From February 2013 through August 2014, the University of Maryland program screened on a routine basis 557 patients undergoing percutaneous coronary intervention (PCI) – with a 5-hour turnaround time on the results – enrolled 446 into the program, found 67 patients with an “actionable” genotype, and actually prescribed an alternative therapy because of the genotype in 37 patients. Patients usually did not receive the genomic-guided treatment because of a contraindication, Dr. Shuldiner said. He concluded that the Maryland experience shows routine screening is doable, and with its strong evidence base warrants use in all catheterization labs.
Dr. Larisa H. Cavallari
PCI patients at the University of Florida in Gainesville also now routinely undergo genomic assessment,said during a separate session at the AHA meeting. “Physicians recently began starting their acute coronary syndrome (ACS) patients on ticagrelor, and then when they get the genotype if the patient has an allele associated with good metabolism and can’t afford ticagrelor and needs to change to clopidogrel we know it will be okay. That’s the way we deal with the delay” in getting the genomic results. “At least you know that the patient is protected [with ticagrelor] during the really hot period,” said Dr. Cavallari, director of the center for pharmacogenomics of the University of Florida.
“For ACS patients if you treat with prasugrel or ticagrelor then you’ve pretty much overcome the roadblock, but for patients on clopidogrel I think it is very reasonable to use genetic testing or platelet-reactivity testing, especially for patients with a stented left main coronary,” Dr. Jessica L. Mega said during a panel discussion with Dr. Cavallari at the meeting. “We have pretty good data to suggest that at least in the peri-PCI patients who are homozygous for the *2 allele [the worst clopidogrel metabolizers] should not be on a standard clopidogrel dosage.”
Dr. Jessica L. Mega
Dr. Mega agreed with other genetic-testing proponents who see a double standard surrounding these tests. “I think there is a little genetic exceptionalism going on, and people feel differently about using genomics compared with other biomarkers. We have good data, and we just need to act on it,” said Dr. Mega, a cardiologist at Brigham and Women’s Hospital in Boston. “If you had an ACS event and received a stent in your left anterior descending coronary and were known to have a *2 allele or had high on-treatment platelet activity would you want to go home on 75 mg a day of clopidogrel?” Dr. Mega asked during a talk at the meeting.
Warfarin dosing
Evidence has implicated polymorphisms in two genes, CYP2C9 and VKORC1, as playing key roles in warfarin metabolism and suggested that determination of a patient’s allele profile for these two genes could assist in more quickly finding the best warfarin dose for a patients requiring oral antithrombotic therapy to reach their target International Normalized Ratio (INR).
In late 2013, researchers reported results from two major prospective trials designed to test the efficacy of genetic analysis of these two genes. The results were split. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial with 455 patients in the United Kingdom and Sweden showed that genotype-based dosing at the start of warfarin therapy increased the time in the therapeutic range, the primary outcome, by 7 percentage points and reduced the incidence of excessive anticoagulation, the time required to reach a therapeutic INR, the time required to reach a stable dose, and the number of adjustments in the dose of warfarin (N. Engl. J. Med. 2013;369:2294-303). But results from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial, which included 1,015 patients at 18 U.S. centers, showed that after 4 weeks genotyping-based warfarin dosing produced no significant between-group difference in the mean percentage of time in the therapeutic range (N. Engl. J. Med. 2013;369:2283-93).These inconsistent results, and especially the COAG study’s inability to show a benefit from genetic analysis in improving warfarin-dose selection, “called into question the clinical utility” of genetic testing, Dr. Cavallari wrote in a comment she coauthored last July (Clin. Pharmacol. Ther. 2014;96:22-4).
But recent data from Dr. Cavallari’s research group suggests that the value of genetic testing in patients starting warfarin may have been masked by the high proportion of African Americans in the COAG study, 27% of enrolled patients, and the finding that these patients did poorly because the alleles they carry most frequently were not covered by the genetic-test panel used in the study.
Before she moved to Gainesville, Dr. Cavallari worked at the University of Illinois in Chicago and she and her associates there began in August 2012 to routinely genotype patients prior to the start of warfarin treatment, using the information to guide initial dosing levels. The analyses they performed included several alleles commonly seen in African Americans – roughly two-thirds of the 389 patients they screened under this program were African American.