ACC 2009: Evidence Growing for Personalized Antiplatelet Therapy

from <a href="" target="_blank">Heart<i>wire</i></a> &#151; a professional news service of WebMD

March 28, 2009

March 28, 2009 (Orlando, FL) — Two more studies suggesting that a personalized approach to antiplatelet therapy may be appropriate were presented today at the American College of Cardiology 2009 Scientific Sessions.

Both studies focused on testing patients for the *2 allele of the CYP2C19 gene responsible for metabolizing clopidogrel to its active form and showed that patients with this genotype were more likely to have a cardiovascular event while taking clopidogrel and therefore would be suitable targets for more intensive antiplatelet regimens. And in one study, it was suggested that using prasugrel was a better strategy for these patients than simply increasing the dose of clopidogrel.

The first study, presented by Dr Paul Gurbel (Sinai Center for Thrombosis Research, Baltimore, MD) investigated the link between platelet nonresponsiveness to clopidogrel, CYP2C19*2 carrier status, and one-year clinical outcome in patients who had undergone elective PCI.

The researchers examined data from 227 patients who had taken part in the previous CLEAR PLATELETS 1 and 2 studies and had undergone platelet-function testing before and after starting treatment with clopidogrel and testing for the CYP2C19*2 genotype.

Results showed that the *2 allele of the CYP2C19 occurred in 30% of the population, with no difference between races, and was associated with a worse outcome at one year.

Cardiovascular Events in Patients With and Without the *2 Allele of the CYP2C19 Gene

Allele type Cardiovascular events, n (%)
*2 allele (n=67) 14 (21)
Wild type (n=160) 16 (10)

While levels of platelet aggregation preclopidogrel treatment were not related to occurrence of the *2 genotype or clinical events, a clear relationship was shown between levels of platelet aggregation on clopidogrel treatment and occurrence of the *2 genotype as well as clinical events; patients with higher levels of platelet aggregation were more likely to carry a *2 allele and more likely to have a cardiovascular event.

Gurbel concluded: "The *2 variant of the CYP2C19 gene encodes a defective enzyme that likely fails to adequately convert clopidogrel to its active metabolite, leading to lesser inhibition of platelet function and diminished cardiovascular protection." But he added that larger prospective studies were needed to confirm these results.

He pointed out that while there was significant overlap, some patients with high platelet reactivity (defined as more than 59% platelet aggregation) did not have the *2 gene, and vice versa; and both these markers were associated with an increased risk of adverse events.

Percentage of Patients With High Platelet Reactivity After Clopidogrel Treatment, the *2 Genotype, Both, or Neither

Patient type Total population, n=188 (%) Patients with events, n=24 (%) Patients without events, n=164 (%)
High platelet reactivity 13 29 11
*2 genotype 11 29 18
Both high platelet reactivity + *2 genotype 20 17 10
Neither high platelet reactivity nor *2 genotype 56 25 61

"This therefore suggests that both these tests may be necessary to have the best chance of picking up those patients who have a reduced clinical response to clopidogrel. These patients can then be targeted with more intense antiplatelet regimens," Gurbel told heartwire . "I cannot recommend that these tests be done routinely, as this is not yet in the guidelines, but if I were having a stent put in, I would like to know whether the antiplatelet drug I was given was actually working or not," he added.

While point-of-care platelet-function tests are available and some centers are now performing such tests on their PCI patients, fast genotype tests are not yet available but are in development.

Place for Prasugrel

The second presentation, by Dr Jean-Philippe Collet (INSERM, Paris, France), reported additional data from the study published in the Lancet last December, in which 259 young post-MI patients taking clopidogrel underwent genetic testing. Results showed that cardiovascular events occurred more frequently in carriers of the CYP2C19*2 polymorphism than in noncarriers, as reported by heartwire.

The new data focused on 76 patients from this study who underwent platelet-function testing--33 who were carriers of the *2 allele and 43 noncarriers. Results showed that the *2 carriers had a 30% increase in platelet reactivity measured by two different methods.

Of 19 patients who had recurrent events, seven were still found to have high platelet reactivity when the clopidogrel maintenance dose was doubled to 150 mg. Of these, six were *2 carriers. In these six patients, the clopidogrel dose was increased every three weeks in a step-by-step process. Four of the seven patients were still found to be resistant when the clopidogrel dose was increased to 225 mg, and when the dose was further increased to 300 mg, two patients had nonbleeding side effects (back pain and gastrointestinal effects) that prevented treatment and the other two were still resistant. "This suggests that simply increasing the clopidogrel dose in these patients is not a good strategy," Collet told heartwire . Under a special program, prasugrel was made available for four of these seven patients, who all showed good platelet responses to the new drug.

Collet concluded: "Genetic testing is a nice addition to platelet-function testing and can just as well guide therapy. Rapid genetic testing is around the corner, and individualized antiplatelet therapy is becoming a possibility."

Collet's group is now planning a larger trial (ARCTIC) in 2500 patients undergoing drug-eluting stent implantation who will either receive conventional doses of clopidogrel or undergo platelet-function testing with the dose of clopidogrel adjusted accordingly. Patients will be followed for one year to assess clinical events.

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