Genotyping Guides Clopidogrel Dosing in CVD

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 ELEVATE-TIMI 56 trial involving 333 patients with stable cardiovascular disease who underwent genotyping for alleles of CYP2C19, which is primarily responsible for producing active metabolite from clopidogrel (Plavix). Research has shown that patients who carry nonfunctional alleles of CYP2C19 such as *2 have reduced plasma active metabolite levels, an increased risk of ex vivo residual platelet activity, and a greater risk of cardiac events such as stent thrombosis.

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, and 300 mg for four 14-day treatment periods, while 247 CYP2C19*2 noncarriers were assigned to daily clopidogrel 75 mg and 150 mg 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.

The mean vasodilator-stimulated phosphoprotein phosphorylation (VASP) platelet reactivity index (PRI) was 70% for carriers vs. 58% for noncarriers, while mean P2Y₁₂ reaction units (PRUs) were 226 vs. 164, respectively.

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. Specifically, the percentage of CYP2C19*2 heterozygotes who did not respond to standard dosing was reduced from 52% to 26% with a 150-mg dose, and to 10% with at least 225 mg of clopidogrel.

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.

Dr. Mega said alternative agents with higher degrees of platelet inhibition are available, but that clopidogrel will become generic next year and continues to be used in a significant number of patients.

"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, Ph.D., director of the center for pharmacometrics and systems pharmacology at the University of Florida in Lake Nona, pointed out that clopidogrel carries a "black box" warning indicating 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 available that can be run by individuals in the catheter laboratory and deliver genotype results in 1 hour.

"So, I don’t think technology is going to be the rate-limiting step," she said.

In the study, VASP PRI was determined from blood samples sent to the Center for Platelet Research Studies in Boston. Platelet function testing was also conducted at each site using the point of care Verify Now P2Y₁₂ test (Accumetrics).

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 simultaneously published online (JAMA 2011 Nov. 16;306[doi:10.1001/jama.2011.1703]).

Bristol-Myers Squibb and Sanofi-Aventis sponsored the trial. Accumetrics and Nanosphere provided research supplies. Dr. Mega reported receiving grants from the National Institutes of Health. Dr. Lesko said he had no relevant financial disclosures.

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 ELEVATE-TIMI 56 trial involving 333 patients with stable cardiovascular disease who underwent genotyping for alleles of CYP2C19, which is primarily responsible for producing active metabolite from clopidogrel (Plavix). Research has shown that patients who carry nonfunctional alleles of CYP2C19 such as *2 have reduced plasma active metabolite levels, an increased risk of ex vivo residual platelet activity, and a greater risk of cardiac events such as stent thrombosis.

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, and 300 mg for four 14-day treatment periods, while 247 CYP2C19*2 noncarriers were assigned to daily clopidogrel 75 mg and 150 mg 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.

The mean vasodilator-stimulated phosphoprotein phosphorylation (VASP) platelet reactivity index (PRI) was 70% for carriers vs. 58% for noncarriers, while mean P2Y₁₂ reaction units (PRUs) were 226 vs. 164, respectively.

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. Specifically, the percentage of CYP2C19*2 heterozygotes who did not respond to standard dosing was reduced from 52% to 26% with a 150-mg dose, and to 10% with at least 225 mg of clopidogrel.

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.

Dr. Mega said alternative agents with higher degrees of platelet inhibition are available, but that clopidogrel will become generic next year and continues to be used in a significant number of patients.

"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, Ph.D., director of the center for pharmacometrics and systems pharmacology at the University of Florida in Lake Nona, pointed out that clopidogrel carries a "black box" warning indicating 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 available that can be run by individuals in the catheter laboratory and deliver genotype results in 1 hour.

"So, I don’t think technology is going to be the rate-limiting step," she said.

In the study, VASP PRI was determined from blood samples sent to the Center for Platelet Research Studies in Boston. Platelet function testing was also conducted at each site using the point of care Verify Now P2Y₁₂ test (Accumetrics).

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 simultaneously published online (JAMA 2011 Nov. 16;306[doi:10.1001/jama.2011.1703]).

Bristol-Myers Squibb and Sanofi-Aventis sponsored the trial. Accumetrics and Nanosphere provided research supplies. Dr. Mega reported receiving grants from the National Institutes of Health. Dr. Lesko said he had no relevant financial disclosures.

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 ELEVATE-TIMI 56 trial involving 333 patients with stable cardiovascular disease who underwent genotyping for alleles of CYP2C19, which is primarily responsible for producing active metabolite from clopidogrel (Plavix). Research has shown that patients who carry nonfunctional alleles of CYP2C19 such as *2 have reduced plasma active metabolite levels, an increased risk of ex vivo residual platelet activity, and a greater risk of cardiac events such as stent thrombosis.

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, and 300 mg for four 14-day treatment periods, while 247 CYP2C19*2 noncarriers were assigned to daily clopidogrel 75 mg and 150 mg 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.

The mean vasodilator-stimulated phosphoprotein phosphorylation (VASP) platelet reactivity index (PRI) was 70% for carriers vs. 58% for noncarriers, while mean P2Y₁₂ reaction units (PRUs) were 226 vs. 164, respectively.

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. Specifically, the percentage of CYP2C19*2 heterozygotes who did not respond to standard dosing was reduced from 52% to 26% with a 150-mg dose, and to 10% with at least 225 mg of clopidogrel.

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.

Dr. Mega said alternative agents with higher degrees of platelet inhibition are available, but that clopidogrel will become generic next year and continues to be used in a significant number of patients.

"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, Ph.D., director of the center for pharmacometrics and systems pharmacology at the University of Florida in Lake Nona, pointed out that clopidogrel carries a "black box" warning indicating 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 available that can be run by individuals in the catheter laboratory and deliver genotype results in 1 hour.

"So, I don’t think technology is going to be the rate-limiting step," she said.

In the study, VASP PRI was determined from blood samples sent to the Center for Platelet Research Studies in Boston. Platelet function testing was also conducted at each site using the point of care Verify Now P2Y₁₂ test (Accumetrics).

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 simultaneously published online (JAMA 2011 Nov. 16;306[doi:10.1001/jama.2011.1703]).

Bristol-Myers Squibb and Sanofi-Aventis sponsored the trial. Accumetrics and Nanosphere provided research supplies. Dr. Mega reported receiving grants from the National Institutes of Health. Dr. Lesko said he had no relevant financial disclosures.