Management of Dabigatran‐Associated Bleeding with Two Doses of Idarucizumab Plus Hemodialysis

Vitamin K antagonists have been a mainstay of treatment for patients requiring anticoagulation for atrial fibrillation, but direct oral anticoagulants, such as dabigatran, have become increasingly prescribed. Compared with warfarin, dabigatran has a significantly lower risk of life‐threatening bleeding; however, bleeding events can still occur, supporting the need for effective reversal strategies. Idarucizumab was recently approved by the U.S. Food and Drug Administration to reverse the anticoagulant effects of dabigatran when life‐threatening bleeding occurs or an urgent need for an invasive medical procedure exists. Before idarucizumab's approval, reversal strategies included hemodialysis, coagulation factor replacement, and, in the setting of acute ingestion, activated charcoal. We describe the case of a 58‐year‐old, obese woman with a history of atrial fibrillation who developed acute kidney injury while taking dabigatran 150 mg twice/day, resulting in coagulopathy. Despite receiving idarucizumab 5 g and hemodialysis, there was a rebound increase in prothrombin time (PT) and activated partial thromboplastin time (aPTT) values, prompting administration of an additional 5‐g dose of idarucizumab and continued hemodialysis, with subsequent PT and aPTT values remaining within their appropriate ranges. To our knowledge, this is the first case report to describe the successful use of repeat dosing of idarucizumab with hemodialysis to reverse the anticoagulant effects of dabigatran. Although two doses of idarucizumab were given to our patient, this dosing regimen is not the current standard of practice. Administration of idarucizumab and the use of additional reversal strategies should involve an assessment of each individual patient's severity of bleeding and subsequent risk of thrombosis. Due to the recent availability of idarucizumab and varying success with alternative reversal strategies, additional knowledge is needed for the optimal reversal of anticoagulation from dabigatran.     

The safety and persistence of non-vitamin-K-antagonist oral anticoagulants in atrial fibrillation patients treated in a well structured atrial fibrillation clinic

Aims To examine the long-term persistence and safety of the non-vitamin-K-antagonist oral anticoagulants (NOACs) dabigatran (D), rivaroxaban (R) and apixaban (A) in patients with non-valvular atrial fibrillation (AF) treated in the framework of a well structured, nurse-based AF unit for initiation and follow-up of NOAC.

Methods Retrospective clinical data were collected for 766 consequent patients from a single cardiology outpatient clinic incorporating the AF unit.

Results The follow-up time, median (q1-q3), was 367 days (183–493) for D patients (n?=?233), 432 days (255–546) for R patients (n?=?282) and 348 days (267–419) for A patients (n?=?251). No significant differences were found between the three groups with regard to age, sex, renal function, or CHA₂DS₂-VASc score. For all bleeding events the incidence rates per 100 patient-years of follow-up (95% confidence interval [CI], p-value) were reported more often for treatment with R (17.2, 12.7–22.8) than for D (7.0, 4.0–11.3, p?=?0.001) and A (8.7, 5.2–13.6, p?=?0.013). The differences remained significant after adjustment for clinically relevant variables. Discontinuation rates (n?=?167) were lower for A (11.5, 7.5–16.8) than for D (30, 23.4–37.9, p?<?0.001) and R (23.9, 18.6–30.1, p?=?0.001), and were mainly attributed to drug-specific side effects and bleedings. The majority of discontinued patients (n?=?142, 85%) proceeded with other types of oral anticoagulants.

Limitation The main limitation of the study is the small patient population with a short follow-up time.

Conclusion In a retrospective study at a single AF clinic, NOACs showed significantly different bleeding rates and varied discontinuation rates when compared to each other, related mainly to agent-specific side effects and bleedings. The majority of patients that discontinued proceeded with other types of oral anticoagulant.     

达比加群酯治疗心肌梗死的效果及对患者凝血功能指标、炎症因子水平的影响

目的 探讨达比加群酯治疗心肌梗死的效果,以为临床该病的治疗提供参考.方法 选取2018年1月1日至2020年12月31日安康市中医医院收治的40例心肌梗死患者作为研究对象,以抽签法将其随机分为对照组和观察组,各20例.对照组给予常规治疗(阿司匹林肠溶胶囊、阿托伐他汀钙片、盐酸曲美他嗪片、注射用尿激酶),观察组在对照组基...     

Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial

Summary. Background: Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity. Objectives: To characterize the pharmacokinetics of dabigatran in patients with non‐valvular atrial fibrillation (AF) from the Randomized Evaluation of Long‐term Anticoagulant Therapy (RE‐LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters. Patients and methods: A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non‐linear mixed‐effects modeling. Results: The pharmacokinetics of dabigatran were best described by a two‐compartment disposition model with first‐order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup ‘South Asian’ exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton‐pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15–30 mL min^?1 and patients with normal renal function receiving 150 mg twice daily. Conclusions: The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE‐LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment.     

Index Volume 5 January- December 1970

Abstract

Dabigatran etexilate is the first oral anticoagulant to be approved in the United States in decades. It works directly by inhibiting clot-bound and free factor IIa (ie, thrombin) and indirectly by inhibiting platelet aggregation induced by thrombin. It is approved in the United States for stroke prophylaxis in nonvalvular atrial fibrillation. There is evidence to suggest that it is also effective for the treatment of acute venous thromboembolism and venous thromboembolism prophylaxis after knee and hip replacement surgery. Dabigatran etexilate therapy does not require laboratory monitoring, an advantage over warfarin. Unlike the earlier direct thrombin inhibitor, ximelagatran, it has demonstrated no potential for serious hepatotoxicity. It is also subject to a much lower degree of interpatient variability in dose response, has no diet–drug interactions, and has fewer clinically significant drug–drug interactions compared with warfarin. Dabigatran etexilate appears to be a valuable addition to our anticoagulant armamentarium.     

Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits

Summary.  Background: Apixaban is an oral, direct factor Xa (FXa) inhibitor in late-stage clinical development. This study assessed effects of the direct FXa inhibitors, apixaban and rivaroxaban, vs. the direct thrombin inhibitor, dabigatran, on venous thrombosis (VT), bleeding time (BT) and clotting times in rabbits. Methods: We induced the formation of non-occlusive thrombus in VT models by placing threads in the vena cava, and induced bleeding by the incision of cuticles in anesthetized rabbits. Apixaban, rivaroxaban and dabigatran were infused IV to achieve a stable plasma level. Clotting times, including the activated partial thromboplastin time (aPTT), prothrombin time (PT), modified PT (mPT) and thrombin time (TT), were measured. Results: Apixaban, rivaroxaban and dabigatran exhibited dose-related efficacy in preventing VT with EC₅₀ of 65, 33 and 194 n m , respectively. At doses for 80% reduction of control thrombus, apixaban, rivaroxaban and dabigatran prolonged BT by 1.13 ± 0.02-, 1.9 ± 0.1-* and 4.4 ± 0.4-fold*, respectively (* P  <   0.05, vs. apixaban). In the treatment model, these inhibitors equally prevented growth of a preformed thrombus. Antithrombotic doses of apixaban and rivaroxaban prolonged aPTT and PT by <3-fold with no effect on TT. Dabigatran was ≥50-fold more potent in prolonging TT than aPTT and PT. Of the clotting assays studied, apixaban, rivaroxaban and dabigatran responded the best to mPT. Conclusion: Comparable antithrombotic efficacy was observed between apixaban, rivaroxaban and dabigatran in the prevention and treatment of VT in rabbits. Apixaban and rivaroxaban exhibited lower BT compared with dabigatran at equivalent antithrombotic doses. The clinical significance of these findings remains to be determined.     

达比加群酯对比华法林二联抗凝方案在高龄心房颤动合并冠心病患者抗栓治疗中的效果评估

[目的]探讨达比加群酯对比华法林二联抗凝方案在高龄心房颤动(AF)合并冠心病(CHD)患者抗栓治疗中的临床效果。[方法]选取本院于2018年8月—2019年12月收治的198例高龄AF合并CHD患者为研究对象,采用随机数字表法分为观察组和对照组各99例。观察组采用达比加群酯治疗,对照组采用华法林二联抗凝方案,即华法林联合抗血小板药物(阿司匹林)治疗。随访1年。比较两组抗栓治疗疗效。比较两组治疗前、治疗后1、6、12个月的凝血酶原时间(PT)、国际标准化比值(INR)、凝血酶时间(TT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(Fib)、D-二聚体(D-D)、血小板计数(PLT)、C反应蛋白(CRP)以及血清尿酸变化情况。观察并记录两组治疗期间的血栓事件、出血事件以及用药不良反应发生情况。[结果]治疗1、6、12个月后,观察组和对照组PLT、CRP、D-D水平均呈逐渐明显下降趋势(F=42.417、18.254、44.582,均P<0.001);两组PT、INR、TT、APTT、Fib相比治疗前均显著改善(F=356.521、5.689、112.526、35.417、5.62...     

骨科大手术中的静脉血栓的预防:口服抗凝药的系统回顾和间接比较

目的:基于有效的循证证据,以低分子肝素为对照组,分析达比加群、阿哌沙班和利伐沙班在骨科大手术后预防静脉血栓的有效性与安全性。方法:在Pub Med和Embase中系统地检索随机对照试验以及参考文献中关键的文章,这些文章评价了以低分子肝素为对照组,达比加群、阿哌沙班和利伐沙班在进行了骨科大手术的病人中的作用。结果:评价的结果包括总静脉血栓(total VTE)、深静脉血栓(DVT)、肺栓塞(PE)、死亡和主要出血事件(major bleeding)。笔者独立地评价了每1篇文章的方法质量同时独立地提取了文献数据。在总静脉血栓预防方面,利伐沙班和阿哌沙班优于达比加群,分别为[RR=0.37,95%CI(0.23,0.60)]和[RR=0.58,95%CI(0.35,0.96)]。利伐沙班和阿哌沙班之间没有区别[RR=0.64,95%CI(0.33,1.25)]。利伐沙班与阿哌沙班相比增加了出血风险[RR=1.57,95%CI(1.20,2.07)],利伐沙班与达比加群相比增加了出血风险[RR=1.25,95%CI(0.93,1.70)]。阿哌沙班和达比加群在出血方面没有差别[RR=0.78,95%CI(0.58,1.07)]。结论:在接受骨科大手术病人之中,利伐沙班和阿哌沙班2种药物与达比加群相比,预防静脉血栓的效果更好,出血风险相似。利伐沙班与阿哌沙班相比,预防静脉血栓的效果相似,但是增加了出血的风险。