A new meta-analysis of clinical trials scrutinizing warfarin dosing methods found that warfarin treatment guided by individual genotypes reduced instances of serious bleeding by more than half compared to standard dosing approaches.
The work lends support to the importance of genetic testing for the genes CYP2C9 and VKORC1, variations of which can influence warfarin’s therapeutic effect. In August 2007, the U.S. Food and Drug Administration revised the drug labeling for Coumadin, a brand name of the anticoagulant warfarin, to describe the genetic factors that affect dose requirements.
The new study, appearing in the September issue of the Journal of Thrombosis and Haemostasis, reviewed nine randomized controlled trials involving 2,812 patients that compared genotype-guided vs. clinically-guided warfarin dosing. Meta-analysis authors Franchini et al. found that the pharmacogenetic-guided dosing of warfarin and other similar medications (collectively referred to as VKAs) reduced major bleeding episodes by 52.5 percent.
Multiple pharmacogenetic-guided dosing algorithms have been developed to guide VKA therapy, the study authors write, as the role of CYP2C9 and VKORC1 variants in VKA response has been realized. Other more general recommendations regarding CYP2C9 and VKORC1 testing also exist, such as a 2008 American College of Medical Genetics policy statement commenting on the the appropriate use of these tests in the context of warfarin treatment.
“The [working group that developed the policy] determined that the analytical validity of these tests has been met, and there is strong evidence to support association between these genetic variants and therapeutic dose of warfarin,” the policy statement says.
“Although the routine use of warfarin genotyping is not endorsed by this work group at this time, in certain situations, CYP2C9 and VKORC1 testing may be useful, and warranted, in determining the cause of unusual therapeutic responses to warfarin therapy.”
Franchini et al. write that some previous studies on this topic, such as large 2013 study in the New England Journal of Medicine (NEJM), found little to no difference in the percentage of time in the therapeutic range of warfarin when clinical and genotype-based dosing strategies were compared. However, the meta-analysis authors contend, reduction of major bleeding may be the more important measure.
“…the right question for the clinician is not how much time patients spend within the therapeutic range during the initial phase of VKA treatment but whether or not the use of pharmacogenetic testing reduces the incidence of clinical complications as compared with clinically-guided dosing,” Franchini et al. write.
The PGx In Practice blog took a look at the 2013 NEJM study earlier this year and made a similar point about the use of time in therapeutic range as a measuring stick for the effectiveness of warfarin dosing guided by pharmacogenetic testing. While the 2013 NEJM study by Kimmel et al. provided valuable information, examination of adverse drug events such as major bleeding may be the more important endpoint for patient safety.
Learn more about CYP2C9 and VKORC1’s influence on warfarin here.