Taking a CHANCE on Clopidogrel Plus Aspirin to Prevent Stroke Recurrence

After a patient has a transient ischemic attack (TIA) or minor stroke, the risk of having another is alarmingly high — 10% to 20% will have another stroke within 3 months and most events occur within 2 days.^1-3  Both the American Heart Association (AHA) and American College of Chest Physicians (ACCP) guidelines recommend aspirin 160-325mg within the first 48 hours of symptom onset.^4-5  The CHANCE (Clopidogrel in High risk patients with Acute Non-disabling Cerebrovascular Events) trial investigators once again question whether these patients should also receive clopidogrel to reduce the risk of recurrent stroke.

For the past decade, most clinicians have prudently avoided the combination of aspirin and clopidogrel for the secondary prevention of stroke due to an increased risk of bleeding and a lack of benefit. The MATCH (Management of AtheroThrombosis with Clopidogrel in High risk patients) trial found that in patients who received both clopidogrel and aspirin for 18 months after TIA or minor stroke, rates of life threatening (2.6% vs. 1.3%, p<0.0001, NNH 77) and major bleeding (1.9% vs. 0.6%, p < 0.0001, NNH 77) were higher than in patients who received aspirin alone. Moreover, clopidogrel plus aspirin was no better than aspirin alone; the MATCH trial found no significant difference in the rate of major vascular events.⁶ More recent data, however, suggests that short-term use of combination therapy in this patient population may have a favorable benefit-risk ratio.  In 2013, the initial report of the CHANCE trial investigators reported that clopidogrel plus aspirin given immediately following a minor stroke or TIA significantly reduced recurrent events at 90 days.⁷  The latest publication by the CHANCE investigators includes 1-year follow-up data.⁸

The CHANCE trial was conducted as a randomized, double blind, placebo controlled, double dummy trial at 114 centers in China.  Funding was provided by the Ministry of Science and Technology of the People’s Republic of China.  Included patients experienced an acute minor stroke or TIA and were able to start the study drug within 24 hours of symptom onset.  Acute Minor Stroke was defined as a National Institute of Health Stroke Score (NIHSS) score ≤ 3.  Transient ischemic attack was defined as focal brain ischemia with resolution of symptoms within 24 hours plus a moderate to high risk of stroke recurrence, defined as an ABCD² (age, blood pressure, clinical features, duration of TIA, and presence of diabetes) score ≥ 4.  The exclusion criteria were lengthy and eliminated patients with a history of hemorrhage, other non-ischemic brain diseases, and any indication for anticoagulation.⁹

Out of 41,561 patients screened for inclusion, only 5,170 patients were randomized due to delayed presentation, moderate or severe stroke, intracranial hemorrhage, low risk TIA defined as an ABCD² < 4, or contraindications to clopidogrel or aspirin.  All patients received one dose of open-label aspirin, 75 to 300 mg at the treating physician’s discretion, on day 1.  Patients in the intervention group also received a loading dose of clopidogrel 300mg on day 1 followed by clopidogrel 75mg daily for 90 days plus aspirin 75 mg daily until day 21.  They received placebo aspirin days 22 through 90.  The control group received aspirin 75mg alone for 90 days plus placebo clopidogrel (loading and daily dose).  After the 90-day treatment period, patients received antiplatelet therapy at the discretion of their treating physicians with either aspirin alone, clopidogrel alone, or aspirin plus clopidogrel.  Baseline characteristics were similar in the two groups (See Table 1).^7-9

     Table 1. Baseline demographics^*7-8

^*All values NOT statistically significantly different

New ischemic or hemorrhagic stroke was the primary endpoint at 90 days⁷ and after 1-year of follow-up.⁸  Secondary endpoints included a new ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death.  For safety, patients were evaluated for mild, moderate, or severe bleeding per the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) criteria.  Statistical analyses were conducted as intention to treat using cox-proportional hazards.^7-9

After 1 year, 197 patients were lost to follow–up (4.3% aspirin alone vs. 3.3% clopidogrel and aspirin) but baseline characteristics remained about the same.  There was no significant difference detected between the proportion of patients who continued clopidogrel plus aspirin, clopidogrel alone, or aspirin alone beyond 90 days (1.4%, 4.8%, 74.9% vs. 1.4%, 5.8%, 74.5%, p=0.55).  Results at 1 year remained consistent with those at 90 days (See Table 2).  Significantly fewer patients had a subsequent stroke in the aspirin plus clopidogrel group as compared to the group who received aspirin alone at both 90 days (8.2% vs. 11.7%, p<0.001, NNT 29) and 1 year (10.6% vs. 14.0%, p=0.006, NNT 29).  During the 3 to 12 month period 2.7% of patients in the aspirin and clopidogrel group and 2.6% of patients in the aspirin alone group had a stroke, which suggests there was not a rebound effect after clopidogrel discontinuation.  Moreover, there was no difference between groups in terms of bleeding at 90 days (2.3% vs. 1.6%, p=0.09) or over the 1 year follow-up study (2.5% vs. 1.8%, p=0.09).^7-8

Table 2. CHANCE Trial Results^7-8

*NS = not significant; in the original CHANCE trial, moderate and severe bleeding were reported separately for treatment and control groups. For moderate bleeding, the rates were 0.2% for aspirin and 0.1% for aspirin-clopidogrel (p=0.68). For severe, the rates were 0.2% and 0.2%, respectively (p=0.94).

Although the early benefit of aspirin and clopidogrel combination therapy persisted after 1-year of follow-up, the external validity of the CHANCE study and its application to North America or other regions of the world must be questioned.  Patients who enrolled in the CHANCE study had a lower average BMI of 25 kg/m² and fewer comorbidities such as diabetes and dyslipidemia when compared to the typical patient we see in the United States.  The average American male has a BMI of 29 kg/m².¹⁰  Moreover, the rate of death due to stroke is five times in higher in China than in the U.S. and the incidence rates of the various stroke subtypes in China are different from the incidence rates seen in developed nations.  Lastly, clopidogrel metabolism is influenced by CYP2C19 polymorphism.  In China, there is a relatively high prevalence of the polymorphisms associated with reduced clopidogrel activation.⁷  Thus, the bleeding risk in the CHANCE participants may be lower than what was observed in the multi-country MATCH trial cohort. Patients in the CHANCE study likely had a higher risk for recurrent ischemia and a lower risk for bleeding which may account for the favorable results.

Another possible explanation may be the difference in the treatment regimens used in these two studies.  While both studies compared clopidogrel plus aspirin to aspirin therapy alone, patients in the CHANCE trial received dual antiplatelet therapy within 24 hours of symptom onset and it was continued for a relatively short period of time (only 21 days).  Patients in the MATCH trial did not receive treatment until a median of 15 days after their stroke and it was continued for the duration of the study (18 months).⁶

While the CHANCE data suggests that dual antiplatelet therapy following a minor stroke or TIA may be beneficial, many clinicians in North America will be (rightfully) hesitant to use clopidogrel plus aspirin.  The POINT (Platelet-Oriented Inhibition in New TIA and minor ischemic stroke) trial is a randomized, double blind, placebo controlled trial currently underway in the United States.  Similar to the CHANCE trial, the investigators are enrolling patients with a recent TIA or minor ischemic event who are taking aspirin 50-325mg daily.  Patients are then randomized to either clopidogrel (600 mg loading dose followed by 75 mg daily) or placebo.¹¹

Although the CHANCE trial results are very promising, we are reluctant to recommend dual antiplatelet therapy given the increased rate of major bleeding observed in the MATCH trial.  Until the results of the POINT trial are released, we believe using the combination of clopidogrel and aspirin should be avoided in most patients.  Will you wait for the results of the POINT trial or take a CHANCE on short-term clopidogrel plus aspirin use to prevent stroke recurrence?