- 學位論文
心房顫動患者使用新型口服抗凝血劑不同劑量之療效及安全性評估
Evaluation of Efficacy and Safety of the Different Dosages of New Oral Anticoagulants in Patients with Atrial Fibrillation
摘要
研究背景: 心房顫動(Atrial fibrillation，AF)是臨床上常見的一種心律不整之一。目前台灣包含dabigatran、apixaban、edoxaban、rivaroxaban等新型口服抗凝血劑(new oral anticoagulants, NOACs)均已被核准用來治療非瓣膜性心房顫動患者，以預防中風及全身性栓塞的發生，然而不同NOACs需依據腎功能選擇其劑量。對於真實世界之亞洲族群NOACs考量不同腎功能區間相對劑量選擇之療效及安全性評估研究仍相對欠缺。 研究目的: 本研究旨在評估台灣現實狀況下新型口服抗凝血劑依據建議處方劑量與療效及安全性之關聯，以提升臨床使用NOACs藥物安全性與可行性。 研究方法: 本研究採回溯性觀察研究， 2014年1月1日至2018年12月31日間於台北市立聯合醫院仁愛及和平婦幼院區門診就診首次使用dabigatran、edoxaban、rivaroxaban或wafarin做治療之AF病人，這些病人首次使用NOACs 治療前3個月內曾監測肌酸酐(serum creatinine)、且連續治療滿30天才被納入研究中，並排除NOACs用於其他適應症、曾經進行心臟瓣膜置換手術或過去病史紀錄不完全、連續治療未滿30天之患者。根據2018年歐洲心律協會治療指引(European Heart Rhythm Association guidelines)對處方劑量進行評估、分組(符合建議劑量、高於建議劑量、低於建議劑量、使用warfarin等4組)，以Cox 比例風險模式(Cox proportional hazards model)評估各組於追蹤期間發生缺血性中風及全身性栓塞、總死亡、急性心肌梗塞、顱內出血、腸胃道出血等事件的比例。研究追蹤病人直至出現任何前述事件、停止藥物治療或至研究結束日期為止。 研究結果: 本研究共收納999人，符合建議劑量的比例為33.4%，反之，61.2%為低於建議劑量。高於建議劑量組、低於建議劑量、符合建議劑量及warfarin組用藥天數中位數為259、462、441及295天。則低於建議劑量及warfarin兩組分別與符合建議劑量為參考組比較，其各事件之風險比[95% 信賴區間]為:缺血性中風及全身性栓塞之風險比分別為0.73 [0.40-1.33] 及0.97 [0.41-2.27]; 總死亡之風險比分別為1.25[0.71-2.21] 及1.47[0.70-3.06]; 急性心肌梗塞之風險比分別為0.75 [0.41-1.37] 及0.86 [0.40-1.83] ; 顱內出血之風險比分別為2.04 [0.38-11.04] 及 1.31 [0.12-14.57] ; 腸胃出血之風險比分別為0.40 [0.15-1.07] 及 0.98[0.28-3.43]。 結論: 本研究結果顯示不論是腎功能正常或異常，均有新型口服抗凝血藥處方劑量不適當之情形，其中以處方劑量低於建議者居多，尤以rivaroxaban為最。低於建議劑量組及warfarin組分別與符合建議劑量組比較，不論是缺血性中風或全身性栓塞風險、急性心肌梗塞、顱內出血、腸胃道出血及總死亡風險，均無統計上顯著差異，可能受限於樣本數較少，目前仍不足以下定論: 是否亞洲族群給予低於準則建議的藥量在療效及安全性上，即可與給予符合準則建議劑量組相當，亦或會因為劑量給予不足增加相對風險。因此，未來仍尚待更大型研究進一步證實。在整體用藥天數分析上可以看到，符合建議劑量的組別及低於建議劑量組整體接受藥物治療的時間較高於建議劑量組和warfarin組長，能夠長期接受藥物治療而不中斷也是後續研究重要議題之一。
並列摘要
Background Atrial fibrillation (AF) is the most common cardiac arrhythmia. Non vitamin K antagonist oral anticoagulants (NOACs) including dabigatran, apixaban, edoxaban, rivaroxaban and other new oral anticoagulants have been approved to treat patients with non-valvular atrial fibrillation(NVAF) to prevent stroke and systemic embolism in Taiwan. Clinical decisions on how to treat an Af patient who needs NOACs require the assessment of renal function. Only limited evidence of renal function has been assessed and considered for recommending NOAC dosage in Asia. Objectives The relationship between the dosage and efficacy and safety of the new oral anticoagulants is investigated according to the guidelines in real-world clinical practice in Taiwan. Methods We conducted a retrospective cohort study of patients diagnosed with NVAf at Taipei City Hospital Renai Branch and Taipei City Hospital Heping Fuyou Branch from January 2014 to December 2018. Patients who had their first prescription of NOACs including dabigatran, rivaroxaban, edoxaban, apixaban, or warfarin treatment from January 1, 2014 to December 31, 2018 were included in the study. Additionally, patients were included only if they had a documented renal function laboratory test (serum creatinine) within 3 months before the index prescription date. Patients received NOACs for less than 30 days and/or for other indications were excluded. The follow-up period was from the index date until the first occurrence of one of the following events, any study outcome、medication discontinued and the end date of study (December 31, 2019). The appropriateness of the prescription was assessed according to the 2018 European Heart Rhythm Association Guidelines. Patients were classified into appropriately dosed、inappropriately dosed (overtreated or undertreated) based on these dosage guidelines. Cox regression analysis was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for evaluating the dosage effect on the risks of the primary outcomes of stroke, systemic embolism(SE), all cause mortality, acute myocardial infarction (AMI), intracranial hemorrhage(ICH), and gastrointestinal bleeding(GIB). Result A total of 999 patients were included in this study, of whom 33.4% were appropriate, 61.2% were undertreated. The median follow-up periods for overtreated, appropriate-dosed, undertreated and warfarin groups were 259、462、441 and 295 days, respectively. For comparing undertreated group and warfarin group repsecitvely to appropriate-dosed group, the two HRs [95% CI] for stroke/systemic embolism were 0.73 [0.40-1.33] and 0.97 [0.41-2.27]; those for all-cause mortality 1.25[0.71-2.21] and 1.47[0.70-3.06]; those for AMI 0.75 [0.41-1.37] and 0.86 [0.40-1.83]; those for ICH 3.74 [0.59-23.76] and 2.76 [0.23-32.84]; and those for GIB 0.40 [0.15-1.07] and 0.98[0.28-3.43]. Conclusion Our results showed that inappropriate NOAC dosing occurred in patients with normal and insufficient renal function. There was a high prevalence of low-dose NOAC prescription (undertreated) among the study cohort, especially for rivaroxaban. Our results also indicated that there were no statistically significant differences in stroke/SE、all cause mortality、AMI、ICH and GIB between the appropriate-dosed and the undertreated groups. Because of small sample size, we cannot conclude that there are no differences in efficacy and safety between NOAC dosages. Further large-scale studies in Asian population are needed. It can be seen that the overall medication days were different between the appropriate-dosed and the overtreated groups. It is also an important topic for future research how to receive medication for a long time without interruption.