New meta-analysis shows 50 percent decrease in serious bleeding with genotype-guided warfarin
Warfarin is used widely to prevent thromboembolic events. Although genetic variability in CYP2C9 and VKORC1 have been shown to influence warfarin dosage requirements, studies investigating the impact of this variability on clinical endpoints have shown conflicting results.
Franchini and colleagues conducted a meta-analysis and systematic review of randomized controlled trials comparing genotype-guided versus clinically-guided warfarin dosing. Included trials were identified from a search of MEDLINE, EMBASE, and Cochrane database through March 2014. The primary study endpoints included incidence of major bleeding, thrombosis, and death during initiation of warfarin and other VKAs. Major bleeding was defined according to criteria from the International Society on Thrombosis and Haemostasis (ISTH).
Investigators analyzed a total of nine trials that included 2,812 patients; warfarin was the most commonly used vitamin K antagonist (VKA). The risk ratio (RR) for major bleeding events was decreased in the pharmacogenetic-guided group as compared with the control group (RR = 0.47; 95% CI 0.23–0.96; P = 0.04). The time in therapeutic range was increased in the pharmacogenetic group (50.9%) versus the control group (46.8%), but results did not reach statistical significance.
Results of this analysis differ from those of recent meta-analysis of the same studies by Stergiopoulos and colleagues, which concluded that genotype-guided dosing of warfarin, acenocoumarol, or phenprocoumon did not result in a greater percentage of patients time in therapeutic range, fewer patients with INR greater than 4, nor fewer major bleeding or thromboembolic events than use of clinical dosing protocols.
While authors of the current study do not address the discrepancies, they may result from differing endpoint definitions for major bleeding. Franchini and colleagues’ primary endpoint included major bleeding during initiation of therapy according to ISTH criteria, which defines bleeding as major if it meets one of the following: association with a drop in hemoglobin ≥ 2 g/dL; overt blood loss needing transfusion of ≥2 units of whole blood or erythrocytes; bleeding involving critical anatomical sites; and fatal bleeding. In contrast, Stergiopoulos and associates analyzed major bleeding as a secondary endpoint and defined this according to the endpoints of the original nine trials.
Authors of the current study commented that although this and similar analyses have not demonstrated decreased incidence of time in therapeutic range with genotype-guided warfarin dosing, the decreased bleeding endpoint is of greater clinical relevance.
“The right question for the clinician is not how much time patients spend within 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,” study authors wrote.
Find more information about these studies and genotype-guided warfarin dosing in the Pharmacogenomics Knowledgebase.
Franchini M et al. Effects on bleeding complications of pharmacogenetic testing for initial dosing of vitamin K antagonists: a systematic review and meta-analysis. J Thromb Haemost. 2014;12:1480-7.