【作者】 王平；

【导师】 孙鹤；

【作者基本信息】 天津大学 ， 药事管理， 2014， 博士

【摘要】 华法令作为目前应用最广的一线口服抗凝药，在临床应用中存在着很多局限性，主要表现为治疗窗较窄，剂量反应的个体差异较大以及严重的药物相互作用，被美国FDA列为不良反应发生率较高的十个药物之一。为减少其局限性，需要对其临床应用进行质量控制与管理。本课题确定了质量控制管理指标TTR，荟萃分析结果表明其与出血和血栓栓塞不良反应事件均存在负相关性。在此基础上，提出了能够提升TTR的三个质量控制管理策略，包括抗凝门诊、患者自我监测与管理以及剂量模型的临床应用，并对剂量模型的临床应用进行了深入研究。首先，通过开展复方丹参滴丸-华法令药物相互作用临床试验研究搜集衍生集数据，构建了基于早期INR监测结果的剂量预测模型，并对模型进行整体适应性和有效性验证。验证结果表明，该模型的实际预测能力优于遗传剂量模型，可以解释86.8%的患者对华法令稳态剂量的个体差异，并且预测剂量的66.7%位于实际剂量±20%范围内。因此，早期的INR监测可以提供包括基因多态性和其他未知影响因素在内的综合信息，替代遗传基因信息反应患者对华法令的敏感性，提高剂量预测的准确性，在华法令临床应用中发挥重要的作用。在此基础上，应用决策树模型结合马尔科夫模型分别对INR剂量模型和遗传剂量模型进行成本-效用分析，为剂量模型在临床中的应用推广提供决策依据。分析结果表明，当TTR提升超过14.5%、INR超出疗效范围比例低于10.4%（TTR提升13.5%）或者CYP2C9和VKORC1基因类型的检测费用低于187.5美元/次（TTR提升13.5%，INR超出疗效范围为10.6%）时，遗传剂量模型才具有成本效用。而本课题建立的INR剂量模型只要较常规治疗对TTR有提升作用，便可在提高患者的质量生命调整年QALY的同时降低治疗费用，其在成本效用方面较遗传剂量模型具有显著的优势。本课题提出的华法令抗凝治疗的质量控制管理策略，特别是所建立的基于早期INR监测结果的INR剂量预测模型从抗凝治疗的有效性、安全性以及社会效益方面提升华法令临床应用的质量，为华法令临床应用的质量控制管理的前瞻性研究提供了决策依据。更多还原

【Abstract】 Warfarin is the most widely used first-line anticoagulant. Despite its effectiveness, ithas long been listed among the top ten drugs causing adverse events by FDA due to itsnarrow therapeutic range, large variations in individual dosing and significant druginteractions. So it is necessary to conduct quality control and management on itsclinical application of anticoagulant therapy.The results of meta-analysis indicated that TTR which was selected as the qualitycontrol index had negative correlations with hemorrhagic and thrombotic adverseevents. Anticoagulantion clinic, patient self-monitor/management and dosing modelcould improve the value of TTR. And dosing model was the most focused researchtopic of this study.Deriving from the warfarin-Dantonic drug-drug interaction clinical trial, a warfarindosing model based on early INR response and subsequent dose was established andeven more accurate than pharmacogenetic model through predicted performancecomparison. The established INR dosing model could explain86.8%of variations inindividual dosing, and the proportion of subjects whose predicted doses were within20%of their actual therapeutic doses was66.7%. Thus, early INR could provideinformation about warfarin sensitivity additional to that provided by genepolymorphism and improve the prediction accuracy of dosing model.Decision tree and Markov models were combined to conduct cost-effectivenessanalysis of INR and pharmacogenetic dosing models for the evidence-based decisionmaking. It indicated that pharmacogenetic dosing model was cost-effect if TTR wasimproved by14.5%, the proportion of INR above the therapeutic range was below10.4%or the costs for the measurements of CYP2C9and VKORC1were below187.5USD/time. However, the established INR dosing model was cost-effect if TTR couldbe improved comparing with the usual care. INR dosing model could increase theQALY and reduce the costs of anticoagulant therapy simultaneously. And it showedsignificant advantage in the cost-effectiveness perceptive comparing with thepharmacogenetic dosing model.Strategies for the quality control and management on warfarin anticoagulant therapyarisen from this study, especially the established INR dosing model could improve theeffectiveness, safety of anticoagulant therapy and its benefit to society. Results of this study provided the evidence for the warfarin clinical application evidence-baseddecision making.更多还原