急性冠心症病人之藥物治療成效與風險分析

Effectiveness and Risk of Pharmacotherapy in Patients with Acute Coronary Syndrome

林珍芳(Chen-Fang Lin)

指導教授 ： 沈麗娟

共同指導教授 ： 林慧玲

國立臺灣大學/醫學院/藥學研究所/博士(2012年)

https://doi.org/10.6342/NTU.2012.01289

摘要

研究背景
臨床研究建議使用aspirin, beta-blockers, angiotensin-converting enzyme inhibitor (ACEI) 或 angiotensin receptor blocker (ARB), statins 以及clopidogrel來治療急性冠心症病人，因為已有許多研究證實這些藥物治療可以降低病人急性冠心症致疾病率以及死亡率。但許多的研究持續發現這些藥物在急性冠心症病人的使用率並未達到理想的標準。本論文將進一步研究影響藥物使用率的病人特質或共病，以提出改善藥物使用率的措施。近年來，老年人以及老年癡呆症的病人數日益增加。對於老年以及老年癡呆症對急性冠心症病人藥物治療的影響，所知有限。合併ezetimibe 以及statins在治療急性冠心症病人的臨床效果如降低心血管風險的再發率，尚未被證實，且目前的臨床研究尚未有定論。另外，對急性冠心症病人有實證益處的藥物，其效果可能會受某些併用藥物的影響。急性冠心症病人合併使用clopidogrel 以及氫離子幫浦抑制劑，對於其心血管風險的再發率的影響，目前的臨床研究尚未有定論。也尚未有研究特別針對5種各別不同的氫離子幫浦抑制劑與clopidogrel併用，對心血管風險再發率的影響，做進一步的探討。
研究目的
基本的分析研究主要分四個部分。第一個研究目的是，急性冠心症病人使用藥物治療的現況。第二個研究目的是，老年癡呆症對於不同年齡層的急性冠心症病人藥物治療的影響。第三個研究目的是，合併使用ezetimibe 以及statins對於急性冠心症病人的臨床效果。第四個研究目的是，合併使用clopidogrel 以及氫離子幫浦抑制劑，對於急性冠心症病人心血管風險再發率的影響。
研究方法
基本分析之方法，主要分四個部分。
第一個研究，從健保資料庫中根據主要的出院診斷，在2006年1月1日到2007年12月31日因急性冠心症而住院的病人有111,347人，經排除在2005年因急性冠心症而住院，年齡小於18歲以及出院日期無法得知之病人，原始的急性冠心症病人共有87,321人。進一步將原始的急性冠心症病人分為以:
在原始的急性冠心症世代87,321人中，其中有1835位老年癡呆症病人，經過1比2的年齡、性別以及醫院別配對後有3670個非老年癡呆症病人。此研究主題為橫斷面研究設計。我們對於分佈於4個年齡層(≤65, 66-75, 76-85, >85)的有無老年癡呆症病人，使用藥物治療以及介入性治療進行比較。並使用多變項的羅吉式迴歸來進行，老年癡呆症對於急性冠心症病人藥物治療以及介入性治療的分析。
在原始的急性冠心症世代87,321人中，有使用statin的病人共有37,753人，合併使用statin以及ezetimibe的病人有1001人。進一步用傾向分數進行1:1配對得到共2002位病人。此研究主題為回溯性世代研究設計。並使用多變項的Cox proportional hazards羅吉式迴歸來進行分析。
在原始的急性冠心症世代87,321人中，有使用clopidogrel的病人共有37,099人，進一步用傾向分數進行1:1配對，得到clopidogrel單獨或合併使用氫離子幫浦抑制劑各組5173人。此研究主題為回溯性世代研究設計。並使用多變項的Cox proportional hazards羅吉式迴歸來進行分析。
研究結果
基本分析之結果，主要分四個部分。
第一個研究，整體來說，急性冠心症病人使用藥物治療的比例，隨著年齡的增加而下降，以aspirin為例，在最年輕組的使用比例為43.2%，最年長組的使用比例為24.8%。男性病人使用藥物治療的比例較女性病人高，以aspirin為例，在男性的使用比例為45.0%，在女性的使用比例為31.9%。
第二個研究，整體來說，老年癡呆症病人有相對較低 27% 機率接受介入性治療(調整後勝算比0.73, 95% 信賴區間0.63-0.83)以及相對較低 22% 機率接受藥物治療(調整後勝算比0.78, 95% 信賴區間0.68-0.89)。急性冠心症病人的藥物治療使用與介入性治療皆隨著病人年齡的增加而下降，如果病人有老年癡呆症，會更降低兩者的使用率。
第三個研究，在原始的世代研究族群中，statins 合併使用ezetimibe組的急性冠心症再發率為13.4 每100個人年 (共268事件)，相對於單獨statins組的急性冠心症再發率為22.6 每100個人年 (共12,724 events事件)，(風險比, 0.69; 95% 信賴區間, 0.62-0.78). 在經配對後的世代研究族群中，statins 合併使用ezetimibe組的急性冠心症再發率為13.4 每100個人年，相對於單獨使用statins組的急性冠心症再發率為20.0 每100個人年，(風險比, 0.62; 95% 信賴區間, 0.53-0.73)。在經配對後的世代研究族群中，相對於單獨使用statins組，因進行冠狀動脈氣球擴張術未加或加支架以及血管再形成術而再入院， statins 合併使用ezetimibe組，風險比分別為 0.61 (95% 信賴區間, 0.50-0.75), 0.62 (95% 信賴區間, 0.48-0.81)以及0.62 (95% 信賴區間, 0.51- 0.76)。
第四個研究，在經傾向分數配對的世代中，相對於單獨使用clopidogrel組，合併使用clopidogrel以及氫離子幫浦抑制劑組的調整後風險比為1.05 (95% 信賴區間, 0.97-1.14, p值為0.21)。在所有的氫離子幫浦抑制劑中，只有omeprazole與clopidogrel併用會增加因急性冠心症再入院風險 (調整後風險比1.23; 95% 信賴區間, 1.07-1.41, p值為0.004). 合併其它氫離子幫浦抑制劑如esomeprazole, pantoprazole, rabeprazole 以及lansoprazole，沒有發現統計上有意義的相關性。
結論
由我們的研究發現，在台灣急性冠心症病人使用預防再次發病治療藥物的比例低於45%，接受介入性治療的比例低於42%。同時，使用預防再次發病治療藥物的比例，也隨著年齡的增加或合併有老年癡呆症而下降。此外，急性冠心症病人合併使用statins以及ezetimibe相對於單獨使用statins，有較低的，因急性冠心症、冠狀動脈氣球擴張術未加或加支架，以及血管再形成術而再入院，有較低的風險比。然而，對於合併使用ezetimibe以及statins的臨床效果之機轉，還有待未來研究的進一步分析。合併使用clopidogrel以及氫離子幫浦抑制劑，對於增加因急性冠心症再入院風險並無統計上意義。但clopidogrel合併使用omeprazole，在增加因急性冠心症再入院風險有統計上的意義。對於合併使用clopidogrel以及omeprazole而增加因急性冠心症再入院風險之機轉，還有待未來研究的進一步分析。

關鍵字

急性冠心症 ； 老年 ； 老年癡呆症 ； statin ； ezetimibe ； clopidogrel ； 氫離子幫浦抑制劑

並列摘要

Background
Clinical studies have supported the beneficial effects of medical therapies (such as aspirin, beta-blockers, angiotensin-converting enzyme inhibitor (ACEI) orangiotensin receptor blocker (ARB), statins and clopidogrel) for reducing the risks of morbidity and mortality in acute coronary syndrome (ACS) patients. Studies have consistently shown that medical therapies such as aspirin, beta-blockers, ACEI or ARB, statins, and clopidogrel remained underused in the management of patients with ACS. In order to find out the strategies for improvement in utilization of the medications, the factors such as patient characteristics and comorbidity associated with the utilization of the medications are required for further investigation. The prevalence of elderly and dementia patients are growing considerately in the recent years. Little is known about how aging and dementia affects therapy after discharge for ACS. Some surrogate endpoints were adopted to investigate the effectiveness of ezetimibe in addition to statins in reducing the risk of cardiovascular events in patients with ACS. However, conflicting results of this combination of ezetimibe and statins were reported. Furthermore, the effectiveness of medications may be affected by combined drug. There are conflicting data regarding to risk of cardiovascular related adverse outcomes in ACS patients who concomitantly used clopidogrel and proton pump inhibitors. The impact of individual PPI on the effectiveness of clopidogrel was not well-explored so far.
Objectives
The research was divided into four parts. Firstly, the study was designed to examine the percentage of use of medical therapy after hospital discharge for ACS patients. Secondly, the study was designed to assess the impact of dementia on therapy after admission for patients with ACS across different age groups. Thirdly, the study was designed to assess the clinical effectiveness of ezetimibe co-administered with statins in patients after hospitalization for ACS. Lastly, the study was designed to examine the impact of concomitant use of clopidogrel and PPIs on the cardiovascular outcomes of patients with ACS. Furthermore, we sought to quantify the effects of concomitant use of clopidogrel and five individual PPIs.
Methods
We identified patients who were hospitalized for the first time for ACS between January 1, 2006 and December 31, 2007 (N=111,347) from the NHIRD. Patients with ACS were defined as those who had primary discharge diagnosis codes of 410.xx, 411.xx, or 414.xx based on the 2001 International Classification of Diseases, Ninth Revision, Clinical Modification codes (ICD-9-CM codes). Patients who were previously admitted to hospitals due to ACS in 2005, were less than 18 years old, or had an unknown discharge date for the first ACS event were excluded from our study. The 87,321 persons who met the inclusion/exclusion criteria were identified as original ACS patients.
The original ACS patients were further categorized into following:
1. Of 87,321 patients, 1835 patients with dementia and 3670 matched patients without dementia (1:2 ratio, matched by age, gender, and admitted hospital level) were identified from Taiwan's National Health Insurance Research Database. This was a cross sectional study. Use of interventional therapies at hospitalization and medications post-discharge were compared between patients with and without dementia across different age groups (≤65, 66-75, 76-85, >85). Multivariate logistic regression models were performed to examine the impact of dementia on these therapies.
2. Of 87,321 patients, those who were prescribed statins (n=37,753) or ezetimibe plus statins (n=1001) within 365 days after the hospitalization were identified. The propensity score method was further used to identify a 1:1 matched cohort (n=2002). This was a retrospective cohort study. The effect was analyzed by a multivariable Cox proportional hazards regression model.
3. Of 87,321 patients, those who were prescribed clopidogrel (n=37,099) during the followed-up period were identified. Propensity score technique was used to establish a matched cohort in 1:1 ratio (n=5173 for each group). This was a retrospective cohort study. The effect was analyzed by a multivariable Cox proportional hazards regression model.
Results
The results were divided into four parts as following:
1. Mostly, the proportion of ACS patients receiving medical therapy decreased with age. The proportions of patients receiving aspirin were 24.8% in the oldest age group versus 43.2% in the youngest age group. The proportions of patients receiving medical therapies were higher in male than in female group (31.9%). The proportions of patients receiving aspirin were 45.0% in the male group than 31.9% in the female group.
2. Overall, dementia was associated with a 27% lower likelihood of receipt of interventional therapies (adjusted odds ratio (OR) = 0.73, 95% CI = 0.63-0.83) and a 22% lower likelihood of medical therapies (adjusted OR = 0.78, 0.68-0.89) in ACS patients. The use of interventional and medical therapies decreased with age, and dementia worsened the underutilization. The proportions of patients receiving interventional therapies were 39.4% (without dementia) versus 21.8% (with dementia) in the youngest age group and 18.6 % (without dementia) versus 14.5% (with dementia) in the oldest age group. Similar results were identified in the use of medical therapies in the youngest and oldest age group with or without dementia.
3. The crude event rate of rehospitalization for ACS in the original cohort was 13.4 per 100 person-year (268 events) for the statins plus ezetimibe group, compared with 22.6 per 100 person-year (12,724 events) for the statins alone group (adjusted hazard ratio(HR), 0.69; 95% CI, 0.62-0.78). The crude event rates of rehospitalization due to ACS in the matched cohort were 13.4 and 20.0 per 100 person-year for the statins plus ezetimibe and statins alone group, respectively, (HR, 0.62; 95% CI, 0.53-0.73). Compared to statins alone, the adjusted HRs for rehospitalization for PTCA without stent, with stent, and revascularization for the statins plus ezetimibe group in the matched cohort were 0.61 (95% CI, 0.50-0.75), 0.62 (95% CI, 0.48-0.81), and 0.62 (95% CI, 0.51- 0.76), respectively.
4. The HR of rehospitalization for ACS due to concomitant use of clopidogrel and PPIs group was 1.05 (95% confidence interval, 0.97-1.14, p=0.214) in the propensity score matched cohort. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for ACS (adjusted HR, 1.23; 95% CI, 1.07-1.41, p=0.004). Concomitant use of esomeprazole, pantoprazole, rabeprazole, and lansoprazole did not increase the risk.
Conclusions
The proportions of ACS patients receiving medical and interventional therapies were under 45% and 42%, respectively in Taiwan from our study. The utilization of medical and interventional therapies decreased with age and diagnosis of dementia. Also, our findings suggested that ezetimibe co-administered with statins was related to a significantly lower risk of rehospitalization due to ACS, PTCA, and revascularization than statins alone in Asian ACS patients. However, more studies are required to elucidate the mechanism of clinical outcomes of co-administration of ezetimibe and statins in ACS patients. Finally, our study indicated no statistically significant increase in the risk of rehospitalization for ACS due to concurrent use of clopidogrel and PPIs. Among individual PPIs, only omeprazole was found to be statistically significantly associated with increased risk of rehospitalization for ACS. The mechanism of increased risk of rehospitalization for ACS in combination of clopidogrel and omeprazole require further investigation.

並列關鍵字

acute coronary syndrome ； aging ； dementia ； statin ； ezetimibe ； clopidogrel ； proton pump inhibitor

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