Double-Dose Clopidogrel Helpful for Some Patients With High Platelet Reactivity on Normal Dose

October 26, 2010

October 26, 2010 (Houston, Texas and La Jolla, California) A new study, dubbed "a warm-up to GRAVITAS," has suggested that doubling the maintenance dose of clopidogrel may be beneficial for those with high platelet responsiveness on the normal dose, but only for about half of such patients. Genomic information did not predict which patients would respond best to the change in dose.

Clopidogrel molecular [Source: Sanofi-Aventis]

The study, published in the October 2010 issue of the Journal of the American College of Cardiology: Cardiovascular Interventions, [1] was conducted by a group led by Dr Colin Barker (University of Texas Medical School, Houston).

They enrolled 41 patients with high on-treatment platelet reactivity (identified by the VerifyNow P2Y12 assay [Accumetrics, San Diego, CA]) on a standard 75-mg/d clopidogrel regimen, 20 of whom were carriers of a CYP2C19 loss-of-function allele. Raising the dose of clopidogrel to 150 mg daily reduced platelet reactivity, but there was no significant differences in antiplatelet effect corresponding to CYP2C19 status, although the reduction in reactivity was minimal in the small number of patients homozygous for loss-of-function alleles.

Mean Platelet Reactivity (Platelet Reactivity Units [PRU]) vs Clopidogrel Dose (N=All Subjects)

Baseline clopidogrel 75 mg/d Clopidogrel 150 mg/d Reduction
285 220 65

Reduction in Platelet Reactivity After Doubling Clopidogrel Dose, by Genotype

Genotype    n    Mean reduction (PRU)
No loss-of-function allele    21    77
At least 1 loss-of-function allele    20    52
2 loss-of-function alleles    3    28

The researchers report that platelet reactivity was "normalized" (PRU<235) by clopidogrel 150 mg/day in 23 subjects (56%). Subjects with persistently high platelet reactivity were more frequently diabetic, had a higher level of platelet reactivity on standard-dose clopidogrel before high-dose administration, and tended to have a greater body-mass index.

For every 10-PRU increase in platelet reactivity on standard therapy, the odds for persistently high reactivity increased by 29%. Therefore, the use of alternative P2Y12 antagonists that provide consistent and powerful inhibition of the P2Y12 receptor despite a poor clopidogrel response might be preferred in patients with very high on-treatment platelet reactivity, the authors suggest.

Genomic Results "Confusing"

Barker commented to heartwire: "Our genomic results are confusing. The hypothesis was that noncarriers of the loss-of-function gene would overcome the resistance to clopidogrel with higher doses more than carriers would, but we actually found that both groups responded fairly well to the 150-mg dose. We also had some patients in our cohort of nonresponders to the 75-mg dose who actually had the gain-of-function genotype and therefore would be expected to produce more of the active metabolite of clopidogrel."


"These results suggest we don't know everything about the genomics of clopidogrel metabolism. There seems to be more to it than just phenotype and genotype. There are probably many more genotype variations that we don't know about yet, and also many environmental factors that play a role in the variability of response to clopidogrel," he added.

Barker continued: "I think genomics still has a role in science, but these results would suggest we are not there yet in terms of using genomics in clinical practice in this situation. But this was only a very small study, and it is not enough to rule out the idea of using genomics. Our results do provide some support for the use of platelet-function tests to guide therapy, but again the study was too small to draw any definite conclusions. I think we need to investigate whether genomics will add anything when used in addition to platelet function data, and I think it probably will."


In an accompanying editorial, Drs Paul Gurbel and Udaya Tantry (Sinai Center for Thrombosis Research, Baltimore, MD) say that on the basis of these latest results, genotyping plays a limited role diagnostically in choosing therapy for patients already receiving clopidogrel, but its role in clopidogrel-naive patients remains unexplored. [2]

The editorialists note that, with only about half the population responding to the double dose, this study also suggests that high-maintenance-dose clopidogrel is not the optimal remedy for high platelet reactivity. But they point out that more information on this strategy will come from the GRAVITAS trial being reported at the forthcoming AHA meeting, adding: "The entire interventional community anxiously awaits the results of this important trial that will provide the best answer thus far."

But other authors of the current study caution against taking too much information from this one small study. Drs Eric Topol and Matthew Price both come from Scripps Clinic, where such genetic testing is now routinely performed for stented patients.

Topol told heartwire : "This small study in 40 patients should not be taken out of context. It is not a panoramic picture. We need to look at all the evidence. The genetic data clearly predict increased risk of stent thrombosis and get us warmed up to think we might need to use a different strategy."

More Genes Are Likely Involved

Topol believes that the reason why the genomic results did not predict who would benefit from the double dose in this study probably means there is more than one gene at play. "OK, so the platelet results and the genomic results don't always correlate. But does that mean we should deny the benefit of the knowledge that we have today?" He added: "The homozygotes for the CYP2C19 loss-of-function alleles almost always show a reduced effect of clopidogrel on platelet responsiveness, and the CYP2C19 story is not simply going to go away."

The CYP2C19 story is not simply going to go away.

Topol continued: "This current study is just a mechanistic study in 40 patients. It was a sort of warm-up to GRAVITAS. It shows you can override the high platelet reactivity with double-dose clopidogrel in some patients. OK, so it is not across the board, but it is a good start. Ideally, each patient would be considered individually and then different drugs could be considered in the rest. This is the era of individualized medicine."

Price agrees with this stance. He told heartwire : "Our paper does not directly address the utility of routine genotyping; it examines the effect of genetics on the response to high-dose clopidogrel if one follows the strategy of platelet-function testing first. Poor metabolizers probably don't get much pharmacodynamic benefit. Also, it doesn't address patients who are not on therapy at the time of presentation. Clearly CYP2C19 is not the whole story, but nothing is a silver bullet." 

Barker is a consultant and has received speaker honoraria from Cordis and Medtronic. Topol is a consultant for Quest Diagnostics and Sanofi-Aventis. Price has received research grant support from Bristol-Myers Squibb, Sanofi-Aventis, and Accumetrics; is a consultant for Bristol-Myers Squibb, Sanofi-Aventis, Accumetrics, Boston Scientific, and Eli Lilly; and has received speaker honoraria from Boston Scientific and Eli Lilly.