on GRADE methodology.
RESULTS: Three eligible trials involving 10 447 participants were identified. Compared with aspirin alone, dual antiplatelet therapy with clopidogrel and aspirin that was started within 24 hours of symptom onset reduced the risk of non-fatal recurrent stroke (relative risk 0.70, 95% confidence interval 0.61 to 0.80, I2=0%, absolute risk reduction 1.9%, high quality evidence), without apparent impact on all cause mortality (1.27, 0.73 to 2.23, I2=0%, moderate quality evidence) but with a likely increase in moderate or severe extracranial bleeding (1.71, 0.92 to 3.20, I2=32%, absolute risk increase 0.2%, moderate quality evidence). Most stroke events, and the separation in incidence curves between dual and single therapy arms, occurred within 10 days of randomisation; any benefit after 21 days is extremely unlikely.
CONCLUSIONS: Dual antiplatelet therapy with clopidogrel and aspirin given within 24 hours after high risk TIA or minor ischaemic stroke reduces subsequent stroke by about 20 in 1000 population, with a possible increase in moderate to severe bleeding of 2 per 1000 population. Discontinuation of dual antiplatelet therapy within 21 days, and possibly as early as 10 days, of initiation is likely to maximise benefit and minimise harms.
This high-quality systematic review assessed the impact of adding clopidogrel to aspirin in patients with minor stroke or TIA. They found that the addition of clopidogrel to aspirin mildly decreases stroke risk and mildly increases bleeding risk, with no effect on mortality - none of which is a surprise. The new information in here, at least to me, was the benefit appears to occur all in the first 10-21 days, and the authors recommend that discontinuation of clopidogrel after that time-point likely maximizes benefit and minimizes harm.
My colleagues and I had a lively discussion about this article because it could change our practice behavior for a relatively common and important presentation. The major criticism I heard that felt valid to me involved the heterogeneity of the studies. The populations were different, treatment durations different, and stroke sub-types were different. If dual antiplatelet therapy is helpful after stroke or TIA, it`s still not clear how after a FEW days we can prescribe to maximize benefit while minimizing risk for bleeding. 10 vs 21 days.
Two papers (see also PMID 30563885) of a BMJ rapid recommendation for dual antiplatelet therapy (clopidogrel + aspirin) results in a small absolute decrease in second CVA after a TIA/small stroke than aspirin alone, with a very small increase in extra-cranial bleeding. A pity this wasn`t generated into a patient decision aid at the same time.
The meta-analysis suggests a small benefit of dual antiplatelet therapy initiated within 24 hours of an event for 10-21 days to maximize the benefit of reducing recurrent non-fatal stroke and minimizing the risk for moderate-to-severe extracranial bleeding. There was no change in overall mortality. The quantified estimate of benefit and cost should help general internists interact with their patients around a decision to start dual antiplatelet therapy immediately after a TIA or stroke.
It is bold to say we should treat within 10-21 days of dual antiplatelet therapy after TIA. We`ll need more data.
As a hematologist, we are not often asked to comment on the initiation of dual antiplatelet therapy after stroke or high-risk TIA, but we are often asked to weigh in on bleeding risk. The most interesting aspect of this paper is the fact that there is a significant reduction in subsequent stroke (20 per 1000) with only modest increase in bleeding (2 per 1000) and that stopping the clopidogrel within 10-21 days maintained benefit while minimizing risk.
Interesting and important article. Helps bring literature together on a confusing topic.
As a "thrombosis expert" who does not follow the neurology literature closely, I found this meta-analysis to be both practice-changing and newsworthy (I had not previously been aware of the hypothesis that dual AP therapy immediately after ischemic stroke may confer net clinical benefit compared with ASA alone).
This systematic review does use a newer technique to estimate the risks. Overall, most of the data are in the Chance and Point trials. As noted in UpToDate, combined therapy may be beneficial in high-risk TIA early on. That is the same conclusion as this review, so I don't think this adds much to the current knowledge.
This and the other associated paper are based on 2 (FASTER was too small) large randomized trials. A meta-analysis is not needed, or maybe not necessarily appropriate as the 2 large trials had different patient populations.