Personalized medicine may not be best means of guiding warfarin therapy, a study published online June 16 in JAMA suggests. In an analysis of outcomes of nine studies across the U.S., Europe and Israel, no benefit to utilizing genetic testing for markers CYP2C9, VKORC1, and CYP4F2 vs. standard algorithms for dosing were seen.
First author Kathleen Stergiopoulos, MD, of the Division of Cardiovascular Medicine at Stony Brook University in New York and colleague reviewed the results of the nine trials, with a total of 2,812 randomized patients taking warfarin, acenocoumarol, or phenprocoumon. They then analyzed outcomes including the incidence of major bleeding and thromboembolitic events, the percentage of time the international normalized ratio (INR) was within the therapeutic range and the percentage of patients with an INR greater than four.
“[G]enotype-based dosing would seem to be an ideal application of personalized medicine. However, the present meta-analysis indicates that genotype-guided warfarin dosing does not result in laboratory or clinical evidence of improved outcomes,” Stergiopoulos et al stated.
Little difference was seen between the groups of patients. Major bleeding was reported in 0.9 percent of patients in the pharmacogenomics cohort, as opposed to 1.6 percent of those receiving clinically based doses. An INR greater than four was seen in 28 percent of the clinical group, as opposed to 25.8 percent of genomic dosing patients.
The percentage of time the INR was within the therapeutic range was 0.14 greater in the genetic treatment group than in the clinical dosage group. The genotype cohort had a risk ratio of 0.92 for an INR greater than four in the genotype-guided cohort.
This seems to point to there being as much to the variance in dosing for warfarin and it’s analogues in the everyday lives of the patients as their alleles.
They noted, however, that the clinically based dosing techniques for the patients across all trials were done in extremely controlled clinical environments with frequent testing, unlike actual clinical practice in adjusting medications where testing happens less frequently. They also noted that variations in the time in therapeutic range across the studies seemed to indicate that different methods were used to determine that outcome.
In an editorial, Dhruv S. Kazi, MD, MSc, MS, of the Department of Medicine at the University of California, San Francisco, and colleague wrote, “[T]he primary use of genotyping is in identifying the starting dose of warfarin, and because patients’ genes do not change while their environment does, there is only a narrow window of time in which genetic testing might be useful in warfarin management.”
Kazi et al went on to state, “Routine use of genetic testing to guide warfarin management cannot be recommended.”
Stergiopoulos et al concluded that, “At this time, it would appear prudent to allocate increasingly scarce financial resources to establishing better infrastructure for INR testing, communication between patient and provider, implementation of validated clinical anticoagulation protocols, and promoting patient adherence rather than to testing for genotype and incorporating that information into genotype-based dosing algorithms.”