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Volume 41 Issue 9
Sep.  2023
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LI Ting, SHI Kourong, LI Zhi, WANG Ziyu, CAO Ailin, QIAN Jiao. Efficacy and safety evaluation of dabigatran etexilate in the treatment of elderly non-valvular atrial fibrillation[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(9): 557-560. doi: 10.12206/j.issn.2097-2024.202207029
Citation: LI Ting, SHI Kourong, LI Zhi, WANG Ziyu, CAO Ailin, QIAN Jiao. Efficacy and safety evaluation of dabigatran etexilate in the treatment of elderly non-valvular atrial fibrillation[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(9): 557-560. doi: 10.12206/j.issn.2097-2024.202207029

Efficacy and safety evaluation of dabigatran etexilate in the treatment of elderly non-valvular atrial fibrillation

doi: 10.12206/j.issn.2097-2024.202207029
  • Received Date: 2022-07-08
  • Rev Recd Date: 2023-04-04
  • Available Online: 2023-09-25
  • Publish Date: 2023-09-25
  •   Objective  To explore the efficacy and safety of dabigatran etexilate in the treatment of elderly patients with non-valvular atrial fibrillation (NVAF), so as to provide reference for clinical treatment and rational drug use.   Methods  Eighty elderly patients with NVAF in The Seventh People's Hospital of Shanghai from December 2020 to June 2021, aged 65 to 80 years, were enrolled in a self-controlled study. Dabigatran etexilate 110 mg was given orally, twice a day (one in the morning and one in the evening) for 6 months. During the follow-up visit, the coagulation function indexes including APTT, TT, FIB and D-D were observed in patients taking medicine for 1 month and 6 months. Liver function indexes including ALT, AST and TBIL, renal function indicators including UREA and eGFR, and blood routine indexes including HGB and ESR, also were observed in patients taking medicine for 1 month and 6 months.   Results  Patients were compared at 1 month and 6 months after treatment with dabigatran and before: the difference of coagulation function indexes as APTT and TT was statistically significant (P<0.05);There was no significant difference in liver function index, renal function index and blood routine index (P>0.05); A total of 25 adverse events occurred, and the incidence rate of adverse reactions was 31.25%, there was no adverse events such as serious hemorrhage, life threatening and organ failure hemorrhage occurred.  Conclusion  Dabigatran has good efficacy and safety in the treatment of the elderly NVAF.
  • [1] 杨波. 心房颤动抗凝治疗的研究进展[J]. 临床内科杂志, 2020, 37(12):823-826.
    [2] LIP G Y H. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe[J]. Chest,2012,142(6):1489-1498.
    [3] KISTLER P M, SANDERS P, FYNN S P, et al. Electrophysiologic and electroanatomic changes in the human atrium associated with age[J]. J Am Coll Cardiol,2004,44(1):109-116. doi:  10.1016/j.jacc.2004.03.044
    [4] REIFFEL J A. Atrial fibrillation and stroke: epidemiology[J]. Am J Med,2014,127(4):e15-e16.
    [5] 李红. 新型口服抗凝药用于我国老年非瓣膜性房颤患者的安全性及有效性的Meta分析[D]. 沈阳: 中国医科大学, 2021.
    [6] 中华医学会心电生理和起搏分会, 中国医师协会心律学专业委员会, 中国房颤中心联盟心房颤动防治专家工作委员会. 心房颤动: 目前的认识和治疗建议(2021)[J]. 中华心律失常学杂志, 2022, 26(1):15-88.
    [7] 中华医学会. 心房颤动基层合理用药指南[J]. 中华全科医师杂志, 2021, 20(02):166-174. doi:  10.3760/cma.j.cn114798-20201210-01241
    [8] LIP G Y, NIEUWLAAT R, PISTERS R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation[J]. Chest,2010,137(2):263-272. doi:  10.1378/chest.09-1584
    [9] PISTERS R, LANE D A, NIEUWLAAT R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey[J]. Chest,2010,138(5):1093-1100. doi:  10.1378/chest.10-0134
    [10] HEIDBUCHEL H, VERHAMME P, ALINGS M, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation[J]. Europace,2013,15(5):625-651. doi:  10.1093/europace/eut083
    [11] CHIN P K, WRIGHT D F, PATTERSON D M, et al. A proposal for dose-adjustment of dabigatran etexilate in atrial fibrillation guided by thrombin time[J]. Br J Clin Pharmacol,2014,78(3):599-609. doi:  10.1111/bcp.12364
    [12] 倪莲芳, 刘梅林, 林箐, 等. 达比加群酯对老年患者抗凝治疗的疗效及影响因素研究[J]. 中华老年医学杂志, 2020, 39(2):133-136.
    [13] LINDAHL T L, BAGHAEI F, BLIXTER I F, et al. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays[J]. Thromb Haemost,2011,105(2):371-378. doi:  10.1160/TH10-06-0342
    [14] 兰博, 胡才友, 杨泽, 等. 老年人心血管用药现状调查研究[J]. 中国老年保健医学, 2021, 19(4):5-8.
    [15] 肖帆, 刘远声. 评价达比加群酯和华法林用于持续心房纤颤患者的抗凝治疗的疗效及安全性差异[J]. 海峡药学, 2019, 31(05):143-145.
    [16] 冯莉, 贾长琪, 李新. 达比加群与利伐沙班在非瓣膜性心房颤动抗凝治疗中的临床监测研究[J]. 心肺血管病杂志, 2022, 41(12):1212-1215, 1220.
    [17] 周明皓. 低分子肝素联合达比加群酯对老年非瓣膜性房颤血栓栓塞的预防效果及安全性分析[J]. 中国处方药, 2022, 20(12):121-123.
    [18] 徐蕾, 杨婉花. 达比加群酯抗凝治疗的安全性研究进展[J]. 世界临床药物, 2016, 37(11):781-785.
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Efficacy and safety evaluation of dabigatran etexilate in the treatment of elderly non-valvular atrial fibrillation

doi: 10.12206/j.issn.2097-2024.202207029

Abstract:   Objective  To explore the efficacy and safety of dabigatran etexilate in the treatment of elderly patients with non-valvular atrial fibrillation (NVAF), so as to provide reference for clinical treatment and rational drug use.   Methods  Eighty elderly patients with NVAF in The Seventh People's Hospital of Shanghai from December 2020 to June 2021, aged 65 to 80 years, were enrolled in a self-controlled study. Dabigatran etexilate 110 mg was given orally, twice a day (one in the morning and one in the evening) for 6 months. During the follow-up visit, the coagulation function indexes including APTT, TT, FIB and D-D were observed in patients taking medicine for 1 month and 6 months. Liver function indexes including ALT, AST and TBIL, renal function indicators including UREA and eGFR, and blood routine indexes including HGB and ESR, also were observed in patients taking medicine for 1 month and 6 months.   Results  Patients were compared at 1 month and 6 months after treatment with dabigatran and before: the difference of coagulation function indexes as APTT and TT was statistically significant (P<0.05);There was no significant difference in liver function index, renal function index and blood routine index (P>0.05); A total of 25 adverse events occurred, and the incidence rate of adverse reactions was 31.25%, there was no adverse events such as serious hemorrhage, life threatening and organ failure hemorrhage occurred.  Conclusion  Dabigatran has good efficacy and safety in the treatment of the elderly NVAF.

LI Ting, SHI Kourong, LI Zhi, WANG Ziyu, CAO Ailin, QIAN Jiao. Efficacy and safety evaluation of dabigatran etexilate in the treatment of elderly non-valvular atrial fibrillation[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(9): 557-560. doi: 10.12206/j.issn.2097-2024.202207029
Citation: LI Ting, SHI Kourong, LI Zhi, WANG Ziyu, CAO Ailin, QIAN Jiao. Efficacy and safety evaluation of dabigatran etexilate in the treatment of elderly non-valvular atrial fibrillation[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(9): 557-560. doi: 10.12206/j.issn.2097-2024.202207029
  • 心房颤动(房颤)是最常见的心律失常之一。据统计,成年人房颤患病率在2%~4%,并且随着年龄的增长不断提高[1]。非瓣膜性心房颤动(NVAF)社区人群发病率为0.1%~4%、住院人群发病率为2.8%~14%[2],研究显示[3]70%以上的NVAF发生人群为65岁及以上老人,其发生率与年龄增加呈正相关。作为中风的独立危险因素,房颤可使包括中风在内的主要心血管事件风险增加5倍[4],因此,合理的抗凝可以降低老年人群中风及其他心血管事件的风险。

    新型口服抗凝药达比加群酯可以直接抑制凝血酶,能够可逆性、竞争性地与凝血酶Ⅱa结合,阻止纤维蛋白原转化为纤维蛋白,从而抑制血小板聚集。达比加群酯口服吸收快,口服后有80%以原形通过肾脏排泄,其余经肝脏代谢,并且经P450酶系代谢的药物不会与其产生相互作用[5]。但是随着达比加群酯在临床上的广泛应用,其引起的出血等不良事件也越来越多,而老年人由于肝肾功能退化,成为了血栓和出血的高危人群[6-7],因此,对于达比加群酯在老年非瓣膜性房颤患者中安全性研究愈加重要。

    • 收集2020年12月至2021年6月上海市第七人民医院门诊和住院的非瓣膜性房颤患者的临床资料,年龄65~80岁,在其他常规对症治疗基础上,选择达比加群酯胶囊抗凝治疗(110mg/片×10片/盒,勃林格殷格翰公司)。用法:110 mg,口服,每天2次(早、晚各1次),治疗6个月。

      本方案经医院伦理委员会批准通过,所有入组患者及其家属对治疗方案均知情并签署知情同意书。

    • 纳入标准:①符合欧洲心脏病学会2010年《心房颤动管理指南》中非瓣膜性房颤的诊断标准;②心脏超声检查排除退行性瓣膜病及风湿性心脏病等瓣膜性心脏病;③既往未进行过规范化抗凝治疗,无抗凝禁忌证,血常规及凝血时间均在正常参考值范围内,尿便隐血阴性;④入选前6个月内未发生任何卒中。

      排除标准:①急性冠状动脉综合征及冠状动脉介入术后1年、心包炎、心肌炎、甲状腺功能亢进症、严重肺部疾病、肝酶异常及肌酐清除率(Ccr)≤30ml/min者;②对本研究药物过敏或不能随访或中途更换抗凝药者。

    • 入选患者于入院后24h内统一抽取静脉血送检。实验室观察指标:包括活化部分凝血活酶时间(APTT)、血浆凝血酶时间(TT)、纤维蛋白原(FIB)和D-二聚体(D-D);肝功能指标包括谷草转氨酶(AST)、丙氨酸氨基转移酶(ALT)、总胆红素(TBIL);肾功能指标包括尿素(UREA)和肾小球滤过率估计值(eGFR);血常规指标包括血红蛋白量(HGB)、红细胞沉降率(ESR)。观察服药1个月后、6个月后与治疗前相比的各项指标变化。

    • 根据指南要求在治疗前对所有研究对象进行血栓栓塞及出血风险评估。血栓栓塞风险采用CHA2DS2-VASc评分进行评价[8]:年龄65~74岁计1分,慢性心衰计1分,高血压计1分,年龄≥75岁计2分,糖尿病计1分,卒中/短暂性脑缺血发作计2分,血管病计1分,女性计1分。CHA2DS2-VASc≥2分的患者推荐使用口服抗凝药物(OAC);CHA2DS2-VASc为1分的患者口服OAC或阿司匹林,但更倾向OAC;CHA2DS2-VASc为0分可服用阿司匹林或者不进行抗栓治疗。出血风险评估采用HAS-BLED评分进行评价[9]:有未控制的高血压,即SPB>160mmHg计1分,肾功能异常(长期透析或肾移植或血清肌酐≥200μmol/L)或肝功能异常(慢性肝病或胆红素>2倍同时转氨酶>3倍)计1或2分,卒中计1分,既往出血史或出血体质、贫血等计1分,INR不稳定计1分,老年(即年龄>65岁)计1分,药物(同时应用抗血小板药和非甾体抗炎药)或酗酒计1分。HAS-BLED评分≥3分为出血高危组,启动OAC或阿司匹林治疗后均须密切随访。不良事件统计采用随访的方法,统计时长共计6个月,记录药物相关不良事件的发生率。

    • 采用SPSS 21.0软件进行数据分析,正态分布计量资料以($ \bar x \pm s $)表示,组间比较采用单因素方差分析和t检验,以P<0.05表示差异有统计学意义。

    • 按照入选标准和排除标准共收集病例80例,男性45例,女性35例,年龄(76.0±0.8)岁,CHA2DS2-VASc评分(4.1±0.2),HAS-BLED评分(2.5±0.1),主要相关症状见表1

      其他相关症状病例数[n, (%)]
      高血压57(71.25)
      糖尿病22(27.50)
      冠状动脉粥样硬化49(61.25)
      心律失常33(41.25)
      脑梗死5(6.25)
      高尿酸血症1(1.25)
    • 患者服药后1个月、6个月的APTT和TT分别与服药前比较,差异有统计学意义(P<0.05);且服药6个月与服药1个月比较,差异亦有统计学意义(P<0.05)。FIB和D-D与服药前比较差异无统计学意义(P>0.05),见表2

      组别APTT(s)TT(s)FIB(g/L)D-D(mg/L)
      服药前34.37±0.5919.98±0.453.17±0. 080.85±0.03
      服药1个月39.99±1.18*75.30±7.38*3.48±0.130.84±0.03
      服药6个月51.08±1.78*#90.79±8.36*#3.34±0.100.83±0.02
      *P<0.05,与服药前比较;#P<0.05,与服药后1个月比较
    • 患者服药后1个月、6个月的ALT、AST、TBIL分别与服药前比较,差异无统计学意义(P>0.05),见表3

      组别ALT(U/L)AST(U/L)TBIL(µmol/L)
      服药前20.85±1.2224.38±0.9516.31±0.64
      服药1个月22.37±1.8325.27±1.4717.58±1.05
      服药6个月25.86±3.2326.29±1.0617.96±0.79
    • 患者服药后1个月、6个月的UREA、eGFR分别与服药前比较,差异无统计学意义(P>0.05),见表4

      组别UREA(mmol/L)eGFR[ml/(min·1.73m2)]
      服药前6.42±0.39106.3±1.273
      服药1个月7.16±0.51105.2±2.310
      服药6个月7.51±0.44104.4±2.687
    • 患者服药后1个月、6个月的HGB、ESR分别与服药前比较,差异无统计学意义(P>0.05),见表5

      组别HGB(g/L)ESR(mm/h)
      服药前138.20±1.9617.38±1.36
      服药1个月143.20±3.2219.90±2.05
      服药6个月146.30±3.7620.94±2.00
    • 患者服用达比加群酯后共发生25例不良事件,其中胸闷9例,牙龈出血10例,消化道出血1例,血栓形成3例,脑卒中2例,分别占全部病例的11.25%、12.5%、1.25%、3.75%和2.50%。

    • 2013年欧洲房颤指南[10]指出APTT谷值高于正常值上限2倍具有较高出血风险;Chin等[11]研究认为TT可作为服用达比加群酯治疗患者的监测指标,并可根据此指标的反馈来调节达比加群酯的剂量。另有研究显示[12],老年患者服用达比加群酯后,APTT和TT较用药前有所增加,达比加群酯剂量、患者肌酐清除率、合用P-gp抑制剂等均可影响APTT;但是不同个体间APTT波动较小,而TT个体间差异大,因此,可将APTT作为监测达比加群酯抗凝疗效的指标,TT作为抗凝疗效监测的补充指标。

      纤维蛋白原(FIB)是凝血过程中的主要蛋白质,Lindahl等[13]研究认为FIB的影响因素较多,与达比加群酯的凝血活性并没有太大关系。本研究也显示该指标受达比加群酯的凝血活性影响不大,因此,可不考虑FIB的变化。

      服用达比加群酯后1个月、6个月患者的凝血功能指标(APTT、TT)与服药前相比差异有统计学意义,且数值有升高趋势,提示达比加群酯可改变患者凝血功能,对预防和治疗老年非瓣膜性房颤患者血栓形成有效。通过研究发现,患者凝血功能指标在治疗6个月后与治疗1个月后相比,数值有升高的趋势。笔者分析可能原因有两方面:一是与患者用药依从性有关,同年轻人相比,老年人往往合并多种慢性疾病,因此需要同时服用多种药物,此时用药的依从性至关重要。兰博等[14]对老年人心血管用药现状调查发现,老年人使用降脂药的依从性与老年人的年龄及文化程度显著相关,其依从性仅为49. 2% ,原因主要为慢性病用药观念不强及初始治疗时忘记服药,随着时间的延长以及研究者推进,用药依从性逐渐好转,因此出现6个月后凝血功能指标数值升高的趋势;二是与抗凝药物的使用有关,根据实验结果,达比加群酯可改变老年患者APTT和TT水平[15-17]

      服药1个月、6个月后患者肝功能指标(ALT、AST、TBIL、D-D)、肾功能指标(UREA、eGFR)与服药前的差异无统计学意义,提示达比加群酯对肝肾功能无明显的毒性作用;服药1个月、6个月后患者血常规指标(HGB、ESR)在服药前后差异无统计学意义,提示达比加群酯对患者血红蛋白量、红细胞沉降率无显著影响。

      患者服药后的不良事件主要表现为胸闷、 牙龈出血、 消化道出血 、血栓形成和脑卒中,并未发生严重出血和威胁生命或器官衰竭的出血。不良事件中较为严重的事件包括3例血栓形成和2例脑卒中发生,分析这5例患者发现,2例血栓形成患者均存在血脂控制不良现象,1例体重较大,考虑血栓形成与血脂控制不良和极端体重相关;2例脑卒中患者年龄分别为75岁和80岁,属高龄患者,考虑高龄患者肾功能减退,从而导致血药浓度增加[18]。近期国内外Meta分析[16-18]也显示达比加群酯出血事件少、使用安全。因此,基于目前的研究数据,可以认为达比加群酯对老年非瓣膜性房颤患者的安全性良好,适于老年患者使用。

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