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Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation
Author(s) -
Serna María José,
RiveraCaravaca José Miguel,
GonzalezConejero Rocío,
EstevePastor María Asunción,
Valdés Mariano,
Vicente Vicente,
Lip Gregory Y.H.,
Roldán Vanessa,
Marín Francisco
Publication year - 2018
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/eci.12929
Subject(s) - medicine , atrial fibrillation , vitamin k antagonist , gastroenterology , vitamin k epoxide reductase , cyp2c9 , warfarin , gastrointestinal bleeding , cardiology , cytochrome p450 , metabolism
Background Polymorphisms in the vitamin K epoxide reductase complex 1 ( VKORC 1 ) and cytochrome P450 2C9 ( CYP 2C9 ) genes increase the bleeding risk in anticoagulated atrial fibrillation ( AF ) patients. Here, we aimed to investigate whether VKORC 1 and CYP 2C9 polymorphisms improved the predictive performance for major bleeding using the HAS ‐ BLED score. Material and methods We recruited 652 consecutive AF patients stable on vitamin K antagonist ( INR 2.0‐3.0) during at least the previous 6 months. A baseline venous blood sample was obtained for DNA extraction. We gave an extra point to the HAS ‐ BLED score if the patient was a simultaneous carrier of the VKORC 1 and CYP 2C9 polymorphisms related to bleeding, and we called this modified score “ GEN | HAS ‐ BLED .” During a median follow‐up of 7.6 years ( IQR 5.6‐8.0), all major bleeding events were recorded. Results During follow‐up, 106 (16.2%) patients experienced a major bleeding (2.81%/y; 42 intracranial haemorrhages and 44 gastrointestinal bleeding) and 24 (3.7%) died from major bleeding (0.48%/y). Cox regression analyses demonstrated a significant association between HAS ‐ BLED or GEN | HAS ‐ BLED and major bleeds, both as continuous or categorical scores. Comparison of receiver operating characteristic ( ROC ) curves shows that original HAS ‐ BLED clinical score had better predictive ability than GEN | HAS ‐ BLED (0.660, 95% CI 0.622‐0.696 vs 0.645, 95% CI 0.607‐0.682; P = .030). Discrimination and reclassification analyses showed that GEN | HAS ‐ BLED did not improve sensitivity compared with the original score and even showed significant negative reclassification. Conclusion Adding pharmacogenetic factors (ie polymorphisms of the VKORC 1 and CYP 2C9 genes) to the HAS ‐ BLED score does not improve the prediction or discrimination performance for major bleeding.