TRITON-TIMI 38 study evaluates response rates in patients with common genetic variant in ABCB1 gene

Eli Lilly and CompanyMar 17 2010

A new analysis of the TRITON-TIMI 38 study evaluated response rates in patients with a common genetic variant in the ABCB1 gene. Patients enrolled in the TRITON-TIMI 38 study were treated with dual antiplatelet therapy with either Plavix® (clopidogrel) plus aspirin or Effient® (prasugrel) plus aspirin and managed with percutaneous coronary intervention (PCI) following an acute coronary syndrome (ACS) event. The results of this retrospective genetic sub-study were presented today at the American College of Cardiology annual meeting.

The ABCB1 gene contains the genetic code for a protein (P-glycoprotein) that plays an important role in how the body absorbs many medications, including antiplatelet drugs. Genetic variants in ABCB1 may reduce response to antiplatelet therapy.

In this sub-study, the TRITON-TIMI 38 investigators analyzed clinical outcomes among 2,943 patients tested for the "C3435T" variant in the ABCB1 gene. More than one out of four (27 percent) patients in the analysis were found to have two C3435T variants in their chromosomes.(1) Clopidogrel-treated patients who had two C3435T variants>

In contrast, Effient-treated patients with two C3435T variants>

"These data are important because they suggest that multiple genetic variations may impact a patient's response to antiplatelet medications, and that these effects appear to differ from medication to medication," said Jessica Mega, M.D., M.P.H., associate physician at Brigham and Women's Hospital and investigator at the TIMI Study Group. "Understanding the full scope of these genetic variations may help determine which drug to prescribe as part of the dual antiplatelet therapy a patient receives after an angioplasty with a stent."

In this subanalysis, there was no association between C3435T genotype and bleeding in either treatment group. In the overall TRITON-TIMI study population, Effient produced higher rates of clinically significant bleeding than clopidogrel.

Study Methodology

TRITON-TIMI 38 was a Phase III, randomized, double-blind, head-to-head clinical trial comparing the effects of Effient versus clopidogrel in patients with ACS who were managed with PCI, a procedure to open blockages in heart arteries, including the use of coronary stenting. The study enrolled 13,608 patients at 707 trial sites in 30 countries.

The primary endpoint of the study was the combined incidence of cardiovascular death, non-fatal heart attack or non-fatal stroke during a median period of at least 12 months following PCI. Patients were randomly assigned to one of two treatment groups and given a loading dose of either Effient 60 mg or the FDA-approved loading dose of clopidogrel 300 mg, followed by a daily maintenance dose of either Effient 10 mg or clopidogrel 75 mg. All patients also received a daily dose of aspirin (75 mg to 325 mg).

This analysis was designed to examine whether specific genetic variations could affect patient response to antiplatelet therapy. The pharmacogenetic analyses examined DNA samples from 2,943 patients from the TRITON-TIMI 38 clinical trial.

The genetic subanalysis was not powered to make efficacy comparisons between clopidogrel and prasugrel based on genetic variations.