Comparing P2Y12 inhibitors in patients with stroke who are CYP2C19 LOF carriers
Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA
In the CHANCE-2 trial, treatment with ticagrelor and aspirin reduces recurrent stroke at 90 days compared to use of clopidogrel and aspirin in Chinese patients with minor ischemic stroke or TIA who are carriers of CYP2C19 LOF alleles. Risk of severe or moderate bleeding was similar between the groups, but risk of any bleeding was higher in the ticagrelor plus aspirin group compared to the clopidogrel plus aspirin group.
Introduction and methods
In the CHANCE and POINT trials, it was shown that dual antiplatelet therapy consisting of clopidogrel and aspirin reduces subsequent minor stroke or transient ischemic attack (TIA) compared to aspirin alone in patients with minor stroke or TIA [1,2]. Clopidogrel, however, is less effective in carriers of CYP2C19 loss-of-function (LOF) alleles. 25% Of white patients and 60% of Asian patients have CYP2C19 LOF alleles [3,4].
The PRINCE trial enrolled patients with minor stroke or TIA and showed that platelet reactivity was lower in patients treated with ticagrelor plus aspirin compared to patients treated with clopidogrel plus aspirin. This was particularly seen in CY2C19 LOF alleles carriers .
Therefore, in the CHANCE-2 trial was examined whether dual treatment with ticagrelor and aspirin was superior to clopidogrel and aspirin in reducing the risk of subsequent stroke in patients with minor ischemic stroke or high-risk TIA who were CYP2C19 LOF alleles carriers.
The CHANCE-2 trial was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial in China that enrolled 11,255 patients. Eligible patients had CYP2C19 LOF alleles determined by point-of-care testing, were ≥40 years, had either an acute nondisabling ischemic stroke with a NIHSS score of ≤3 or a high-risk TIA determined according to an ABCD score of ≥4. Within 24 hours after symptom onset, patients were randomly assigned in a 1:1 ratio to receive ticagrelor-aspirin or clopidogrel-aspirin.
Primary efficicacy outcome was new ischemic or hemorrhagic stroke at 90 days. Primary safety outcome was severe or moderate bleeding defined by the GUSTO criteria at 90 days.
- In the ticagrelor-aspirin group, 191 (6.0%) of patients had a primary efficacy outcome event and 243 (7.6%) of patients in the clopidogrel-aspirin group had an event (HR 0.77, 95%CI: 0.64-0.94, P=0.008).
- New stroke within 30 days occurred in 156 patients (4.9%) in the ticagrelor-aspirin group and in 205 (6.4%) patients in the clopidogrel-aspirin group (HR 0.75, 95%CI:0.61-0.93).
- The secondary outcomes vascular event and ischemic stroke were also reduced in the ticagrelor-aspirin group compared to the clopidogrel-aspirin group.
- A primary safety outcome of moderate or severe bleeding occurred in 9 patients (0.3%) in the ticagrelor-aspirin group and in 11 patients (0.3%) in the clopidogrel-aspirin group (HR 0.82, 95%CI:0.34-1.98).
- Intracranial hemorrhage occurred in 3 patient (0.1%) in the ticagrelor-aspirin group and in 6 patients (0.2%) in the clopidogrel-aspirin group.
- Fatal bleeding occurred in 3 patients (0.1%) in each group.
- Incidence of any bleeding was 5.3% in the ticagrelor-aspirin group and 2.5% in the clopidogrel-aspirin group.
In this randomized trial that enrolled Chinese patients with acute minor ischemic stroke or high-risk TIA who were carriers of the CYP2C19 LOF alleles, DAPT consisting of ticagrelor plus aspirin reduced the risk of subsequent stroke at 90 days compared to DAPT consisting of clopidogrel and aspirin. Risk of moderate or severe bleeding was similar between the two groups, but risk of any bleeding was higher in the ticagrelor plus aspirin group compared to the clopidogrel plus aspirin group.