No Routine Genetic or Platelet-Function Testing for Clopidogrel Nonresponsiveness: ACC, AHA

July 01, 2010

July 1, 2010 (Washington, DC) — The American College of Cardiology (ACC) and the American Heart Association (AHA) urge clinicians to adhere to the existing guidelines when using antiplatelet therapy but are reminding doctors about genetic variability altering clopidogrel metabolism, which in turn affects drug's inhibition of platelet function [1].

The new report stops short of recommending routine genetic testing or assessments of platelet function because the evidence base is currently insufficient but does state that "genetic testing to determine if a patient is predisposed to poor clopidogrel metabolism (poor metabolizers) may be considered before starting clopidogrel in patients believed to be at moderate or high risk for poor outcomes."

The ACC/AHA recommendations, chaired by writing committee member Dr David Holmes (Mayo Clinic, Rochester, MN) and published June 28, 2010 in the Journal of the American College of Cardiology, are in response to the new Food and Drug Administration (FDA)–approved boxed warning about the diminished effectiveness of clopidogrel in patients with an impaired ability to convert the drug into its active form.

"There are people who are very strong advocates of genetic testing, and there are others who believe that genetic testing is less helpful and that we should do the platelet-function testing, which is really where the action is," Dr Gregory Dehmer (Texas A&M Health Science Center, Temple), a member of the writing committee, told heartwire . "I think what the professional organizations wanted to do was provide a little bit more information to the clinician, going beyond the black-box warning from the FDA. At the same time, we can't venture off into areas where we just don't have enough data to support our feelings at this point."

At present, added ACC/AHA writing committee member Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA), there are too many unknowns, with physicians having no idea whether or not genetic testing would result in improved efficacy outcomes and safety. Using other drugs in patients unable to effectively metabolize clopidogrel, such as prasugrel and ticagrelor, is not without risks, he added, noting that both drugs are associated with higher bleeding rates, although ticagrelor is shorter acting and can be stopped before clinical procedures.

"Right from the very outset, it was quite clear the evidence base was too sparse to make any sweeping conclusions for definitive recommendations to inform or guide clinical practice," Kaul told heartwire . "But clinicians are always called upon to make decisions in the face of uncertainty, and so what we decided to do was summarize the evidence base, talk about some of the trials currently under way that will hopefully resolve this uncertainty, and in the meantime provide some guidance to the practicing clinician."

The New Boxed Warning

The new label, announced on March 12, 2010 and reported by heartwire at that time, outlines the availability of genetic tests to identify poor metabolizers of clopidogrel and also advises clinicians to consider other antiplatelet medications or alternative dosing strategies for clopidogrel in nonresponders. Despite the label, some cardiologists felt the label was premature and that there was insufficient guidance regarding how to treat these patients. In March, Dr Dean Kereiakes (Christ Hospital Heart and Vascular Center, Cincinnati, OH) told heartwire the new boxed warning was "irresponsible, if not reprehensible," given that doctors had no direction on how to treat clopidogrel nonresponders.

"The ACC and AHA felt that the FDA did an important service to the cardiology community by identifying this risk, but it did appear to fall a little bit short of recommendations for the average clinician out there making decisions day by day," Dehmer told heartwire .

Kaul agreed, saying that that in fairness the agency was simply trying to make clinicians aware of the "poor-metabolizer" phenomenon and that genetic testing is available, and that this, along with other clinical variables, should be taken into account on a patient-by-patient basis. In the new clinical alert, the ACC/AHA committee makes several recommendations, namely that doctors should adhere to the existing guidelines for antiplatelet therapy and that, while the evidence is thin, some patients at moderate or high risk for poor outcomes, such as those undergoing elective high-risk PCI procedures, might be candidates for genetic or platelet-function testing.

"We have to remember that the turnaround time for getting information from genetic testing is anywhere from five to seven days, it's not covered by the insurance companies, and so its utility in the acute setting is questionable," said Kaul. "If you have an elective, high-risk intervention planned, like complex angioplasty involving multiple vessels or left main stenting, perhaps you can a priori test them if you want to be sure the patient is going to be 100% protected with clopidogrel. In that setting, you have the option of doing it because you have luxury of time on your side."

Overall, however, the evidence is insufficient to recommend routine genetic or platelet-function testing at the present, according to the ACC/AHA writing committee.

In addition to these recommendations, the writing committee notes that there are several therapeutic options for patients experiencing an adverse event taking clopidogrel, such as switching to prasugrel or increasing the dose of clopidogrel to 150 mg/day. Higher loading doses, double-dose loading, and higher maintenance doses have also been shown to improve platelet inhibition in high-risk patients who respond poorly to standard loading or maintenance doses. Several functional tests assessing the platelet response to clopidogrel might also be used.

To heartwire , Kaul noted that the clinical alert was a "turbocharged" process, written in less than 12 weeks after the FDA boxed warning appeared, leading to "many late nights," according to Dehmer. The reason, he said, was that many clinicians wanted answers about how to treat patients based on the new label, and while the new alert attempts to answer some of those questions, Dehmer noted that clinicians continue to learn more in the area of genetic and platelet-function testing and that the field is evolving very rapidly.

Looking at the State of the Field

In the clinical alert, the committee reviews the results of a number of small pharmacodynamic studies of platelet responsiveness to different clopidogrel dosing regimens as well as the effect of different clopidogrel dosing on patient outcomes in ARMYDA-4 RELOAD, HORIZONS-AMI, and CURRENT OASIS-7. They also review some of the ongoing trials, including studies of antiplatelet therapy in genotyped patients, as well as testing tailored antiplatelet therapy based on platelet responsiveness.

In addition to reviewing some of the ongoing trials, the group lists some of the current challenges in the field, such as a glut of specific assays, definitions, and protocols with platelet-function testing, and high cost and lack of reimbursement with CYP219 genotyping assays. Moreover, with regard to genotyping, there is the inability to determine a patient's genetic makeup in the acute-care setting, as well as a number of different reduced-function polymorphisms of CYP2C19 that might affect clinical outcomes.

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