The New England journal of medicine 2018-07-19
Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.
Abstract
Background
Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population.
Methods
In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days.
Results
A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02).
Conclusions
In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).
Related Questions
Do you generally switch aspirin to another antiplatelet agent if a patient has a non-embolic ischemic stroke and isn't a candidate for DAPT?
I do tend to switch, mainly to impress the patient that I am trying hard to prevent another stroke, and not because there is clear evidence of one antiplatelet over another. Clopidogrel or ticagrelor would be candidates, or I might add cilostazol to aspirin, as this combination has little bleeding r...
When do you consider starting short-term DAPT in patients who present more than 24 hours after the onset of a high-risk TIA or minor stroke syndrome?
The literature states that DAPT is most effective when started within the first 24 hours after such an event, but is still effective as far as 72 hours later. So if the patient presents more than 24 hours later, but not later than 72 hours, I would still start it then but would want a CT scan first.
Would you consider dual antiplatelet therapy for stroke prevention for ICAD in patients with a history of SAH?
It depends on the strength of the indication for DAPT and the cause of SAH. It is important to keep things in perspective: the absolute risk reduction from DAPT for secondary stroke prevention in the POINT, CHANCE, and THALES trials was small (on the order of 1-3% absolute risk reduction) for minor ...
Does the overall conclusion of the CHANCE-2 trial make ticagrelor + ASA a worthwhile transition given the data showing cumulative hazard of stroke diverged during the first week and was subsequently similar, which suggests the benefit of ticagrelor over clopidogrel is seen predominantly soon after stroke?
Given the fact that clopidogrel costs 11 cents a day and ticagrelor costs almost $8/day and the fact that most patients will not be tested for slow CYP2c19 metabolizer (or have the results back in a timely fashion), it seems that the combination of ASA plus clopidogrel is the best option from a publ...
Would you generalize the data from the CHANCE-2 trial to a broader clinic population given that the study was specific to Han Chinese patients?
I believe the results of CHANCE-2 (Wang et al., PMID 34708996) are generalizable to non-Chinese populations. CHANCE (Wang et al., PMID 23803136), performed in China, and POINT (Johnston et al., PMID 29766750), performed worldwide but excluding China, produced strikingly similar results in dual antip...
Would you recommend short-term dual antiplatelet therapy for a patient who received tPA, and is otherwise eligible for dual antiplatelet therapy per POINT or SAMMPRIS trial?
I would agree. tPA is not a contraindication to the later prescription of dual antiplatelet therapy. I do not see a definite answer to the question of 21 days versus 90 days, the CHANCE trial (Wang et al., PMID 23803136) supports 21 days and the POINT trial (Johnston et al., PMID 29766750) 90 days. ...
What duration of dual antiplatelet therapy do you use for secondary prevention of ischemic stroke due to intracranial atherosclerotic disease?
It is a fair question that we don't have a solid evidence-based answer for. I agree that the SAMMPRIS trial was driven by events within the first 30 days, although this was primarily driven by procedure-related events in the stented group. We do know that intracranial athero (ICAS) risk of stroke re...