OBJECTIVE: The aim of this study was to investigate whether genetic variants can identify patients with venous thromboembolism (VTE) at an increased risk of bleeding with warfarin.
METHODS: Hokusai-venous thromboembolism (Hokusai VTE), a randomised, multinational, double-blind, non-inferiority trial, evaluated the safety and efficacy of edoxaban versus warfarin in patients with VTE initially treated with heparin. In this subanalysis of Hokusai VTE, patients genotyped for variants in CYP2C9 and VKORC1 genes were divided into three warfarin sensitivity types (normal, sensitive and highly sensitive) based on their genotypes. An exploratory analysis was also conducted comparing normal responders to pooled sensitive responders (ie, sensitive and highly sensitive responders).
RESULTS: The analysis included 47.7% (3956/8292) of the patients in Hokusai VTE. Among 1978 patients randomised to warfarin, 63.0% (1247) were normal responders, 34.1% (675) were sensitive responders and 2.8% (56) were highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders had heparin therapy discontinued earlier (p<0.001), had a decreased final weekly warfarin dose (p<0.001), spent more time overanticoagulated (p<0.001) and had an increased bleeding risk with warfarin (sensitive responders HR 1.38 [95% CI 1.11 to 1.71], p=0.0035; highly sensitive responders 1.79 [1.09 to 2.99]; p=0.0252).
CONCLUSION: In this study, CYP2C9 and VKORC1 genotypes identified patients with VTE at increased bleeding risk with warfarin.
TRIAL REGISTRATION NUMBER: NCT00986154.
Common to many other analyses, this one confirms that certain genotypes are associated with different responses to warfarin. In addition, the analysis found that there was more bleeding in patients who were sensitive to warfarin. This is important, and I am not sure that it has been shown before. However, I did not delve into how warfarin was dosed (maybe they should have done better), and the clinical implications are uncertain (unlikely to justify doing the genetic testing in patients started on warfarin).
Overanticoagulation is associated with more bleeding. It would be nice to know the time frame.