- 學位論文
痛風或高尿酸病人使用allopurinol及benzbromarone對冠狀動脈疾病的預防效果
The Use of Allopurinol and Benzbromarone for Coronary Artery Disease Prophylaxis in Patients with Gout
摘要
緒論 冠狀動脈疾病（coronary artery disease）為冠狀動脈因狹窄或阻塞所致，近年來已有研究指出冠狀動脈疾病與痛風有關。然而，目前關於降尿酸藥物治療能否用以預防冠狀動脈疾病，相關研究仍不甚充足，故本研究欲針對服用異嘌呤醇（allopurinol）及苯溴香豆酮（benzbromarone）之痛風患者，初步觀察其罹患冠狀動脈疾病之風險變化，並進一步分析藥物累積劑量多寡，是否和冠狀動脈疾病之罹病風險有關。 研究方法 本研究為一回溯性世代研究，自臺灣全民健康保險研究資料庫所提供之承保抽樣歸人檔中，選出二○○一年至二○○八年間診斷為痛風者，並將有冠狀動脈疾病、心衰竭、慢性腎臟病、癌症及痛風病史者，以及在痛風確診前曾服用異嘌呤醇或苯溴香豆酮者予以除卻。上述各疾病須經醫師開立兩次以上門診診斷，或一次以上住院診斷，方視為確診；而藥物處方開立即視為服藥。痛風病患依降尿酸藥物之用藥選擇，分為A組（異嘌呤醇單用）、B組（苯溴香豆酮單用）、A+B組（兩藥兼用）三組，並排除二○○九年後始服用異嘌呤醇或苯溴香豆酮者，以確保病患至久可追蹤三年。為確立上述兩降尿酸藥物預防冠狀動脈疾病之時序關係，本研究亦剔除服藥前即罹病、服藥後一百八十日內即罹病，或服藥起一百八十日內服藥天數未及九十日者，共得8,227名實驗組病患。其中A組1,437名、B組4,241名，和A+B組2,549名病人，分別依性別及年齡以一比一配對未曾服用異嘌呤醇或苯溴香豆酮之痛風病人，得8,227名對照組（C組）病人。實驗組以異嘌呤醇或苯溴香豆酮初次開立日期為觀察起始日（index date），對照組則以痛風確診日期為觀察起始日；各組配對追蹤迄任一病人發生冠狀動脈疾病止，或屆三年追蹤期滿。 研究結果 整體而言，共變數（covariate）經校正後，不論病人單用異嘌呤醇、單用苯溴香豆酮，抑或兩藥兼用，罹患冠狀動脈疾病之風險在統計學上與對照組之罹病風險均無二致。然而，若進一步分析藥物累積劑量對冠狀動脈疾病罹病風險之影響，則發現三組實驗組病人經服用三百六十個定義每日劑量(defined daily dose, DDD)後，冠狀動脈疾病之罹病風險皆明顯較對照組低；其中，又以單用異嘌呤醇之病患之罹病風險最低。此外，A組及A+B組服用藥物之累積劑量與冠狀動脈疾病之罹病風險成線性關係，其斜率為負。 結論 雖整體而言病人服用異嘌呤醇或苯溴香豆酮後，冠狀動脈疾病之罹病風險在統計學上並無異於對照組；然一旦藥物累積達一定劑量，各實驗組皆顯示罹病風險較對照組顯著下降。是故，筆者認為異嘌呤醇和苯溴香豆酮或許可用以輔助預防冠狀動脈疾病之發生，但本研究結果猶亟待後續研究予以佐證。
並列摘要
Background Coronary artery disease (CAD), caused by narrowing or obstruction of coronary artery, has been recently reported to be associated with gout. However, studies on the preventive effect of urate-lowering agents on CAD are still limited. The present study, therefore, attempted to preliminarily observe the change in risk of CAD in gout patients prescribed with allopurinol and/or benzbromarone, and further to analyze the dose-response relationship of the both drugs. Methods This retrospective cohort study was conducted using the claims data provided by the National Health Insurance Research Database. Both inpatients and outpatients diagnosed with gout between 2001 and 2008 were enrolled in our study. Patients were excluded from this study if they had history of CAD, heart failure, chronic kidney disease, cancer, or gout; or took either allopurinol or benzbromarone prior to diagnosis of gout. Each disease required at least two separate outpatient diagnostic codes or one inpatient diagnostic code, be it defined in an inclusion criterion, an exclusion criterion, or as a covariate. Besides, prescription with a medication was regarded as exposure to the medication in our study, irrespective of the patients’ medication adherence. To ascertain the effects of allopurinol and benzbromarone on lowering the risks of CAD, we excluded those who were prescribed with allopurinol or benzbromarone after December 31, 2008, who were identified as having CAD before or within 180 days of administration of either allopurinol or benzbromarone, and who took either allopurinol or benzbromarone for fewer than 90 days within 180 days of starting either of the medications. A total of 8,227 gout patients remained and were regarded as the experimental groups. Each patient of the experimental groups was exclusively matched with a gout patient who had never been prescribed with either drug by age and gender in the ratio of 1:1. The matched non-allopurinol-or-benzbromarone- exposed patients were categorized as the comparison group (Group C). We further divided the experimental groups into allopurinol-treated (Group A, N = 1,437), benzbromarone-treated (Group B, N = 4,241), and both-treated groups (Group A+B, N = 2,549). The index date was defined as the date newly prescribed with either drug for the experimental groups or newly diagnosed with gout for Group C. Results Patients of the experimental groups, in general, had no statistically significant change in risk of CAD with the covariates adjusted in comparison with those who were not exposed to either drug (Group C). However, the risk of CAD was negatively correlated with the number of doses in Group A and Group A+B. Each experimental group, in fact, had a lower risk of CAD than Group C after receiving over 360 defined daily doses (DDDs), after which Group A presented the lowest risk of CAD. Conclusion Our findings indicated that a considerable number of doses of allopurinol and benzbromarone are required for CAD prophylaxis, and hence the two drugs might be recommended for gout patients only as an adjuvant medication against the onset of CAD.