Long-term outcomes of elderly patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists.

Nagler, Michael; Angelillo, Anne; Méan, M; Limacher, A; Abbal, C; Righini, M; Beer, J H; Osterwalder, J; Frauchiger, B; Aschwanden, M; Matter, C M; Kucher, N; Cornuz, J; Banyai, M; Husmann, M; Staub, D; Mazzolai, L; Hugli, O; Rodondi, Nicolas and Aujesky, Drahomir (2017). Long-term outcomes of elderly patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists. Journal of thrombosis and haemostasis, 15(11), pp. 2165-2175. Wiley-Blackwell 10.1111/jth.13810

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BACKGROUND

The long-term effect of polymorphisms of the vitamin K-epoxide reductase (VKORC1) and the cytochrome P450 enzyme gene (CYP2C9) on clinical outcomes remains unclear.

OBJECTIVES

We examined the association between CYP2C9/VKORC1 variants and long-term clinical outcomes in a prospective cohort study of elderly patients treated with vitamin K antagonists for venous thromboembolism (VTE).

METHODS

We followed 774 consecutive patients aged ≥65 years with acute VTE from nine Swiss hospitals for a median duration of 30 months. The median duration of initial anticoagulant treatment was 9.4 months. The primary outcome was the time to any clinical event, i.e. the composite endpoint of overall mortality, major- and non-major bleeding, and recurrent VTE.

RESULTS

Overall, 604 (78%) patients had a CYP2C9 or VKORC1 variant. Three hundred thirty-four patients (43.2%) had any clinical event, 119 (15.4%) died, 100 (12.9%) had major and 167 (21.6%) non-major bleeding, and 100 (12.9%) recurrent VTE. After adjustment, CYP2C9 (but not VKORC1) variants were associated with any clinical event (hazard ratio [HR] 1.34; 95% confidence interval [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] 1.39; 95% CI 1.02-1.89), but not with major bleeding (SHR 1.03; 95% CI: 0.69-1.55) or recurrent VTE (SHR 0.95; 95% CI 0.62-1.44). Patients with genetic variants had a slightly lower anticoagulation quality.

CONCLUSIONS

CYP2C9 was associated with long-term overall mortality and non-major bleeding. While genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence. This article is protected by copyright. All rights reserved.

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