評估抗血栓藥品用於慢性腎臟疾病合併心房撲動病人之心血管風險

Evaluating Risk of Cardiovascular Events in Chronic Kidney Disease with Atrial Flutter using Different Oral Antithrombotic Drugs

王映珽(Ying-Ting Wang)

指導教授 ： 陳崇鈺

高雄醫學大學/藥學院/藥學系臨床藥學碩士班/碩士(2019年)

摘要

研究背景與目的：
血栓阻塞是心房撲動常見的併發症，也是導致病人死亡的主要原因之一。因此臨床上會依照心房顫動的治療指引給予病人用藥建議降低中風風險。其中，部分病人有心房撲動同時合併慢行腎臟疾病。然而，抗血栓藥品在腎臟損害的病人當中會影響藥物動力學而導致療效不佳或是出血的風險。但目前尚未有相關文獻評估抗血栓藥品用於在心房撲動合併有慢性腎臟疾病的研究。因此，本研究欲探討口服抗血栓藥品在心房撲動合併有慢性腎臟疾患者的療效與安全性。
研究方法：
本研究利用衛福部全人口資料檔篩選出同時合併有心房撲動與慢性腎臟疾病的病人進行回溯型觀察性研究。所有病人會依照之前是否發生過中風被歸到cohort I以及cohort II。並將納入研究分析的病人分成使用抗血小板或抗凝血或合併藥品組。另外，此研究會將這群病人透過CHA2DS2-VASc區分不同的中風風險。主要觀察事件為缺血性中風、全身性栓塞或綜合性中風事件;次要觀察事件包含心血管不良事件、嚴重出血事件、任何原因死亡事件以及心血管死亡事件。統計分法使用Cox比例風險模型計算相對療效與安全性比值與95%信賴區間。同時，也會藉由ROC曲線 (receiver operating characteristic curve) 找出CHA2DS2-VASc的切點並區分欲探討事件的風險。另外，次群組分析則藉由CHA2DS2-VASc分層風險並進一步評估各組間事件風險。敏感度分析則用來將口服抗凝血藥品區分成warfarin以及新型口服抗凝血藥品並放入Cox比例風險模型分析事件風險。
研究結果：
共有2,468人被納入且患有心房撲動以及慢性腎臟疾病。經過篩選後，有1,458以及259人分別被歸到cohort I與cohort II。關於缺血性中風、全身性栓塞、綜合性中風事件或心血管不良事件的發生風險，三種口服抗血栓藥品組並沒有達到統計上顯著差異。在嚴重出血事件層面，三組間也沒有達到統計顯著結果。但cohort I在任何原因死亡事件指出使用口服抗凝血藥品相對於使用抗血小板藥品可以有效降低76% (hazard ratio [HR]: 0.24; 95% confidence interval [CI]: 0.10-0.55; p-value = 0.001)或相對合併藥品組降低約65% (HR: 0.35; 95% CI: 0.18-0.68; p-value = 0.002)的任何原因死亡風險; 而在心血管死亡事件亦顯示口服抗凝血藥品相對抗血小板藥品(HR: 0.24; 95% CI: 0.08-0.73; p-value = 0.012)或合併藥品(HR: 0.38; 95% CI: 0.16-0.94, p-value=0.037)有較低的心血管死亡風險。
經由次分析將CHA2DS2-VASc在各組間分層相同中風風險後，除了cohort I在任何原因死亡事件方面，使用抗凝血藥品在CHA2DS2-VASc小於5分相對使用抗血小板藥品(HR: 0.32; 95% CI: 0.13-0.78; p-value = 0.012)或合併組合(HR: 0.47; 95% CI: 0.24-0.93; p-value = 0.029)有較低的死亡風險；而在心血管不良事件發現使用抗凝血藥品比抗血小板藥品有更低的死亡風險(HR: 0.30; 95% CI: 0.09-0.99; p-value = 0.048)以外其他結果都沒有達到統計顯著差異。另外，ROC曲線結果指出cohort I中CHA2DS2-VASc是缺血性中風(area under curve [AUC]: 0.63; 95% CI: 0.51-O.75; p-value = 0.033)、任何原因死亡事件(AUC: 0.56; 95% CI: 0.52-0.60; p-value = 0.002)以及心血管死亡事件(AUC: 0.56; 95% CI: 0.50-O.61; p-value = 0.039)的重要預測指標且統計學上達顯著結果。
將口服抗凝血藥品細分為使用warfarin或新型口服抗凝血藥品的敏感度分析模型中指出，warfarin與新型口服抗凝血藥品之間在各個事件風險中並沒有達到統計上顯著差異。且只有在cohort I的任何原因死亡事件發現使用無論warfarin或新型口服抗凝血藥品都是能夠顯著降低死亡風險，其餘事件則沒有統計顯著結果。
研究結論：
在心房撲動併有慢性腎臟疾病的病人預防中風的口服抗血栓藥品可以首選單線藥品(抗凝血藥品或抗血小板藥品)。此外，服用口服抗凝血藥品能夠有效降低死亡率。Warfarin則與新型口服抗凝血藥品在預防中風具有相當的療效與安全性。未來仍須有隨機對照試驗進一步探討使用抗血栓藥品用於慢性腎臟疾病合併心房撲動病人之心血管風險。
此外，本篇研究指出CHA2DS2-VASc並不適用在心房撲動併有慢性腎臟疾病評估中風或是死亡風險。因此，仍須透過其他研究進一步使用於此族群評估中風風險的量表。

關鍵字

抗凝血藥品 ； 抗血小板藥品 ； 心房撲動 ； 慢性腎臟疾病 ； 心血管事件

並列摘要

Background and objectives：
Nowadays, antithrombotic therapies are commonly prescribed for patients with atrial flutter (AFL) and chronic kidney disease (CKD) to reduce ischemic stroke incidence in clinical practice based on the treatment recommended used in atrial fibrillation (AF). However, the pharmacokinetics of drugs in the patients with renal impairment will change. To date, there was no relevant study to assess the effectiveness and safety of different antithrombotic in these population. In the study, this cohort study evaluated the effectiveness and safety of different antithrombotic in patients with AFL and CKD. This study also investigated the cardiovascular events risk with antithrombotic drug through different risk profile of stroke stratified by CHA2DS2-VASc score.
Methods：
The cohort study performed in patients with AFL and CKD extracted from the National Health Insurance (NHI) Database in Taiwan. The patients, who were diagnosed with AFL after CKD diagnosed date from Jan.1st, 2011 to Dec.31th, 2015, were included. Furthermore, two cohorts were performed based on with/without previous stroke. User groups were separated into antiplatelet (APT), anticoagulant (OAC) and combination therapy. Primary outcome included ischemic stroke, systemic embolism and composite of stroke; secondary outcome included major adverse cardiac event (MACE), major bleeding, all-cause mortality and cardiovascular-related death. Cox regression hazard models were performed to calculate hazard ratio (HR) and 95% confidence interval (CI). Furthermore, the study also did the receiver operating characteristic (ROC) curve in two cohorts to explore the cutoff point of event risk stratified with CHA2DS2-VASc score. Subgroup analysis was performed to evaluate clinical outcomes by stratified event risk with CHA2DS2-VASc score. In addition, this study also did sensitivity analysis to estimate the effectiveness and safety of Novel oral anticoagulants (NOACs) for stroke prophylaxis in AFL and CKD.
Results：
A total 2,468 patients were included in this study. After screening with exclusion criteria, 1458 and 295 patients, respectively, classified into cohort I and cohort II. Both of two cohorts showed no statistical significant difference of risk in ischemic stroke, systemic embolism, composite of stroke and MACE among APT, OAC and combination therapy. There was also no significant difference of risk in major bleeding among all the antithrombotic regimens in patients with AFL and CKD. However, pool result indicated HR for all-cause mortality in OAC was 0.24 (95% CI= 0.10-0.55, p-value=0.001) compared to combination therapy and 0.35 (95% CI= 0.18-0.68, p-value=0.002) compared to APT in cohort I. In addition, cohort I also indicated HR for cardiovascular-related death in OAC was 0.24 (95% CI= 0.08-0.73, p-value=0.012) compared to combination therapy and 0.38 (95% CI= 0.16-0.94, p-value=0.037) compared to APT.
After performing subgroup analysis to stratify event risk with CHA2DS2-VASc score, it demonstrated similar result as pool data, except cardiovascular-related death. According to the report of subgroup analysis, OAC had similar risk in cardiovascular-related death as APT. In addition, the result in ROC of Cohort I presented that CHA2DS2-VASc score was a significant predictor only in systemic embolism (area under curve [AUC]: 0.63; 95% CI: 0.51-0.75; p-value = 0.033), all-cause mortality (AUC: 0.56; 95% CI: 0.52-0.60; p = 0.002) and cardiovascular-related death (AUC: 0.56; 95% CI: 0.50-0.61; p = 0.039).
Moreover, in sensitivity analysis, warfarin and NOACs had similar effectiveness and safety for stroke prophylaxis in patients with AFL and CKD. After separating OAC into warfarin and NOACs, it showed that both of two had similar risk in cardiovascular-related death as APT and combination therapy.
Conclusions：
Single therapy could be the first choice of oral antithrombotic drugs in patients with AFL and CKD for stroke prophylaxis. Furthermore, OAC might reduce the mortality rate compared to APT. And NOACs had similar effectiveness and safety as warfarin for stroke prophylaxis. Randomized controlled trials are needed for evaluating effectiveness and safety in patients with CKD and AFL using different oral antithrombotic drugs.
Whether CHA2DS2-VASc score can be used to assess risk of stroke or mortality in patients with AFL and CKD should be reevaluated in the future.

並列關鍵字

oral anticoagulants ； oral antiplatelet ； atrial flutter ； chronic kidney disease ； cardiovascular events

參考文獻

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