HMG-CoA還原酶抑制劑對慢性腎臟病患發生心血管事件及腎功能之影響

Effects of HMG-CoA Reductase Inhibitors on Cardiovascular Events and Renal Function in Patients with Chronic Kidney Disease

陳潔瑩(Chieh-Ying Chen)

指導教授 ： 黃尚志

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2013年)

摘要

研究背景：台灣成人之慢性腎臟病盛行率為12%，其與發生心血管疾病與死亡相關。HMG-CoA還原酶抑制劑(statin)為治療高膽固醇血症之首選藥物，目前研究已證實statin可降低一般族群與輕中度慢性腎臟病患之心血管疾病發生率，然而其對重度腎臟病患之有效性及安全性仍多有議論。此外，近年有研究探討statin對慢性腎臟病患腎功能指標之影響，也仍未有定論。
研究目的與目標：本研究目的為藉由系統性回顧(systematic review)及整合分析(meta-analysis)的方法，探討statin對透析族群之影響；並利用醫院資料庫研究瞭解statin於慢性腎臟病患之臨床使用情形、評估影響此族群心血管疾病與腎功能之相關因素及安全性。
研究方法：本研究主要分為兩部分。第一部分為系統性回顧與整合分析研究，利用系統性方法蒐集並評讀國內外探討HMG-CoA還原酶抑制劑使用於透析族群之文獻。收納之文獻類型探討statin與安慰劑或無使用降血脂藥物治療相比，用於透析患者(含血液透析與腹膜透析)之隨機對照試驗與觀察性研究。主要有效性評估指標為心血管事件、腦血管事件、心因性死亡、總死亡率，次要有效性評估指標為血脂改變量；安全性評估含發生嚴重藥物不良反應、因不良反應離開試驗、肌酸磷酸酶上升與肝臟酵素增加。第二部分為利用南部某醫學中心病歷資料進行回溯性世代研究，追蹤2006年1月1日至2006年12月31日間所有新使用statin之成年慢性腎臟疾病之病患，紀錄自statin首次處方日至試驗終止(2012年12月31日)、死亡或失去追蹤間之基本資料與疾病相關資訊，以評估statin於慢性腎臟病患之處方型態、影響發生心血管疾病與腎功能之相關因素與安全性。
研究結果：系統性回顧與整合分析研究共納入23篇隨機臨床試驗(8299人)與6篇世代研究(13849人)。心血管疾病相關之整合分析結果顯示，statin與對照組相比，顯著減少8%心血管事件發生率(HR 0.92, 95% CI 0.85, 0.98)、減少17%心因性死亡風險(HR 0.83, 95% CI 0.71, 0.98)並減少22%總死亡率(HR 0.78, 95% CI 0.66, 0.91)，但不會影響腦血管事件發生率。在血脂方面，statin與對照組相比顯著降低血中總膽固醇、低密度脂蛋白與三酸甘油酯並增加血中高密度脂蛋白。Statin相較於對照組不會顯著影響嚴重藥物不良反應等不良事件發生率。回溯性世代研究共納入101名個案，平均追蹤時間為5.3年。Statin之平均處方持有率為43%。冠狀動脈疾病史之個案較無冠狀動脈病史者增加42倍動脈硬化事件風險，使用血管收縮素轉化酶抑制劑及血管收縮素受體Ⅱ阻斷劑與減少心血管事件風險相關。此外，個案於試驗初始之腎絲球過濾率增加可能降低末期腎臟病發生風險；而statin處方持有率高與加速腎絲球過濾率下降速率相關。
結論：系統性回顧與整合分析結果發現statin顯著減少透析族群之心血管事件發生率、心因性死亡率與總死亡率，但對腦血管事件沒有顯著影響。此外，本研究結果顯示statin用於透析族群，不會增加或減少發生嚴重藥物不良反應等安全性結果之風險。同時發現冠狀動脈病史之慢性腎臟病患，有增加心血管疾病風險，使用血管收縮素轉化酶抑制劑及血管收縮素受體Ⅱ阻斷劑與減少心血管事件風險相關；而腎絲球過濾率與statin處方持有率為影響腎功能進展之相關因素。

關鍵字

系統性回顧與整合分析 ； HMG-CoA還原酶抑制劑 ； 慢性腎臟病 ； 腎功能 ； 心血管疾病

並列摘要

Background: In Taiwan, the prevalence of chronic kidney disease (CKD) among adult is 12%. CKD is one of the risk factors of cardiovascular disease (CVD). HMG-CoA reductase inhibitors (statin) is the first-line agent for treatment of hypercholesterolemia. There are evidences that statin improve the CVD morbidity and mortality in mild-to-moderate CKD patients. However, the efficacy and safety of statin in severe CKD population is still unsure. Recently, there are some studies that assessed the effect of statin on renal function but the influence of statin on renal function is controversial.
Aim and objectives: The study aimed to explore the effect of statin on CVD and adverse reaction in dialysis population by systematic review and meta-analysis. Otherwise, the study also used hospital-based database to investigate the medical utilization of statin in CKD patients, the factors related to CVD and renal function.
Methods: This study divided into two parts. The first part was systematic review and meta-analysis. It explored the effects of statin comparing with placebo or no treatment on CVD, cerebrovascular disease, cardiovascular mortality, all-cause mortality and lipid profiles in dialysis patients among randomized controlled trials (RCTs) and observational studies. This study also examined the safety of statin using in dialysis population. The other part was the hospital-based retrospectively cohort study. We included CKD patients who using statin between January 2006 and December 2006. We followed from the date of first prescription for a statin to the end of the study (December 31, 2012), death or loss to follow-up. We recorded all patients’ baseline characteristics and study-related medical record to evaluate prescribing pattern of statin, the factors associated with CVD and renal function and safety.
Results: The systematic review and meta-analysis identified a total of 23 RCTs with 8299 participants and 6 cohort studies with 13849 patients. The result of SR and MA showed that statin significantly decrease the CVD rate (HR 0.92, 95% CI 0.85, 0.98), cardiovascular mortality (HR 0.83, 95% CI 0.71, 0.98) and all-cause mortality (HR 0.78, 95% CI 0.66, 0.91) but there was no statistically significant difference on cerebrovascular disease between the two groups. Stains significantly decrease total cholesterol, low density lipoprotein, triglyceride and increase high density lipoprotein. There was similar occurrence of all safety outcomes with statin in comparison to placebo. In the hospital-based cohort study, there were 101 patients with mean follow-up period of 5.3 years were included. The mean prescription possession ratio (MPR) of statin was 43%. Coronary artery disease (CAD) history was associated with increasing the risk of atherosclerotic events, but use of angiotensin converting enzyme inhibitors or angiotensin Ⅱ receptor was related to decreasing cardiovascular risk. Patient’s baseline estimated glomerular filtration rate (eGFR) was associated with renal progression to end-stage renal disease, and high MPR of statin was related to enhancing the decrease of eGFR.
Conclusion: The systematic review and meta-analysis showed that statin significantly reduced the CVD rate, cardiovascular mortality and all-cause mortality in dialysis population. Statin appeared to be safe in dialysis population. The retrospective cohort study found CAD was associated with increasing CVD risk in CKD patients using statin. Patients’ baseline eGFR and MPR of statin were related to renal progression.

並列關鍵字

systematic review and meta-analysis ； HMG-CoA reductase inhibitor ； chronic kidney disease ； renal function ； cardiovascular disease

參考文獻

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