PARSIPPANY, New Jersey and INDIANAPOLIS, March 15, 2010 /PRNewswire/ --
-- More than one out of four patients in analysis had variant in ABCB1 gene
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 clopidogrel plus aspirin or prasugrel (Efient(R)) 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 (n=414) had a 66 percent increased risk of experiencing the primary composite endpoint of cardiovascular death, heart attack or stroke compared to clopidogrel-treated patients with one or no variants (12.9 percent vs. 8.2 percent, HR=1.66; p = 0.033). The overall ABCB1 genetic analysis, which included clopidogrel patients with two, one or no C3435T variants, also showed a significant increase in the primary endpoint for patients with two variants (p=0.0064).
In contrast, prasugrel-treated patients with two C3435T variants (n=390) did not have a statistically significant increased risk of experiencing the primary composite endpoint compared to prasugrel-treated patients without the variant (11 percent vs. 9.7 percent, HR=1.12; p = 0.64), and the differences in the overall ABCB1 analysis were likewise not significant (p=0.40).
"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, prasugrel produced higher rates of clinically significant bleeding than Plavix.
Study Methodology
TRITON-TIMI 38 was a Phase III, randomized, double-blind, head-to-head clinical trial comparing the effects of prasugrel 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 prasugrel 60 mg or the FDA-approved loading dose of clopidogrel 300 mg, followed by a daily maintenance dose of either prasugrel 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.
About Prasugrel
Daiichi Sankyo Company, Limited, and Eli Lilly and Company co-developed prasugrel, an oral antiplatelet agent discovered by Daiichi Sankyo and its Japanese research partner, Ube Industries, Ltd. Prasugrel helps keep blood platelets from clumping together and developing a blockage in an artery. The European Commission granted marketing authorization for prasugrel for the prevention of atherothrombotic events in patients with ACS undergoing PCI.
About Acute Coronary Syndromes
Acute coronary syndrome includes heart attacks and unstable angina (chest pain). Coronary heart disease, which can result in ACS, is the single most common cause of death in the European Union, accounting for more than 741,000 deaths in the EU each year.(2) In addition, ACS affects nearly 1.5 million people in the United States annually.(3) Heart attack is a major manifestation of coronary heart disease, which occurs when the arteries become narrowed or clogged by cholesterol and fat deposits. In some cases the plaque can rupture, resulting in a blood clot, which may partially or totally block the blood supply to portions of the heart, resulting in ACS.(4) Many ACS patients undergo PCI to re-open the artery, which usually includes a stent placement.
Important Safety Information about Prasugrel
In TRITON, the risk of non-coronary artery bypass graft (non-CABG) major bleeding, including fatal bleeding, was higher with prasugrel (2.2 percent incidence) compared with clopidogrel (1.7 percent incidence). Compared with the overall study population, a higher risk of serious bleeding among prasugrel patients was most evident in three distinct patient populations that are readily identifiable: patients who weighed less than 60 kg (132 lbs), patients who were 75 years of age or older and patients who have had a prior transient ischemic attack (TIA) or stroke. A 5 mg maintenance dose is recommended for patients who weigh less than 60 kg. Prasugrel is generally not recommended for use in patients 75 years or older. Patients with prior TIA or stroke should not be treated with prasugrel.
About Daiichi Sankyo
A global pharmaceutical innovator, Daiichi Sankyo Co., Ltd., was established in 2005 through the merger of two leading Japanese pharmaceutical companies. This integration created a more robust organization that allows for continuous development of novel drugs that enrich the quality of life for patients around the world. Areas of primary focus for Daiichi Sankyo research and development are thrombotic disorders, malignant neoplasm, diabetes mellitus, and autoimmune disorders. Equally important to the company are hypertension, hyperlipidemia or atherosclerosis and bacterial infections. For more information, visit http://www.daiichisankyo.com.
About Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers - through medicines and information - for some of the world's most urgent medical needs. Additional information about Lilly is available at http://www.lilly.com.
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