Impact of four direct oral anticoagulants on rotational thromboelastometry (ROTEM)

Introduction

Rotational Thromboelastometry (ROTEM) is a point of care method used to monitor coagulation during surgery and to guide transfusion strategies in patients presenting with severe bleeding. The aim of our study was to determine the impact of four direct oral anticoagulants (DOACs) on 3 commonly used ROTEM tests.

Methods

Whole blood samples from 20 healthy donors were spiked in vitro with apixaban, edoxaban, rivaroxaban or dabigatran at 5 different plasma concentrations (0‐1000 ng/mL). EXTEM, INTEM and FIBTEM tests were systematically performed.

Results

There was a linear relationship between the increase in clotting time (CT) and plasma DOAC concentrations in both the EXTEM and INTEM tests. We found that the DOAC concentration required to double EXTEM CT was 1042 ± 225 ng/mL for apixaban, 134 ± 38 ng/mL for edoxaban, 176 ± 26 ng/mL for rivaroxaban and 284 ± 73 ng/mL for dabigatran. INTEM CT was less sensitive than EXTEM CT whatever the anticoagulant. EXTEM CT was above the normal range for 5 of 5 spiked samples when the plasma concentrations were ~1000 ng/mL for apixaban, ~100 ng/mL for edoxaban, ~200 ng/mL for rivaroxaban and ~200 ng/mL for dabigatran. Maximum Clot Firmness in EXTEM, INTEM and FIBTEM tests was not affected whatever the DOAC or its concentration.

Conclusion

This study found a DOAC dose‐dependent increase in ROTEM CTs. ROTEM tests were only poorly impacted by low levels of edoxaban, rivaroxaban or dabigatran. Apixaban had only a low effect even at high concentrations.     

Cost-effectiveness analysis of dabigatran versus rivaroxaban for stroke prevention in patients with non-valvular atrial fibrillation using real-world evidence in elderly US Medicare beneficiaries

Objective: Dabigatran and rivaroxaban have been approved by the US FDA to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients. Newly published real-world evidence based on the US population found that elderly Medicare patients with NVAF treated with rivaroxaban experienced statistically significant increases in intracranial hemorrhage (ICH) and major extracranial bleeding, and statistically nonsignificant decreases in thromboembolic stroke and acute myocardial infarction (AMI) compared with dabigatran. This study assessed the cost-effectiveness of dabigatran vs. rivaroxaban for the treatment of US Medicare NVAF patients.

Methods: A previously published Markov model was adapted to compare dabigatran and rivaroxaban. The model considered thromboembolic stroke, bleeding events, and AMI based on the published real-world event risks. Model outputs included clinical event rates, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).

Results: Dabigatran patients experienced fewer ICH and major extracranial bleeding events than rivaroxaban patients, but more stroke and AMI events. Dabigatran was found to yield lower costs and higher QALYs than rivaroxaban, with incremental costs of ?$3534 and incremental QALYs of 0.004. Results remained consistent in sensitivity analyses, with a positive net monetary benefit (willingness-to-pay thresholds of $50,000 and $100,000 per QALY) for dabigatran over rivaroxaban for all model inputs tested.

Conclusions: In this study using US Medicare real-world data, dabigatran was found to dominate rivaroxaban. The analyses were limited by the short follow-up period of the real-world data and results may not be generalizable to other patient populations.     

三维有序大孔淀粉材料改善达比加群酯的溶出行为

目的 制备三维有序大孔淀粉材料（three-dimensional ordered macroporous starch material,3DOMS）,改善难溶性药物达比加群酯（dabigatran etexilate,DBET）的溶出度。方法 通过硬模板法制备3DOMS;溶剂挥发法进行载药;借助X射线衍射法、差示扫描量热法和傅里叶红外光谱法表征考察药物存在状态;溶出度实验验证DBET溶出度改善情况。结果 3DOMS具有三维有序的纳米级连通孔道结构,借助其纳米级空间抑制效应能够有效抑制难溶性药物的结晶度,载药样品（DBET-3DOMS）中DBET以无定形态存在,体外溶出度实验表明药物溶出效果明显改善。结论 3DOMS能够有效改善DBET的溶出,作为生物可降解材料在改善难溶性药物水溶性方面具有较大潜力。     

Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics,safety, and tolerability

Essentials

• Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism.
• Children aged 1 to < 12 years were given dabigatran etexilate in an open‐label, single‐arm study.
• The pharmacokinetic–pharmacodynamic relationship was similar to that seen in adult patients.
• There were no serious adverse events, bleeding events or recurrent venous thromboembolism.

Summary

Background

The current standard‐of‐care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option.

Objectives

To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE.

Patients/Methods

Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age‐adjusted and weight‐adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics‐related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)–pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs).

Results

Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady‐state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non‐linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single‐dose group (screening period) and in one patient in the multiple‐dose group (on‐treatment period).

Conclusion

The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.     

The risk of gastrointestinal bleeding in patients receiving dabigatran etexilate: a systematic review and meta-analysis of the literature

Background: Evidence on the risk of gastrointestinal (GI) bleeding associated with dabigatran etexilate (DE) is contrasting. We performed a meta-analysis of literature to address this issue.

Methods and Results: Studies on GI bleeding risk in patients receiving DE or vitamin-K antagonists (VKA) were systematically searched. Twenty-three studies (26 datasets) showed no difference in the GI bleeding risk between the 250,871 patients treated with DE and the 460,386 receiving VKA (OR: 1.052, 95% CI: 0.815, 1.359). Similar results were obtained when pooling together adjusted ORs/HRs, obtained by means of multivariate analysis (OR: 1.06, 95% CI: 0.914, 1.222). Compared with VKA, DE use was associated with a significantly lower risk of upper GI (OR: 0.742, 95% CI: 0.569, 0.968), but not of lower GI bleedings (OR: 1.208, 95% CI: 0.902, 1.619). Furthermore, no significant difference in the GI bleeding risk was found when data on DE 110?mg and DE 150?mg twice-daily were separately compared with VKA.

Conclusions: No difference in GI bleeding risk was found between DE and VKA. These results were confirmed for both dosages of DE and when specifically analyzing lower GI bleeding. In contrast, the risk of upper GI bleeding was lower with DE than with VKA.

• KEY MESSAGES

• No difference in the risk of gastrointestinal (GI) bleeding can be found between dabigatran etexilate (DE) and vitamin K-antagonists (VKA).

• These results are confirmed for both dosages of DE.

• The risk of upper GI bleeding is lower with DE than with VKA.

     

胺碘酮联合达比加群酯治疗非瓣膜性心房颤动的疗效和安全性分析

目的探讨胺碘酮联合达比加群酯治疗非瓣膜性心房颤动的疗效和安全性。方法将2014年1月至2014年7月收治的76例非瓣膜性心房颤动患者随机分为治疗组和对照组,治疗组予以胺碘酮联合达比加群酯治疗,对照组予以胺碘酮联合华法林,观察凝血指标变化,心电图、生化指标变化和不良反应等情况。结果与治疗前相比,治疗后两组凝血酶原时间(PT)、凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶时间(TT)均升高(P0.05)。治疗后,两组间各凝血指标比较,差异无统计学意义(P0.05),两组患者心率明显降低(P0.05),其他心电图表现均无明显变化(P0.05)。治疗组发生消化道反应9例(23.7%),高于对照组的5.3%(P0.05)。而治疗组栓塞或血栓以及出血的发生率均低于对照组(P0.05)。结论胺碘酮联合达比加群酯治疗非瓣膜性心房颤动安全有效,值得在临床推广。