A look at Tx timing. Since these initial attempts failed to show a long-term benefit with CLO-ASA, subsequent trials attempted to establish an appropriate balance between the optimal time to initiate CLO-ASA and the optimal duration of therapy. The FASTER (Fast Assessment of Stroke and Transient ischaemic attack to prevent Early Recurrence) trial was a small pilot study of 392 patients randomized to CLO-ASA or aspirin within 24 hours of stroke or TIA onset and continued for only 3 months.15 While this trial did not find a significant reduction in ischemic or hemorrhagic stroke with combination therapy, there was a large numerical difference in event rates between the 2 groups (7.1% CLO-ASA vs 10.8% aspirin).15 An underpowered sample size (due to difficulty recruiting participants) is likely responsible for the lack of statistical significance.15 Despite the trial’s failure to show a benefit with acute use of CLO-ASA, it suggested a possible benefit that led to further investigation in the CHANCE (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events)5 and POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) 4 trials.
The CHANCE trial conducted in China included more than 5000 patients with acute minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤ 3) or high-risk TIA (ABCD2 [a scale that assesses the risk of stroke on the basis of age, blood pressure, clinical features, duration of TIA, and presence or absence of diabetes] score ≥ 4).5 Similar to FASTER, patients were randomized within 24 hours of symptom onset to CLO-ASA or aspirin. However, CHANCE utilized combination therapy for only 21 days, after which the patients were continued on clopidogrel monotherapy for up to 90 days; the aspirin monotherapy group continued aspirin for 90 days.
After 90 days, patients initially using combination therapy had significantly lower rates of ischemic or hemorrhagic stroke vs those assigned to aspirin monotherapy. This result was driven heavily by the reduction in ischemic stroke (7.9% CLO-ASA vs 11.4% aspirin; P < .001). Additionally, there was no significant difference in moderate or severe bleeding events between the 2 groups.5 Efficacy and safety results were similar among a subgroup of patients who were randomized to treatment within 12 hours rather than 24 hours from symptom onset.16 The CHANCE trial was the first major study to demonstrate a clinical benefit of CLO-ASA to prevent recurrent stroke. Accordingly, the 2018 AHA/ASA guidelines included a new recommendation regarding secondary prevention for the use of CLO-ASA initiated within 24 hours and continued for 21 days following a minor stroke or TIA.11
A drawback of the CHANCE trial was its narrow patient population of only Chinese patients, which may limit applicability in clinical practice. There are known genetic variations in cytochrome P450 2C19 (CYP2C19) that may affect clopidogrel metabolism. CYP2C19 is responsible for the conversion of clopidogrel into its activated form in vivo. Carriers of a CYP2C19 loss-of-function allele may have reduced clopidogrel activation and subsequent reduced antiplatelet activity. Such loss-of-function alleles are more common in Asian populations vs non-Asian populations.17
A substudy of CHANCE found that CLO-ASA’s efficacy benefit was preserved in noncarrier patients; however, patients with the CYP2C19 loss-of-function allele did not benefit from combination therapy.18 Interestingly, these genetic differences did not affect bleeding outcomes. Given that approximately 60% of patients in the CHANCE substudy were loss-of-function allele carriers and that the overall study results still showed benefit with combination therapy, application of CHANCE’s findings to broader populations may not be a concern after all.18
Continue to: In efforts to gain insight...