Clopidogrel 225 mg for Patients With CYP2C19*2 Allele?

November 16, 2011

Updated November 16, 2011 (Orlando, Florida) — Tripling the maintenance dose of clopidogrel to 225 mg daily in stable heart disease patients carrying one clopidogrel loss-of-function allele (CYP2C19*2) achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in noncarriers, according to the results of the ELEVATE-TIMI 56 trial [1].

In contrast, in patients with two loss-of-function alleles, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition.The study was presented today at the American Heart Association 2011 Scientific Sessions by Dr Jessica Mega (Brigham and Women's Hospital, Boston, MA) and published simultaneously in the Journal of the American Medical Association.

Speaking in a morning press conference, Mega said the findings will have an influence on her practice. "If I knew someone's genotype [indicated loss of function], I would feel uncomfortable treating them with standard doses of clopidogrel," she said, adding that there are also other agents available, prasugrel and ticagrelor, that have been shown to reduce events in "all-comers."

That's despite the fact that ELEVATE did not look at effects on patient outcomes. As Mega commented to heartwire : "It is important to understand that this is a pharmacodynamic study . . . but I think it gives us a great deal of insight into the optimal ways of treating different patients with clopidogrel."


In the study, 333 patients were genotyped and then received various maintenance doses of clopidogrel dependent on genotype for four 14-day treatment periods. The 247 noncarriers of a loss-of-function CYP2C19*2 allele received clopidogrel doses of 75 mg and 150 mg daily (two periods each), whereas 86 carriers (80 heterozygotes, six homozygotes) received doses of 75 mg, 150 mg, 225 mg, and 300 mg daily. At the end of each study period, platelet-function testing was performed with both VASP and VerifyNow assays.

When treated with a standard clopidogrel maintenance dose of 75 mg daily, both CYP2C19*2 heterozygotes and homozygotes had significantly higher on-treatment platelet reactivity than did noncarriers.

Among CYP2C19*2 heterozygotes, each 75-mg increase in clopidogrel dose led to an approximate 8% to 9% absolute reduction in platelet-reactivity index as measured by the VASP test. Similar results were seen with the VerifyNow test.

Effect of Clopidogrel Dose and Loss-of-Function Genotype on Platelet-Reactivity Index (PRI) as Measured by the VASP Test

Group 75 mg 150 mg 225 mg 300 mg p
Noncarriers 57.5 46.9 -- -- <0.001
CYP2C19*2 heterozygotes 70.0 61.4 52.7 48.9 <0.001
CYP2C19*2 homozygotes 86.6 77.8 73.0 68.3 0.003

Effect of Clopidogrel Dose and Loss of Function Genotype on Platelet Reactivity Units as Measured by the VerifyNow Test

Group 75 mg 150 mg 225 mg 300 mg p
Noncarriers 163.6 126.7 -- -- <0.001
CYP2C19*2 heterozygotes 225.6 188.1 152.9 127.5 <0.001
CYP2C19*2 homozygotes 328.8 310.2 286 287.0 0.32


Encouraging Results

She said it was encouraging that a dose of 225 mg of clopidogrel gave the same degree of platelet inhibition in heterozygous CYP2C19*2 carriers as a 75-mg dose gives in normal patients. "This means we can work with clopidogrel in the vast majority of patients."

This means we can work with clopidogrel in the vast majority of patients.

She continued, "It appears that it is only the patients who are homozygous CYP2C19*2 carriers--and these make up only 2% of the population--who are really difficult to treat with clopidogrel, and they probably do need to be treated with one of the other agents--prasugrel or ticagrelor," Mega added.

Asked if this study might prompt more doctors to test for clopidogrel loss-of-function genotypes, Mega said she thought this would happen as new, easier-to-use devices for genotyping become available. "At the moment, you still have to send a sample off for the results, which puts many doctors off, but this will change in the not-too-distant future, and I think people are becoming more comfortable with the idea. If you are homozygous for CYP2C19*2, I think you do really need to know about it."

In the morning press conference, Mega pointed out that even if without genotype information, clinical factors such diabetes or previous MI can also sway decisions on dose or medication.

"We need to pay attention to genotype, as well as their clinical characteristics, to give the right drug to the right patient to reduce thrombotic events."

Dr Lawrence J Lesko

Dr Lawrence J Lesko (University of Florida, Gainesville), who discussed the trial following Mega's presentation, praised its "actionable information," namely that physicians have "clear dose information," at least for patients with one clopidogrel loss-of-function allele.

But there are other nuances to take into account, he noted. For example, the sensitivity and specificity of both genotyping and platelet-function tests are "less than 100%," Lesko told the press.

"I could be tested as a *2 carrier and still respond adequately to a 75-mg dose. . . . Likewise, some *1--about 20% of them--won't respond to 75 mg at all, even if they are extensive metabolizers."

Lesko also made a distinction between test utility at a population level and the patient level.

"I've been both a patient and a scientist. There is clinical utility that is generally speaking to the population benefit of doing the test--does it change treatment decisions? And then there is personal utility: what this test means for me. If I were a patient, I'd very much want this genetic test if I were going on Plavix today. And I would work with my physician to make a personal decision--that's what genetics brings."

Reinforces the Need to Know Genotype

Commenting on the study for heartwire , Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA) said: "This is quite a novel and impressive study---by [increasing the usual] dose of clopidogrel to three times in heterozygote loss-of-function carriers, Mega and colleagues nicely show suppression of platelet function. These findings are indeed important, confirming the vital pharmacogenomic clopidogrel story in CYP2C19 loss-of-function carriers and, further, the inability to address this even with tripling of dose in homozygotes." He added: "All of this reinforces the need to know genotype in patients at risk, such as those with stent implantation."


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