PLATO: Ticagrelor found superior to clopidogrel in CV death, MI and stroke, despite CYP2C19, ABCB1 genotypes

European Society of Cardiology Congress 2010

Ticagrelor produced superior results vs. clopidogrel for prevention of CV death, MI and stroke, regardless of CYP2C19 and ABCB1 genotypes known to affect the response to clopidogrel, according to findings from a substudy of the PLATO trial.

This trial included patients (n=18,624) with acute coronary syndrome randomly assigned ticagrelor (Brilinta, AstraZeneca) 180-mg loading dose and 90-mg twice-daily maintenance dose vs. clopidogrel (Plavix, Sanofi-Aventis) 300- to 600-mg loading dose and 75-mg maintenance dose for 6 to 12 months.

Researchers obtained DNA samples from 10,285 patients (ticagrelor, n=5,137; clopidogrel, n=5,148) who were genotyped for the CYP2C19 wild type (*1), loss-of-function alleles *2, *3, *4, *5, *6, *7 and *8, plus the gain-of-function *17 and ABCB1 (MDR1/P-glycoprotein) C3435T single nucleotide polymorphism. They used Cox regression to evaluate treatment by genotype subgroup interactions accounting for ethnicity, gender, proton pump inhibitor use, aspirin dose, smoking and diabetes.

According to study data, the effect of ticagrelor vs. clopidogrel on the primary efficacy outcome of CV death, MI and stroke for CYP2C19 did not vary significantly by genotype grouping. However, the genotype group for clopidogrel carrying any gain-of-function allele had a numerically increased rate of total major bleeding compared with *1/*1. For ABCB1 genetic groups, ticagrelor event rates (8.1% to 9% per year) were consistently lower vs. clopidogrel in regard to low (9.9% per year), intermediate (9.3%) and high expression (11.5% per year) groups.

“Ticagrelor seems to be a more efficacious treatment for acute coronary syndrome than clopidogrel, irrespective of genotyping,” Lars Wallentin, MD, a professor of cardiology at Uppsala Clinical Research Center in Uppsala, Sweden, and researcher on the trial, said in the concluding remarks of his presentation. “Therefore, use of ticagrelor instead of clopidogrel seems to eliminate the need for presently recommended genetic testing before dual antiplatelet treatment.”

Wallentin L. Session 709007–709008.

Certain SNPs (CYP2C19) play a role for low response to clopidogrel by influencing pharmacokinetics (metabolism), pharmacodynamics (platelet function testing) as well as clinical outcome. Genetic disorders explain only a part of clopidogrel resistance. Based on current data and missing outcome results of prospective intervention trials, I think genetic profiling should not be recommended for routine use at present, but it will remain a very important and interesting tool for scientific studies. The use of more efficient antiplatelet agents, especially in patients with medium- to high-risk profile for thrombotic complications after stenting, has been shown to be effective and safe and makes genetic profiling, at least at the moment, less important.

– Kurt Huber, MD

Director, 3rd Medical Department, Cardiology and Emergency Medicine
Wilhelminen Hospital, Vienna

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