胺碘酮对华法林安全性的影响

,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,胺碘酮对华法林安全性的影响,汇报人：杨剑辉 王颖,2013.07.24,1,背景：,华法林是目前最常用的抗凝血药，用于血栓栓塞性疾病的一级预防、二级预防和植入心脏瓣膜、房颤的全身栓塞预防。其最大的问题是用药剂量个体差异大，易受饮食、临床和人口因素、药物和病理生理因素的影响。,胺碘酮是最有效的抗心律失常药之一，用于预防和治疗室性和室上性心律失常。,胺碘酮,房颤,华法林,2,凝血因子,活化的凝血因子,还原型VK,氧化型VK,VK环氧化物还原酶,CYP2C9,VKORC1,靶点,代谢,华法林,基因多态性,3,文献一,回顾性队列研究（,1994-2009,）,配对对照，总共,7124,对。观察组和对照组在年龄，性别，入组时间上互相匹配。,年龄,66,岁，合用前至少,6,个月的华法林治疗，有稳定剂量。观察组有胺碘酮治疗，对照组没有胺碘酮的治疗。,观察时间：给予胺碘酮后30天内。,1,Lam, J., et al., Hospitalization for Hemorrhage Among Warfarin Recipients Prescribed Amiodarone. Am J Cardiol, 2013.,4,文献一,观察组,56,（,0.8%,）和对照组,23,（,0.3%,）个患者在给予胺碘酮后（观察组为入组时间）,30,天内因出血而住院，校正风险比,2.45,（,95%CI1.49-4.02,）。其中观察组因出血住院的,56,个患者中有,7,个在住院过程中死亡。,结论：老年人在服用华法林后开始使用胺碘酮，因出血而住院的风险增加两倍，且死亡率高，对这部分病人更密要切监测。,1,Lam, J., et al., Hospitalization for Hemorrhage Among Warfarin Recipients Prescribed Amiodarone. Am J Cardiol, 2013.,5,文献二,特点：胺碘酮和华法林同时使用，而不是在华法林剂量稳定后加用胺碘酮。,配对试验，,18,对。患者在年龄、性别和射血分数上互相匹配。,观察组同时使用胺碘酮（,600mg,）和华法林（,5mg,），对照组单独使用华法林（,5mg,）。华法林根据,INR,调整。,观察时间：同时使用5天内。,2,Edwin, S.B., D.L. Jennings and J.S. Kalus, An evaluation of the early pharmacodynamic response after simultaneous initiation of warfarin and amiodarone. J Clin Pharmacol, 2010. 50(6): p. 693-8.,6,文献二,结果：,1、5天观察期限内观察组的华法林总剂量和平均剂量均低于对照组。,2、5天观察期限内观察组有更多的患者INR2。,3、5天观察期限内观察组有更多的患者偏离INR的预期值。（第2、3、4和5天INR预期值分别为1.5、1.9和3）,结论：同时使用华法林和胺碘酮会导致早期华法林药效的提升，须在早期同时使用华法林和胺碘酮时加强监测。,2,Edwin, S.B., D.L. Jennings and J.S. Kalus, An evaluation of the early pharmacodynamic response after simultaneous initiation of warfarin and amiodarone. J Clin Pharmacol, 2010. 50(6): p. 693-8.,7,2,Edwin, S.B., D.L. Jennings and J.S. Kalus, An evaluation of the early pharmacodynamic response after simultaneous initiation of warfarin and amiodarone. J Clin Pharmacol, 2010. 50(6): p. 693-8.,8,文献三,研究胺碘酮与华法林在一个较长的时间内的相互作用的特征，胺碘酮的维持剂量和调整华法林剂量之间的关系。,病例数：43名。规律服用华法林的基础上加用口服胺碘酮，华法林的剂量根据INR值（2.03.0）调整。,开始使用胺碘酮之前的华法林基线剂量是 5.22.6 mg/d。,观察时间：两药至少同服1年。,3,Sanoski, C.A. and J.L. Bauman, Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest, 2002. 121(1): p. 19-23.,9,文献三,结果：这两种药物之间的相互作用的程度达到顶峰需7 周时间，此时，华法林剂量的平均最大减少 44%。华法林剂量与胺碘酮维持剂量成反比 。5 名患者 （12%）发生轻微出血 。对于接受胺碘酮维持剂量的 400、 300、 200或 100 mg/d 的患者，则建议每日的华法林剂量分别减少了约 40%、 35%、 30%或 25%。,结论：胺碘酮与华法林相互作用的程度是高度依赖于胺碘酮维持剂量。可根据胺碘酮剂量来调整华法林的剂量。,3,Sanoski, C.A. and J.L. Bauman, Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest, 2002. 121(1): p. 19-23.,10,其他关于合用华法林剂量调整,在华法林抗凝血功能稳定后加用胺碘酮，华法林需减量6-65%。,4,根据临床经验，稳定抗凝治疗的患者加用胺碘酮，推荐华法林减量30%。,5,5,Kurnik D, Loebstein R, Farfel Z, et al. Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid glandJ. Medicine, 2004, 83(2): 107-113.,4,McDonald M G, Au N T, Wittkowsky A K, et al. WarfarinAmiodarone DrugDrug Interactions: Determination of (u)/K(I,u) for amiodarone and its plasma metabolitesJ. Clinical Pharmacology & Therapeutics, 2012, 91(4): 709-717.,11,文献四,病例数：82（合用卡马西平组5，合用胺碘酮组6，合用他汀组17，单独华法林组54）,入选标准：CYP2C9*1/*1,服用华法林6个月，维持稳定剂量两个月。,年龄：73.14 (7.28）,观察指标：华法林剂量，体内华法林对映体血药浓度（S/R），华法林代谢物7-和10-羟基华法林。,6,Herman, D., et al., The influence of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose. Eur J Clin Pharmacol, 2006. 62(4): p. 291-6.,12,文献四,胺碘酮组与单独华法林组的各个参数都没有统计学意义。,可能原因：病例数少，胺碘酮剂量低（200mg/d）,6,Herman, D., et al., The influence of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose. Eur J Clin Pharmacol, 2006. 62(4): p. 291-6.,13,文献五,华法林和胺碘酮合用导致华法林抗凝血功能增强和出血风险增高的可能机制：,胺碘酮通过抑制CYP2C9而抑制S-华法林代谢为S-7-羟基华法林。,通过抑制CYP1A2而抑制R-华法林代谢为R-6-羟基华法林，然而该做用对抗凝血功能影响小。,7,另有文献报导，胺碘酮转化为活性代谢产物去乙基胺碘酮竞争性地抑制CYP2C9。,8,7,Heimark L D, Wienkers L, Kunze K, et al. The mechanism of the interaction between amiodarone and warfarin in humansJ. Clinical Pharmacology & Therapeutics, 1992, 51(4): 398-407.,8,Naganuma M, Shiga T, Nishikata K, et al. Role of desethylamiodarone in the anticoagulant effect of concurrent amiodarone and warfarin therapyJ. Journal of cardiovascular pharmacology and therapeutics, 2001, 6(4): 363-367.,14,小结,在稳定服用华法林的基础上加用胺碘酮会使出血风险加倍，且导致的死亡率较高。同时使用华法林和胺碘酮时，胺碘酮在早期就可以使华法林疗效提升，因此早期就需加强监测。胺碘酮与华法林相互作用的程度是高度依赖于胺碘酮维持剂量。可根据胺碘酮剂量调整华法林剂量，根据文献报道加用胺碘酮可使华法林剂量减少6-65%，临床经验是减少1/3-1/2，密切监测INR。,胺碘酮通过抑制CYP2C9而抑制华法林代谢为无活性产物，其是否与CYP2C9的基因多态性有关可为将来的研究提供方向。,15,参考文献,1,Lam J, Gomes T, Juurlink D N, et al. Hospitalization for Hemorrhage Among Warfarin,Recipients Prescribed AmiodaroneJ. The American journal of cardiology, 2013.,2 Edwin S B, Jennings D L, Kalus J S. An evaluation of the early pharmacodynamic response after simultaneous initiation of warfarin and amiodaroneJ. The Journal of Clinical Pharmacology, 2010, 50(6): 693-698.,3 Sanoski C A, Bauman J L. Clinical Observations With the Amiodarone/Warfarin InteractionDosing Relationships With Long-term TherapyJ. CHEST Journal, 2002, 121(1): 19-23.,4 McDonald M G, Au N T, Wittkowsky A K, et al. WarfarinAmiodarone DrugDrug Interactions: Determination of (u)/K(I,u) for amiodarone and its plasma metabolitesJ. Clinical Pharmacology & Therapeutics, 2012, 91(4): 709-717.,5 Kurnik D, Loebstein R, Farfel Z, et al. Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid glandJ. Medicine, 2004, 83(2): 107-113.,6 Herman D, Locatelli I, Grabnar I, et al. The influence of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance doseJ. European journal of clinical pharmacology, 2006, 62(4): 291-296.,7 Heimark L D, Wienkers L, Kunze K, et al. The mechanism of the interaction between amiodarone and warfarin in humansJ. Clinical Pharmacology & Therapeutics, 1992, 51(4): 398-407.,8,Naganuma M, Shiga T, Nishikata K, et al. Role of desethylamiodarone in the anticoagulant effect of concurrent amiodarone and warfarin therapyJ. Journal of cardiovascular pharmacology and therapeutics, 2001, 6(4): 363-367.,16,Thank You !,17,