台灣地區高血壓病患血管張力素轉換酶抑制劑及第二型血管張力素受體阻斷劑之藥物使用評估

Drug Utilization Evaluation of Angiotensin-Converting Enzyme Inhibitors and AngiotensinⅡ receptor blockers on Hypertensive Patients in Taiwan

張文怡(Wen-Yi Chang)

指導教授 ： 黃耀斌

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2010年)

摘要

背景：
血管張力素轉換酶抑制劑（angiotensin-converting enzyme inhibitors；ACEIs）及第二型血管張力素受體阻斷劑（angiotensinⅡ receptor blockers；ARBs）均為台灣常使用的高血壓用藥，使用者眾且用量漸增，影響健保藥費支出甚鉅。且目前有越來越多的文獻建議併用此兩類藥品降壓效果較佳，但仍然缺乏臨床實證資料支持ACEIs和ARBs併用的合理性和安全性。
本研究為ACEIs與ARBs的藥物使用評估，以了解此二類藥物在台灣用以治療高血壓的使用現況、處方型態、及藥品併用情形（處方日期相同或治療期間重複），並探討用藥與可能嚴重不良反應（急性腎衰竭或急性胰臟炎）發生風險的相關性，為藥物安全性評估之初探。

方法：
本研究採用兩種健保申報資料來源和研究設計。首先，以橫斷式研究漸進式地先分析高屏地區申報資料，再探討2005年全國百萬抽樣歸人檔中，高血壓患者ACEIs和ARBs的藥品用量、申報金額、藥品併用、交互作用處方及處方類別改變等處方形態。以描述性統計敘述ACEIs/ARBs的用藥情形和病患疾病狀況，使用卡方檢定、雙樣本t檢定分析上述研究變項的差異，以p值小於0.05界定統計學上顯著差異。
其次，以病例對照研究納入2005年全國百萬抽樣歸人檔中，在2006年至2008年首次因嚴重不良反應（急性腎衰竭或急性胰臟炎）而住院的高血壓病患為病例組；以年齡和性別以1:4的比例作配對後，其未發生不良反應的高血壓住院病患為對照組，回溯觀察納入研究病患至2003年的ACEIs/ARBs暴露史。利用邏輯迴歸分法計算並校正病患基本疾病狀態和共病症，以校正後勝算比（adjusted odds ratio；aOR）及95% Wald信賴區間（95%CI）表示用藥和不良反應的風險關係。最後，利用傾向分數比對病患用藥和疾病狀態的關係。

結果：
在全國資料的七種降壓藥中，ACEIs及ARBs藥品的申報處方佔率分別為9~12%及13~17%，但ARBs的申報金額高居所有降壓藥的第二位（佔27~34%）而ACEIs類藥品申報金額也佔8~14%左右。無論是何種資料庫，ARBs的申報處方筆數較ACEIs多；但全國141,082位高血壓病患中，有10.6%（14,898人）曾使用ACEIs，8.7%（12,343人）曾使用ARBs，有4%病患曾併用與ACEIs/ARBs類藥品具有一級至三級潛在藥物交互作用的藥品。比較兩藥的用量和申報金額，ACEIs類藥品呈現逐漸減少，而ARBs類藥品呈現逐漸增加的趨勢。
分析兩資料庫高血壓病患的慢性病連續處方箋含ACEIs或ARBs類藥品的申報資料，僅有少於5%的病患曾併用ACEIs和ARBs，累計併用天數以30天以下的病患為最多（72.6~94.3%），病患常見的合併疾病是糖尿病（40.2~42.5%）。有將近20%病患有ACEIs或ARBs藥品類別改變情形，以「先使用ACEIs，再使用ARBs」的病患最多（54.3~57.3%）。
研究期間首次因急性腎衰竭住院的病患有較高比例曾使用ACEIs（aOR:1.23，95%CI: 0.87, 1.75），曾併用ACEIs和ARBs的機會也較高（aOR:1.94，95%CI: 0.81, 4.47）。至於發生急性胰臟炎病患則顯著地較少比例曾使用ACEIs（aOR:0.73，95%CI: 0.56, 0.95），但卻較常併用ACEIs和ARBs（aOR: 1.03，95%CI: 0.45, 2.14）。而發生嚴重不良反應的病患併用ACEIs/ARBs的人數和對照組相比，卻不具統計學上顯著差異。

結論：
2006年至2008年台灣地區高血壓病患ACEIs和ARBs的用藥趨勢不同，病患曾有ACEIs/ARBs併用，也有藥物交互作用的疑慮。雖然研究未證實ACEIs和ARBs併用與嚴重不良反應（急性腎衰竭或急性胰臟炎）的相關性，但結果發現有發生不良反應的病患有較高比例曾併用ACEIs和ARBs。未來仍需進行長期追蹤，也需要臨床果效資料以評估ACEIs/ARBs的合理性和安全性。

關鍵字

血管張力素轉換酶抑制劑 ； 第二型血管張力素受體阻斷劑 ； 藥物使用評估

並列摘要

BACKGROUND:
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensinⅡ receptor blockers (ARBs) have substantially contributed to the escalating antihypertensive drug cost in Taiwan. Increasing literature has proposed potential benefits of combing ACEIs/ARBs in controlling blood pressure, but there is still a lack of evidence to support the rationale of ACEIs/ARBs combination in treating hypertension.
This study aims to analyze the current utilization and prescribing patterns of ACEIs/ARBs, and to explore the relationship between ACEIs/ARBs and severe adverse drug reactions in Taiwan.

METHODS:
Cross-sectional studies were conducted from 2006 to 2008, using a regional reimbursement claim database from Kaoping Division of National Health Insurance (NHI) to establish research and hypothesis framework, and then exploring a nation-representative, million-sampled, longitudinal NHI dataset (LHID2005) published by National Health Research Institute. Individual prescription data of hypertensive outpatients using ACEIs or ARBs were extracted from 2006 to 2008. Demographic, co-morbidities, prescribing patterns of ACEIs, ARBs, their combination and changes of prescribing patterns were assessed by descriptive statistic. Wald chi-square tests and Student’s t-test were conducted to examine the differences between variables.
Also, we conducted case-control studies from 2003 to 2008 using LHID2005 dataset. Cases were defined as hypertensive patients who were newly diagnosed and hospitalized for acute renal failure (ARF) or acute pancreatitis (AP) during 2006 to 2008, four controls were matched to each case by gender and age. Detailed information on drug use and potential confounders were followed retrospectively back to 2003. Logistic regression was used to examine the relationship between drug and adverse drug reactions presenting by adjusted odds ratio (aOR) and 95% confidence interval (95%CI), and propensity score was calculated to evaluate the potential indication bias.

RESULTS:
During the 3-year study period, ACEIs and ARBs were at good proportions in utilization and drug costs of the total antihypertensive drugs. The cost of ACEIs was 8~14% among antihypertensive drugs during 2006~2008, ARBs was 27~34%. Number of prescriptions for ARBs was higher than ACEIs, but among 141,082 hypertensive patients in Taiwan, 10.6% (n=14,898) had ever used ACEIs, 8.7% (n=12,343) used ARBs, nearly 4% patients had combined ACEIs/ARBs with drugs having potential Level-1 to Level-3 drug-drug interactions with ACEIs/ARBs. Compare the consumption and cost between ACEIs and ARBs, we found an increased use of ARBs, but decreased use of ACEIs.
From the two datasets, there were less than 5% hypertensive outpatients prescribed ACEIs or ARBs by chronic continuous prescriptions had ever use ACEIs/ARBs combinations, the cumulated combination days were less than 31 days (72.6~94.3%), and the most common co-morbidities was diabetes mellitus (40.2~42.5%). Furthermore, nearly 20% patents had switched between ACEIs and ARBs, mostly shifted from ACEIs to ARBs (54.3~57.3%).
ARF patients had an increased use of ACEIs (aOR: 1.23; 95%CI: 0.87, 1.75) and ACEIs/ARBs combination (aOR: 1.94; 95%CI: 0.81, 4.47). Otherwise, AP patients had a significantly decreased use of ACEIs (aOR: 0.73; 95%CI: 0.56, 0.95) but an increased use of ACEIs/ARBs combination (aOR: 1.03; 95%CI: 0.45, 2.14).

CONCLUSIONS:
We found a small proportion of ACEIs/ARBs combination and potential drug-drug interactions, yet no relationship was found between ACEIs/ARBs combination and adverse drug reactions (acute renal failure and acute pancreatitis). Further studies are needed to explore the effectiveness and rationality of this combination using a longitudinal data source with sufficient patients’ characteristic data.

並列關鍵字

Angiotensin-Converting Enzyme Inhibitors ； AngiotensinⅡ receptor blockers ； Drug Utilization Evaluation

參考文獻

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