兒童注意力不足過動症使用Methylphenidate及Atomoxetine與長期心血管事件風險之相關性探討

Abstract

研究背景 兒童注意力不足過動症是小兒族群常見的精神相關疾病之一，methylphenidate以及atomoxetine為目前最廣泛使用的兩種治療藥品，且被認為是有效、安全的藥物選擇。然而，心血管副作用仍然是此藥物治療的潛在問題，以前的研究中顯示，methylphenidate和增加血壓有關，並與增加猝死、心律不整之不良反應風險相關，且長期使用methylphenidate和atomoxetine的安全性尚未被良好評估。 研究方法 本研究為一回溯性的世代研究，使用衛生福利部衛生福利資料科學中心之全人口檔進行分析，納入2006年至2017年間，3至18歲新診斷之兒童注意力不足過動症病人。病人被分為三組─methylphenidate使用組、atomoxetine使用組及非藥物治療組，並在主要分析中評估兩種藥物暴露狀態，分別為初始治療大於7天及大於180天。研究中透過傾向分數的計算，將methylphenidate與atomoxetine使用組以一對一的方式與非藥物治療組進行比較。研究結果包含急性心血管事件、中風事件、心因性休克、心因性死亡及全因死亡，其風險以COX比例風險模型進行統計分析。 研究結果 本研究共納入224,732位病人，曾接受藥物治療的病人中，98 %之初次處方為methylphenidate，2 %為atomoxetine，自atomoxetine在2007年進入台灣市場以來，使用量從0.08 %增加至2017年之5.5 %。主分析之研究結果顯示接受藥物治療大於7天的病人，其急性心血管疾病的風險與非藥物治療組別相似，並在使用藥物大於180天的組別中發現相似的趨勢。敏感性分析與次群組分析裡，在不同累積劑量、先天性心臟病等族群的研究結果中，也發現了同樣的趨勢。 結論 超過一半患有小兒專注力失調及過度活躍症的兒童及青少年接受了藥物治療，其中methylphenidate是治療的主要選擇，近年來atomoxetine的使用量大幅增加，但總體利用率仍然較低。藥物治療與急性心血管事件風險之間的相關性研究中，methylphenidate和atomoxetine使用者相較於未曾暴露於藥物的病人，其心血管事件風險沒有顯著增加，長期藥物使用和慢性心血管疾病風險之相關性仍需更多研究去佐證。

Background Attention-Deficit/hyperactivity disorder (ADHD) is the most common psychotic disorder among the pediatric population. Methylphenidate and atomoxetine are widely used to treat ADHD around the world. They are usually considered as an effective and safe medication. However, cardiovascular (CV) side effects are still a potential concern about ADHD medications uses. Previous studies suggested that methylphenidate was related to increased blood pressure and risk of CV events and increased the risk of sudden death and arrhythmia. Safety of long-term use of methylphenidate and atomoxetine has not been evaluated yet. Methods We conducted a retrospective cohort study which included newly diagnosed ADHD patients aged 3 to 18 years between 2006 and 2017 from the Health and Welfare Database in Taiwan. Patients were separated into three groups: methylphenidate users, atomoxetine users, and non-ADHD medication users. Patterns of methylphenidate and atomoxetine uses were documented. Two exposure status was assessed in the main analysis: initial treatment ≥ 7 days and ≥ 180 days. Methylphenidate and atomoxetine users were compared to non-ADHD medication users respectively by one-to-one propensity score matching. The studied outcome included acute cardiovascular events, which were acute coronary syndrome, stroke events, cardiogenic shock, cardiogenic death and all-cause mortality. Cox proportional hazards model and Kaplan-Meier method were used to estimate cardiovascular risk. Results We began with 307,459 ADHD patients. After exclusion, 224,732 patients were included in the final cohort. 126,202 patients received medication treatment, with 98 % of them received methylphenidate and 2 % received atomoxetine. Atomoxetine uses increased from 0.08 % since it first entered the market in Taiwan in 2007 to 5.48 % in 2017. Compare to non-ADHD medications users, the results showed that patients who exposed ADHD treatment for more than 7 days have similar risk of acute CV events. Identical trends were found in the groups who exposed for more than 180 days. Several sensitivity and subgroup analyses were completed, and the findings were consistent with our main analysis. Conclusion More than half of pediatric patients with ADHD received pharmacotherapy, which methylphenidate as the predominant choice of treatment. Atomoxetine use increased considerably since it entered the market, but the utilization rate remained low overall. For the association between ADHD medications and the risk of acute CV events, there was no significantly increased risk among both methylphenidate and atomoxetine users. More evidence on long-term ADHD medications uses and chronic CV disease remains needed.