心衰竭病人使用非類固醇抗發炎藥產生急性腎損傷之風險評估

Risk of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)-Induced Acute Kidney Injury in Heart Failure Patients

陳柏霖(Po-Lin Chen)

指導教授 ： 李啟明

國立臺灣大學/醫學院/臨床藥學研究所/碩士(2016年)

https://doi.org/10.6342/NTU201601736

摘要

背景： 文獻報導大眾族群使用非類固醇抗發炎藥與急性腎損傷的發生有關，而後續研究也顯示心衰竭病人使用此類藥品會增加因心衰竭的住院率。臨床上，醫師經常處方非類固醇抗發炎藥以緩解退化性關節炎、痛風與上呼吸道感染等症狀。一旦心衰竭病人暴露到此類藥品，可能會發生急性腎損傷，進而惡化其心衰竭病情，但目前少有文獻探討心衰竭病人使用非類固醇抗發炎藥造成急性腎損傷的風險因子。
目的： 藉由回溯病歷建立某醫學中心資料庫，探討心衰竭病人使用非類固醇抗發炎藥造成急性腎損傷之機率，並找出潛在風險因子，藉此突顯藥師及個案管理師在心衰竭病人用藥安全與健康照護的重要性。
方法： 本研究為一病歷回顧世代性研究，利用個案報告表彙集某一醫學中心心衰竭門診病人資料。自2006年1月1日至2016年1月31日被診斷有心衰竭的病人，若期間曾經使用非類固醇抗發炎藥，每一次暴露(exposure)作為一個事件(episode)，暴露的第一天定義為進入研究世代日期(cohort entry date)，並且在當天記錄病人的年齡、血清肌酸酐濃度、左心室射出率、共病症等基礎特徵、併用藥品，每個事件會追蹤至最近一次心衰竭門診就診日，定義為visiting date (VD)，且在當天評估病人是否發生試驗目標(study outcomes)。主要試驗目標定義為急性腎損傷(VD的血清肌酸酐濃度比基礎值上升≥0.5 mg/dL)；次要試驗目標包括收縮壓上升(VD的收縮壓≥140 mmHg，且比基礎收縮壓上升≥5 mmHg)、下肢水腫惡化(VD的水腫程度比上次門診更嚴重)。資料分析利用描述性分析，描述有無發生試驗目標者之間，基礎特性、併用藥品與非類固醇抗發炎藥開方模式等差異。
結果： 本研究共收納145位病人、91個非類固醇抗發炎藥暴露事件。排除8個末期腎疾病的事件，剩餘83個事件，由於有37個事件在VD沒有血清肌酸酐濃度的檢驗數值，因此，在主要試驗目標剩餘的46個事件適合做分析，當中有5個事件發生急性腎損傷(10.9%)，這群病人的基礎血清肌酸酐濃度(1.6 vs. 1.1 mg/dL, p=0.01)與血清尿素氮(29.7 vs. 19.5 mg/dL, p=0.01)較高、糖尿病(80.0% vs. 26.8%, p=0.03)與慢性腎疾病(80.0% vs. 22.0%, p=0.02)的盛行率較高；在次要試驗目標中，2個事件沒有血壓的紀錄，剩餘的81個事件中有10個發生收縮壓上升(12.4%)，這些病人的年紀較大(77.5 vs. 65.0 歲, p<0.01)、基礎收縮壓(137.5 vs. 123.0 mmHg, p=0.03)與脈搏壓(63.0 vs. 50.0 mmHg, p=0.02)較高；此外，1個事件沒有下肢水腫的紀錄，在82個當中有10個事件發生下肢水腫惡化(12.2%)，這些病人的基礎血清尿素氮較高(23.9 vs. 18.0 mg/dL, p=0.04)、使用indomethacin的比例較高(20.0% vs. 1.4%, p=0.04)。
結論： 本研究證明心衰竭病人使用非類固醇抗發炎藥造成急性腎損傷的個案，為一群基礎腎功能較差、糖尿病與慢性腎疾病盛行率較高的病人；發生收縮壓上升的個案，為一群年紀較高的老年人(定義為≥75歲)，以及基礎收縮壓與脈搏壓較高的病人；發生下肢水腫惡化的個案，為一群基礎血清尿素氮較高、使用indomethacin比較較高的病人。

關鍵字

心臟衰竭 ； 非類固醇抗發炎藥 ； 急性腎損傷 ； 風險因子 ； 病歷回顧研究

並列摘要

Background: Previous studies found that non-steroidal anti-inflammatory drugs (NSAIDs) were associated with acute kidney injury (AKI) in general population, thereafter some studies showed that NSAIDs might increase the rate of heart failure (HF) hospitalization in HF patients. In clinical practice, physicians usually prescribe NSAIDs for reliving the symptoms of osteoarthritis, gout, or upper respiratory infection. Once HF patients are exposed to these drugs, they may develop AKI which could deteriorate the condition of HF. However, there is few study to explore the risk factors of AKI in HF patients exposed to NSAIDs.
Objective: We reviewed the medical records to establish the database of the selected medical center and to study the risk factors associated with AKI in HF patients exposed to NSAIDs. We would address the importance of pharmacists and case managers in engaging medication safety and healthcare for HF patients.
Methods: This is a retrospective cohort study by using medical record review. The patients’ information was collected by the case report form and these patients who had been diagnosed with HF have been followed up at the specialized HF clinic over a 10-year interval from January 1, 2006, through January 31, 2016. Study episode was defined as a patient who was ever exposed to NSAID and each exposure was regarded as one episode. The date of the initial NSAID prescription was defined as the cohort entry date. We documented the baseline characteristics (including age, serum creatinine (SCr), left ventricular ejection fraction, comorbidities) and concomitant medications at the cohort entry date. Each episode was followed from the cohort entry date to the nearest specialized HF clinic visit, and the date was assigned as visiting date (VD). At the VD, we evaluated the study outcomes as follows: primary outcome as AKI, defined as the change of SCr from baseline ≥0.5 mg/dL; one of secondary outcomes as elevated systolic blood pressure (SBP), defined as the SBP of VD ≥140 mmHg and the change of SBP from baseline ≥5 mmHg; the other secondary outcome as aggravated leg edema, defined as the exacerbation of leg edema compared to the last clinic visit. Descriptive analysis was used for depicting the distribution between with- and without-outcome groups including baseline characteristics, concomitant medications and the patterns of NSAIDs prescription.
Results: A total of 145 patients were included, and there were 91 episodes ever exposed to NSAIDs. Because 8 end-stage renal disease episodes were excluded, 83 episodes remained in the study. In the primary outcome, since 37 episodes were dearth of SCr detection on VD, there were 46 evaluable episodes. A total of 5 out of 46 episodes (10.9%) developed AKI. Not only were their baseline SCr (1.6 vs. 1.1 mg/dL, p=0.01) and BUN (29.7 vs. 19.5 mg/dL, p=0.01) higher than those of episodes in the non-AKI group, but they were also prevalent in diabetes mellitus (DM) (80.0% vs. 26.8%, p=0.03) and chronic kidney disease (CKD) (80.0% vs. 22.0%, p=0.02). In secondary outcome as elevated SBP, because of the absence of BP documentation in 2 episodes, remaining 81 episodes were eligible. A total of 10 out of 81 episodes (12.4%) presented with this outcome, and they were the extreme elderly (77.5 vs. 65.0 years, p<0.01) with higher baseline SBP (137.5 vs. 123.0 mmHg, p=0.03) and pulse pressure (63.0 vs. 50.0 mmHg, p=0.02). In addition, as a result of the missing of leg edema documentation in 1 episode, 82 episodes were eligible for the other secondary outcome as aggravated leg edema. A total of 10 out of 82 episodes (12.2%) developed this outcome, and they were with higher blood urea nitrogen level (23.9 vs. 18.0 mg/dL, p=0.04) and the higher proportion of indomethacin use (20.0% vs. 1.4%, p=0.04).
Conclusion: This study demonstrates that the distributions of HF patients exposed to NSAIDs who developed AKI were with worse baseline renal function and prevalent in DM and CKD; who presented with elevated SBP were the extreme elderly (≥75 years) and with higher baseline SBP and pulse pressure; who manifested as aggravated leg edema were with higher baseline BUN level and more indomethacin use.

並列關鍵字

Heart failure ； Non-steroidal anti-inflammatory drugs (NSAIDs) ； Acute kidney injury ； Risk factors ； Medical record review

參考文獻

1. Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med 1998;104:2S-8S.

2. Marnett LJ, Rowlinson SW, Goodwin DC, et al. Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition. J Biol Chem 1999;274:22903-6.

3. Bjorkman DJ. The effect of aspirin and nonsteroidal anti-inflammatory drugs on prostaglandins. Am J Med 1998;105:8S-12S.

4. Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: Structural, cellular, and molecular biology. Annu Rev Biochem 2000;69:145-82. 

5. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433-42.