New Data Suggests Results of PLATO Genetic Sub-Study Outcomes for Ticagrelor (Brilinta®) Not Driven by Poor Metabolizers of Clopidogrel
CHICAGO, Ill. — March 25, 2012 — AstraZeneca announced results from a sub-analysis of the PLATO genetic sub-study that evaluated the impact of poor metabolizers of clopidogrel. Data suggests results were consistent with the overall outcome of the PLATO study, with ticagrelor (Brilinta®) compared to clopidogrel, even after poor clopidogrel metabolizers were excluded. Results of this sub-analysis were presented at the American College of Cardiology Scientific Sessions (ACC), in Chicago, Ill.
A poor metabolizer to clopidogrel is defined as a patient with two loss-of-function (LOF) CYP2C19 alleles, one of the main genetic factors affecting the conversion of clopidogrel to its active form. In this sub-analysis, 10,285 DNA samples from patients in the PLATO trial, (which randomized 18,624 ACS patients to ticagrelor or clopidogrel for 6 – 12 months), underwent CYP2C19 genotyping for wildtype (*1); LOF alleles *2, *3, *4, *5, *6, *7, & *8; and gain of function allele *17. Patients with any combination of two LOF alleles were denoted as a poor metabolizer. Analysis of PLATO primary efficacy and safety outcomes were conducted after excluding poor metabolizers from both treatment groups.
Below are the results from the sub-analysis:
• After removal of poor metabolizers (121 of 5,137 ticagrelor patients; 125 of 5,148 clopidogrel patients), the remaining non-poor metabolizers cohort (n=10,039) showed a reduction in the primary endpoint consistent with overall results of the PLATO study with ticagrelor compared to clopidogrel at 12 months (8.8% vs 10.4 %; hazard ratio [HR] 0.85, 95% confidence interval 0.74-0.96, P=0.01)
• Rates of total major bleeding at 12 months did not differ between treatment groups, 10.7%; non-CABG major bleeding trended higher with ticagrelor (4.0%) than with clopidogrel (3.3%)
• Ticagrelor similarly reduced the primary endpoint in the poor metabolizers group at 12 months (8.8% vs 9.7%, HR=0.87), although there were only 22 events in this very small subgroup of patients
These data suggest that the effects of ticagrelor compared to clopidogrel on thrombotic events and bleeding were not affected by CYP2C19 genotype, and data suggests results were consistent with the overall outcomes of the PLATO study, regardless of the 2C19 clopidogrel genetic metabolizer status in patients with ACS.
Ticagrelor is indicated to reduce the rate of thrombotic cardiovascular events in patients with ACS (unstable angina [UA] non–ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). Ticagrelor has been shown to reduce the rate of a combined end point of CV death, MI, or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with an artery-opening procedure known as percutaneous coronary intervention (PCI), Ticagrelor reduces the rate of stent thrombosis.
Ticagrelor has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily.