慢性阻塞性肺病病人使用吸入性類固醇之相對安全性及效果研究

Abstract

吸入性類固醇（inhaled corticosteroids，ICS），常用於氣喘及慢性阻塞性肺病（chronic obstructive pulmonary disease，COPD）的症狀控制，然而在過去的臨床試驗及觀察性研究中卻發現COPD病人使用ICS可能會增加肺炎事件的發生風險，在不同的ICS藥品間也存在著此風險的差異，過往的文獻大多針對成份為budesonide、fluticasone propionate之ICS藥品進行探討，目前仍缺少有關於beclomethasone的使用與肺炎事件相關性的研究。本研究欲分析不同的ICS和長效β2致效劑（long-acting β2 agonist，縮寫為LABA）複方吸入劑在肺炎事件的發生風險差異，以及探討此風險是否存在劑量相關性，次要目的為分析不同的ICS/LABA在急性惡化的預防效果，以提供此類藥物完整的相對安全性及療效性資訊。本研究為回溯性世代研究，使用台灣全民健康保險資料庫2009-2015年之全人口檔，分析在2011/1/1-2015/06/30間新使用且連續開方至少兩次ICS/LABA藥品的COPD病人，依據不同成份、吸入器劑型之藥品使用分為四組，分別為budesonide乾粉吸入劑（dry-powder inhaler，DPI）、beclomethasone定量噴霧劑（metered-dose inhaler，MDI）、fluticasone propionate乾粉吸入劑及fluticasone propionate定量噴霧劑），在不同ICS成分但屬同一吸入器劑型之藥物間，以傾向分數1:1做配對，使用根據治療的分析方式(as-treated analysis)與Cox 迴歸模式分別分析嚴重肺炎事件、嚴重急性惡化事件之相對風險，。此外，更進一步計算ICS平均每日使用劑量，將其視為時間相依變項，分析追蹤期間內藥品使用的低、中、高劑量是否與肺炎事件存在劑量相關性。在次群組分析中則探討不同基礎特性之病人在風險上的是否有差異。最後，在敏感度分析中使用不同的研究世代、研究終點及追蹤時間的定義來檢驗結果的穩健性。本研究共納入42,393位ICS/LABA藥品新使用者，經過1:1傾向分數配對後，各組的基礎特性皆達到平衡。budesonide/formoterol DPI和fluticasone propionate/salmeterol DPI的組別中各有7,060位病人，分析結果發現budesonide/formoterol DPI相較於fluticasone propionate/salmeterol DPI有較低的嚴重肺炎事件與嚴重急性惡化事件發生風險，風險比（[hazard ratio，HR]）分別為0.82 (95% CI 0.70-0.98)及0.87 (95% CI 0.78-0.97)。另外，在beclomethasone/formoterol MDI和fluticasone propionate/salmeterol MDI的比較中各有5,282位病人，分析結果發現beclomethasone MDI相較於fluticasone propionate MDI有較低的嚴重肺炎事件與嚴重急性惡化事件發生風險，風險比分別為0.67 (95% CI 0.57-0.78)及0.76 (95% CI 0.68-0.85)，而在校正ICS相等劑量（equivalent dose）後，嚴重肺炎事件之風險比提高至0.81 (95% CI 0.67-0.99)，嚴重急性惡化事件之風險比提高至0.88 (95% CI 0.77-1.00)。在劑量相關性的分析中，僅發現fluticasone propionate MDI在高劑量（每日大於500 微克）的使用下會增加肺炎事件的發生，校正所有共變項後風險比為1.77 (95% CI 1.23-2.78)。次群組分析則發現在年齡較低或過去一年不曾有COPD急性惡化病史的病人中，beclomethasone/formoterol MDI與fluticasone propionate/salmeterol MDI的肺炎事件風險存在有更大的差異。敏感度分析皆呈現和主要分析一致的結果。COPD病人使用budesonide/formoterol DPI或beclomethasone/formoterol MDI，分別相較於fluticasone propionate/salmeterol DPI及MDI得到比較低之肺炎發生風險及急性惡化頻率。我們建議臨床上在為COPD病人選擇ICS/LABA藥品時，需要考慮不同ICS藥品的特性、病人特性及使用最低有效劑量，未來仍需要進一步的研究以確立ICS的使用造成肺炎事件之詳細機轉。

Inhaled corticosteroids (ICS) are commonly used in patients with asthma or chronic obstructive pulmonary disease (COPD) for symptom control. However, a number of randomized controlled trials and observational studies have shown that the use of ICS was associated with an increased risk of pneumonia in patients with COPD. The risk of pneumonia has been reported to be different across ICS, and most of the evidence was for comparison between budesonide and fluticasone propionate. There is a lack of evidence to reveal the risk-benefit profile of beclomethasone. This study aimed to compare the risk of pneumonia and effectiveness in preventing acute exacerbations (AE) among different ICS/long-acting β2 agonist (LABA) formulations in patients with COPD. In addition, we aimed to examine if a dose-response relationship exists between the daily dose of ICS and risk of pneumonia. We conducted a retrospective cohort study using claims data of the year 2009-2015 from the National Health Insurance program in Taiwan. We included COPD patients with new ICS/LABA use and having at least two continuous index ICS/LABA prescriptions between 2011/1/1-2015/6/30. Patients were classified into four treatment groups based on types of ICS and inhaler device, including budesonide dry-powder inhaler (DPI), beclomethasone metered-dose inhaler (MDI), fluticasone propionate DPI, and fluticasone propionate MDI. Treatment groups with the same inhaler device were compared. We used 1:1 propensity score matching to balance the patient characteristics, and the risk of severe pneumonia and severe acute exacerbation event was respectively compared by Cox regression models with an as-treated approach. We calculated time-dependent ICS average daily dose to examine if a dose-response relationship exists and to control for potential dose effect as needed. A series of subgroup analyses were conducted to investigate the differential risks in special sub-populations. Sensitivity analyses with different definitions of COPD cohort, outcome and follow-up period were performed to test the robustness of the results. A total of 42,393 COPD patients initiating ICS/LABA were identified. After matching, 7,368 patients were included in each of the budesonide/formoterol DPI and fluticasone propionate/salmeterol DPI comparison groups. A lower risk of severe pneumonia (hazard ratio [HR], 0.82, 95% CI 0.70-0.98) and severe AE (HR 0.87, 95% CI 0.78-0.97) was found in the budesonide/formoterol DPI users. Moreover, 5,282 pairs of patients were included in the beclomethasone/formoterol MDI and fluticasone propionate/salmeterol MDI comparison groups. Beclomethasone/formoterol users, compared to fluticasone/salmeterol MDI users, were less likely to experience severe pneumonia event (HR 0.67, 95% CI 0.57-0.78) and severe AE (HR 0.76, 95% CI 0.68-0.85). When adjusting for ICS equivalent daily dose, the effect difference between beclomethasone/formoterol and fluticasone/salmeterol MDI decreased but remained significant for severe pneumonia (HR 0.81, 95% CI 0.67-0.99]). Only fluticasone propionate/salmeterol MDI revealed a dose-response relationship—patients with higher average dose (>500 mcg/day) of fluticasone propionate in MDI, compared to low-dose users, were associated with a 77% increased risk of severe pneumonia (adjusted HR 1.77, 95% CI 1.23-2.78). In subgroups who were younger or those without severe AE in the past year, the lower risk of pneumonia with beclomethasone/formoterol MDI, compared to fluticasone propionate/salmeterol MDI, was even more compelling. All the sensitivity analyses showed consistent results. Both budesonide/formoterol DPI and beclomethasone/formoterol MDI, compared to fluticasone propionate/salmeterol in the same device, were associated with better effectiveness and safety outcomes in patients with COPD. It is suggested that physicians should consider the properties of different ICS and patient characteristics, and use the lowest effective dose when prescribing them for COPD treatment. Further research is needed to unravel the mechanism underlying the elevated risk of pneumonia with ICS use.