Higher Dosing Improves Clopidogrel Response in Carriers of Variant Genes

ORLANDO, FL—Tripling the maintenance dose of clopidogrel in patients who are poor responders to the drug due to a variant genetic allele can increase their responsiveness to the level of those on the standard dose who have no such genetic predisposition. Results from the ELEVATE –TIMI 56 trial were presented during a late breaking clinical trial session on Wednesday, November 16, 2011, at the American Heart Association Scientific Sessions and simultaneously published online in the Journal of the American Medical Association.

Researchers for the TIMI Study Group led by Jessica L. Mega, MD, of Brigham and Women’s Hospital (Boston, MA), enrolled 335 patients with stable cardiovascular disease 1 to 6 months after MI or PCI at 32 US centers. All but 2 of the patients underwent blinded genotyping. The 247 noncarriers of the CYP2C19*2 loss-of-function allele were randomized to receive 75-mg or 150-mg daily doses of clopidogrel. Of the 86 carriers of the CYP2C19*2 allele, 80 had single copies and 6 had 2 copies. CYP2C19*2 carriers were randomized to receive daily clopidogrel in 4 dosages: 75 mg, 150 mg, 225 mg, and 300 mg.

Approximately 14 days after each dosing, a platelet reactivity index (PRI) was determined based on vasodilator-stimulated phosphoprotein (VASP) assay. Platelet function also was tested using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) to determine P2Y12 reaction units (PRU).

Dr. Mega noted that the study focused on the patients who carried single copies of CYP2C19*2 because they comprise approximately 25% of the study population.

Carriers See More Inhibition with Higher Dose

When given the standard dose of 75 mg clopidogrel, patients who carried CYP2C19*2 genetic variants had significantly higher platelet reactivity than noncarriers. Mean VASP PRI was 70.0% for heterozygotes, 86.6% for homozygotes, and 57.5% for noncarriers (P for trend < 0.001). Higher clopidogrel maintenance doses produced significant stepwise reductions in platelet reactivity among heterozygotes. From a mean VASP PRU of 70.0% following a dose of 75 mg, platelet reactivity declined to 50% after a dose of 300 mg in these patients.

Every 75-mg increase in the daily dose of clopidogrel was associated with an 8% to 9% absolute reduction in mean VASP PRI.

VerifyNow testing results were similar. After the standard 75 mg dose, noncarriers had a mean PRU value of 163.6; heterozygotes had a PRU of 225.6 and homozygotes had a PRU of 328.8.

Even when given a 150-mg daily maintenance dose of clopidogrel, CYP2C19*2 heterozygotes had higher platelet reactivity (188.1 PRU) than noncarriers who had been treated with 75 mg. A 225-mg dose produced platelet reactivity equal to that of noncarriers who received the standard 75-mg dose (152.9 PRU), and a 300-mg daily dose produced platelet reactivity below that of noncarriers (127.5 PRU). In addition, the percentage of CYP2C19*2 heterozygotes above a nonresponse cutoff of 230 PRU fell from 52% at the 75-mg dose to 26% with the 150-mg dose to 10% with the 225- and 300-mg doses (P < 0.001 for trend).

On the other hand, for homozygotes, even a 300-mg daily dose of clopidogrel did not produce the same degree of platelet inhibition that a 75-mg daily dose produced in noncarriers. At 300 mg, VASP PRI was 68.3% in homozygotes, while VerifyNow PRU was 287 in carriers of both variant alleles.

Clopidogrel Not ‘One Size Fits All’ 

“The results of this study point us in the direction of higher doses for patients who carry CYP2C19*2 alleles,” discussant Lawrence J. Lesko, MD, of the University of Florida Institute of Therapeutic Innovation (Lake Nona, FL), said. “The question in my mind is, What do we do next in terms of integrating genotype more routinely in medical practice in patients who are about to go on long-term clopidogrel or are already on it?”

“We are at a point where we realize that clopidogrel may not be a one-size-fits-all drug, and we need to figure out what’s right for our patients,” Dr. Mega commented. “The onus is on us to be sure dosing is appropriate. We need to be creative in how we use clopidogrel.”

Routine genotyping is one way. Assays can be performed within an hour, so the technology is available for rapid gene testing at the point of care. In addition, the costs of genotyping are coming down. “It’s up to us to decide clinically whether this is important information for us,” Dr. Mega said.

Study Details

Carriers and noncarriers of CYP2C19*2 alleles were similar in age and clinical characteristics, including systolic and diastolic blood pressure, heart rate, and body mass index. Fifty-four percent of noncarriers and 56% of carriers had a previous MI; 97.2% of noncarriers and 97.7% of carriers had undergone PCI; 17.4% of noncarriers and 18.6% of carriers had undergone CABG.

 


Source:
Mega JL, Hochholzer W, Frelinger III AL, et al. Dosing clopidogrel based on CYP2C19*2 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA. 2011;Epub ahead of print.

 

 

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Higher Dosing Improves Clopidogrel Response in Carriers of Variant Genes

ORLANDO, FL—Tripling the maintenance dose of clopidogrel in patients who are poor responders to the drug due to a variant genetic allele can increase their responsiveness to the level of those on the standard dose who have no such genetic
Disclosures
  • The study was supported by an investigator-initiated grant from Bristol-Myers Squibb and Sanofi-Aventis, and research supplies were provided by Accumetrics and Nanosphere.
  • Dr. Mega reports receiving research grants from Bristol-Myers Squibb/Sanofi-Aventis, Daiichi Sankyo, Eli Lilly, and Johnson and Johnson/Bayer; other research support from Accumetrics and Nanosphere; and serving on consulting/advisory boards for AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, Novartis, and Sanofi-Aventis.

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