研究背景與目的

乙型交感神經阻斷劑（beta-blocker, BB）的藥理作用為抑制交感神經，臨床上常用於控制病人血壓以及調節心律，在心血管疾病的治療扮演重要的角色。然而在肺部疾病患者身上使用乙型交感神經阻斷劑，可能有導致病人肺功能惡化的風險。根據文獻及目前臨床情境，當病患患有COPD時，beta-blocker的使用會趨於保守。但是針對合併患有心衰竭或是心肌梗塞之COPD患者，近年來有許多觀察性研究指出：使用beta-blocker並不會促使其COPD急性惡化（AECOPD），且使用beta-blocker對於病患之存活預後仍有助益。惟針對合併患有心房震顫（AF）之COPD患者，在現有文獻及國內外的治療指引並無明確建議，且在心率控制的藥物選擇上，使用beta-blocker後對於急性惡化的安全性研究尚無明確定論。本研究希望藉由beta-blocker與non-DHP CCB之相對研究提供臨床參考依據，促進病患的用藥安全。
研究方法
本觀察性研究採取回溯性世代研究，利用健保資料庫2009年至2018年所紀錄之病歷資料，篩選出已具有COPD診斷，且新診斷為AF之病人。指標藥物（index drug）含研究組：乙型交感神經阻斷劑（BB）及對照組：非DHP類鈣離子通道阻斷劑（non-DHP CCB）。在病患診斷AF後，第一次使用指標藥物的日期為指標日期，於指標日期後持續追蹤一年，觀察是否有因為COPD急性惡化所導致的急診或是住院之事件。本研究採取治療意象（intention-to-treat, ITT）設計，且利用傾向分數配對（propensity score matching, PSM）之方法進行主要分析，並將病患依據COPD嚴重程度（急性惡化病史）分組進行比較，最後利用競爭風險模型（Competing risk）進行敏感性分析。本研究亦利用多變量線性迴歸（multivariate linear regression）進行次群體分析（subgroup analysis）：共病症之分層分析以及BB藥品選擇性之分析。
研究結果

最終收錄之研究族群共13,462人，其中7,590人為BB組，5872人為non-DHP CCB組。在病患的基本特性比較中，BB組的組別平均年齡較低，在過去一年平均發生AECOPD的次數也較少。BB組嚴重COPD的人數佔比為8.2%，non-DHP CCB組則占比為17.7%。經PSM配對後，兩組人數皆為4,486人，與non-DHP CCB組相比，BB組其COPD急性惡化風險比為0.80（95% 信賴區間= 0.72-0.89），結果顯示使用BB有顯著降低AECOPD的風險。依據COPD嚴重程度分別檢視，輕微COPD組經PSM配對後之風險比為0.73（95%信賴區間=0.64-0.84），然而在嚴重COPD組經PSM配對後之風險比為0.95 (95%信賴區間=0.78-1.16)。在次群體分析中顯示不論病患是否有心衰竭或是心肌梗塞病史，以及使用的BB是否具有選擇性，結果皆指出使用BB能顯著降低AECOPD之風險。最後，在敏感性分析中以競爭風險死因以及指標期間檢視病患用藥順從性之分析，使用BB組別相較於non-DHP CCB 組別皆能顯著降低AECOPD風險。

結論
本研究結果指出在慢性阻塞性肺病合併心房纖維顫動患者，使用BB相較於non-DHP CCB發生因COPD急性惡化之風險顯著降低約22%。在輕微COPD患者之次族群分析仍顯示使用BB能顯著降低27%之風險；但在嚴重COPD族群使用BB並無顯著效益。因此，當慢性阻塞性肺病合併心房纖維顫動患者，如臨床需要使用BB時，須考量病患COPD之嚴重程度。若病患之COPD病情為容易惡化之族群，仍需小心使用BB，並監測使用BB後是否發生急性惡化之情形。

Background

People who coexisted with COPD and cardiovascular diseases (CVD) are associated with a higher risk for hospitalization and all-cause mortality. Given that, the co-administration of COPD and CVD medication are important to these patients. Beta blockers (BB) had benefit of decreasing mortality and were widely used in CVD. A systematic review and meta-analysis had summarized the results of studies and showed that using BBs would reduce not only all-cause mortality but also exacerbations of COPD.11 In addition, several studies had proved the benefit of BB reducing AECOPD in COPD with chronic heart failure and myocardial infarction. Due to the safety of BBs used in COPD with AF patients was still unknown, and there is no local data from Taiwan. Therefore, we conducted this study to compare the safety of BBs and CCBs in COPD patients with AF in different COPD severity.

Material and methods

We conducted a retrospective cohort study with new user design, active comparator. By using Taiwan’s National Health Insurance Data (2009-2018), we enrolled patients with prevalent COPD and incident AF. The index date was the first prescription date of BB or CCB after AF diagnosis. Outcome was AE-related emergency room visits or hospitalizations. COPD severity was classified by prior exacerbation history (mild and severe group). We used propensity score matching (1:1) and Cox proportional hazard model to estimate hazard ratio (HR) and the 95% confidence interval (CI). Multivariate linear regression was applied to subgroup analysis, which included different comorbidities and cardioselectivity of BBs. Sensitivity analysis including sub-distribution hazard model and landmark period analysis were performed.
Results
Total 13,462 patients were enrolled in study. Compared to CCB group, BB group was younger and consisted of more mild COPD patients. After propensity score matching, we found 4,486 matched pairs. The results indicated that using BB reduced risk of AE (HR= 0.80, 95% CI 0.72-0.89). When stratifying by COPD severity, BB group still reduced risk of AE compared with CCB group in mild COPD (HR=0.75, 95% CI 0.66-0.85), but not in severe COPD cases (HR=0.95, 95% CI 0.75-1.20). In subgroup analysis, results showed consistent protective effect in patients without heart failure and myocardial infraction (aHR= 0.95, 95% CI 0.75-1.20). Subgroup of cardioselective BB and non-selective BB users also showed significant benefit of reducing risk of AECOPD, especially in mild COPD group. Sensitivity analysis revealed the consistent result that BB group had lower risk of AECOPD.

Conclusions

This study indicated that using BB in COPD and AF population would not increase risk of AECOPD. The significant benefit of BB reducing AECOPD is confined to mild COPD patients among COPD with AF patients. In severe COPD group, there is BB is not associated with AECOPD. In conclusion, the study suggests that in COPD with AF patients, using BB in mild group had benefit of reducing AECOPD. In severe COPD group, using BB is cautious when there is only AF for cardiovascular indication.

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