Pharmacogenetics Puzzle

Conflicting clinical trial results leave researchers unsure whether genetic information is useful for determining initial Warfarin dosage.

By | November 20, 2013

WIKIMEDIA, CDCWhen touting the benefits of pharmacogenetic testing, researchers often point to screening for variants in CYP2C9 and VKORC1 to determine dosing of the anticoagulant drug Warfarin as a prime example. But results released yesterday (November 19) from the Clarification of Optimal Anticoagulation Through Genetics (COAG) Phase 3 trial suggest that the use of genetic information in determining a patient’s initial dose of the blood thinner does not result in better drug response than when dosage assessments are based on clinical data alone. Further, the results showed that considering genetic information when dosing African American patients actually led to poorer anticoagulation control, compared with initial prescriptions based solely on clinical data. The work was published online in the New England Journal of Medicine (NEJM).

“Given the lack of definitive information on whether or not pharmacogenetics can improve the care of patients and the need to study a broad range of patients being treated with warfarin, we needed a large clinical trial like COAG to help resolve this important question,” University of Pennsylvania Perelman School of Medicine’s Stephen Kimmel, principal investigator of the trial, said in a statement. “At this point, genetic information on top of clinical information doesn’t make a difference,” Kimmel told Reuters.

Meanwhile, a separate team reported in NEJM this week (November 19) that CYP2C9 and VKORC1 genotype information led to fewer incidences of excessive anticoagulation, and helped researchers determine a patient’s proper dosage more quickly.

Speaking at the American Heart Association (AHA) meeting being held in Dallas, researchers expressed mixed feelings about the new data. “The bottom line is it looks like, although genetic testing does give you incremental information, [but] the knowledge that you gain is not enough to really have a big impact clinically; enough to make it worth the considerable trouble and cost it takes to do it,” MedPage Today quoted Duke University’s Robert Califf, a coauthor on the COAG study, as saying at the AHA conference.

Brian Olshansky from the University of Iowa added: “For the overall populations that are involved here, the benefits are so small compared to the amount of effort that is taken—and perhaps the expense—that I don’t really see it fitting into clinical medicine at this point unless we can really better define the populations,” MedPage reported.

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Avatar of: geneyouin


Posts: 6

November 21, 2013

The most critical factor in PGx trials is test's sensitivity - i.e. the ability to idenify enthnic-specific rare variations that impact drug dose. Based on trial's results it is evident that the study used very limited set of markers in CYP2C9 and VKORC1, and as a result most of African Americans were misclassified, so no wonder the trial failed!  

It is very disappointing when physicians do not consult genetic experts and are trying to cut corners to "reduce the cost" of testing, but acheive opporite result. Similar story pappened with clopidogrel's trial (Pare 2010 NEJM) - another case of misclassified metabolizers.

Single drug tests are doomed to be not cost effective, as they ignore all other medications and potential interactions. How many patients take ONLY warfarin??? Most of these people are on statins and antihypertensives, so testing for all of them with incremental cost of a few $$ can make huge difference on cost-efficiency and clinical outcomes.

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