Genetic Influences on Antiplatelet Therapy Outcomes Stir Debate

STOCKHOLM – Patients’ possession of a clopidogrel loss-of-function genetic polymorphism is likely to worsen outcomes when the antiplatelet agent is prescribed for acute coronary syndromes that are likely to be treated with coronary stenting, but not when the drug is given for atrial fibrillation or chronic coronary artery disease.

This was the prevailing interpretation of two high-profile studies that were presented at the annual congress of the European Society of Cardiology with what at first glance seemed to be disparate results.

The studies drew strong interest because they addressed an issue that was brought dramatically to the fore in the Food and Drug Administration’s black box warning for clopidogrel, issued in March 2010: namely, clopidogrel’s reduced effectiveness in protecting against cardiovascular events in patients who are poor metabolizers of the drug because they have loss-of-function alleles of the CYP2C19 gene that is responsible for converting the prodrug into its active metabolite.

The black box warning was based mainly on data from studies of clopidogrel in ACS patients with high rates of coronary intervention. But a study presented at the congress by Dr. Guillaume Pare suggested that the black box may have been painted with too broad a brush. Dr. Pare reported that clopidogrel was consistently more beneficial than placebo, regardless of CYP2C19 loss-of-function carrier status in other sorts of patients (such as those with atrial fibrillation or those with low-risk, conservatively managed ACS).

This suggests that there is no need for genetic profiling studies in such patients in order to identify poor metabolizers of clopidogrel (Plavix) prior to starting the drug, according to Dr. Pare of McMaster University in Hamilton, Ont.

The study involved the genotyping of 5,059 patients with conservatively managed ACS who participated in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial and 1,156 participants in ACTIVE A (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events A). Both CURE and ACTIVE A were randomized, double-blind, placebo-controlled trials with primary results that have previously been published.

Patients in CURE who carried one or more loss-of-function alleles had an 8.0% rate of the primary efficacy end point consisting of cardiovascular death, nonfatal MI, or stroke, compared with an 11.6% rate with placebo. This translated into a highly significant 31% relative risk reduction, closely similar to the 28% risk reduction seen in noncarriers. A similar pattern was seen among the patients with atrial fibrillation in ACTIVE A.

The other major clopidogrel loss-of-function genotyping study that was presented at the congress was a secondary analysis from the previously reported PLATO (Platelet Inhibition and Patient Outcomes) study. Dr. Lars Wallentin of Uppsala (Sweden) University presented genetic profiling data on 10,285 PLATO participants with ACS who were randomized in double-blind fashion to aspirin plus either 75 mg of clopidogrel once daily or the investigational oral antiplatelet drug ticagrelor (Brilinta) at 90 mg twice daily. In contrast to the CURE study, in which only 14% of ACS patients underwent coronary intervention, invasive treatment was already planned at baseline in two-thirds of PLATO participants.

Among the 39% of subjects with any loss-of-function allele, the 1-year composite primary end point of cardiovascular death, nonfatal MI, or stroke occurred in 8.6% of the ticagrelor group, compared with 11.2% of those on clopidogrel. Among patients without a loss-of-function allele, the rates were 8.8% in the ticagrelor group and 10.0% in the clopidogrel group. In other words, patients on ticagrelor benefited equally from the drug regardless of whether they possessed a loss-of-function mutation, unlike those on clopidogrel, presumably because ticagrelor doesn’t depend upon CYP2C19 for its metabolism.

“These findings emphasize that ticagrelor will be a simple and reliable treatment to further improve survival and reduce the risk of recurrences in almost all patients with acute coronary syndrome without the need for any specific tests of its activity before or during routine treatment,” according to Dr. Wallentin.

He and his colleagues also genotyped the PLATO patients for ABCB1 polymorphisms. The ABCB1 gene is believed to be responsible for clopidogrel absorption. Event rates at 1 year were consistently lower in the ticagrelor than the clopidogrel group in high, intermediate, and low expressers of the ABCB1 polymorphism.

The 30-day event rate in clopidogrel-treated patients was significantly higher in those with any loss-of-function CYP2C19 alleles by a margin of 5.7%, compared with 3.8% in those without such alleles. However, after 30 days and out to 1 year, there were no significant differences in event rates between clopidogrel-treated patients with and without loss-of-function alleles. This supports the notion that the loss-of-function alleles in the CYP2C19 gene are influential in the early phase of ACS, when thrombosis is particularly important, the cardiologist said.