- 學位論文
低劑量阿斯匹靈在台灣糖尿病人作為重大心血管事件初級預防之相關性評估
The Association between Low Dose Aspirin and Primary Prevention of Major Cardiovascular Events in Taiwanese Patients with Diabetes
摘要
研究背景 心血管疾病事件為糖尿病病人主要造成發病及死亡的併發症之一，與一般族群相比，糖尿病病患在10年內有大於2倍的風險得到心血管疾病相關併發症，主要涵蓋心肌梗塞與缺血性中風。在臺灣2012年統計十大死因當中，心臟及腦血管疾病分居第二及第三大死因。阿斯匹靈(aspirin)為一抗血小板藥品，對於心肌梗塞及中風的次級預防有很強的證據佐證，同時已列入該藥品之適應症。近幾年，美國預防醫學小組以及美國糖尿病學會分別針對心血管疾病高風險族群以及糖尿病族群，提出使用低劑量阿斯匹靈初級預防的使用。然而，多數的建議乃基於西方國家的研究，西方國家與亞洲是否因為種族差異而產生不同的影響目前並未有充分的文獻佐證，國人目前使用低劑量阿斯匹靈作為初級預防成效之文獻尚未明確。 研究目的 本研究將以釐清低劑量阿斯匹靈對於臺灣糖尿病患，心肌梗塞及中風的初級預防效果之探討為標的。希望研究成果能夠提供為臨床醫師在糖尿病患藥物選擇之參考依據。 研究方法 本研究為一回溯性的世代研究，所分析資料取自臺灣全民健保資料庫2005年百萬抽樣歸人檔 (LHID 2005)。研究資料庫長度共有12年(2000-2012)，本研究世代收錄2001至2006有被診斷為糖尿病40歲以上的病人，以低劑量阿斯匹靈 (81 - 165 mg) 處方紀錄來定義暴露組，再進一步以1:1的比例進行年齡、性別配對，定義出非暴露組。在曝露組中，我們將第一次低劑量阿斯匹靈處方紀錄做為研究起始日。本研究屬於新使用者設計(New User Design)，將過去一年曾經有低劑量阿斯匹靈處方紀錄者予以排除。研究追蹤期間為起始日往後6年，利用Logistic Regression Model以及Cox Proportional Hazard Model分析低劑量阿斯匹靈與新發生心血管事件: (i)心肌梗塞，(ii)缺血性中風之相關性，並調整及排除可能影響的干擾因子。次分析中我們分析使用低劑量阿斯匹靈的糖尿病人中新發生心血管事件與年平均處方量的相關性。 研究結果 在回溯性世代研究中，經過排除及納入條件後共收錄20,416位糖尿病患，追蹤期間為6年，再調整可能影響因子後，與非暴露組相比，低劑量阿斯匹靈處方暴露與增加新發生重大心血管事件的風險(定義為心肌梗塞,缺血性中風)具有相關性。新發生心血管事件比例在暴露組為26.2%及非暴露為14.4% (crude OR = 2.12; 95% CI = 1.97-2.27; adjusted OR = 1.86; 95% CI = 1.73-2.00)，進一步利用Cox Proportional Hazard Model分析，結果顯示與前者相關性一致 (adjusted HR = 1.78; 95% CI = 1.67-1.90)。針對阿斯匹靈暴露組進行的次分析當中發現，年平均處方量越高相對於對照組有顯著增加44%-165%心血管疾病的危險 (? 30 aspirin group: Reference group; 30 to 90 aspirin group: OR = 1.69, 95% CI = 1.43-1.95; 91 to 180 aspirin group: OR = 1.66, 95% CI = 1.42-1.93; 181 to 270 aspirin group: OR = 1.44, 95% CI = 1.22-1.71; > 270 aspirin group: OR = 2.65, 95% CI = 2.33-3.01)。然而，在Kaplan-Meier曲線中發現低劑量阿斯匹靈處方相較於未使用者阿斯匹靈者所增加心血管疾病的風險，從追蹤第一年兩組的風險差異為6.9%至追蹤第六年逐漸降低為0.7%，發現長期使用低劑量阿斯匹靈可能具有潛在的好處。 研究結論 在回溯性世代研究中發現低劑量阿斯匹靈處方暴露與增加新發生的重大心血管疾病具有關聯性，特別是在年平均處方量越高的情況下更為顯著。這個關聯性同時符合美國針對糖尿病病人的指引提出糖尿病病患使用低劑量阿斯匹靈的條件趨進保守。然而，再進一步經存活曲線分析看出長期使用低劑量阿斯匹靈可能具有潛在的好處。因此，臨床醫師在未來針對糖尿病病人是否該處方低劑量阿斯匹靈做為預防使用可能需要更謹慎的評估。 未來的研究方向能朝向更長的觀察時間，或者以隨機分派試驗來確定兩者的因果關係。
並列摘要
Background Cardiovascular disease (CVD) is one of the complications which could lead to morbidity and mortality in diabetic patients. Compared to general population, there are doubled ten-year risk of detrimental cardiovascular events including myocardial infraction (MI) and ischemic stroke. In Taiwan, heart disease and cerebrovascular disease are the second and third leading cause of death, respectively in 2012. Aspirin is an antiplatelet agent for preventing secondary recurrence of MI and ischemic stroke. To date, several studies have investigated the effects of low dose aspirin on primary prophylaxis of CVD. Although most of guidelines have developed their recommendations in the United States, but these recommendations may not fit well in Asian patients, particularly Taiwanese. Whether the use of low dose aspirin could be prevented primary CVD remains unclear in patients with diabetes. Objective The objective of present study is to evaluate the association between prescription of low dose aspirin and the risk of first-time occurrence of major cardiovascular events (MCE) in Taiwanese patients with diabetes. Methods This is a retrospective cohort study using the Longitudinal Health Insurance Database 2005 (LHID 2005) from January 2000 to December 2012. The enrollment period was set from January1st, 2001 to December 31st, 2006 in order to identify prevalent diabetic patients with and/or over aged 40 years old. The key independent variable was whether newly prescribed of low dose aspirin, defined as 81 to 165 mg in Taiwanese with diabetes and the date of newly prescribed aspirin was defined as index date. In order to conduct the new user design study, those who were prescribed low dose aspirin within one year before the index date were excluded. Each patient in the aspirin-exposed group was individual-matched one patient in the non-aspirin-exposed group by age and gender. In the subgroup analysis, data were further analyzed the association between amount of average annual prescription of low dose aspirin and risk of MCE in the aspirin-exposed patients with diabetes. The primary endpoints were the firs-time occurrence of major cardiovascular events (MCE) which includes MI and ischemic stroke. All patients had an over the six-year follow up period. Covariates selected in this study included the comorbidities and confounding medication. The Logistic Regression Model and the Cox Proportional Hazards Regression Model were performed to evaluate the association between the prescription of low dose aspirin and risk of MCE. Results During the six-years follow up period, the major findings suggested that low dose aspirin was associated with increased risk of first-time occurrence of major cardiovascular events in patients with diabetes. Among the 20,416 subjects, 26.2% were diagnosed with major cardiovascular events (MCE) in the aspirin-exposed group when comparing with 14.4% in the non-aspirin-exposed group. The unadjusted odds ratios (OR) of MCE was 2.12 (95% CI = 1.97-2.27). After adjusting for confounding covariates, the present results still show a significant 86% increase in the risk of cardiovascular events (adjusted OR = 1.86; 95% CI = 1.73-2.00). A significant 78% increase in the adjusted risk of cardiovascular events in the aspirin-exposed group analyzed by the Cox proportional hazard analysis (adjusted HR = 1.78; 95% CI = 1.67-1.90). Furthermore, subgroup analysis of the aspirin-exposed group, revealed an association between risk of developing of MCE and the average annual prescribed of low dose aspirin (30 to 90 aspirin group: OR = 1.69, 95% CI = 1.43-1.95; 91 to 180 aspirin group: OR = 1.66, 95% CI = 1.42-1.93; 181 to 270 aspirin group: OR = 1.44, 95% CI = 1.22-1.71; > 270 aspirin group: OR = 2.65, 95% CI = 2.33-3.01) when comparing with the reference group (≤ 30 aspirin group). However, the present results based on the Kaplan-Meier curve found that the observed increase MCE risks subsided from 6.9% to 0.7% after a long-term prescription of low dose aspirin in the aspirin exposed group for more than six years. Conclusion The results of the present retrospective cohort study suggest that low dose aspirin exposure in patients with diabetes was associated with an increased risk of major cardiovascular events when compared with the non-aspirin exposed group. These results support the recommendation of the U.S. guideline restricts use of low dose aspirin in patients with diabetes. However, the observation of increased risk of developing MCE in the aspirin exposure group which subsided yearly with a prolonged observation period extended from one year to six years. It is recommended that physicians need to carefully monitor low dose aspirin prescription for primary prophylaxis of CVD in diabetic patients. Future studies on possible long-term beneficial effects of low dose aspirin should be conducted to clarify this association, either longer cohort studies or randomized longitudinal control trials.