Statins用於亞洲老年族群作為心血管疾病初級預防之療效評估

Abstract

背景及目的 隨著醫療水準的進步，高齡化已是全球趨勢，現今老年人功能狀態較過去同齡老年人佳，且預期餘命長，老年人的預防醫學成為醫療工作者應重視的問題。心血管疾病位居全球死因之首，而心血管疾病的預防除了從飲食控制及生活習慣著手外，透過藥物控制三高疾病（高血壓、高血糖、高血脂）亦是重要的一環，其中HMG-CoA reductase inhibitors（簡稱statins）即是高血脂治療的首選藥品，然而由於過去臨床試驗缺乏老年人使用statins作為心血管疾病初級預防的療效證據，目前並無充足證據支持statins於老年人的預防性使用。本研究為一使用次級資料庫之回溯性世代研究，旨在描述65歲以上過去未有心血管疾病之老年人，使用statins作為心血管疾病初級預防的治療形態與療效。 方法 本研究使用台大醫療體系整合資料庫（NTUH-iMD）串連台灣衛生福利資料科學中心提供之健保資料庫，此NTUH-iMD包含2006-2017年間曾在台大醫院具有三高或心血管疾病診斷的病人之資料。研究期間為2008年2月至2017年12月，收入2008年至2015年間於台大醫院門診就診之65歲以上的病人，排除過去有相關心血管病史及statins之使用，並以年紀（±2歲）、性別、糖尿病史有無、就診日期（±30天）、低密度脂蛋白膽固醇（簡稱LDL-C）數值及傾向分數，對治療組及對照組進行1:4的配對，使用Cox比例回歸模型分別對重大心血管事件（包括心肌梗塞、缺血性中風及心血管相關死亡）、心肌梗塞、缺血性中風、心血管相關死亡、廣義心血管事件（包括重大心血管事件、暫時性腦缺血發作、不穩定心絞痛及血管再成形術）及全因性死亡進行statins的療效評估。為確保研究結果之穩健性，我們對研究終點定義及族群定義進行敏感性分析，另外針對LDL-C如此會隨時間變化的干擾因子，我們亦使用marginal structural model (MSM)對每年LDL-C數值進行校正。最後，我們在次族群分析中亦評估statins於不同族群的療效差異。 結果 本研究病人經過配對，共納入2,761位statin新使用者與9,503位非使用者，整體而言，平均年齡為72歲，有30%具糖尿病史，67%具高血壓病史，61%病人之LDL-C >130 mg/dL。在主要分析（intention-to-treat）中，statins能顯著降低65歲以上老年族群的重大心血管事件（風險比[hazard ratio, HR] 0.80, 95% CI 0.65-0.99），而心肌梗塞、缺血性中風、心血管相關死亡及全因性死亡等其他終點則無顯著關係，各項敏感性分析中亦得到相似的結果，以MSM校正隨時間改變的LDL-C後，statins能降低重大心血管事件（HR: 0.75, 95% CI: 0.60-0.93）、廣義心血管事件（HR: 0.77, 95% CI: 0.65-0.92）及全因性死亡（HR: 0.79, 95% CI: 0.68-0.93）的風險，而在次族群分析中並無觀察到statins的療效因次族群分組而有顯著差異。 結論 本研究證明statins在65歲以上有三高疾病且不具心血管病史的亞洲老年人，能夠顯著降低心血管疾病的風險，進一步支持statins於三高老年族群作為初級預防的使用療效。建議未來研究可擴大研究族群範圍，並針對老年人的不同風險因子分組進行分析，探究具最佳療效的病人群組，此外亦可進行成本效益分析，提供醫療人員或政策決策者更完整的藥品評估參考依據。

Background/Aims: Population aging and increasing life expectancy are both global trends, and there is no exception in Taiwan. Therefore, preventive medicine for the elderly has become an important health issue nowadays. As cardiovascular disease (CVD) is a leading cause of death worldwide, lifestyle modification and control of metabolic syndrome play essential roles for both secondary and primary prevention of CVD. There has been rigorous evidence that use of HMG-CoA reductase inhibitors (statins) can significantly improve the outcomes in elderly with atherosclerotic CVD (ASCVD). Nevertheless, the effectiveness evidence of statins for primary prevention is limited in the elderly, especially in those aged ≥75 years. This retrospective cohort study was aimed to describe the treatment pattern of statin use for primary prevention in those aged aged ≥65 years. We also evaluate the effectiveness of statins for preventing ASCVD and the related major events in elderly Asians. Methods: We conducted a retrospective cohort study using 2006-2017 linkage of the Integrated Medical Database of National Taiwan University Hospital (NTUH-iMD) and the National Health Insurance Research Database. The NTUH-iMD includes data files for patients who had a diagnosis of hypertension, diabetes, dyslipidemia or CV disease between 2007 and 2017. Patients aged over 65 and visited NTUH between 2008 and 2015 were included as the initial study cohort. We further excluded those with history of CVD or statin use before the start of outcome follow-up (index date). Statin new users were identified and 1:4 randomly matched to nonusers on age (±2 years), gender, index date (± 30 days), presence of diabetes, LDL-C level and propensity score. Effectiveness of statins for ASCVD primary prevention was analyzed by Cox proportional hazards model. Outcomes of interest were major adverse cardiovascular event (MACE; includes myocardial infarction [MI], ischemic stroke [IS] and cardiovascular death [CV death]), MI, IS, CV death, broad definition of MACE (includes MACE, transient ischemic attack, unstable angina and revascularization), and all-cause mortality. The unbalanced covariates after matching were adjusted in the final model. A series of sensitivity analyses with different definitions of cohort and outcomes were performed to test the robustness of the results. Moreover, we adjusted for the time-varying, yearly LDL-C level by marginal structural model (MSM). The effect of statins was also assessed in different subgroups. Results: There were a total of 2,761 statin new users and 9,503 nonusers included after matching. The mean age was 71.8 years, and 63% were female. As a whole, 30% of the patients had diabetes, 67% had hypertension, and 61% had baseline LDL-C level over 130 mg/dL. Statin use was associated with a significantly reduced risk of MACE (hazard ratio [HR]: 0.80, 95% CI 0.65-0.99). Similar results were found in the sensitivity analyses. After adjusting time-varying LDL-C with MSM, statins significantly reduced the risks of MACE (HR: 0.75, 95% CI: 0.60-0.93), broad definition of MACE (HR: 0.77, 95% CI: 0.65-0.92) and all-cause mortality (HR: 0.79, 95% CI: 0.68-0.93). No significant difference was detected in the effect across subgroups. Conclusion: Statin use could be beneficial for primary prevention of cardiovascular disease in the Asian elderly over 65 years. Further study, with a larger number of patients and wider population, is needed to identify the risk group among the elderly who may benefit most from the preventive treatment. Cost-effectiveness analysis is also required to weigh the treatment costs and benefits so that more evidence reference can be provided for clinical decision making.