本文選題：華法令 + 質(zhì)量控制與管理　； 參考：《天津大學(xué)》2014年博士論文

【摘要】：華法令作為目前應(yīng)用最廣的一線口服抗凝藥，在臨床應(yīng)用中存在著很多局限性，主要表現(xiàn)為治療窗較窄，劑量反應(yīng)的個體差異較大以及嚴重的藥物相互作用，被美國FDA列為不良反應(yīng)發(fā)生率較高的十個藥物之一。為減少其局限性，需要對其臨床應(yīng)用進行質(zhì)量控制與管理。 本課題確定了質(zhì)量控制管理指標TTR，薈萃分析結(jié)果表明其與出血和血栓栓塞不良反應(yīng)事件均存在負相關(guān)性。在此基礎(chǔ)上，，提出了能夠提升TTR的三個質(zhì)量控制管理策略，包括抗凝門診、患者自我監(jiān)測與管理以及劑量模型的臨床應(yīng)用，并對劑量模型的臨床應(yīng)用進行了深入研究。 首先，通過開展復(fù)方丹參滴丸-華法令藥物相互作用臨床試驗研究搜集衍生集數(shù)據(jù)，構(gòu)建了基于早期INR監(jiān)測結(jié)果的劑量預(yù)測模型，并對模型進行整體適應(yīng)性和有效性驗證。驗證結(jié)果表明，該模型的實際預(yù)測能力優(yōu)于遺傳劑量模型，可以解釋86.8%的患者對華法令穩(wěn)態(tài)劑量的個體差異，并且預(yù)測劑量的66.7%位于實際劑量±20%范圍內(nèi)。因此，早期的INR監(jiān)測可以提供包括基因多態(tài)性和其他未知影響因素在內(nèi)的綜合信息，替代遺傳基因信息反應(yīng)患者對華法令的敏感性，提高劑量預(yù)測的準確性，在華法令臨床應(yīng)用中發(fā)揮重要的作用。 在此基礎(chǔ)上，應(yīng)用決策樹模型結(jié)合馬爾科夫模型分別對INR劑量模型和遺傳劑量模型進行成本-效用分析，為劑量模型在臨床中的應(yīng)用推廣提供決策依據(jù)。分析結(jié)果表明，當TTR提升超過14.5%、INR超出療效范圍比例低于10.4%（TTR提升13.5%）或者CYP2C9和VKORC1基因類型的檢測費用低于187.5美元/次（TTR提升13.5%，INR超出療效范圍為10.6%）時，遺傳劑量模型才具有成本效用。而本課題建立的INR劑量模型只要較常規(guī)治療對TTR有提升作用，便可在提高患者的質(zhì)量生命調(diào)整年QALY的同時降低治療費用，其在成本效用方面較遺傳劑量模型具有顯著的優(yōu)勢。 本課題提出的華法令抗凝治療的質(zhì)量控制管理策略，特別是所建立的基于早期INR監(jiān)測結(jié)果的INR劑量預(yù)測模型從抗凝治療的有效性、安全性以及社會效益方面提升華法令臨床應(yīng)用的質(zhì)量，為華法令臨床應(yīng)用的質(zhì)量控制管理的前瞻性研究提供了決策依據(jù)。
[Abstract]:As the most widely used first-line oral anticoagulant, warfarin has many limitations in clinical application, such as narrow therapeutic window, large individual difference in dose response and severe drug interaction.It is listed as one of the ten drugs with high incidence of adverse reactions by FDA in the United States.In order to reduce its limitation, it is necessary to control and manage its clinical application.The quality control index TTRs were determined in this study. The results of meta-analysis showed that TTRs were negatively correlated with hemorrhage and adverse events of thromboembolism.On this basis, three quality control strategies to improve TTR are proposed, including anticoagulant clinic, patient self-monitoring and management, and clinical application of dose model.Firstly, a dose prediction model based on early monitoring results of INR was constructed by collecting derived data from the clinical trial of compound Danshen drop pill and warfarin drug interaction, and the overall adaptability and validity of the model were verified.The results show that the actual predictive ability of the model is better than that of the genetic dose model, which can explain the individual difference of the steady-state dose of warfarin in 86.8% of the patients, and 66.7% of the predicted dose lies within the range of 鹵20% of the actual dose.Therefore, early INR surveillance can provide comprehensive information, including gene polymorphism and other unknown factors, to substitute the sensitivity of patients with genetic information response to warfarin and improve the accuracy of dose prediction.It plays an important role in the clinical application of propofol.On this basis, the cost-utility analysis of INR dose model and genetic dose model is carried out by using decision tree model and Markov model respectively, which provides the decision basis for the application and popularization of dose model in clinic.The results showed that the genetic dose model was cost-effective only when the proportion of TTR elevation over the therapeutic range was lower than that of 10.4%(TTR (13.5g) or the detection cost of CYP2C9 and VKORC1 gene types was less than $187.5 / time.As long as the dose model of INR can improve the quality of patients with TTR, it can reduce the cost of QALY while improving the quality of patients. It has a significant advantage over the genetic dose model in terms of cost utility.The quality control strategy of warfarin anticoagulant therapy proposed in this paper, especially the effectiveness of the established INR dose prediction model based on early INR monitoring results.Improving the quality of Warfarin clinical application in terms of safety and social benefits provides a basis for the prospective research on quality control management of Warfarin clinical application.
【學(xué)位授予單位】：天津大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R973

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