Feature: UNC to investigate necessity of Plavix black box warning

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After the FDA issued black box warnings about clopidogrel (Plavix) in March because evidence showed that some patients may not be able to properly metabolize the drug, researchers at the University of North Carolina in Chapel Hill began to develop a clinical trial that will further develop reasons for patient resistance and test other forms of treatment.

“For the last several years there’s been an accumulation of evidence that a significant number of patients do not respond normally to Plavix and certainly over the last two or three years there has been more evidence of the ideology that that lack of response is probably genetic,” Joseph S. Rossie, MD, PhD, assistant professor of medicine, UNC division of cardiology, told Cardiovascular Business.

According to Rossie, patients who lack the ability to metabolize Plavix due to abnormal gene alleles have the potential to be at greater risk for repeat MI, hence the increased push from the FDA to slap warnings on the drugs labels.

In an interview, George “Rick” Stouffer, III, MD, PhD, professor of medicine and director of the cardiac cath lab at UNC, explained that clopidogrel is not an active drug.

The drug is only activated after it is absorbed and metabolized by a patient's CYP2C19 liver pathway. “If the individual does not have that enzyme working for a genetic reason, then there is no way he or she is going to convert the tablets to an active drug,” he said.

After the FDA issued the warnings regarding Plavix, the agency recommended that genotyping be done on patients to genetically detect whether or not the patient has one or two abnormal alleles, or two normal alleles.

Via a blood test, physicians at the lab can detect whether or not a patient’s platelets are responding to the drug.

“It’s sort of a complicated area,” said Rossie. “Right now if we get an abnormal test, we have to ask what does that mean and how can you overcome the abnormality?”

“What we’ve decided to do is to start testing our patients in the context of a clinical trial to determine if we can come up with a strategy that makes sense,” he said.

The researchers at UNC will enroll 200 patients into the clinical trial and will perform genetic testing and platelet function testing to identify a patient's ability to activate clopidogrel.

For patients identified as having two abnormal alleles, the researchers will test the function of a double dose of Plavix to investigate whether an increased dose can overcome an abnormal genotype, said Rossie.

He said that homozygous patients—patients with two abnormal alleles—are at the highest risk for adverse events because they do not hold the ability to break down the drug. Rossie speculated that these patients comprise 2 to 10 percent of the population.

Additionally, he estimated that 15 to 30 percent of the population is heterozygous—having one abnormal allele and one normal allele. While these patients aren’t at as high of a risk for adverse events compared to homozygous patients, the risk for repeat MI and other adverse events is still there, he explained.

Rossie said that while a majority of the patients will be identified as having normal gene function with the ability to metabolize the drug, it is expected that 20 to 30 percent of the study cohort will have at least one abnormal gene.

“We are hoping to identify 50 patients who have the abnormal gene function and we will be able to do platelet function testing and increase their clopidogrel dose to see if they respond to it,” he said.

For these participants, researchers will test platelet function using VerifyNow, a commercially available platelet function test (Accumetrics), to record data before and after the double dose of Plavix to assess whether or not the drug was metabolized.

Additionally, the researchers will perform light transmittance aggregometry (LTA) to measure patient responses to the drug. According to Rossie, a platelet function test home-grown by one of UNC’s own hematologists that assesses a patient’s circuit charges will also be used.

While genetic testing has become less expensive compared to years ago, Rossie said that the tests would still cost a patient around $200 to complete—more to test platelet function. However, the costs associated with refilling prescriptions for Plavix or the alternatively used treatment prasugrel (Effient, Eli Lilly), could soak up almost $100 per month.

According to Stouffer, for patients who cannot metabolize Plavix, prasugrel is a good alternative treatment. Prasugrel functions on a similar mechanism as clopidogrel, but is metabolized through a different pathway so patients with abnormal alleles have the ability to metabolize it.

Rossie formulated that this genetic and platelet testing would be most beneficial in patients who have had a prior stent or a previous case of MI, who are administered medicine and are at high-risk for a potential ventilator in the future.

“For the vast majority, [clopidogrel] is still a very good medicine but what we are trying to do is to individualize therapy and find those patients who don't respond to Plavix and then through the study sort out the best way to treat those patients,” Stouffer concluded.

Rossie and Stouffer said that they expect results of the study to be released early next year.