Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism

Schulman, Sam; Kearon, Clive; Kakkar, Ajay K.; Schellong, Sebastian; Eriksson, Henry; Baanstra, David; Kvamme, Anne Mathilde; Friedman, Jeffrey; Mismetti, Patrick; Goldhaber, Samuel Z.; Schul, S.

doi:10.1056/nejmoa1113697

Cited by 883 publications

(697 citation statements)

References 20 publications

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“…Dosing according to the nomogram has led to comparable exposure between pediatric and adult VTE patients and, in addition, the PK/PD relationship is found to be similar between these two patient populations in phase 2a studies 33, 34. Routine coagulation monitoring is not required during its use for the treatment and secondary prevention of VTE in adults 16, 17, 18, 19, 20. The available PK and PD data from this study along with study NCT01895777 will be used to refine the nomogram procedure for determining pediatric dabigatran etexilate dosages.…”

Section: Discussionmentioning

confidence: 99%

“…The starting dose for each participant will be determined based on individual body weight and age using a specially developed nomogram, with the aim of attaining a target steady‐state plasma concentration of dabigatran comparable with the observed plasma dabigatran concentration in adult VTE patients 20, 36. As dabigatran is predominantly (approximately 80%) renally excreted,27, 28 and its PK/PD relationship in children appears to be similar to that in adults,33, 34 the doses in the nomogram were estimated using a scaling method developed by Hayton et al 29.…”

Section: Methodsmentioning

confidence: 99%

“…These include the acute treatment of VTE,16, 17, 18 the acute treatment of VTE in the presence of cancer,19 and extended treatment for secondary prevention of VTE,20 for which dabigatran etexilate was shown to be non‐inferior to well‐controlled warfarin, with an overall reduced risk of bleeding, and superior in efficacy compared with placebo.…”

Section: Introductionmentioning

confidence: 99%

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Phase 3, single‐arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design

Luciani

Albisetti

Biss

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundAnticoagulant therapy for venous thromboembolism (VTE) in children is largely based on treatment recommendations for adults. However, differences in both physiology (ie, renal maturation and drug excretion) and developmental hemostasis must be considered when treating children, as such differences could affect dose appropriateness, safety and efficacy.ObjectivesTo address these concerns, a study was designed to evaluate the safety of dabigatran etexilate in children requiring secondary thrombus prevention in whom an initial VTE was associated with an identified risk factor that persisted after the acute VTE treatment period. We report herein the rationale and design of the study.Patients/MethodsThis phase 3, open‐label, single‐arm, multicenter, multinational, prospective cohort study will be conducted in ≥100 children aged 0 to <18 years at ~100 specialist sites worldwide. Children will be treated with dabigatran etexilate for 12 months, or for a shorter duration if their identified VTE risk factor resolves, as per current American College of Chest Physicians recommendations. A nomogram will be used to determine starting doses for each patient.ResultsThe primary outcomes of the study will be VTE recurrence, bleeding events, overall mortality, and VTE‐related mortality. Secondary outcomes will include occurrence of post‐thrombotic syndrome, the pharmacokinetics of dabigatran, and the need for dose adjustments during treatment. Data on adverse events during the study will also be collected.ConclusionThis study will evaluate the safety of dabigatran etexilate for the secondary prevention of VTE in children, in addition to providing further data to guide pediatric dosing with dabigatran.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phase 3, single‐arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design

Luciani

Albisetti

Biss

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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“…Placebo für weitere 6-12 Monate untersucht haben [22,[26][27][28]. Im Durchschnitt konnten in den AMPLIFY-EXT (Apixaban), RE-SONATE (Dabigatran) und EINSTEIN-extension (Rivaroxaban) Studien eine 67-92 % relative Risikoreduktion für wiederkehrende oder tödliche VTE gezeigt werden, wobei schwere Blutungsereignisse nicht häu-figer als unter Placebo auftraten [26][27][28] [22,24]. Edoxaban wird gegenwärtig zur Prävention wiederkehrender VTE bei Patienten mit Tumorerkrankung klinisch geprüft (NCT02073682).…”

Section: Dauer Der Therapieunclassified

Edoxaban zur Schlaganfallprophylaxe bei Patienten mit nicht-valvulärem Vorhofflimmern und zur Behandlung venöser Thromboembolien: ein interdisziplinäres Positionspapier

Weiss

Rohla

Dieplinger

et al. 2017

Wien Med Wochenschr

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“…Dabigatran etexilate (DE), the prodrug of dabigatran, is approved for prevention of stroke in patients with atrial fibrillation (AF) and for the treatment and secondary prevention of venous thromboembolism. In clinical trials and real‐world observational studies, dabigatran was at least as effective as warfarin, with a favorable bleeding profile 1, 2, 3, 4, 5…”

Section: Introductionmentioning

confidence: 99%

Safety, pharmacokinetics and pharmacodynamics of idarucizumab, a specific dabigatran reversal agent in healthy Japanese volunteers: a randomized study

Yasaka

Ikushima

Harada

et al. 2017

Research and Practice in Thrombosis and Haemostasis

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Essentials Idarucizumab, a monoclonal antibody fragment, binds dabigatran with high affinity and specificity.In this phase 1 trial, healthy Japanese males received idarucizumab alone or with dabigatran.Idarucizumab achieved immediate, complete and sustained reversal of dabigatran anticoagulation.Idarucizumab was well tolerated and demonstrated no pro‐coagulant effects. BackgroundIdarucizumab is a humanized monoclonal antibody fragment that specifically binds with high affinity to dabigatran.ObjectivesThis study investigated the safety, tolerability and pharmacokinetics of idarucizumab alone and with dabigatran at steady state, and the effects of idarucizumab on dabigatran‐induced anticoagulation.Patients/MethodsThis was a two‐part, phase I, randomized, placebo‐controlled, double‐blind, rising‐dose trial in healthy Japanese males. Part 1: 32 subjects (males) received single idarucizumab doses (1, 2, 4 or 8 g [n=6/dose group]) or placebo (n=2/dose group). Part 2: 48 males received dabigatran (220 mg bid) followed by idarucizumab (n=9/dose group) 1, 2, 4 or 5 g (2×2.5 g), or placebo (n=3/dose group). Anti‐idarucizumab antibodies (ADAs) and idarucizumab effect on anticoagulation parameters (diluted thrombin time [dTT], ecarin clotting time [ECT], activated partial thromboplastin time [aPTT] and thrombin time [TT]) were assessed.ResultsNo adverse events were reported in subjects receiving idarucizumab. After single doses of idarucizumab (alone or at steady state of dabigatran), maximum plasma concentration was achieved around the end of each infusion. Mean all anticoagulation parameters fell below the upper limit of normal immediately after idarucizumab infusion in all dose groups; the effect was sustained at 4 and 2×2.5 g over the entire measurement period until 72 h. At 1‐ and 2‐g doses, partial return of the anticoagulant effect occurred. Idarucizumab alone had no effect on coagulation parameters. Treatment‐emergent ADAs occurred in 6/60 males receiving idarucizumab.ConclusionsIdarucizumab infusion achieved immediate, complete and sustained reversal of dabigatran‐induced anticoagulation in Japanese volunteers. Idarucizumab was well tolerated with no procoagulant effects. Trial registration number: ClinicalTrials.gov NCT02028780 (completed)

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Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism

Cited by 883 publications

References 20 publications

Phase 3, single‐arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design

Phase 3, single‐arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design

Edoxaban zur Schlaganfallprophylaxe bei Patienten mit nicht-valvulärem Vorhofflimmern und zur Behandlung venöser Thromboembolien: ein interdisziplinäres Positionspapier

Safety, pharmacokinetics and pharmacodynamics of idarucizumab, a specific dabigatran reversal agent in healthy Japanese volunteers: a randomized study

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