ELEVATE-TIMI 56: High-dose clopidogrel reduced platelet reactivity in CYP2C19*2 carriers

AHA Scientific Sessions 2011

ORLANDO — Higher doses of clopidogrel, up to 300 mg daily, were more effective than standard doses in patients with the CYP2C19 gene variant, according to late-breaking research from the ELEVATE-TIMI 56 trial.

These findings suggest that it may be possible to adjust clopidogrel (Plavix, Sanofi-Aventis) dosage in these patients to improve its effect, according to Jessica L. Mega, MD, MPH, and colleagues.

It is estimated that one-third of patients do not respond optimally to the currently recommended dose of clopidogrel (Plavix; Bristol-Myers Squibb, Sanofi Aventis).

ELEVATE-TIMI 56 is the first study to examine systematically maintenance doses of clopidogrel up to four times the usual dose in patients with particular CYP2C19 gene variations, researchers said. The multicenter, randomized, double blind trial included 335 patients with coronary artery disease (mean age, 60 years; 88% white; 75% men). Three-quarters of the study cohort were non-carriers of the CYP2C19*2 allele, 24% were heterozygotes and 2% were homozygotes.

Non-carriers of the CYP2C19*2 allele received 75-mg or 150-mg doses in 2-week sequences. Carriers received doses of 75 mg, 150 mg, 225 mg and 300 mg daily in random sequence. Each dose was administered every 2 weeks, followed by platelet assessment, for 8 weeks.

Mega, of the department of cardiovascular medicine at Brigham and Women’s Hospital, and the ELEVATE-TIMI 56 researchers found no significant increase in adverse events as dosage increased during the study duration.

According to results, platelet reactivity was higher in both heterozygotes (P<.001) and homozygotes (P<.001) at the 75-mg dose. However, boosting clopidogrel doses resulted in a graded reduction in platelet reactivity among heterozygous patients (P<.001). As doses increased, the number of non-responders decreased (52% at 75 mg, 26% at 150 mg and 10% at both 225 mg and 300 mg).

When doses were tripled (225 mg) or quadrupled (300 mg), responses among heterozygous carriers were comparable to non-carriers who were given the standard dose.

Among homozygotes, however, despite a graded response with higher doses, a small number of patients did not reach a range comparable to non-carriers, even with the 300-mg dose. Compliance was good, with 97% to 98% across all doses, according to Mega. Though only administered in a 14-day series, during the time patients took clopidogrel there were no notable differences in adverse events among the groups, she said.

“Among patients with stable CV disease, looking at CYP2C19*2 heterozygotes, tripling the maintenance dose of clopidogrel to 225 mg daily achieved levels of platelet reactivity similar to the standard 75-mg dose in non-carriers. However, among homozygotes, even 300 mg of clopidogrel daily is unlikely to result in optimal degrees of platelet inhibition.” – by Stacey L. Fisher and Katie Kalvaitis

For more information:

• Mega JL. LBCT.05. Presented at: American Heart Association Scientific Sessions 2011; Nov. 12-16, 2011; Orlando.
• Mega JL. JAMA. 2011;doi:10.1001/jama.2011.1703

Disclosure: The study was supported by an investigator-initiated grant from Bristol-Myers Squibb and Sanofi-Aventis. Research supplies were from Accumetrics and Nanosphere. Dr. Mega reports no relevant financial disclosures.

There are pretty clear data that CYP2C19 genotype influences response to clopidogrel including retrospective genetic analyses from a number of prospective clinical trials suggesting influence on outcomes. As a result, the FDA in 2010 revised the product label for clopidogrel to make clear the influence of genotype on outcomes, and suggested that in patients who carry the loss of function *2 allele - the name of the genotype associated with reduced generation of active metabolite and a higher rate of outcomes - that physicians might consider alternative approaches, which may mean an increase in dose or an alternate drug. The reality is that there were very little data to support the recommendation for an increased dose, although pharmacologically it made sense. There have been some other smaller studies that were a bit mixed in terms of what an increased dose might do. Some people thought doubling the dose would be enough.

Based on this study and others, it is clear that just doubling the dose is not enough. What's really helpful from this study is that it suggests that those who carry one copy of the *2 allele (or heterozygotes) can achieve adequate antiplatelet effect by taking 225 mg rather than 75 mg daily. On the other hand, data from this trial suggest that for those who are homozygous for the loss of function allele (or *2 genotype), it is not possible to overcome the inadequate antiplatelet effect by increasing the dose as much as fourfold. Clinically, this begins to provide clinicians with better data in terms of what the options are. If they have a patient who is heterozygote now it would appear their option is either to increase clopidogrel dose to 225 a day or, alternatively, they may consider an alternate antiplatelet drug. In *2 homozygotes on the other hand, it appears that their best option may be an alternative antiplatelet agent. It now begins to provide a firm foundation on the influence of increasing the dose and ability to overcome that genetic variability, at least for heterozygotes.

One of the questions that remains unsolved from this study is that, if you achieve the same antiplatelet effect, do patients then still have results that are as good, in terms of CV outcomes? I think that's the next obvious question.

– Julie A. Johnson, PharmD
Distinguished Professor of Pharmacy and Medicine
Director of the Center for Pharmacogenomics
University of Florida, Gainesville

Disclosure: Dr. Johnson reports no relevant financial disclosures.

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