Philip Chang, MD
In the setting of the new acute ischemic stroke guidelines this year, one of the new recommendations is a Class IIa, Level of Evidence B-R recommendation that treatment for 21 days with dual antiplatelet therapy (aspirin and clopidogrel) beginning within 24 hours for patients presenting with minor stroke can be beneficial for early secondary prevention for a period up to 90 days from symptom onset. This recommendation was based solely off the CHANCE trial. In the original CHANCE cohort, they found that DAPT reduced stroke recurrence by about 30%.
Dual antiplatelet therapy had a positive effect on preventing recurrent ACS in the patients with unstable angina in the cardiac population based on the CURE and CREDO trials. Based on these trials, there was a great excitement for the use of dual antiplatelet agents for prevention of secondary stroke recurrence. However, in the subsequent years, SPS3, CHARISMA, and MATCH trials have shown that dual antiplatelet therapy (DAPT) did not carry a benefit in the long-term for secondary stroke prevention, and SPS3 found this particularly true in the lacunar stroke population. However, these trials did not include the same pathophysiologic disease corollary as the population CURE and CREDO studied. The pathophysiology of unstable angina has often been suggested to be unstable or ruptured plaque causing embolization and/or occlusion of the coronary arteries causing myocardial ischemia. It is a very common mechanism for heart disease. However, we know that this is NOT the mechanism of many strokes. The closest pathophysiologic corollary to this would be unstable plaque embolism due to large artery atherosclerosis. Therefore, a popular (but formally untested) hypothesis is to use dual antiplatelet therapy in patients with symptomatic large artery disease for a short period of time. Small studies such as CARESS and CLAIR suggest that DAPT may reduce microembolism of transcranial dopplers compared to aspirin, but were underpowered to detect a clinical difference. Other studies, such as SAMMPRIS or ARCH, suggest that DAPT has a lower than historically expected recurrent stroke rate, but was stopped early, and the DAPT was not compared to a single antiplatelet agent.
Then finally, CHANCE came out showing DAPT for 21 days after stroke reduced the 90-day stroke recurrence risk by about 30%. This was somewhat shocking given the failed trials of SPS3, CHARISMA and MATCH. Some experts believe that CHANCE may have had too broad of an inclusion criteria (any ischemic stroke with NIHSS≤3 or TIA with ABCD2≥4) to put such patients on DAPT. There is a hypothesis that running CHANCE in the Chinese population was what drove it to be positive, given the Chinese population has a higher rate of intracranial atherosclerosis. This CHANCE subgroup analysis may help us see what subgroups of patients may benefit from DAPT for early prevention of stroke recurrence.
This paper took about 20% of the original CHANCE cohort (~1000 patients) who received adequate MRI sequences and grouped them into infarction patterns on DWI: No acute infarct (NAI), Single acute infarct (SAI), and multiple acute infarct (MAI). They further subgrouped the SAI into lacunar and non-lacunar via TOAST definition. They found 3 distinct natural histories of recurrent stroke risk independent of aspirin or DAPT in the 3 groups, with NAI being lowest risk, and MAI being highest risk. DAPT did not change recurrent stroke risk in any group except in those with multiple acute infarctions on MRI. Further subgroup analysis found that those with MAI in addition to large artery atherosclerosis (by TOAST criteria) had significant reduction in recurrent stroke risk, while those with MAI without large artery atherosclerosis did not have reduction in recurrent stroke risk.
This goes to confirm my personal suspicion that DAPT is a great temporizing measure to prevent embolization of unstable plaque, but is unlikely to offer additional benefit to either single antiplatelet or anticoagulation in other stroke mechanisms (small vessel disease or cardioembolic). It will be very interesting to see the results of the international POINT trial.
