非類固醇抗發炎藥物的使用與轉換之胃腸道副作用評估

Evaluating Gastrointestinal Adverse Events in Users of Non-Steroidal Anti-Inflammatory Drugs and their Switching Patterns

陳家蓁(Jia-Jhen Chen)

指導教授 ： 黃耀斌

共同指導教授 ： 楊奕馨(Yi-Hsin Yang)

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2012年)

https://doi.org/10.6832/KMU.2012.00125

摘要

目的：分析病人使用不同類型的非類固醇抗發炎藥物所引起的胃腸道副作用而導致住院或藥物轉換之用藥安全性評估。
方法：研究設計是以回溯性世代研究，分析「2000年全民健康保險承保抽樣歸人檔」(1997-2008)資料。擷取自1998年至2007年，具有類風濕性關節炎(ICD-9-CM: 714.0~714.3)或退化性骨關節炎(ICD-9-CM: 715.0~715.9)診斷的病患，每位病患追蹤至少一年的追蹤時間，非類固醇抗發炎藥物分為三大類：(1) 傳統的、(2) 偏向選擇性COX-2 抑制、(3) 較專一性COX-2 抑制，同時並分析是否加上胃保護劑(gastro-protective agent, GPD)。胃腸道副作用定義為第一次住院診斷上胃腸道疾病(ICD-9-CM: 530-535,578或下胃腸道疾病 (ICD-9-CM: 555,562,569)。藥物劑量是以每日定義劑量(Defined Daily Dose, DDD)表示。追蹤研究共分兩部分探討其用藥安全：
第一部份以人為追蹤單位，觀察其不同用藥組與發生胃腸道副作用而住院之風險相關性；第二部分以連續用藥間隔為追蹤單位，觀察其不同用藥組與藥物轉換、產生胃腸道副作用而住院風險的相關性。統計分析針對不同藥物治療組，以存活曲線(Kaplan-Meier estimates) 及COX廻歸(COX proportional hazards regression) 分析，並將可能的影響因子，包括病人年齡、性別、是否有腸胃道病史、共同服用易出血的藥品、共病症分數作調整後，分析比較在不同治療組當中，病人因為腸胃道副作用而住院和轉換藥物的風險比(hazard ratio)。
結果：總共擷取24,163 位新診斷類風濕性關節炎和144,041 位新診斷退化性關節炎的病人。當中有98.70%病人曾處方過傳統的非類固醇消炎藥(tNSAID)，53.37% 病人僅使用tNSAID，而42.33% 病人除了使用tNSAID，還曾用過其他類的NSAIDs (tNSAID augmentation)。
第一部分結果：與僅使用tNSAID的病人比較，曾使用tNSAID +pC2SI 和tNSAID+COXIB 有較低的風險產生上、下消化道副作用 (曾有腸胃道病史病人HRs=0.78 and 0.70, 95%CI= 0.70~0.87 and 0.58 ~0.85; 無腸胃道病史 HRs=0.83 and 0.81, 95%CI= 0.79~0.87 and 0.74 ~0.88 )。然而，同樣地與僅使用tNSAID比較，在有使用質子幫浦抑制劑的治療組且無腸胃道病史的病人當中，產生上、下消化道副作用的風險較高 (在tNSAID+PPI治療組，HR=1.21, 95%CI= 1.09~1.34；tNSAID +pC2SI+PPI治療組，HR=0.95, 95%CI= 0.86~1.05; tNSAID +COXIB +PPI治療組，HR=1.14, 95%CI= 0.93~1.39)。
第二部分結果：從166,762病人當中，擷取總共890,833連續用藥間隔， 91.73% 連續用藥間隔是以處方tNSAID 為主。與僅使用tNSAID 且無消化道病史的病人比較，tNSAID+PPI的用藥型態是比較不易換藥 (HR=1.62, 95%CI= 1.45~1.81)，而pC2SI 單獨使用或有加上PPI的用藥型態是比較容易換藥 (HR=8.43, 95%CI=8.30~8.56 和 HR=8.81, 95%CI= 7.36~10.5)；COXIB單獨使用或加上PPI之處方也比較容易換藥(HR=6.75, 95%CI=6.60~6.89)和 HR=6.48, 95%CI= 5.35~7.86)。 而就胃腸道的風險比較而言，在無消化道病史的病人中，單獨使用COXIB或pC2SI用藥組，有顯著較低產生上胃腸道的風險 (HR= 0.82, 95%CI=0.74~0.92; HR=0.88, 95%CI=0.82~0.95)，也有較低產生下胃腸道的風險 (HR=0.83, 95%CI=0.55~1.24; HR=0.96, 95%CI= 0.73~1.27)。
結論：結果顯示具COX-2選擇性的非類固醇抗發炎藥物相對於傳統的非類固醇抗發炎藥物是有比較低發生胃腸道副作用的風險。 而tNSAID+PPI治療組，結果顯示較少換藥的處方型態，為減少胃腸副作用，tNSAID+PPI是臨床上可建議的療法。

關鍵字

非類固醇抗發炎藥物 ； 胃腸道副作用 ； COX-2選擇性抑制劑(selective/preferential COX-2 inhibitor) ； 藥品轉換 ； 質子幫浦抑制劑

並列摘要

Objectives: To examine the risk of hospitalization for GI adverse events and drug switching events with regard to early discomfort of gastrointestinal (GI) adverse events among users of non-steroidal anti-inflammatory drugs (NSAIDs) with or without co-medication with gastro-protective drugs (GPDs).
Methods: This is a retrospective cohort study. The Taiwan Longitudinal Health Insurance Database (LHID) 2000 during 1997 to 2008 was used to identify patients with newly diagnosis of RA (ICD-9-CM: 714.0~714.3, n=22,968) or OA (ICD-9-CM: 715.0~715.9, n=156,933) in 1998-2007 to allow for at least one follow-up year.
To observe the association of different treatment groups and GI events (or switching events), there were two follow-up designs: the first one was followed by person and the second one was followed by medication intervals of consecutive use. The medical utilization of NSAIDs was classified into three main classes: traditional non-steroidal anti-inflammatory drugs (tNSAIDs), preferential COX-2 selective inhibitors (pC2SIs), and specific COX-2 selective inhibitors (COXIBs) with or without combination with proton pump inhibitors (PPIs).
The study endpoints are the first diagnosis of hospitalization for GI events (ICD-9-CM of upper GI: 530~535,578 or of lower GI: 555, 562, 569) in the first follow-up study, and drug switching to another class of NSAID or GI events (same as the first study) in the second study.
Drug dose dispensed was presented as total amount of defined daily dose (DDD). Statistical analysis, for different treatment groups , we used Kaplan-Meier estimates and the Cox proportional hazards regressions with covariates of patient’s age, gender, prior GI history times, co-medication, and comorbidity score to estimate the hazard ratios (HR) of hospitalization for GI events and drug switching among different treatment groups.
Results: A total of 24,163 newly diagnosis RA patients and 144,041 newly diagnosis OA patients were identified from LHID 2000. A majority (98.70%) of users had been prescribed tNSAID, 53.37% were classified as tNSAID alone and 42.33% as tNSAID augmentation.
Use of tNSAID+COXIB and tNSAID+pC2SI was statistically significantly associated with lower risk of hospitalization for upper GI events when comparing to use of tNSAID alone (HRs=0.78 and 0.70, 95%CI 0.70~0.87 and 0.58-0.85 for patients with prior GI history; HRs=0.83 and 0.81, 95%CI 0.79~0.87 and 0.74~0.88 for patients without prior GI history). However, compared to tNSAID alone, those treatment groups with PPI use and without prior GI history had higher risk of developing GI events (HR=1.21, 95%CI=1.09~1.34 for tNSAID+PPI; HR=0.95, 95%CI= 0.86~1.05 for tNSAID+pC2SI+PPI; HR=1.14, 95%CI = 0.93~1.39 for tNSAID+COXIB+PPI).
There were 890,833 intervals identified from 166,762 patients. A majority of patient-intervals (91.73 %) of consecutive use were prescribed with tNSAID use. Given no prior GI history, patients in the tNSIAD+PPI treatment group was less likely to switch (HR=1.62, 95%CI=1.45~1.81) than tNSAID alone. However, the HRs for switching to COXIB, COXIB+PPI, pC2SI and pC2SI+PPI were 6.75 (95%CI= 6.60~6.89), 6.48 (95%CI= 5.35~7.86), 8.43 (95%CI=8.30~8.56) and 8.81 (95%CI=7.36~10.5) respectively. For the relative risk of GI events comparison, patient-intervals with COXIB or pC2SI alone had significantly lower risk of developing upper GI adverse events (HR= 0.82, 95%CI=0.74-0.92; HR=0.88, 95%CI=0.82-0.95) and had a trend of lower risk for developing lower GI adverse events (HR=0.83, 95%CI =0.55~1.24; HR=0.96, 95%CI= 0.73~1.27).
Conclusions Our results provide that COX-2 selective inhibitors (pC2SI and COXIB) compared to tNSAID have a lower risk to develop GI adverse events. Due to the regimen of tNSAID+PPI was less likely to switch, it could be an acceptable augmentation in clinical practice for reducing potential GI adverse events.

並列關鍵字

Non-steroidal anti-inflammatory drugs (NSAIDs) ； gastro -intestinal (GI) adverse events ； selective/preferential COX-2 inhibitor ； drug switching ； proton pump inhibitors (PPIs)

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