M Nagler1,2, A Angelillo-Scherrer1,2, M Méan3,4, A Limacher5, C Abbal6, M Righini7, J H Beer8, J Osterwalder9, B Frauchiger10, M Aschwanden11, C M Matter12, N Kucher13, J Cornuz14, M Banyai15, M Husmann16, D Staub11, L Mazzolai17, O Hugli18, N Rodondi3,19, D Aujesky4. 1. Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 2. Department of Clinical Research, University of Bern, Bern, Switzerland. 3. Department of General Internal Medicine, Bern University Hospital, University of Bern, Bern, Switzerland. 4. Division of General Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland. 5. CTU Bern, and Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland. 6. Division of Hematology, Lausanne University Hospital, Lausanne, Switzerland. 7. Division of Angiology and Hemostasis, Geneva University Hospital, Geneva, Switzerland. 8. Cantonal Hospital of Baden, Baden, Switzerland. 9. Emergency Department, Cantonal Hospital of St Gallen, St Gallen, Switzerland. 10. Department of Internal Medicine, Cantonal Hospital of Frauenfeld, Frauenfeld, Switzerland. 11. Division of Angiology, Basel University Hospital, Basel, Switzerland. 12. Center for Molecular Cardiology, University of Zurich and University Heart Center, University Hospital Zurich, Zurich, Switzerland. 13. Division of Angiology, Bern University Hospital, University of Bern, Bern, Switzerland. 14. Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland. 15. Division of Angiology, Cantonal Hospital of Lucerne, Lucerne, Switzerland. 16. Division of Angiology, Zurich University Hospital and University of Zurich, Zurich, Switzerland. 17. Service of Angiology, Lausanne University Hospital, Lausanne, Switzerland. 18. Emergency Department, Lausanne University Hospital, Lausanne, Switzerland. 19. Institute of Primary Health Care, University of Bern, Bern, Switzerland.
Abstract
Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients ≥65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding. Patients with genetic variants have a slightly lower anticoagulation quality only. SUMMARY: 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 and 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 had (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. Although genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence.
Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients ≥65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding. Patients with genetic variants have a slightly lower anticoagulation quality only. SUMMARY: 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 and 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 had (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. Although genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence.
Authors: Tamara Mertins; Henning Nilius; Robin Boss; Matthias Knuchel; Andri Signorell; Carola A Huber; Eva Blozik; Johanna Anna Kremer Hovinga; Lucas M Bachmann; Michael Nagler Journal: Front Cardiovasc Med Date: 2022-08-03