Gene-Based Algorithm Allows Individualized Warfarin Dosing

ST. LOUIS, Aug. 22 -- Safer, more predictable warfarin therapy could come from pretreatment genotyping to individualize dosing, investigators reported.

Combining data on polymorphisms for two genes with clinical variables resulted in an algorithm that accounted for 79% of the variability in therapeutic dose in orthopedics patients, Brian F. Gage, M.D., of Washington University here, and colleagues reported online and in the Sept. 1 issue of Blood.

"Ultimately, with further validation and refinement, this pharmacogenetic model should yield a streamlined approach to refining the dose and improving the safety and efficiency of warfarin initiation," the authors concluded.

Marked variation in individual dosing requirements and a narrow therapeutic index have long complicated the use of warfarin. Doses that are too high or too low increase the risk of potentially serious adverse events, including fatal bleeding.

Two common single nucleotide polymorphisms in the cytochrome P450 2C9 system are associated with impaired warfarin metabolism, the authors noted. SNPs in the VKORC1 gene for vitamin K epoxide reductase complex correlate with warfarin sensitivity and resistance.

Last week the FDA announced labeling changes for warfarin to reflect the availability of genotyping tests for VKORC1 and the two CYPC29 variants (See FDA Alters Warfarin Label to Reflect Gene Tests for Bleeding Risks).

"Given the current knowledge about these markers, we hypothesize that for a given [international normalized ratio] a patient who is a slow metabolizer of warfarin may need a more cautious adjustment in their dose than a similar patient who is a normal metabolizer," the authors stated.

To test their hypothesis, the investigators used genetic and clinical information to develop a dose-refinement nomogram. They used data on two groups of patients who had participated in two prospective studies of pharmacogenetic-based warfarin therapy. All the patients were scheduled for primary or revisions of total knee or hip arthroplasty.

For genotyping the investigators collected a sample of anticoagulated blood from each patient. Each sample was genotyped for SNPs in the CPY2C9 and VKORC1 genes.

The study involved a total of 118 patients whose median age was 59. The therapeutic daily warfarin dose ranged from 1.36 to 13.75 mg. The arithmetic mean dose was 5.4 mg/d, and the geometric mean was 4.9 mg/d. Third-dose international normalized ratio (INR) averaged 1.7.

The final statistical model consisted of seven factors that were significantly associated with a higher therapeutic warfarin dose:

• Lower INR₃ (47% reduction per 0.25 unit rise)
• Higher first dose of warfarin (+7% per 1 mg)
• CYP2C9*2 and CYP2C9*3 (-38% and -17% per allele)
• VKORC1 (-11% per copy of haplotype A)
• Estimated blood loss (interaction with INR₃)
• Current smoking status (+20% in current smokers)

When combined into an algorithm, the factors accounted for about 80% of the variability in warfarin dosing.

Same-day genotyping is probably unavailable in many clinical settings, the authors pointed out. However, even poor metabolizers of warfarin who carry one copy of CYP2C9*2 OR CYP2C9*3 alleles have subtherapeutic doses for at least three days. So frequent INR monitoring should identify poor metabolizers before the INR reached supratherapeutic levels.

"Thus, provided the initial warfarin doses are not excessive and the INR is closely monitored, physicians may have a 3-day window between the time that they start warfarin and the time when they need to know genotype," the authors stated.

"The principle of a moderate initial dose followed by genetically tailored dose refinement should be broadly applicable. This knowledge, and the approach developed here, should allow for more effective and less expensive pharmacogenetics-based warfarin therapy," they concluded.

Although Dr. Gage and colleagues emphasized the need to validate the model in additional studies, they have made the dosing model available for free at www.warfarindosing.org.