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17-11-2011 | Cardiology | Article

Triple-dose clopidogrel overcomes resistance in some patients


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MedWire News: Using a triple dose of clopidogrel may overcome the blunted response to the drug seen in some patients with genetic variants in CYP2C19, a study suggests.

The randomized, double-blind trial included 333 patients with stable cardiovascular disease who were genotyped for CYP2C19 alleles and treated with different clopidogrel maintenance doses for four treatment periods of about 2 weeks each.

"Among patients with stable cardiovascular disease, if you look 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 noncarriers. Among the CYP2C19*2 homozygotes, however, even 300 mg of clopidogrel is unlikely to result in optimal degrees of platelet inhibition," reported lead investigator Jessica Mega (Brigham & Women's Hospital, Boston, Massachusetts, USA) at the 2011 American Heart Association Scientific Sessions in Orlando, Florida.

Clopidogrel at a 75 mg daily maintenance dose has been shown to be effective at preventing adverse cardiovascular events in patients with acute coronary syndromes (ACS). It is also known that normal genetic variants in CYP2C19 - in particular the CYP2C19*2 variant - can confer resistance to the platelet inhibiting effects of clopidogrel. CYPC2C19 is a cytochrome P450 enzyme that is required to convert the prodrug clopidogrel into its active metabolite.

The ELEVATE TIMI 56 (Escalating Clopidogrel by Involving a Genetic Strategy - Thrombolysis In Myocardial Infarction 56) trial was designed to test whether increasing clopidogrel dosing up to 300 mg daily for maintenance therapy could improve the response to the drug in carriers of the loss-of-function CYP2C19*2 allele.

A total of 333 patients from sites across the USA were assigned, based on their genotype, to a blinded sequence of four treatment periods of approximately 14 days each. Noncarriers (n=247) were assigned to receive 75 mg and 150 mg of clopidogrel in various orders. Carriers of CYP2C19*2 (80 heterozygotes and six homozygotes) were assigned to doses of 75, 150, 225 and 300 mg of clopidogrel in randomly chosen sequences.

All patients were on daily aspirin. Patients currently taking a proton-pump inhibitor, a class of drugs that interfere with clopidogrel's mechanism of action, were excluded.

At the end of each treatment period, patients were assessed for platelet function using the VASP platelet reactivity index and the VerifyNow P2Y12 assay.

On the 75 mg dose, both heterozygous and homozygous carriers had significantly higher on-treatment platelet reactivity than noncarriers (p<0.001). On both the VASP and VerifyNow tests, heterozygous carriers had significantly greater reductions (p<0.001) in platelet reactivity with each successive dose escalation.

Among heterozygous carriers on the 75 mg dose, 52% were classified as non-responders. This compared with 26% on the 150 mg dose (p vs 75 mg <0.001 ), and 10% on both the 225 mg and 300 mg doses (p vs 150 mg=0.002). The 225 mg dose allowed heterozygous carriers to achieve a mean ratio of platelet reactivity units of 153, similar to the mean ratio of 164 seen among noncarriers.

However, for CYP2C19*2 homozygotes, although there was a graded response to increased clopidogrel doses, even 300 mg daily did not get their platelet reactivity levels within the range of noncarriers.

There were no deaths, cerebrovascular events, or episodes of TIMI major or minor bleeding.

Discussant Lawrence Lesko (University of Florida, Lake Nona) said ELEVATE TIMI 56 was an important study that raises questions about the possible need to genotype patients assigned to clopidogrel therapy, but added that more research is needed to answer these questions.

"The perfect study has not been done in this area: a study that correlates dose, active metabolite levels, platelet reactivity and clinical outcomes… would be the gold standard study, and whether or not we need to begin to move toward genotyping of 2C19 for clopidogrel remains open for discussion," he said.

The study is published in the Journal of the American Medical Association.

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By Neil Osterweil

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