ANAHEIM, CALIF. – The boxed warning recommending pharmacogenomic testing of patients receiving clopidogrel to identify reduced metabolizers seems to be playing to a largely deaf audience.
Even when handed information on whether each clopidogrel-treated patient was a poor metabolizer of the drug, treating physicians usually did not switch them to a different antiplatelet drug, ticagrelor, that would be fully effective despite the patient’s reduced-metabolizer status. And clinicians who started patients on ticagrelor did not usually switch those with a good clopidogrel-metabolizing profile to the safer drug, clopidogrel, after learning that clopidogrel would be fully effective.
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Dr. E. Magnus Ohman
The findings came from a secondary analysis of data from a trial with 3,037 acute coronary syndrome patients, who, for regulatory reasons, had to submit routine pharmacogenomic testing for clopidogrel-metabolizing status when they entered the study. More than 99% of patients had testing done, with results reported back within a week to attending clinicians.
“Routine reporting of pharmacogenomics test results for acute coronary syndrome patients treated with P2Y12-inhibitor therapy had an uncertain yield and little impact on P2Y12-inhibitor switching,” E. Magnus Ohman, MBBS, said at the American Heart Association scientific sessions.
The study’s design gave each participating clinician free rein on whether to prescribe clopidogrel or ticagrelor (Brilinta) initially, and switching between the drugs was possible at any time after the initial prescription. At the trial’s start, 1,704 patients (56%) were on ticagrelor and 1,333 (44%) were on clopidogrel.
Pharmacogenomic testing showed that 34% of all patients were ultrametabolizers and 38% were extensive metabolizers. Patients in either of these categories metabolize enough clopidogrel into the active form to get full benefit from the drug and derive no additional efficacy benefit from switching to another P2Y12 inhibitor, such as ticagrelor or prasugrel (Effient) – drugs unaffected by metabolizer status. Testing also identified 25% of patients as intermediate metabolizers, who carry one loss-of-function allele for the CYP2C19 gene, and 3% were reduced metabolizers, who are homozygous for loss-of-function alleles. Standard practice is not to treat intermediate or reduced metabolizers with clopidogrel because they would not get an adequate antiplatelet effect; instead, these patients are usually treated with ticagrelor or with prasugrel when it’s an option.
After receiving the results regarding the clopidogrel-metabolizing status for each patient, attending physicians switched the drugs prescribed for only 7% of all patients: 9% of patients initially on ticagrelor and 4% of those initially on clopidogrel, reported Dr. Ohman, professor of medicine at Duke University in Durham, N.C. In addition, Dr. Ohman and his associates asked each participating physician who made a switch about his or her reasons for doing so. Of the patients who switched from clopidogrel to ticagrelor, only 23 were switched because of their pharmacogenomic results; this represents fewer than half of those who switched and only 2% of all patients who took clopidogrel. Only one patient changed from ticagrelor to clopidogrel based on pharmacogenomic results, representing 0.06% of all patients on ticagrelor.
“We believed the findings do not support the utility of mandatory testing in this context, as most did not act on the information,” Dr. Ohman said.
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Dr. Paul A. Gurbel
These findings “provide insight into perceptions of the utility of pharmacogenomic testing” for clopidogrel metabolism, commented Paul A. Gurbel, MD, a professor of medicine at Johns Hopkins University in Baltimore and director of the Inova Center for Thrombosis Research and Translational Medicine in Falls Church, Va. “The switching was low, and when patients were switched, it usually wasn’t for genetic reasons but for other reasons,” said Dr. Gurbel, designated discussant for the report. “We need to do better. We need to treat patients based on their biology,” he said in an interview.
A major reason for the inertia, Dr. Gurbel suggested, may be the absence of any compelling data proving whether there’s any effect on clinical outcomes for switching reduced metabolizers off of clopidogrel or switching good metabolizers onto it.
“We have no large-scale, prospective data supporting pharmacogenomic-based personalization” of clopidogrel treatment leading to improved outcomes, but “we need to get over that,” he said. “It’s a challenge to get funding for this.” But “the answer is not to give ticagrelor or prasugrel to everyone because then the bleeding rate is too high.”
The findings Dr. Ohman reported came from the Study to Compare the Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome (GEMINI-ACS-1), which had the primary goal of comparing the safety in acute coronary syndrome patients of a reduced dosage of rivaroxaban plus either clopidogrel or ticagrelor with the safety of aspirin plus one of these P2Y12 inhibitors. The primary endpoint was the rate of clinically significant bleeding events during a year of treatment. The study ran at 371 centers in 21 countries and showed similar bleeding rates in both treatment arms (Lancet. 2017 May 6; 389[10081]:1799-808).
The analysis also showed that patients identified as reduced metabolizers were fivefold more likely to be switched than patients identified as ultra metabolizers, and intermediate metabolizes had a 50% higher switching rate than ultra metabolizers. The rates of both ischemic and major bleeding outcomes were roughly similar across the spectrum of metabolizers, but Dr. Ohman cautioned that the trial was not designed to assess this. Dr. Gurbel urged the investigators to report on outcomes analyzed not just by metabolizer status but also by the treatment they received.
The boxed warning that clopidogrel received in 2010 regarding poor metabolizers led to “regulatory guidance” during design of the GEMINI-ACS-1 trial requiring routine pharmacogenomic testing for clopidogrel-metabolizing status, Dr. Ohman explained.
The trial was funded by Janssen and Bayer, the two companies that jointly market rivaroxaban (Xarelto). Dr. Ohman has been a consultant to Bayer and several other companies including AstraZeneca, the company that markets ticagrelor (Brilinta). He has also received research funding from Janssen, as well as Daiichi Sankyo and Gilead Sciences. Dr. Gurbel holds patents on platelet-function testing methods.
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