JAMA: Tripling Plavix maintenance dose benefits some poor metabolizers

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Patients with stable cardiovascular disease who carry the CYP2C19*2 heterozygotes and were administered 225 mg daily doses of clopidogrel responded at levels seen in noncarriers, according to results of the ELEVATE-TIMI 56 trial. But carriers of CYP2C19*2 homozygotes given 300 mg daily doses failed to achieve comparable levels of platelet reactivity. The results appeared online first Nov. 16 in the Journal of the American Medical Association.

The study was presented simultaneously at the 2011 American Heart Association scientific sessions in Orlando, Fla.

Clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Aventis) is a readily available therapy for reducing cardiovascular events in patients with acute coronary syndromes and those who undergo PCIs. But response to the antiplatelet drug is variable, particularly among patients who carry loss-of-function CYP2C19*2 alleles that affect metabolism of clopidogrel.

Drugs such as prasugrel (Effient, Eli Lilly/Daiichi-Sankyo) and ticagrelor (Brilinta, AstraZeneca) use different pathways, providing an alternative for CYP2C19*2 alleles carriers, but these newer drugs typically are comparatively more expensive and not as widely available. Clopidogrel, on the other hand, already sells as a generic in some countries and is expected to be available as a generic in the U.S. in 2012, Jessica L. Mega, MD, MPH, of Brigham and Women’s Hospital in Boston, and colleagues wrote.

For the ELEVATE-TIMI 56 trial, they enrolled 333 patients between October 2010 and September 2011 with known cardiovascular disease who were prescribed 75 mg doses of clopidogrel daily, the standard maintenance dose. At baseline, patients underwent a clinical evaluation and provided a blood sample that then was blind genotyped and platelet function tested.

Patients then were randomized into a noncarrier group (247 patients) and a carrier group (86 patients). Of the noncarriers, 166 patients randomly were assigned to receive a sequence of blinded daily clopidogrel doses of 75 mg and 150 mgs daily for 14 days. The remaining 117 noncarriers received blinded daily doses of 150 mg and 75 mg.

In the carrier group, 41 patients were randomized to blinded daily doses of clopidogrel of 225 mg and 300 mg for 14 days and the other 41 patients followed a sequence of 300 mg and 225 mg daily doses. A total of 28 patients from both groups were discontinued before randomization. Adherence rates ranged between 97.3 percent and 98.6 percent.

The outcome measures were platelet function test results and adverse events.

Carriers with CYP2C19*2 heterozygotes had higher on-treatment platelet reactivity compared with noncarriers when administered 75 mg daily doses (mean platelet reactivity index [PRI] of 70 percent vs. 57.5 percent) while at doses up to 300 mg, this group’s mean PRI decreased to 48.9 percent. CYP2C19*2 heterozygote carriers given 225 mg daily doses of clopidogrel had platelet reactivity levels similar to levels of noncarriers who received the standard 75 mg clopidogrel dose.

In the 75 mg regime, 52 percent of CYP2C19*2 heterozygotes were nonresponders; that dropped to 10 percent with 225 mg or 300 mg dosages. But CYP2C19*2 homozygotes carriers failed to respond, even at 300 mg daily doses of clopidogrel.

“We now show that higher maintenance doses of clopidogrel in patients carrying a CYP2C19*2 allele significantly reduce platelet reactivity,” Mega and colleagues wrote, “and daily maintenance doses of 225 mg of clopidogrel or greater in CYP2C19*2 heterozygotes can achieve on-treatment platelet reactivity at least comparable with what is achieved with 75 mg daily of clopidogrel in noncarrier patients with cardiovascular disease.”

They added that patients tolerated the higher maintenance doses but cautioned that the trial covered only a two-week period. They noted that use of proton pump inhibitors (PPI) was among their exclusion criteria, and further studies examining PPI use, clopidogrel and genotyping were warranted.