Jiménez-Varo E, Cañadas-Garre M, Henriques C I, Pinheiro A M, Gutiérrez-Pimentel M J, Calleja-Hernández M Á
Marisa Cañadas-Garre, PhD, Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain, Tel.: +34 958020108, Fax: +34 958020004, E-mail:
Thromb Haemost. 2014 Sep 2;112(3):522-36. doi: 10.1160/TH13-11-0941. Epub 2014 Jun 12.
Vitamin K antagonists (VKAs) remain as the most prescribed drug for treatment and prevention of thrombotic disorders in many countries, despite the recent approval of the new oral anticoagulants (NOACs). Although effectiveness and safety of VKAs are tightly associated to maintaining the patient within the international normalised ratio (INR) therapeutic range (TWR), they have been likened to NOACs when patients are in good INR control (≥66% of TWR). Therefore, assessing the safety of patients should be a priority in the selection of the anticoagulation therapy. The aim of this study was to evaluate the association between CYP2C92, CYP2C93, VKORC1, CYP4F23, ABCB1 C3435T, APOE, CYP2C192 and CYP2C1917 gene polymorphisms and treatment safety in 128 patients diagnosed with atrial fibrillation or venous thromboembolism during the initial first seven months of acenocoumarol therapy. After the first month, VKORC1-T-allele and APOE-E3/E3 genotype were independently associated to higher time above therapeutic range (TAR) and lower time below the therapeutic range (TBR). After seven months, VKORC1 T-allele predicted higher TAR, and was also associated to increased INR>4, particularly the TT-genotype (odds ratio [OR]: 32; 95% confidence interval [CI95%]: 6-175; p=810⁻⁵). C-alleles for CYP2C93 (OR: 5.5; CI95%: 1.8-17; p=0.003) and ABCB1 (OR: 8.9;CI95%: 1.1-70; p=0.039) independently influenced on INR>6 . Patients VKORC1-TT/ABCB1-C remained 26.8% [19.7-38.9] TAR, with associated relative risk (RR) for INR>4 1.8 higher (CI95%: 1.2-2.5; p=0.015). Patients VKORC1-TT also presented the highest risk of bleeding events (RR: 3.5;CI95%: 1.4-8.4; p=0,010). In conclusion, VKORC1, CYP2C9*3, APOE and ABCB1 genotypes should be considered in prevention of overanticoagulation and bleeding events in the initiation of acenocoumarol therapy.
尽管新型口服抗凝药（NOACs）最近已获批准，但在许多国家，维生素K拮抗剂（VKAs）仍是治疗和预防血栓性疾病最常用的药物。虽然VKA的有效性和安全性与将患者维持在国际标准化比值（INR）治疗范围（TWR）内密切相关，但当患者的INR控制良好（≥TWR的66%）时，VKA的效果与NOACs相当。因此，在选择抗凝治疗时，评估患者的安全性应是首要任务。本研究的目的是评估128例在醋硝香豆素治疗的最初七个月内被诊断为房颤或静脉血栓栓塞的患者中，CYP2C92、CYP2C93、VKORC1、CYP4F23、ABCB1 C3435T、APOE、CYP2C192和CYP2C1917基因多态性与治疗安全性之间的关联。第一个月后，VKORC1 - T等位基因和APOE - E3/E3基因型分别独立与高于治疗范围的时间（TAR）增加和低于治疗范围的时间（TBR）减少相关。七个月后，VKORC1 T等位基因预示着更高的TAR，并且还与INR>4增加相关，尤其是TT基因型（优势比[OR]：32；95%置信区间[CI95%]：6 - 175；p = 8×10⁻⁵）。CYP2C93的C等位基因（OR：5.5；CI95%：1.8 - 17；p = 0.003）和ABCB1的C等位基因（OR：8.9；CI95%：1.1 - 70；p = 0.039）分别独立影响INR>6。携带VKORC1 - TT/ABCB1 - C的患者TAR为26.8%[19.7 - 38.9]，INR>4的相关相对风险（RR）高1.8倍（CI95%：1.2 - 2.5；p = 0.015）。携带VKORC1 - TT的患者发生出血事件的风险也最高（RR：3.5；CI95%：1.4 - 8.4；p = 0.010）。总之，在醋硝香豆素治疗开始时预防过度抗凝和出血事件时，应考虑VKORC1、CYP2C9*3、APOE和ABCB1基因型。
