Long-term clinical outcomes of patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists: A prospective, multicenter cohort study of elderly patients with venous thromboembolism.

M. Nagler1, A. Angelillo-Scherrer1, M. Mean1, A. Limacher1, C. Abbal2, M. Righini3, H.-J. Beer4, J. Osterwalder5, B. Frauchiger6, M. Aschwanden7, C. Matter8, N. Kucher1, J. Cornuz2, M. Banyai9, M. Husmann8, D. Staub7, L. Mazzolai2, O. Hugli2, N. Rodondi1, D. Aujesky1 (1Bern, Switzerland, 2Lausanne, Switzerland, 3Geneva, Switzerland, 4Baden, Switzerland, 5St. Gallen, Switzerland, 6Frauenfeld, Switzerland, 7Basel, Switzerland, 8Zurich, Switzerland, 9Lucerne, Switzerland)

Antithrombotic treatment
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: The application of individualized medicine based on genetic factors to patients requiring anticoagulant treatment is hampered by a lack of knowledge on their long-term effects on relevant clinical outcomes. To fill this gap, we examined the association between polymorphisms of the vitamin K-epoxide reductase (VKORC1) as well as the cytochrome P450 enzyme gene (CYP2C9) and long-term clinical outcomes in a prospective, multicenter cohort study of elderly patients treated with vitamin K antagonists (VKA) for venous thromboembolism (VTE; SWITCO65+).

Methods: Consecutive patients aged 65 years or older with an acute, objectively confirmed VTE were identified between 2009 and 2013 in all five university hospitals and four high-volume non-university hospitals in Switzerland. The primary outcome was the time to any event, i.e. overall mortality, major- and non-major clinically relevant bleeding, or recurrent VTE.

Results: Overall, 774 patients were followed for a median duration of 30.1 months. The primary outcome occurred in 334 patients (43.2%) and 119 patients died (15.4%). Major bleeding happened in 100 patients (12.9%), clinically relevant non-major bleeding in 167 patients (21.6%), and recurrent venous thromboembolism in 100 patients (12.9%). After adjustment, the presence of CYP2C9 variants was significantly associated with any clinical event (hazard ratio [HR] 1.34; 95% CI 1.08, 1.66), death (HR 1.74; 95% CI 1.19, 2.52) and clinically relevant non-major bleeding (sub hazard ratio [SHR] 1.38; 95% CI 1.01, 1.55). It was not associated with major bleeding (sub hazard ratio [SHR] 1.03; 95% CI: 0.69, 1.55) and recurrent VTE (SHR 0.95; 95% CI 0.62, 1.44). The presence of VKORC1 variant was not associated with any clinical event. No relevant differences in the percentage of time spent within the therapeutic range were observed in patients with and without CYP2C9 variants.

Conclusion: In conclusion, our results demonstrate a significant association between CYP2C9 polymorphisms and deaths, probably because of effects independent from quality of anticoagulation and major bleeding. Future investigations shall confirm this observation in independent cohorts as well as patients with atrial fibrillation and address the causal relationship.