影響住院病患使用warfarin劑量適當性的相關因素分析

Factors affecting the maintenance dose of warfarin in hospitalized patients

黃獻民(Shiann-Min Huang)

指導教授 ： 顏銘宏

高雄醫學大學/藥學院/藥學研究所碩士在職專班/碩士(2011年)

摘要

研究背景：
Warfarin雖然在臨床上廣泛被應用於預防深部靜脈栓塞、心房纖維顫動或機械瓣膜置換所引起之栓塞疾病，但是卻也一直存在著讓人困擾的問題：就是它的治療指數太過狹窄，容易因個體間對於劑量反應程度不一，而且也潛藏著許多藥物與食物的交互作用等種種因素的影響，造成未能很有效的達到治療濃度。然而近年來藥物基因學(pharmacogenetics)的進步，透過許多研究結果發現，病患使用warfarin治療疾病的建議劑量與人類維他命K環氧化物還原酶(vitamin K epoxide reductase complex 1；VKORC1)及cytochrome P450(CYP)2C9基因的多型性(polymorphism)有關，將來只要抽血檢定病患的基因型，或許就能縮短達到有效濃度的時間，不過基因檢測的額外花費昂貴，以至於限制了推行的普遍性。而目前在臨床上，實際使用warfarin治療的情形，常常會發現給予建議劑量於老年人或體重過輕的病患時，其測得的國際標準凝血時間比(International Normalized Ratio; INR)值往往會超過目標範圍內，而可能存在出血併發症的風險。

研究目的：
本研究的目的希望能歸納出較確切的研究數據來作為warfarin用藥的依歸，所以藉由回溯性分析南台灣某區域教學醫院病患使用warfarin的劑量與年齡、性別、身高、體重、疾病狀態、凝血時間等種種相關因素，統合出影響用藥適當性的研究數據，並藉此規範出使用warfarin最適當的劑量，以提供醫師開立處方及用藥的參考，讓病患用藥更加安全。

研究方法：
本研究以回溯性方式納入南台灣某區域教學醫院在93年7月1日至98年12月31日期間藥歷記錄檔中連續使用warfarin至少7天的住院病患，並追蹤病患在住院前的用藥處方型態，以確認病患過去未曾使用warfarin治療或目前病患體內warfarin的藥物濃度已經排除等條件做為研究收案的標準。而後記述病患於研究期間使用warfarin的用藥紀錄、病患基本資料（包括年齡、性別、身高、體重、有無抽菸或喝酒習慣、有無服用中草藥）、疾病、出血併發症的紀錄以及住院期間所有國際標準凝血時間比(INR)的檢驗數值，甚至這些病患在第一次使用warfarin治療後的72-96小時期間，必須要常規的監測INR值至少一次，這樣的限制條件下，才能進一步分析這些病患在初次使用warfarin治療後，影響藥物使用劑量的相關因數。次分析再將病患族群分組探討，以瞭解老年族群及體重過重其身體質量指數(Body Mass Index; BMI)＞24的這類型病患在使用warfarin治療後，其治療劑量與INR的關係。

研究結果：
本研究共納入305位符合研究條件的住院病患，平均年齡69.3 ± 14.8歲，BMI為22.2 ± 3.7，男性與女性的比例為1.47:1。住院治療中都曾使用warfarin治療，其適應症包括有深層靜脈栓塞128人；心房顫動93人；肺栓塞35人；心肌梗塞20人；瓣膜性心臟病11人；心臟瓣膜置換18人，而這些病患的病史也相當複雜，還合併有其他可能影響warfarin治療的疾病因素，其中較常見的有高血壓(52.1%)、糖尿病(24.9%)、心臟衰竭(20.3%)、中風(16.4%)、冠狀動脈疾病(12.4%)、慢性阻塞性肺病(6.8%)、痛風(5.6%)、高血脂(5.2%)、B型肝炎(3.6%)等多種疾病因子，期望透過本研究的分析探討warfarin的治療劑量與各項因子的關聯性。研究結果發現：影響warfarin治療劑量的相關因子有中風(p＝0.01)、B型肝炎(p＝0.012)、C型肝炎(p<0.001)、肝硬化(p＝0.022)、BMI(p<0.001)、年齡(p<0.001)，而這些影響因子中以年齡及BMI值的相關性較高：warfarin治療劑量與年齡為負相關，相關係數＝–0.198(p＝0.001)；warfarin治療劑量與BMI為正相關，相關係數＝0.152(p＝0.008)，而且在進行次級分析發現，年齡大於65歲且BMI大於24的患者，warfarin的建議劑量應該小於或等於2.5 mg，這樣病患相對應的INR值落在正常範圍的比率才能提高。

結論：
雖然目前市面上還有許多抗凝血藥物可供醫療選擇使用，但是warfarin的使用量仍然相當龐大，所以藥物的療效及安全性仍然需要探討。透過本研究結果，可以瞭解到在初次施予warfarin治療時，其建議劑量應該多考量到病患的年齡、身體質量指數及疾病因素，以期較快達到適合病患疾病治療的目標INR值範圍，減少使用warfarin治療時發生出血副作用。
關鍵詞：warfarin建議劑量、年齡、身體質量指數、國際標準凝血時間比

關鍵字

warfarin建議劑量 ； 年齡 ； 身體質量指數 ； 國際標準凝血時間比

並列摘要

Background:
Warfarin is widely used to prevent deep vein thrombosis (DVT), arterial fibrillation (Af.) or mechanical valve replacement embolism for decades. However, there have been a nagging problem that therapeutic index is too narrow and failed to achieve an ideal treatment outcome, which was particularly associated with individuals / groups, co-prescribed drugs intake like vitamin K or other co-existing diseases. Although, some studies were found that warfarin maintenance dose was related to human vitamin K epoxide reductase complex 1(VKORC1) and cytochrome P450(CYP)2C9 gene polymorphisms. However, additional genetic testing is too expensive to be broadly used in clinical practice. Furthermore, it is found that International Normalized Ratio (INR) values tend to exceed the target range while giving dosage for the elderly or underweight patients and to increase the bleeding risk.
Objectives:
The purpose of this study hope to summarize the warfarin medication consensus guideline more accurately; therefore, retrospective study will be applied to analyze the affecting factors to warfarin dosage known as inpatients’ age, gender, body weight, body height, other conventional risk factors (hypertension, diabetes, smoking, alcoholism) and intervals of INR examination. This study hopes to identify the factors associated with warfarin appropriate dosage, to provide the prescription reference for physicians, and to enhance the drug safety.
Methods:
Inpatients who received warfarin treatment at least 7 days were recruited in this retrospective study form July 1 2004 to December 31 2009. Then we tracked these patients’ medication records and identified those did not treat with warfarin previously or not been found in plasma concentrations. Before going to analyze the research data, we described these inpatients’ medication records, INR values and basic information (including age, gender, body height, body weight, whether smoking or drinking habits, whether herbal medicine), past medical history (including major illnesses, any previous operations, any current ongoing illness), and bleeding complications. Under the conditions, this study performed a meta-analysis in dose-related factors affecting drug safety. In the second analysis, we classified these patients into four groups to understand individualized warfarin initiation program for older population and overweight patients.
Results:
This study included 305 inpatients in the criteria, and the average age of the inpatients was about 69.3 ± 14.8 years old; the ratio of male to female was 1.47:1. These inpatients had took warafrin for the indications including deep vein thrombosis (128 patients), atrial fibrillation (93 patients), pulmonary embolism (35 patients), myocardial infarction (20 patients), valvular heart disease (11 patients), heart valve replacement (18 patients), and these patients’ medical histories were quite complicated, that might be some factors affecting the treatment of warfarin. Including hypertension (52.1%), diabetes (24.9%), heart failure (20.3%), stroke (16.4%) , coronary artery disease (12.4%), chronic obstructive pulmonary disease (6.8%), gout (5.6%), hyperlipidemia (5.2%), hepatitis B (3.6%). We expected that we could understand the relationship between therapeutic dosage of warfarin and various factors through this study. The results showed: the affecting factors to warfarin dosage, including stroke (p = 0.01)、hepatitis B (p = 0.012)、hepatitis C(p <0.001)、 liver cirrhosis (p = 0.022)、BMI (p <0.001)、age (p <0.001). Among these affecting factors, that age and BMI were more relative to warfarin dosage (it was a negative correlation with age, correlation coefficient = - 0.198, p = 0.001, and it was a positive correlation with BMI, correlation coefficient = 0.152, p = 0.008). The secondary analysis found that patients’ age greater than 65 years old and BMI values over than 24, that it was suggested dosage should be less than or equal to 2.5 mg, the relative INR values of patients would be more successful falling in correctly therapeutic range.
Conclusions:
Although there were many kinds of anti-clotting drug to choose, but it was still quite large amount of warfarin therapy. So it still needed to monitor the efficacy and safety of drug treatment. Through this research results, I could understand the suggestion dose of warfarin that should be more considerate of the patient's age, BMI and disease influence. We hoped to shorten the time of INR values, and reduced the positions of bleeding side effects.
Keywords: The recommended dose of warfarin, age, Body mass index, INR

並列關鍵字

The recommended dose of warfarin ； age ； Body mass index ； INR

參考文獻

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