某醫學中心服用Warfarin之心房纖維顫動患者最低有效抗凝血強度以及維持劑量之研究

The Lowest Effective Intensity of Anticoagulation for Patients with Atrial Fibrillation and the Predictor Factors of Maintenance Dose Requirement at a Medical Center

周冠妙(Guann-Miaw Chou)

指導教授 ： 陳燕惠

國立臺灣大學/醫學院/臨床藥學研究所/碩士(2006年)

https://doi.org/10.6342/NTU.2006.02556

摘要

Warfarin屬於治療指數狹窄的藥物，需要適當的療效監測，以避免療效不足或是發生出血併發症，因此，適當的療效監測是絕對必要的。Warfarin在國外臨床使用上已經建立了使用準則：特定的適應症及其相對應的目標INR範圍。一般皆認為亞洲人較白種人不易栓塞，所以多把目標INR值降低一些；國內在臨床處置上也多維持在較低的目標INR範圍內，然而，對於國人的目標INR範圍是否不需要維持在國外準則的建議範圍之內，在兼顧療效性以及安全性下，是否維持較低的INR即可，尚未有較完整的討論。另一方面，warfarin維持劑量的高低變異極大，也是醫師開方時的一大困擾。

本研究納入民國93年1月1日至94年9月30日期間，在台大醫院內有使用warfarin的門診紀錄的患者，依照American College of Chest Physicians(ACCP)準則選取符合目標INR建議值為2-3的心房纖維顫動患者，收集病患於研究期間內的warfarin用藥紀錄、栓塞併發症或是出血併發症的紀錄、以及研究期間內所有INR檢驗值。栓塞併發症　(thromboembolism)定義為急診或是住院診斷中出現缺血性中風、暫時性腦部缺血性發作、動脈栓塞、以及心肌梗塞。重大出血併發症(major bleeding)定義為急診或是住院診斷中出現胃腸道出血或是腦部出血。病患追蹤時間起始於warfarin的第一次開方日期，終止於研究結束、停止服用warfarin或是出現併發症的診斷碼，取三者中最早出現的。INR分層為：INR<1.5, 1.5-1.9, 2.0-2.5, 2.6-3.0, 3.1-3.5, >3.5;估算暴露於各INR分層下的時間以及併發症的發生率。

　　本研究共收錄699位病患，總計追蹤時間為867人年。結果顯示，病患維持INR值於2-3的時間只佔了所有追蹤時間的34%，約有56%的時間是維持在INR<2。病患大部份的時間是維持在INR=1.5-3.0。為了檢測國人降低木INR 值的可行性，分析病患暴露在INR=1.5-2.5的併發症發生率(3.96%/年)是比INR<1.5(10%/年)以及INR>2.5(16.9%/年)分層下的發生率都來的低 (p=0.038)。因此，在ACCP建議目標INR=2-3的心房纖維顫動患者，維持較低的目標在1.5-2.5，是可行的。

　　另外，分析病患發生栓塞併發症或是出血併發症的危險因子，納入分析病患年齡、性別、合併疾病狀態，包含：高血壓、冠狀動脈疾病、糖尿病、心臟衰竭、僧帽瓣瓣膜疾病、貧血、惡性腫瘤、先前曾發生中風、暫時性腦部缺血性發作、或是胃腸道出血。冠狀動脈疾病是栓塞併發症的危險因子(odds ratio=2.17, 1.11-4.26)，但是在校正過其他因素後的勝算比無統計上顯著的意義(odds ratio=1.93, 0.83-3.11)。較大的年齡，≧75歲是出血併發症的危險因子(odds ratio=3.34, 1.52　-7.36)，在校正過其他因素後勝算比為3.17 (1.54-6.29)。　　　　

本研究分析病患維持劑量的預測因子，納入分析病患年齡、性別、
合併疾病狀態，包含：高血壓、冠狀動脈疾病、糖尿病、心臟衰竭、僧帽瓣瓣膜疾病、貧血、惡性腫瘤、先前曾發生中風、暫時性腦部缺血性發作、或是胃腸道出血、amiodarone平均劑量。結果顯示：年齡越大，使用的劑量越少，呈現負相關，γ＝-0.32, p=0.039。

　　本研究提供了心房纖維顫動的國人降低目標INR至1.5-2.5的可行性，也發現年齡大於75歲的患者是出血的高危險群，以及維持劑量隨年齡增加而減少。希望有助於國人在使用warfarin的時候可以兼顧療效性與安全性，也可以提供醫師在開方時的參考資料。然而，這樣的結果無法完全解釋，國人較白種人不易栓塞，仍需要更進一步的研究。

關鍵字

心房纖維顫動患 ； 最低有效抗凝血強度 ； 維持劑量

並列摘要

The pharmacokinetic profile of warfarin is complex. Monitoring is required to avoid both thromboembolic events associated with low intensity anticoagulation and hemorrhagic complications associated with high intensity. Target levels of oral anticoagulation are disease- specific and measured with the international normalized ratio (INR). To attain applicable INR values, patients are routinely monitored and their doses are adjusted when necessary. In practice, it is difficult to maintain a stable and optimal INR because of unexpected fluctuations of the INR values. This can be attributed to many factors including changes in diet, poor compliance with medication, alcohol consumption, and drug-drug interactions.

It has been suggested to keep Asian patients at a lower intensity of anticoagulation because Asians seem to be less vulnerable to thrombotic diseases than White people.Although evidence to support the practice is lacking, most clinicians are cautious to keep at a lower INR. The gudeline of the American College of Chest Physicians (ACCP) recommended the optimal INR for patients with atrial fibrillation at 2-3. However, this range for Europeans and Americans has been questioned as being excessively high for Taiwanese with atrial fibrillation. We performed a retrospective study in National Taiwan University Hospital (NTUH) on patients with atrial fibrillation taking warfarin for storke prevention from January 1, 2004,to September 30,2005.Patients were excluded if they had any a histiry of mechanical heart valve replacement before the recorded AF diagnosis because the target INR range is higher for this indication.We systemically collected the records of warfarin use, comorbid diseases, and all INR results. Thromboembolic episodes included ischemic stroke, transient ischemic attack ,arterial embolism and thrombosis and myocardial infarction .Major bleeding episodes included intracranial hemorrhage and gastrointestinal bleeding .The INR at the time of events or defined temporally related within the past 7 days of the thromboembolic and bleeding episodes were recorded. The INR range was divided into 6 categories: <1.5, 1.5-1.9, 2.0-2.5, 2.6-3.0,3.1-3.5,>3.5.The number of events was recorded for each catogories and this formed the numerator.The denominator was the summation of time each patients stayed in each category of INR.The event rate was calculated for each INR category.

Six hundreds and sixty nine patients were included in the analysis , which constituted 867 patient -years. The time spent in INR=2-3 was 34%. Most time(70.8%) was spent in INR=1.5-3.0. The overall event rate was lowest in the range from 1.5-2.5(3.96%), compared to INR<1.5(10%) or INR>2.5(16.9), p=0.038. This supports the clinical feasibility of lower intensity anticoagulant therapy for Taiwanese patients with atrial fibrillation. Among these patients, coronary artery disease was a risk factor for thromboembolism in univariate analysis. However,older age(≧75 years)was a risk factor for bleeding in multivariate analysis.Among patients taking warfarin longer than 4 weeks,age correlated negatively with the maintenance dose of warfarin (γ=-0.32,p=0.004).

In conclusion, our retrospective study showed that an INR between 1.5-2.5 was associated with lower complications in Taiwanese patients treated with warfarin.

並列關鍵字

Atrial Fibrillation ； The Lowest Effective Intensity of Anticoagulation ； Maintenance Dose

參考文獻

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