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ACCF/AHA Advises Docs to Apply 'Careful Clinical Judgment' in PGx-Guided Administration of Plavix

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By Turna Ray

Three months after the US Food and Drug Administration added a boxed warning to the label of Plavix (clopidogrel) informing doctors that variants in the CYP2C19 gene may diminish response to the anti-platelet drug, an expert review panel has issued a clinical alert to healthcare professionals cautioning that "the science for personalized medicine isn't there yet."

"It would be nice to match a specific drug to each patient," but specifically with regard to administering Plavix with the help of genetic testing, "we are left with different groups of patients, different medicines, and an attempt by clinicians to carefully balance the risks and benefits of all the different therapeutic strategies to optimize outcomes," said David Holmes, chair of the recommendation group, which included members from the American Heart Association and the American College of Cardiology Foundation.

"Although there is increasing information about specific genetic variations that might affect clopidogrel metabolism, leading to suboptimal clinical responses in some patients, there is not sufficient evidence upon which to develop specific recommendations related to genetic testing in patients," the group said in a statement.

After reviewing the available clinical evidence and FDA's labeling updates, the review group came to the conclusion that "many questions remain about how and when to use genetic tests, which tests to use, as well as whether they will be reimbursed." As such, ACCF/AHA's top recommendation to doctors is to follow professional society guidelines and to apply "careful clinical judgment" in weighing the risks and benefits of administering Plavix, particularly in patients with poor CYP2C19 function.

Furthermore, the experts noted that new alternative medications to Plavix, such as Lilly's Effient (prasugrel), may further complicate the clinical scenario for doctors when it comes to choosing the appropriate medication for their patients. While Effient does not harbor the genetic issues that Plavix does, it is more expensive and has been shown to have a higher risk of bleeding in patients.

Based on these observations, the ACCF/AHA review panel issued seven guidelines informing doctors of the various considerations they may have to account for when administering Plavix. Specifically, the workgroup notes that there is insufficient evidence to recommend routine genetic testing, but recommends that doctors consider testing to determine whether a patient is a poor CYP2C19 metabolizer if that patient is already believed to be at moderate or high risk for poor outcomes. Additionally, doctors are advised to consider alternative treatments or different Plavix doses in patients who experience an adverse reaction while taking Plavix.

At least one cardiologist, Eric Topol, disagrees with the ACCF/AHA recommendations and believes that genetic testing should be more broadly adopted by the cardiologist community when it comes to administering Plavix in certain patient populations. "Systematic genotyping for CYP2C19 should be performed in all patients who are undergoing coronary stenting procedures," Topol, director of the Scripps Translational Research Institute, told Pharmacogenomics Reporter this week.

Topol introduced pharmacogenomics testing for Plavix at Scripps Green Hospital in San Diego last year. Under the effort, all stent procedure patients presenting at the hospital obtain their CYP2C19 status using Quest's testing service (PGx Reporter 10/28/09).

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In its recommendations, while the ACCF/AHA review group advises doctors to "consider" genetic testing before dosing Plavix in patients thought to be at high risk for adverse events, the group asserted that there is "no information that routine testing improves outcome in large subgroups of patients." Additionally, the review group stated that the treating patients without genetic testing or functional testing "is excellent" for the majority of patients.

"'Consider' is a very weak recommendation in light of the compelling data," Topol said. He cited a meta-analysis of 23 studies published this week by Jean-Sebastien Hulot and colleagues in the Journal of the American College of Cardiology, which reported recently that out of nearly 12,000 patients, carriers of the loss-of-function CYP2C19*2 allele displayed a 30 percent increase in the risk of major adverse cardiovascular events. The loss-of-function allele was also associated with excess mortality and stent thrombosis.

"The arguments against genotyping are not in keeping with the ability to provide the best possible care for such patients today," Topol added.

Perhaps genetic testing shouldn't be done on "every patient who undergoes stenting, but certainly there should be a systematic approach to either genotype or checking platelet function testing (or both) ─ to assure that the dose of Plavix or the drug at any dose is effective in targeting platelet suppression," he explained over e-mail.

The FDA updated the label for Plavix in May and November 2009, and then issued a black box warning for the drug earlier this year. In the initial labeling update, the agency simply informed healthcare providers that poor CYP2C19 metabolizers have limited response to Plavix. The November update went a bit further and recommended doctors avoid prescribing clopidogrel "in patients with impaired CYP2C19 function due to known genetic polymorphisms or due to drugs that inhibit CYP2C19 activity."

Then in March, the agency issued a boxed warning telling doctors to "consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers." In thrice updating the labeling of the drug, the agency noted that large, ongoing clinical trials will shed more light on the impact of pharmacogenetic testing in prescribing Plavix (PGx Reporter 03/17/10).

The most recent version of the Plavix label mentions a study of 40 healthy subjects harboring different degrees of CYP2C19 metabolism function. The study reported that poor CYP2C19 metabolizers had decreased active metabolite exposure and increased platelet aggression compared to other groups.

The ACCF/AHA clinical alert noted that this study was "a small unpublished crossover trial," and stressed that the completion of large, prospective randomized trials may fill in some of the knowledge gaps with regard to the role of CYP2C19 testing in clinical practice.

FDA's "recent boxed warning on clopidogrel is of great importance in understanding the issues related to variability in clinical outcomes of patients with both acute and chronic coronary artery disease," the ACCF/AHA review panel notes. But these experts also add that while the information in the boxed warning "may have applicability for patients with stroke and peripheral arterial disease … there are no robust data in these populations."

The alert highlights eight of such genotyping/phenotyping studies, including CLOVIS-2, GIFT, and ELEVATE-TIMI 56. "Results from ongoing clinical trials in large groups of patients will provide more information about the predictive value of genetic testing and better inform the role genotyping might play in personalizing medicine and optimizing outcomes," the ACCF/AHA recommended.

The alert includes a laundry list of gaps in the current knowledge, including the fact that CYP2C19 polymorphisms account for only around 12 percent of variability in clopidogrel platelet response; "the specific role of an individual genetic polymorphism in influencing outcome for the individual patient remains unknown;" and evidence that other genetic polymorphisms — such as ABCB1 — may also contribute to variation in response to clopidogrel.

The alert also notes that CYP2C19 testing is expensive, around $500, and "typically not reimbursed by major payors." As an alternative, platelet function assays may be used to "directly or indirectly measure the platelet inhibitor effect" of Plavix, the reviewers point out. Whether the use of residual high platelet reactivity following Plavix administration improves patient outcomes is currently being investigated in clinical studies.

The ACCF/AHA review panel emphasizes that its recommendations are in line with the most recent FDA label, which "only informs physicians and patients that genetic testing is available; it neither mandates, requires, nor recommends genetic testing, thereby allowing for flexibility in clinical decisions."

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