Ticagrelor superior to clopidogrel in individuals predicted to be clopidogrel responders

A new study has assessed the effect of genotype on platelet function in patients who received ticagrelor or clopidogrel in two multicenter, randomized, double-blind, double-dummy, phase II clinical trials—ONSET/OFFSET and RESPOND. Ticagrelor was found to be a more-efficacious antiplatelet agent than clopidogrel, even in those individuals predicted to be clopidgrel responders on the basis of genotype.

Clopidogrel is often used in combination with aspirin in the treatment of patients with acute coronary syndromes. However, the efficacy of clopidogrel varies widely and response to this drug is known to be influenced by single-nucleotide polymorphisms of the cytochrome P450 isoenzymes, which convert clopidogrel to its active metabolite, and of a transmembrane transporter P-glycoprotein gene, ABCB1. Alternative P2Y₁₂-receptor inhibitors have, therefore, been sought.

Ticagrelor is a new-generation antiplatelet agent that directly, reversibly, and noncompetitively antagonizes the P2Y₁₂ receptor. Although metabolized by a cytochrome P450 isoenzyme, the metabolite and free drug inhibit P2Y₁₂ with the same efficacy. Ticagrelor has previously been demonstrated to significantly reduce clinical outcomes and to better inhibit platelet function in patients with acute coronary syndromes than clopidogrel.

In this analysis of genetic data from ONSET/OFFSET and RESPOND, ABCB1 genotype had no effect on platelet function, even in the clopidogrel treatment group. This result is somewhat at odds with previous data demonstrating an influence of the ABCB1 genotype on clopidogrel response.

As expected, among ticagrelor-treated individuals, the patient's CYP2C19 genotype did not impact on platelet function; however, in those treated with clopidogrel, the patient's CYP2C19 genotype was shown to influence platelet function and this influence was greater during maintenance therapy than 8 h after the loading dose.

Study participants were assigned a 'metabolizer status' on the basis of their genotype. Individuals with CYP2C19 ^*17/^*17 or ^*1/^*17 genotypes (n = 55) were classified as 'ultrarapid metabolizers'. Those with CYP2C19 ^*1/^*1 genotype (n = 59) were assigned an 'extensive metabolizer' status and those with CYP2C19 ^*1/^*2–^*8 or ^*2–^*8/^*17 genotypes (n = 55) were labelled as 'intermediate metabolizers'. 'Poor metabolizers' were those individuals with a CYP2C19 ^*2–^*8/^*2–^*8 genotype (n = 5). Among all metabolizer statuses, except in the poor metabolizers (a small group that had wide confidence intervals), ticagrelor was associated with better inhibition of platelet function than clopidogrel.

“Taken together,” comments Dr Paul Gurbel, senior author of this new report, “the results of [this analysis] and the PLATO genetics study strongly suggest that ticagrelor is the optimal P2Y₁₂ inhibitor for patients with acute coronary syndromes, irrespective of ^*2 carrier.” He goes on to state that the findings of this analysis of ONSET/OFFSET and RESPOND patients are “strongly suggestive that determination of genotype or platelet function prior to ticagrelor therapy is not needed.”