探討新型口服抗凝血劑用於心房顫動病人的有效性及安全性

Investigating the Effectiveness and Safety of New Oral Anticoagulant Drugs in Atrial Fibrillation Patients in Taiwan

李美娟(Mei-Chuan Lee)

指導教授 ： 楊奕馨

高雄醫學大學/藥學院/藥學系碩士在職專班/碩士(2018年)

摘要

背景
心房顫動(Atrial fibrillation, AF)是缺血性中風的危險因子，使用抗凝血劑可以有效降低事件的發生。近年來新型的口服抗凝血劑在臨床試驗中證實療效與warfarin相似，且出血的比例較warfarin低，加上不須常規性抽血監測，所以在臨床上已漸漸廣泛被使用。然而研究指出亞洲人使用抗凝血劑的出血率比其他非亞洲人高，因此新型抗凝血劑在台灣的有效性及安全性仍須進一步確認。
目的
本研究之目的為研究分析新型抗凝血劑（dabigatran、rivaroxaban、apixaban），在預防缺血性腦中風事件的有效性及顱內出血副作用等安全性，是否優於傳統抗凝血劑。
方法
利用衛生福利部衛生福利資料科學中心的2010年 200 萬人抽樣歸人檔，截取2010-2015年心房顫動且使用口服抗凝血劑（傳統與新型）的病人，並根據藥物使用情況將收錄病人分為dabigatran、rivaroxaban、apixaban和warfarin，並根據藥物使用劑量分為低劑量(dabigatran 110mg、rivaroxaban 10mg和15mg、apixaban 2.5mg)以及標準劑量(dabigatran 150mg、rivaroxaban 20mg、apixaban 5mg )進行次分組分析。以warfarin為對照組進行統計分析。統計方式使用Kaplan-Meier estimates, Log-rank tests和 Cox regressions。
結果
在dabigatran組有85%使用低劑量，rivaroxaban組中有90.52%，在Apixaban組中則全部使用標準劑量。整體而言，dabigatran在預防缺血性腦中風(HR 0.78, 95% CI 0.36 - 1.66, p=0.51)、顱內出血(HR 0.56, 95% CI 0.12 - 2.57, p=0.45)和整體死亡率(HR 0.86, 95% CI 0.48 - 1.54, p=0.61)皆未達統計上的差異。次分組分析中，低劑量的dabigatran在預防缺血性腦中風(HR 0.70, 95% CI 0.30 - 1.62, p=0.41)、顱內出血(HR 0.63, 95% CI 0.14 - 2.91, p=0.56)和整體死亡率(HR 0.84, 95% CI 0.47 - 1.52, p=0.57)，也未達統計顯著；標準劑量在預防缺血性腦中風(HR 1.31, 95% CI 0.31 - 5.54, p=0.71)和整體死亡率(HR 1.86, 95% CI 0.23 - 15.17, p=0.56)也無統計上的差異。
Rivaroxaban在預防缺血性腦中風、顱內出血和整體死亡率也未達統計上的差異，低劑量的rivaroxaban亦然。然而高劑量rivaroxaban有較高顱內出血的風險 (HR:8.07, 95% CI 1.51-43.20, p=0.01)。Apixaban在預防缺血性腦中風也未觀察到統計上的差異。
結論
台灣臨床上dabigatran和rivaroxaban的使用，多以低劑量為主，Apixaban則以標準劑量為優先考量。本研究顯示高劑量rivaroxaban在台灣人，有較高顱內出血風險的趨勢，但未達統計上顯著性差異。低劑量的rivaroxaban可能是較適合台灣族群的劑量選擇，然未來仍需要樣本數較大的研究來證實。

關鍵字

心房顫動 ； 新型口服抗凝血劑 ； 中風

並列摘要

Background
Atrial fibrillation (AF) patients have a higher risk of ischemic stroke (IS), and anticoagulants are generally used for the stroke prevention. Non-vitamin K antagonist oral anticoagulants (NOACs) had been shown to have similar efficacy and fewer bleeding events as compared to warfarin by clinical trials. However, since some studies indicated that Asian people tended to have higher incidence of bleeding, it is crucial to evaluate the real world evidence for the effectiveness and safety of NOACs in Taiwan setting.
Aims
This study aims to construct a cohort study with the National Health Insurance (NHI) Database to compare the effectiveness of IS prevention and the safety of intracranial hemorrhage (ICH) between the NOACs and warfarin in AF patients.
Methods
We used the 2-million random sample 2010 cohort of the NHI database between January 1st, 2010, and December 31, 2015. The patients with AF and with any anticoagulants were extracted during this follow-up period. We conducted subgroup analyses of low dose (dabigatran 110 mg, rivaroxaban 10mg and 15mg and apixaban 2.5mg) and standard dose (dabigatran 150mg, rivaroxaban 20 mg and apixaban 5mg). The primary outcomes were IS and intracranial hemorrhage. Regarding the outcome measurements, we used survival analysis and calculate hazard ratio (HR) with 95% confidence intervals (CIs) for each event.
Result
In NOAC group, the proportion of using low dose was 85% (194/228) in dabigatran and 90.52% (191/211) in rivaroxaban, but in apixaban group 100% using standard dose. In general, dabigatran had no significant difference in IS prevention (HR 0.78, 95% CI 0.36 - 1.66, p=0.51), ICH (HR 0.56, 95% CI 0.12 - 2.57, p=0.45) and all-cause mortality (HR 0.86, 95% CI 0.48 - 1.54, p=0.61) comparing with warfarin. In subgroup analysis, there was no significant difference between low dose dabigatran and warfarin in IS (HR 0.70, 95% CI 0.30 - 1.62, p=0.41), ICH (HR 0.63, 95% CI 0.14 - 2.91, p=0.56) and all-cause mortality (HR 0.84, 95% CI 0.47 - 1.52, p=0.57). In standard dose dabigatran group, we did not find any significant difference in IS prevention (HR 1.31, 95% CI 0.31 - 5.54, p=0.71) and all-cause mortality (HR 1.86, 95% CI 0.23 - 15.17, p=0.56). In general, rivaroxaban and low dose rivaroxaban had no significant difference in IS prevention, ICH and all-cause mortality. In subgroup analysis, more ICH events had been noticed in standard dose rivaroxaban group (hazard ratio 8.07; 95% CI 1.51-43.20, p=0.01). Apixaban had no significant difference in IS prevention.
Conclusion
In Taiwan, most of patients were prescribed low dose of dabigatran and rivaroxaban, and standard dose of apixaban in clinical practice. Our study results showed that the use of standard dose rivaroxaban have higher risk of ICH comparing to warfarin group, but this trend did not reach statistical significance. Low dose rivaroxaban may be a better agent for Taiwanese rather than standard dose rivaroxaban. However, future research with larger sample size will be needed.

並列關鍵字

Atrial fibrillation ； NOAC ； Ischemic stroke

參考文獻

1.Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370-5.

2.Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27:1760-4.

3.January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071-104.

4.Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016;18:1609-78.

5.Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 2007;50:309-15.