AHA: Genetics May Hold Key to Anticoagulant Dosing

ORLANDO, Nov. 8 -- Genotype-driven dosing may not make warfarin (Coumadin) safer, researchers were surprised to find, but cardiologists said the strategy may still be useful.
Action Points
Explain to interested patients that the study suggested that certain subgroups of patients may benefit from genotype-driven warfarin dosing, but further study is needed to confirm this exploratory finding.
Out-of-therapeutic-range prothrombin times were not less common with the pharmacogenetic algorithm than with standard empirical dosing, according to results of a randomized trial presented here at the American Heart Association meeting and released simultaneously online in Circulation: Journal of the American Heart Association.
But initial doses chosen based on genotype were closer to patients' eventual stable doses (P0.001) and subsequent dosing adjustments were smaller (P=0.002) and less frequent (P=0.03) than with empirical dosing, reported Jeffrey L. Anderson, M.D., of Intermountain Healthcare and the University of Utah in Salt Lake City, and colleagues.
These results were promising, said Gordon F. Tomaselli, M.D., of Johns Hopkin, who moderated a press conference in which the results were presented.
The study demonstrated that genotyping could prospectively determine an appropriate and nonarbitrary warfarin dose for patients, and "that's actually useful," he said.
The FDA has recommended genotyping to optimize warfarin dosing, for which "clinical management is difficult because of a narrow therapeutic index and marked interpatient variability in metabolism leading to unpredictable and variable (up to 20-fold) dosing requirements," the researchers said.
The Couma-Gen study included 200 adults with an indication for warfarin who were randomized to receive the drug according to a standard algorithm of 10 mg on days one and two followed by 5 mg daily or by a pharmacogenetic algorithm based on genotype, age, sex, and weight.
A measure of prothrombin time, the international normalized ratio (INR), was monitored periodically throughout the study and as indicated clinically. An out-of-range INR was considered anything outside of the 1.8 to 3.2 range because ratios lower than two are associated with increasing risk of thrombotic events and ratios higher than three carry a bleeding risk.
The researchers collected buccal DNA samples from all patients. The DNA was run through polymerase chain reaction using probes on commercially available equipment and tested with high-resolution melting profile analysis to identify genotype of CYP2C9 *2 and *3 and VKORC1.
Variants of these genes, age, and weight together account for half of dose variability, Dr. Anderson said. These factors were used to determine initial doses for the pharmacogenetic group, which ranged from 7 to 56 mg per week whereas the standard initial dose was 35 mg per week.
Overall, 79.6% of patients in the standard warfarin-dosing arm and 61% of those in the pharmacogenetic dosing arm had at least one variant.
Pharmacogenetic-guided dosing failed to reduce the percentage of INRs per patient that were outside the therapeutic range compared with standard dosing (30.7% versus 33.1%, P=0.47), which was the primary endpoint.
However, there was a significant benefit when excluding patients with only one variant (41% of patients overall). Together, wild-type allele carriers (about 80% for each genotype) and multiple variant carriers showed a 10% reduction in percentage of INRs outside the therapeutic range with pharmacogenetic dosing (29% versus 39%, P=0.03).
Wild-type patients required higher doses (P=0.001), whereas multiple variant carriers required lower doses (P0.001).
Adverse events were not significantly different between groups (34 versus 42, P=0.26).
One reason the study failed overall could have been that patients in both groups were aggressively managed, commonly with daily measurement of INRs, the researchers noted.
The pharmacogenomic strategy might be more beneficial in "less closely managed and outpatient-based initiation programs," they said.
The study was funded by grants from the Deseret Foundation, Intermountain Healthcare, and the Critical Path Institute.
The researchers and Dr. Tomaselli reported no conflicts of interest.
Additional source: Circulation: Journal of the American Heart AssociationSource reference: Anderson JL, et al "Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation"Circulation 2007; DOI: 10.1161/CIRCULATIONAHA.107.737312.