CHANCE Trial: Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack

A history of transient ischemic attack (TIA) or previous ischemic stroke places patients at a higher risk of future ischemic events. There are several components of secondary stroke management that focus on vascular risk factors like smoking, diabetes, and hypertension, among others. Additionally, antiplatelet therapy is a standard of care in secondary stroke prevention for patients without a history of atrial fibrillation or hypercoagulable state. However, there are many different medications that have antiplatelet properties. Which one is the best? Are two better than one? If so, for how long? Various combinations of anti-platelet agents are still the subject of extensive ongoing research.

The CHANCE (Clopidogrel in High-risk patients With Acute Non-disabling Cerebrovascular Events) trial studied the combination of clopidogrel with aspirin (existing standard of care at that time) compared to aspirin alone for secondary stroke prevention. It was a double-blind, placebo-controlled, multi-center trial in China that recruited 5170 patients into two treatment groups; (1) clopidogrel (300 mg loading dose followed by 75 mg daily for 90 days) + aspirin 75 mg daily for 21 days and (2) placebo + aspirin 75 mg daily for 90 days. Enrolled patients must have had a minor ischemic stroke (NIHSS ≤ 3) or high-risk TIA (ABCD2 score ≥4).

The CHANCE trial’s primary outcome was the rate of stroke at 90 days. The primary safety outcome was the rate of bleeding. The results demonstrated a lower rate of stroke at 90 days in the clopidogrel-aspirin treatment group (8.2%) compared to the aspirin-alone group (11.7%) with a hazard ratio of 0.68 (95% CI 0.57 to 0.81). Additionally, there were no statistically significant differences in the bleeding rate between the two groups.

Despite these positive results, the CHANCE trial’s generalizability was challenged, as it recruited a patient population only in China and tested a single dose of daily aspirin. Would similar results be seen in the United States where there is a more diverse patient population and a higher incidence of cardioembolic stroke than in China?

The POINT (Platelet-Oriented Inhibition in New TIA and minor ischemic stroke) trial helped to answer these questions by repeating a comparable study on an international scale. There were some slight differences in the study design. The clopidogrel-aspirin combination groups had variable aspirin doses in the range of 50 to 325 mg daily. They also used a higher loading dose of clopidogrel (600 mg) and continued the dual antiplatelet therapy (DAPT) group for 90 days. The POINT trial demonstrated a lower rate of ischemic stroke in the clopidogrel-aspirin treatment group (4.6%) compared to the aspirin-alone group (6.3%) with a hazard ratio of 0.72 (95% CI 0.56 to 0.92). However, unlike the CHANCE trail, it demonstrated an increased rate of major hemorrhage in the clopidogrel-aspirin group (0.9%) compared to the aspirin-only group (0.4%).

Subsequent follow-up of the CHANCE trial participants after 1 year revealed a retained advantage in those who received the initial clopidogrel-aspirin dual antiplatelet therapy (10.6%) compared to the aspirin-only group (14%) with a hazard ratio of 0.78 (95% CI 0.65-0.93) and no statistically significant difference in hemorrhage risk.

Since 2018 when the POINT trial was published there have been other studies evaluating dual antiplatelet therapy. Also, being that CYP2C19 loss of function mutations lead to poor activation of clopidogrel (a prodrug), there has been growing interest in using ticagrelor, a drug that does not require activation, in combination with aspirin for secondary stroke prevention. The THALES and CHANCE-2 trials, for example, further evaluated the efficacy of DAPT with aspirin-ticagrelor.

Nonetheless, the “POINT” of this newsletter was to showcase that dual antiplatelet therapy decreases the “CHANCE” of a stroke in certain patient populations within 90 days.