骨關節炎合併心房顫動病人使用 NSAIDs藥物與中風風險相關性之回溯性世代研究

The Risk of Stroke Associated with Nonsteroidal Anti-Inflammatory Drugs among Osteoarthritis Patients with Atrial Fibrillation: A Population-based Retrospective Cohort Study

劉家豪(Chia-Hao Liu)

指導教授 ： 林珍芳

國立臺灣大學/醫學院/藥學研究所/碩士(2018年)

https://doi.org/10.6342/NTU201801782

摘要

背景及目的
已有眾多文獻顯示NSAIDs（non-steroidal anti-inflammatory drug）與心血管風險存在相關，本研究探討在骨關節炎OA (osteoarthritis) 合併非瓣膜性心房顫動且無中風病史的群族，長期使用非aspirin的NSAIDs與缺血性中風風險之關係，及該族群的NSAIDs使用現況，提供臨床上處方NSAIDs時相對安全的選擇。
方法
本研究為回溯性世代研究，使用2005年到2011年的台灣健保資料庫資料，分析使用NSAIDs 的OA群族，以缺血性中風為研究終點。使用cox proportional hazards regression校正潛在的干擾因素，以hazard ratio (HR) 以及95% 信賴區間 (cofidence interval, CI) 呈現風險結果。
結果
共3826位病患納入研究，其中NSAIDs non-user佔3105人；NSAIDs user佔721人。整體NSAIDs user的平均年齡為65.4±13.7歲，平均CHA2DS2-VASc Score為3.4±1.7分，除了心律不整之外，高血壓為最常見的共病症比例為72.5 %，最常見的共藥為steroid比例為 86.9%。處方量最多的傳統NSAIDs以diclofenac最多占28.5%。另外，COX-2抑制劑中celecoxib占全部使用量13.5%。研究結果顯示以non-user為參考時，naproxen有較低的缺血性中風風險 (adjHR=0.759; 95%CI=0.101-5.685)，其餘藥物皆與上升的缺血性中風風險有相關，特別是celecoxib有達到統計上顯著 (adjHR=1.879; 95%CI=1.003-3.522)。其他藥物則無統計上顯著etoricoxib (adjHR=1.897; 95%CI=0.682-5.281)，ibuprofen (adjHR= 1.497; 95%CI= 0.365-6.152)，diclofenac (adjHR=1.462; 95%CI=0.837-2.553)，meloxicam (adjHR=1.111; 95%CI=0.63-1.958)。
結論
根據本研究結果，在高風險的骨關節炎合併非瓣膜性心房顫動的族群，NSAIDs user 相比non-user時，celecoxib呈現較高的缺血性中風風險，相反的，naproxen則呈現較低的風險。然而結果與過去文獻略有不同，仍需要進一步之研究釐清NSAIDs與缺血性中風風險之相關性。

關鍵字

非類固醇抗發炎藥 ； 骨關節炎 ； 心房顫動 ； 中風 ； 回溯性世代研究

並列摘要

Background: A great number of studies implied that the NSAIDs（non-steroidal anti-inflammatory drug）including COX-2 inhibitors（selective inhibitors of cyclooxygenase-2）and traditional NSAIDs are related to higher risk of vascular events such as myocardial infarction, thromboembolism, and stroke. In addition, atrial fibrillation may also increase the opportunity to cause vascular events. Stroke would lay a serious burden on the medical care system. Consequently, establishing the safety profile of NSAIDs is necessary. This study aims to clarify the association between risk of ischemic stroke and use of non-aspirin NSAIDs in osteoarthritis (OA) patients with non-valvular atrial fibrillation.

Methods: A retrospective cohort study is devoted to the analysis of the Taiwan National Health Insurance Database. A total of 3826 subjects diagnosed with OA with atrial fibrillation were eligible in the study. The endpoint was defined as ischemic stroke. The hazard ratio (HR) and 95% confidence interval of outcomes were calculated by Cox regression models.

Results: In demographic analysis, diclofenac accounted for 28.5% and celecoxib accountd for 13.5% among all NSAIDs prescriptions in user group. Compared to non-user, some drugs were associated with increased risk of ischemic stroke such as etoricoxib (adjHR=1.897; 95%CI=0.682-5.281), diclofenac (adjHR=1.462; 95%CI=0.837-2.553), meloxicam (adjHR=1.111; 95%CI=0.63-1.958), ibuprofen (adjHR= 1.497; 95%CI= 0.365-6.152). Especially, celecoxib (adjHR=1.879; 95%CI=1.003-3.522) show higher and statistically significant risk of ischemic stroke.

Conclusion: Our study finds that in OA patients with non-valvular atrial fibrillation, celecoxib was related to a higher risk of ischemic stroke. In contrast, naproxen was associated with decreased risk. Further research is needed to clarify the relationship between NSAIDs and ischemic stroke risk.

並列關鍵字

Retrospective Cohort Study ； Ischemic Stroke ； NSAIDs ； COX-2 inhibitor ； Osteoarthritis

參考文獻

1. Vioxx and drug safety. 12-18-2004. (Accessed 06, 2017, at https://www.fda.gov/newsevents/testimony/ucm113235.htm.)

2. FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. 7-9-2015. (Accessed 06, 2017, at https://www.fda.gov/Drugs/DrugSafety/ucm451800.htm.)

3. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiological reviews 2011;91:265-325.

4. Chugh SS, Roth GA, Gillum RF, Mensah GA. Global burden of atrial fibrillation in developed and developing nations. Global Heart 2014;9:113-9.

5. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology 2011;57:223-42.