New analysis assesses impact of common genetic variation on benefit of antiplatelet therapy

New analysis assesses impact of common genetic variation on benefit of antiplatelet therapy

More than one out of four patients in analysis had variant in ABCB1 gene

TORONTO, April 14 /CNW/ - 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, which included Canada, were treated with dual antiplatelet therapy with either clopidogrel plus aspirin or 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 recently presented at the American College of Cardiology annual meeting in Atlanta, GA.

The ABCB1 gene contains the genetic code for a protein (P-glycoprotein) that plays an important role in how the body absorbs many medications,(1) including certain antiplatelet drugs. Genetic variants in ABCB1 may reduce response to these therapies.(2)

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 per cent) patients in the analysis were found to have two C3435T variants (TT homozygotes) in their chromosomes.(3) Clopidogrel-treated patients who had two C3435T variants (n=414)(4) had a 66 per cent increased risk of experiencing the primary composite endpoint of cardiovascular death, heart attack or stroke compared to clopidogrel-treated patients with no variant (12.9 per cent vs. 8.2 per cent, HR=1.66; p = 0.033).(3) 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 (p=0.0064).(3)

In contrast, prasugrel-treated patients with two C3435T variants (TT homozygotes n=390)(4) did not have a statistically significant increased risk of experiencing the primary composite endpoint compared to prasugrel-treated patients without the variant (11 per cent vs. 9.7 per cent, HR=1.12; p = 0.64), and the differences in the overall ABCB1 analysis for prasugrel were likewise not significant (p=0.40).(3)

"These findings are important because they teach us more about how a person's genetic make-up can affect the way in which they respond to antiplatelet medications," said cardiologist Dr. Jean-Fran├žois Tanguay, MD, Senior Research Scientist at the Montreal Heart Institute and Associate Professor in the Faculty of Medicine at the University of Montreal. "The fact that so many patients are affected by this particular genetic variant or other genetic variants demonstrates that there is a need for alternatives in antiplatelet therapies in order to provide a more personalized approach for patients who have undergone a PCI procedure."

In this subanalysis, there was no association between C3435T genotype and bleeding in either treatment group.(3) In the overall TRITON-TIMI study population, prasugrel produced higher rates of clinically significant bleeding than Plavix.(5)

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 including Canada.(5)

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.(6) 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 162 mg).(5)

This new analysis was designed to examine whether specific genetic variations could affect patient response to the antiplatelet therapies clopidogrel and prasugrel. The pharmacogenetic analysis examined DNA samples from 2,943 patients from the TRITON-TIMI 38 clinical trial.(3)

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

About Prasugrel

Prasugrel helps keep blood platelets from clumping together and developing a blockage in an artery. Prasugrel is currently approved in the United States and the European Union, for the treatment of acute coronary syndromes being managed with percutaneous coronary intervention. Prasugrel is currently under review by Health Canada.

About Acute Coronary Syndromes

Acute coronary syndrome includes heart attacks and unstable angina (chest pain). There are an estimated 70,000 heart attacks each year in Canada. That's one heart attack every seven minutes. Over 17,000 Canadians die each year as the result of a heart attack.(7)

Heart attacks, a major manifestation of coronary heart disease, occur 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.(8) Many ACS patients undergo PCI to re-open the artery, which usually includes a stent placement.

About Lilly

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Indiana, Lilly provides answers - through medicines and information - for some of the world's most urgent medical needs. Eli Lilly Canada, headquartered in Toronto, Ontario, employs more than 500 people across the country. Additional information about Eli Lilly Canada can be found at www.lilly.ca<http://www.lilly.ca>.

References

1. Marzolini, C, et al, Polymorphisms in human MDR1 (P-gylcoprotein): Recent advances and clinical relevance. Clinical Pharmacology & Therapeutics, 2004;75(1):13-33.

2. Tabassome Simon, et al. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. New England Journal of Medicine. January 2009;360:363-75.

3. Mega, Jessica, L., et al. ABCB1 Genetic Variants, Pharmacodynamic Response, and Cardiovascular Outcomes Following Treatment With Clopidogrel and Prasugrel. Poster presentation at the American College of Cardiology Annual Scientific Session. Presented March 14, 2010.

4. Mega, Jessica, L., et al. ABCB1 Genetic Variants, Pharmacodynamic Response, and Cardiovascular Outcomes Following Treatment With Clopidogrel and Prasugrel. Abstract of poster presentation at the American College of Cardiology Annual Scientific Session. Presented March 14, 2010.

5. Wiviott, S, Braunwald, E, et al. Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. New England Journal of Medicine. November 2007;357:2001-15.

6. Data on file. Eli Lilly and Company and/or one of its subsidiaries.

7. Heart and Stroke Foundation, Statistics, http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm#coronaryangio. Last accessed March 16, 2010.

8. WebMD Medical Reference in Collaboration with the Cleveland Clinic. Heart Disease: Coronary Artery Disease, http://www.webmd.com/heart-disease/guide/heart-disease-coronary-artery-disease. Last accessed March 5, 2010.

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For further information: Jennifer Gordon, Eli Lilly Canada Inc., (416) 693-3571; Laura Grice, MS&L, (416) 847-1319

Posted: April 2010

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