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Study Finds Genomic/Clinical Combo to Be Best Predictor of Complications in Stent Patients on Plavix


By Molika Ashford

A predictive model combining patients' clinical features and genetic testing results is better than genetic or clinical factors alone at gauging which patients treated with the antiplatlet drug Plavix after a coronary stent procedure are at risk of experiencing stent thrombosis, a recently published study found.

The four-year multi-center, case-control study by French researchers found that three genes and two clinical factors were independently associated with early stent thrombosis, a rare but serious complication of percutaneous coronary interventions involving stent implantation.

When the researchers combined the genetic and clinical risk factors into a single model, it was better able to discriminate early stent thrombosis than either a clinical-only or a genetic-only model, which performed similarly to each other. PCI patients in the highest risk group using the combined model had seven times the risk of developing thrombosis than patients in the lowest risk group, the authors reported last week in the Journal of the American Medical Association.

The US Food and Drug Administration updated the labeling for Plavix last year to note that patients with diminished CYP2C19 function are at greater risk of cardiovascular adverse events after an acute coronary syndrome or percutaneous coronary intervention. The label further notes that there are available tests "to identify a patient's CYP2C19 genotype [that] can be used as an aid in determining therapeutic strategy" (PGx Reporter 3/17/2010). Plavix is marketed by Sanofi-Aventis and Bristol-Myers Squibb.

While the close performance of the clinical-only and genetic-only models would seem to suggest a limited benefit from genetic testing for variants linked to increased risk of thrombosis with clopidogrel treatment, the improved predictive power of the French team's combined model supports the utility of genetic testing in assessing thrombosis risk, and adjusting treatment accordingly, Gilles Montalescot, one of the study's authors, told PGx Reporter this week.

"If you can't genotype your patient, we provide the clinical and angiographic characteristics that are related with stent thrombosis, and physicians could look [just] at these variables," he said. "But if you have at the bedside one of these assays that can give you one [of the predictive gene variants], go for it. It's one additional piece of information.

"When we put all these variants together in this model with all the clinical, angiographic, genetic factors, the genetic [data] added strongly to the predictive value," Montalescot added.

The group designed the study to test a variety of genetic variants that have been previously associated with clopidogrel pharmacogenetics and arterial thrombosis to determine their relative contribution to early stent thrombosis alongside and against clinical and angiographic factors.

The project used a French national registry of patients with stent thrombosis following PCI called ONASSIST. Ten centers performing about 18,500 stent procedures participated in the registry between January 2007 and May 2010, the authors reported. For the JAMA study, the researchers selected patients who experienced stent thrombosis fewer than 30 days after implantation from this group and matched them to twice as many controls.

Among 223 patients chosen from ONASSIST, 123 made the final cut and were matched with 246 controls. The researchers collected clinical and angiographic information, and genotyped subjects using TaqMan SNP arrays from Applied Biosystems. The group tested for the common CYP2C19*2 loss-of-function allele, as well as more than 20 other variants in multiple genes.

Using a multivariable statistical analysis, the team identified variables independently associated with ST. Of the 23 pre-selected genetic variants, researchers found that four variants were independently associated, including CYP2C19. According to the results of the investigation, patients homozygous for the CYP2c19*2 allele were seven times more prevalent in the group of ST sufferers than in the control cohort. In addition, CYP2c19*17 allele carriers were at lower risk.

Montalescot's group also confirmed a significant association between patients carrying the ABCB1 3435 TT genotype and early ST, and found that PLA2 polymorphism was less frequent in patients with the complication, which contradicted earlier findings and requires further replication.

Along with findings linking diabetes and angiographic features to ST risk, the researchers reported that higher loading doses of clopidogrel were associated with lower risk, and the use of protein pump inhibitor medications conferred greater risk.

"Many of the clinical factors were not a big surprise," Montalescot said. "We found the usual suspects – diabetic patients, for example, are exposed to more frequent thrombosis."

But, he said, some findings were surprising, including the clopidogrel-associated, clinically modifiable features. "There has been big debate around PPIs and clopidogrel, but in our study we found that PPIs were related to stent thrombosis," he said. "There has also been debate around the dose of clopidogrel, [with previous findings] suggesting high loading doses have a negative effect. But in this study, when you look at the PCI patients, patients that received higher dose had less thrombosis."

Genetic variations were not linked to these two potentially modifiable clinical factors at all, the authors wrote.

The group created models based on clinical factors only, genetic factors only, as well as a combined stratifier, and compared their predictive performance. The combined model had significantly greater power to discriminate early stent thrombosis than the clinical-only model, they reported, with greater sensitivity and specificity than either single model alone.

For patients who had a low clinical likelihood of ST, the influence of genetic factors in predicting the complication was important, the authors wrote.

"What was really interesting," Montalescot said, "was that when you look … only at what you have in routine practice, which is clinical characteristics and the angiographic characteristics, you can predict stent thrombosis.

"On the other hand, if you look only at the [genomic] factors and you don't know anything from the patients — you don’t look at medical reports, you don’t look at the film — just at the genome, with the four gene variants we identified, we were as accurate as with the clinical and angiographic characteristics," he said.

"So not even looking at the patient, but only at the genomes, we were as good," he said, but the combined model was even better.

Some critics of pharmacogenomically guided testing for Plavix have noted that the approach has limited utility as long as knowledge of a patient's genetic status isn't associated with specific recommended treatment changes like doubling or halving a dose (PGx 7/27/2011).

Montalescot stressed, though, that the study suggests there are in fact therapeutic actions that can be taken for high-risk patients based on both clinical and genetic factors, even if there aren't specific guidelines on exactly how to adjust dosing for those at risk. "This is important information for the patient and the physician," he said. "And I think [measuring] the gene variants is getting easier these days — you can even get that at the bedside."

Based on the predictive model outlined in the paper, Montalescot advised that if doctors calculate a high score for a patient, they may want to adapt the treatment strategy for that patient. Specifically, on the clinical factors side, if a patient is on PPIs and scheduled for stenting, he suggested doctors "think twice" about prescribing them. "You have alternatives. You could use … H2 antagonists," he said.

Similarly, with genetic testing, Montalescot also advised physicians to consider alternative treatments that don't depend on CYP2C19 genotypes if the patient is at high genetic risk for having a poor response to clopidogrel.

One of these new drugs is Lilly's Effient (prasugrel), which does not harbor the genetic issues that Plavix does, though it is more expensive and has been shown to have a higher risk of bleeding in patients.

The pharmacy-benefit manager Medco is planning a study to examine the impact that the PPI Prevacid has on patients' ability to metabolize either Effient or a double dose of Plavix. In the study, researchers will also genetically test patients to see if they harbor mutations hindering Plavix metabolism (PGx 7/28/2011).

Additionally, Medco is also conducting a head-to-head study of clopidogrel and Effient, called the Genotype-Guided Comparison of Clopidogrel and Prasugrel Outcome Study, or GeCCO, which is measuring how genetics impacts patients' response to these drugs. In GeCCO, Medco researchers will compare outcomes of “extensive metabolizers” of clopidogrel with patients taking Effient (PGx Reporter 10/21/2009).

Montalescot said that because stent thrombosis is a rare complication and the study size was relatively low, the group is encouraging other groups to independently validate their results.

"We know that out there other teams have [stenting] registries, registries on thrombosis, and may even have DNA of patients. We need to reproduce this prospectively elsewhere, in different populations. We really want to see that," he said.

"At the same time," he said. "We are quite confident that the data we have are robust."

The researchers are currently expanding the study and are still collecting data. They plan to further look at other complications of stenting procedures beyond thrombosis. "You would imagine [some of] these variables are also important for these [other adverse events], so we are testing these hypotheses now," he said.

Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at mashford [at] genomeweb [.] com.

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