臺灣博碩士論文加值系統

過去個案報告曾陸續指出鈣離子阻斷劑 (calcium-channel blockers, CCBs) 與巨環類抗生素 (macrolides) 併用，會造成病人有低血壓之情形，2012年美國食品藥物管理局 (Food and Drug Administration, FDA) 亦發出警告，提醒醫師併用Biaxin○R (clarithromycin) 和鈣離子阻斷劑時可能會導致嚴重低血壓。藥物的交互作用&;#63847;僅會影響療效，也是造成藥物&;#63847;&;#63868;反應的重要原因之一。尤其是心血管方面的用藥，多數需由CYP 450酵素系統代謝，因此，更是容易受CYP 450誘導劑或抑制劑影響，進而造成治療濃度的起伏，而有不良反應發生。鈣離子阻斷劑須由CYP 3A4酵素進行代謝，巨環類抗生素中之erythromycin或clarithromycin則是CYP 3A4強力抑制劑，因此兩者併用，極有可能會造成鈣離子阻斷劑血中濃度上升而產生不良反應。過去文獻多為觀察性研究，再者，於台灣地區巨環類抗生素普遍用於治療非典型肺炎、幽門螺旋桿菌等治療，而鈣離子阻斷劑亦為常用之降血壓藥，兩者併用機率相當高。
本研究希望探討台灣地區，鈣離子阻斷劑與巨環類抗生素兩者併用後病人發生低血壓及休克之機率，並進一步探討是否會導致急性腎損傷。
本研究以國衛院全民健康保險資料庫之2005年百萬歸人檔資料進行三部分分析：首先針對同一門診開立併用處方之開立醫師科別及醫療院所層級進行敘述性統計；第二部分則是了解巨環類抗生素與鈣離子阻斷劑併用後發生低血壓、休克或急性腎損傷之發生率；第三部分為針對各種危險因子進行關聯性分析。
研究組別以使用erythromycin或clarithromycin者為實驗組，azithromycin為對照組，巨環類抗生素處方日即為指標日 (index date)，取巨環類抗生素或鈣離子阻斷劑使用天數中較短者作為併用天數，評估併用後30天內發生急性腎損傷、低血壓或休克之情形。統計分析先計算兩組之傾向分數 (propensity score)，分析過程再以傾向分數進行加權比較。
本研究發現2000至2012年間，於同一門診開立之併用處方，以內科為最多，占全部的59.37%，並以地區醫院以上之層級開立的比例最高占60.53%。
於2002至2012年間，於長期使用鈣離子阻斷劑之病人共1,774人，其中使用erythromycin或clarithromycin者1,407人，使用azithromycin者367人。併用erythromycin或clarithromycin後30天內發生急性腎損傷者之比例 (3.20%) 低於使用azithromycin者 (7.08 %)，勝算比 (odds ratio, OR)為0.43 (95% CI: 0.26~0.71, p=0.001)；兩組之低血壓或休克發生率並無統計學上顯著，OR為0.55 (95% CI: 0.29~1.05, p=0.065)。然而，由於azithromycin組之病人患有共病程度較嚴重，且具有慢性腎病之比例亦較實驗組高。因此，另外獨立分析患有慢性腎病共病者，則發現於erythromycin/ clarithromycin組之慢性腎病共病者發生急性腎損傷之機率為14.52%，azithromycin組則為12.70%，故經傾向分數調整後，OR為 1.77 (95% CI: 0.98~3.18, p= 0.73)；於患有慢性腎病共病者發生低血壓或休克之機率則分別為3.23% 和6.35%，經傾向分數調整後，OR為1.50 (95 % CI: 0.61~3.69, p= 0.45)，無統計學上顯著差異。此外，對於使用erythromycin/ clarithromycin者來說，高齡、多共病症、本身具慢性腎病病史、併用天數較長者皆發生急性腎損傷的危險因子。
本研究結果與先前的文獻不同，以併用azithromycin者發生急性腎損傷之機率較高，但於低血壓或休克之發生率兩組並無統計學上差異。

Background: Previous case reports revealed that concomitant therapy with calcium channel blockers and macrolides resulted in hypotension. In 2012, the U.S. FDA issued a warning to remind physicians that the combination of clarithromycin and calcium channel blockers may cause severe hypotension. Drug-drug interactions not only affect the effectiveness, but also cause adverse effects, especially in cardiovascular drugs. Because a lot of cardiovascular drugs are metabolized by cytochrome P450 enzyme systems, simultaneous use with CYP 3A4 inhibitors or inducers, will lead to fluctuations of therapeutic levels, and further resulted in some adverse effects. Contrary to azithromycin, erythromycin and clarithromycin have inhibitory activity of cytochrome P450 3A4 (CYP 3A4). Therefore, co-administration with some calcium channel blockers which are the substrates of CYP 3A4 system will increase the risk of hypotension. Consequently, while hypotension occurs, poor kidney perfusion may also be a concern.
Objective: We conducted a population-based cohort study to investigate the incidence of acute kidney injury, hypotension and shock from the possible drug-drug interaction of calcium channel antagonists-macrolides.

Methods: The study used the 2005 National Health Insurance Research Database (NHIRD) from 2000 to 2012. We identified patients who had concurrent usage of calcium channel blockers and macrolides in 2002~2012. According to CYP 3A4 inhibitor activity, users of erythromycin/clarithromycin were in the treatment group, and azithromycin users were the control group. The incidences of hypotension, shock, and acute kidney injury after concurrent usage were identified. The propensity scores (PS) weighting were adapted in the statistical analysis.
Results: In the period between 2000~2012, those combinations at the same prescription,were frequently prescribed by internists, accounting for 59.37%% of all, and it had more frequency of occurrence in local community hospitals (60.53%) than in the clinic. We also identified 1,774 patients who received a coprescription with calcium channel blockers and macrolides in the period between 2002~2012, including 1,407 patients in erythromycin/clarithromycin group and 367 patients in azithromycin group. The incidence of acute kidney injury in azithromycin group (7.08%) was higher than in erythromycin/ clarithromycin group (3.20%) with odds ratio (OR) of 0.43 (95% CI: 0.26~0.71). But the incidence of hypotension or shock was not statistical significance from the two groups (OR: 0.55, 95% CI: 0.29~1.05). However, in azithromycin group, there were more comorbidities, and more renal disease patients. Therefore, propensity score was used to balance the two groups. In those who had underlying disease with renal disease, the incidence of acute kidney injury outcome in erythromycin/ clarithromycin group was 14.52%, and in azithromycin group was 12.70% (p= 0.73, weighted OR: 1.77, 95% CI: 0.98~3.18). Similarly, incidences of hypotension or shock were respectively 3.23%, 6.35% (p= 0.45, weighted OR: 1.50, 95% CI: 0.61~3.69). Furthermore, in our study, older age, multiple comorbidities, chronic renal disease, and the longer length of combinated days seemed to relate between acute kidney injury in erythromycin/clarithromycin group.
Conclusions: The finding did not support the theory that combination with azithromycin would be more risk than erythromycin/clarithromycin group. There was no statistical significance in incidences of hypotension or shock between two groups in 18 years older Taiwanese.

致謝 i
中文摘要 ii
Abstract v
目錄 viii
第一章 緒論 - 1 -
第一節 研究背景 - 1 -
第二節 研究目的 - 3 -
第二章 文獻探討 - 4 -
第一節 erythromycin、clarithromycin與鈣離子阻斷劑併用之現行安全監視措施 - 4 -
第二節 併用發生低血壓之危險因子探討 - 5 -
第三節 此藥物交互作用發生機轉及定義 - 5 -
第四節 研究設計相關定義之文獻探討 - 7 -
第五節 文獻探討總結 - 9 -
第三章 研究方法 - 10 -
第一節 研究資料與對象 - 10 -
第二節 研究藥品之定義 - 13 -
第三節 結果變項之定義 - 13 -
第四節 分析變項之定義 - 14 -
第五節 資料庫整理及統計分析方法 - 16 -
第四章 結果 - 18 -
第一節 同一門診併用處方型態分析 - 18 -
第二節 病人特質分析 - 19 -
第三節 研究指標結果 - 21 -
第四節 年齡對於發生不良反應之影響 - 22 -
第五節 共病嚴重程度對於發生不良反應之影響 - 23 -
第六節 慢性腎病之共病對於發生不良反應之影響 - 24 -
第七節 併用天數長短對於不良反應之影響 - 26 -
第八節 鈣離子阻斷劑處方型態分析 - 27 -
第五章 討論 - 29 -
第一節 同一門診併用處方型態討論 - 29 -
第二節 研究指標結果之分析 - 29 -
第三節 年齡、共病嚴重程度、慢性腎病共病對於併用所造成之影響………….. .- 30 -
第四節 併用天數分析之討論 - 31 -
第五節 鈣離子阻斷劑處方型態之討論 - 32 -
第六節 研究特色及限制 - 33 -
第六章 結論與未來方向 - 35 -
表格 - 36 -
表1 CYP 3A4強力抑制劑和中度抑制劑 - 36 -
表2 鈣離子阻斷劑成分 - 37 -
表3 巨環類抗生素成分 - 39 -
表4 主要指標與次要指標診斷碼 - 40 -
表5 研究變項及調整變項之定義 - 41 -
表6 同一門診之就醫科別、醫療院所層級、開立處方年份統計……… - 42 -
表7 病人基本特質(baseline characteristics) - 44 -
表8 研究結果 - 46 -
表9急性腎損傷發生與否之年齡分布 - 46 -
表10低血壓或休克發生與否之年齡分布 - 47 -
表11年齡與不良反應發生之關聯性 - 47 -
表12共病嚴重程度與不良反應發生之關聯性 - 48 -
表13 慢性腎病對急性腎損傷發生率之影響 - 49 -
表14 慢性腎病與不良反應發生之關聯性 - 50 -
表15 腎臟疾病對低血壓或休克發生率之影響 - 51 -
表16急性腎損傷發生與併用天數之分布 - 52 -
表17經IPTW調整後之併用天數 (急性腎損傷) - 52 -
表18低血壓或休克發生與併用天數之分布 - 53 -
表19經IPTW調整後之併用天數 (低血壓或休克) - 53 -
表20 併用天數與不良反應發生之關聯性 - 54 -
表21 併用不同鈣離子阻斷劑與急性腎損傷發生率 - 54 -
表22 併用不同鈣離子阻斷劑與低血壓或休克發生率 - 55 -
表23 鈣離子阻斷劑與不良反應發生之勝算比 - 55 -
圖 - 56 -
圖1 鈣離子阻斷劑及巨環類抗生素併用及事件時序示意圖 - 56 -
圖2 研究架構圖 - 56 -

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