Genetics Altered Blood Results in Cardiovascular Study

Abstract

Orlando – Genotyping can provide more targeted use of the commonly prescribed drug clopidogrel among patients with cardiovascular disease, according to data from the ELEVATE-TIMI 56 trial. “We’re at the point that clopidogrel may not be a one-size-fits-all drug for our patients,” Dr. Jessica Mega said at the annual scientific sessions of the American Heart Association. She reported on the prospective trial involving 333 patients with stable cardiovascular disease who were genotyped for alleles of CYP2C19, which is primarily responsible for producing the active metabolite from clopidogrel (Plavix). Research has shown that patients who carry nonfunctional alleles of CYP2C19 such as *2 have less active metabolite, increased risk of residual platelet activity, and a greater risk of cardiac events. Based on the genotyping results, 86 carriers (80 heterozygotes and 6 homozygotes) of the CYP2C19*2 allele were randomized to daily clopidogrel doses of 75 mg, 150 mg, 225 mg, or 300 mg for four 14-day treatment periods, while 247 noncarriers of CYP2C19*2 were assigned to daily 75 mg or 150 mg doses for two 14-day periods each. Platelet testing at the end of each treatment period revealed that both CYP2C19*2 heterozygotes and homozygotes had significantly higher platelet reactivity than did noncarriers, said Dr. Mega, a cardiologist at Brigham and Women’s Hospital, Boston. Among CYP2C19*2 heterozygotes, tripling the daily maintenance dose of clopidogrel to 225 mg was needed to reduce platelet reactivity to the levels achieved with a standard 75-mg dose in noncarriers, she said. Among CYP2C19*2 homozygotes, who made up 2% of the study population, even 300 mg, or four times the standard dose, of clopidogrel did not result in optimal degrees of platelet inhibition. “It’s good news for patients that we’re able to optimize their [platelet] inhibition with clopidogrel,” she said. “I think we need to get creative in how we use clopidogrel, and this study is one step in the right direction.” Invited discussant Lawrence Lesko, PhD, director of the center for pharmacometrics and systems pharmacology at the University of Florida in Lake Nona, noted that clopidogrel carries a “black box” warning that poor metabolizers are at heightened risk for cardiovascular events, and that ELEVATE-TIMI 56 fills in some of the gaps in the labeling of what to do with these patients as well as intermediate metabolizers. “The results of this study point us in the direction of higher doses for the *1 and *2 genotypes to normalize them to the active metabolites of 75 mg,” he said. “The most important open question in my mind after the study is, What do we do next to integrate genotyping more routinely into clinical practice for patients about to go on clopidogrel or already on clopidogrel?” Dr. Mega responded that point of care tests are already available that can be run by individuals in a laboratory and deliver genotype results in 1 hour. “So, I don’t think technology is going to be the rate-limiting step,” she said. ELEVATE-TIMI 56 included patients taking 75 mg clopidogrel for a myocardial infarction and/or undergoing percutaneous coronary intervention at least 4 weeks and not more than 6 months prior to study entry. Compliance during the study was 97.3% at the 75-mg dose, 98.1% at the 150-mg dose, 98.6% at the 225-mg dose, and 98.3% at the 300-mg dose. There were no deaths, cerebral events, or Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding events, Dr. Mega said. The study was also published online in JAMA. Bristol-Myers Squibb and SanofiAventis sponsored the trial. Accumetrics and Nanosphere provided research supplies. Dr. Mega and Dr. Lesko reported having no relevant financial conflict of interest. CfA