| 摘要: | 研究背景
阿茲海默症為最常見的失智症類型，是一種具有認知功能障礙的神經退化性疾病。主要的影響族群為老年人，且在60歲以後的發病率每五年會增加兩倍。膽鹼酯酶抑制劑是第一線用來症狀治療阿茲海默症的藥物。最近研究指出，膽鹼酯酶抑制劑透過刺激副交感神經，具有預防心血管疾病的潛在益處。然而，針對膽鹼酯酶抑制劑的使用是否會降低台灣阿茲海默症患者的心血管疾病風險的研究仍相當有限。
研究目的
本研究主要分為三個研究目的。第一個研究目的為評估在台灣50歲以上的阿茲海默症患者中，使用膽鹼酯酶抑制劑與發生心血管疾病風險的相關性。第二個研究目的為評估在使用膽鹼酯酶抑制劑的阿茲海默症患者中，不同的膽鹼酯酶抑制劑治療策略與發生心血管疾病風險的相關性。第三個研究目的為評估在使用膽鹼酯酶抑制劑的阿茲海默症患者中，不同的累積劑量與發生心血管疾病風險的相關性。
研究方法
本研究為回溯性的世代研究，並使用新使用者與活性對照的設計 (new user design and active comparator design)。資料來源為2005年至2014年台灣衛生福利部之衛生福利資料科學中心的台灣全人口檔，其中包含了2300萬所有的台灣納保人。
第一個研究目的中，研究族群為在2006年1月1日至2010年12月31日之間曾被診斷為阿茲海默症的50歲以上患者。實驗組為第一次使用膽鹼酯酶抑制劑的阿茲海默症患者，並須連續使用六個月 (六個月暴露期)。而對照組為非使用膽鹼酯酶抑制劑的阿茲海默症患者。第一個膽鹼酯酶抑制劑的處方日期為實驗組的研究起始日期。實驗組會依據出生年份和性別與四個對照組進行配對，使對照組具有相同的研究起始日期。本研究之觀察結果為心血管事件，包含中風、冠狀動脈性心臟病、心衰竭與心血管死亡事件。所有的患者將於六個月暴露期結束後開始追蹤3.5年。之後利用傾向分數配對法 (propensity score matching) 平衡兩組之間可測量的干擾因子。最後，使用競爭風險Cox比例風險回歸模型來評估兩組間的心血管事件相對風險。
在第二與第三個研究目的中，研究族群為膽鹼酯酶抑制劑使用者。第二個研究目的中的膽鹼酯酶抑制劑使用者會根據研究起始日期所使用的膽鹼酯酶抑制劑劑量分為兩種治療策略: 保守組 (Rescue approach) 和負荷劑量組 (Forward-loading)。在第三個研究目的中，膽鹼酯酶抑制劑使用者會依據六個月暴露期內所累積的劑量，分成高累積劑量組和低累積劑量組。在這兩個研究目的中，研究結果與追蹤時間與第一個研究目的是一樣的。之後利用治療權重倒數機率 (Inverse probability treatment weighting) 來平衡兩組之間潛在的干擾因子，並使用競爭風險Cox比例風險模型來評估心血管事件的相對風險。
研究結果
在第一個研究目的中，膽鹼酯酶抑制劑使用者的心血管事件風險顯著低於非使用者 (Hazard ratio [HR]= 0.57, 95% confidence interval [CI]= 0.51-0.62)。在第二個研究目的中，相較於保守組，負荷劑量組並無顯著降低心血管事件發生之風險 (HR= 0.82, 95％ CI= 0.64-1.03)。然而在第三個研究目的中發現，高累積劑量的患者相較於低累積劑量的患者能顯著降低心血管事件發生之風險 (HR= 0.82, 95% CI= 0.70-0.96)。
結論
本研究證實了在台灣的阿茲海默症患者中，使用膽鹼酯酶抑制劑與降低心血管事件發生之風險的相關性。膽鹼酯酶抑制劑的心血管保護效果具有劑量效應關係，但與不同的治療策略無關。未來需要其他研究去觀察膽鹼酯酶抑制劑的心血管保護作用是否也適用於預防復發性的心血管疾病。
Background
Alzheimer’s disease (AD) is the most common type of dementia, and it is a progressive neurodegenerative disease with cognitive function impairment. Alzheimer’s disease mainly affects the elderly, and the incidence rate doubles every five years after the age of 60 years. Cholinesterase inhibitors (ChEIs) are the first-line symptomatic treatment for Alzheimer’s disease. Recent studies reported that cholinesterase inhibitors had potential benefit of preventing cardiovascular disease through stimulating parasympathetic nerves. However, whether the use of cholinesterase inhibitors is associated with a decreased risk of cardiovascular events among patients with Alzheimer’s disease in Taiwan is still limited.
Objectives
The objectives of this study were:
(1) Aim 1: To determine whether the use of cholinesterase inhibitors could decrease the risk of incident cardiovascular events among older patients with Alzheimer’s disease.
(2) Aim 2: To evaluate the association between different treatment strategies of cholinesterase inhibitors (the forward-loading strategy and the rescue approach strategy) and the risk of incident cardiovascular events among cholinesterase inhibitor users.
(3) Aim 3: To investigate whether patients with a high cumulative dose of cholinesterase inhibitors are associated with a lower risk of incident cardiovascular events among cholinesterase inhibitor users.
Method
This retrospective cohort study was conducted with the new-user design and active comparator design. The data source was the 2005-2014 Full Population file, which contained all Taiwanese beneficiaries from the Health and Welfare Database.
In Aim 1, the study population was patients aged 50 and over, and diagnosed with Alzheimer’s disease between January 1, 2006 and December 31, 2010 (the enrollment period). The new users of cholinesterase inhibitors with a six-month exposure period were selected to be ChEI-exposure group, while the non-users were selected to be the control group. The first date of cholinesterase inhibitor prescription was the index date. To assign the same index date to the non-users, cholinesterase inhibitor users were matched to 4 non-users on birth year and gender. The outcome of this study was cardiovascular event which included stroke, coronary heart disease, heart failure and cardiovascular death. All of patients had a 3.5-year follow-up period from the end of six-month exposure period. Furthermore, 1:1 propensity score matching was performed to balance the measurable confounders between cholinesterase inhibitor users and non-users. Finally, the Cox proportional hazard regression model with competing risks was used to estimate the hazard ratio (HR) of cardiovascular events between the two groups.
In Aim 2 and Aim 3, the study population was restricted to the cholinesterase inhibitor users. In Aim 2, cholinesterase inhibitor users were categorized into two treatment strategies (the rescue approach group and the forward-loading group), based on the dose of cholinesterase inhibitors on the index date. In Aim 3, cholinesterase inhibitor users were divided into high cumulative dose group and low cumulative dose group according to the total cumulative dose of cholinesterase inhibitors within the six-month exposure period. In these two aims, the outcome definition and the follow-up period were the same as Aim 1. Furthermore, the inverse probability of treatment weighting (IPTW) was used to balance the potential confounders and the Cox proportional hazard model with competing risks was used to evaluate the hazard ratio of cardiovascular events.
Results
In Aim 1, cholinesterase inhibitor users had a significantly lower risk of cardiovascular events than non-users (HR= 0.57, 95% CI= 0.51-0.62). In Aim 2, compared to rescue approach strategy, the forward-loading strategy was not associated with a significantly lower risk of cardiovascular events among cholinesterase inhibitor users (HR=0.82, 95% CI= 0.64-1.03). However, in Aim 3, patients with a high cumulative dose significantly reduced the risk of cardiovascular events than those with a low cumulative dose (HR= 0.82, 95% CI= 0.70-0.96).
Conclusion
This study provided evidence that the use of cholinesterase inhibitors was associated with a decreased risk of incident cardiovascular events among patients with Alzheimer’s disease in Taiwan. The cardioprotective effect of cholinesterase inhibitors showed a dose-response relationship, but was not related to the different treatment strategies. Future studies are needed to investigate whether cholinesterase inhibitors can further prevent recurrent cardiovascular disease. |
