以實證醫學觀點探討質子幫浦抑制劑與抗組織胺-2 接受體拮抗劑預防重症病人壓力性潰瘍之臨床效果及經濟評估

背景：壓力性潰瘍是加護病房病人常見的併發症，而病人因壓力性潰瘍造成腸胃道出血後之死亡率也明顯增加。部分研究發現，針對產生壓力性潰瘍之高危險群病人給予預防性藥物可以有效減少病人潰瘍的產生。抗組織胺-2 接受體拮抗劑 (histamine-2 receptor antagonists, H2RAs)是之前整合分析研究(meta-analysis)中建議之首選藥物；新一代的抗潰瘍藥物-質子幫浦抑制劑(proton pump inhibitors,PPIs)，其對於胃酸的抑制效果較H2RAs 更佳，但相關的臨床研究並未被包括在之前所發表的整合分析中。研究目的：本研究除了要了解目前國內的壓力性潰瘍預防藥物使用情形外，旨在利用實證醫學方式比較及分析H2RAs 與PPIs 對於預防壓力性潰瘍之臨床效果及安全性，並進而利用整合分析結果進行成本效益分析(cost-effectiveness analysis)，以提供適當之醫療決策。研究方法：本研究首先將執行壓力性潰瘍預防之藥物使用評估，接著將利用實證醫學方式進行系統性文獻回顧及整合分析研究以探討 PPIs 與H2RAs 用於預防壓力性潰瘍之臨床效果及安全性，最後將進行藥物經濟學評估以了解最具成本效益之藥物。研究結果與討論：初步的評估結果顯示，有50.7%的高危險群病人被處方壓力性潰瘍預防藥物，全部的病人都被選擇使用PPIs。針對具有危險因子產生壓力性潰瘍的病人，與未給予預防性藥物相較，投予預防性藥物可顯著減少上腸胃道出血的比例(13.9% vs 42.9%, p=0.0086)。評估PPIs 及H2RAs 預防壓力性潰瘍之效果，結果顯示兩種藥品使用後在效果及安全性部分並沒有顯著差異。整合分析研究共收錄7 個隨機對照試驗(共936 個病人)，結果顯示PPIs 較 H2RAs 減少4%的危險產生壓力性潰瘍，但這樣的結果並未達到統計學的差異但卻具有顯著的異質性；分析結果亦顯示兩者產生肺炎及造成死亡的比例並沒有顯著的差異。藥物經濟學的評估顯示腸道投予的PPIs 具有較佳的成本效果，但若病人無法口服時應選擇 H2RAs，並不建議注射劑型的PPIs 做為重症病人預防壓力性潰瘍的首選藥物。結論：我國健康保險目前採全民健康保險制度，相較於其他國家有更沉重之經濟壓力，利用實證醫學的角度執行藥效及安全性分析及經濟評估除了能提供臨床醫療人員最適當的藥物選擇更能提供決策制定者最具經濟考量的選擇。

關鍵字

壓力性潰瘍；質子幫浦抑制劑；抗組織胺-2 接受體拮抗劑；整合分析研究；藥物經濟學

並列摘要

Objective: To evaluate the usage for stress-related upper gastrointestinal bleeding prophylaxis in a medical center in Taiwan and examine the efficacy and safety of proton pump inhibitors (PPIs) in comparison with histamine-2 receptor antagonists (H2RAs) for stress-related upper gastrointestinal (UGI) bleeding prophylaxis among critical care patients. To perform a pharmacoeconomic evaluation to explore the most costeffectiveness agent for stress-related gastrointestinal bleeding prophylaxis. Methods: A retrospective drug usage evaluation, systematic review and meta-analysis of comparing histamine-2 receptors to proton pump inhibitors for stress ulcer prophylaxis in critically ill patients were performed. And then a decision tree analysis was performed to calculate the incremental cost-effectiveness ratio to explore the most cost-effectiveness agent for stress ulcer prophylaxis. Results and discussions: All patients with risk for stress ulcer evaluated were all prescribed PPIs and the risk of gastrointestinal bleeding was decreased when comparing to without prophylaxis. We identified 7 randomized controlled trials with a total of 936 patients for systematic review and meta-analysis. The overall pooled risk deference (95% confidence interval, p value; I2 statistics) of stress-related UGI bleeding comparing PPIs versus H2RAs was -0.04 (-0.09, 0.01, p=.08; I2=66%). In the sensitivity analysis, removing Levy study significantly reduced the heterogeneity (from I2=66% to 26%) and shifted the overall risk difference closer to the null (pooled risk difference –0.02, 95% CI –0.05 to 0.01, p=.19). There was no difference between PPIs and H2RAs therapy in the risk of pneumonia and ICU mortality with pooled risk differences of 0.00 (-0.04, 0.05, p=.86; I2=0%) and 0.02 (-0.04, 0.08, p=.50; I2=0%) respectively. In the pharmacoeconomic analysis, enteral PPIs were the most cost-effectiveness agents for stress ulcer prophylaxis. Conclusions: This study did not find strong evidence that PPIs were different from H2RAs in terms of stress-related UGI bleeding prophylaxis, pneumonia, and mortality among patients admitted to ICUs. Due to limited trial data, future well-designed and powerful randomized clinical trials are warranted. From the point of decision maker, enteral PPIs may be the best choice for prophylaxis.