The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients

Reilly, Paul; Lehr, Thorsten; Haertter, Sebastian; Connolly, Stuart J.; Yusuf, Salim; Eikelboom, John W.; Ezekowitz, Michael D.; Nehmiz, Gerhard; Wang, Susan; Wallentin, Lars

doi:10.1016/j.jacc.2013.07.104

Cited by 742 publications

(489 citation statements)

References 17 publications

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“…Idarucizumab administered alone at doses up to 8 g demonstrated no effect on coagulation (assessed by dTT, ECT, aPTT, or TT) in these healthy Japanese volunteers. These findings are consistent with preclinical and clinical studies showing no prothrombotic effect resulting from idarucizumab use 19, 20, 21…”

Section: Discussionsupporting

confidence: 90%

“…At the 220 mg bid dose the median steady state C max on day 4 was 286 ng/mL for total dabigatran, with 10‐90th percentiles of 136‐432 ng/mL. The steady state C max at the 90th percentile was comparable to the dabigatran exposure at 2 hour post‐dose steady state plasma concentration at the 90th percentile (383 ng/mL, 150 mg bid) as observed in the RE‐LY study 20. The increase in plasma concentrations of total dabigatran observed immediately after idarucizumab administration reflected redistribution of dabigatran from the peripheral compartment and bound to idarucizumab in the central compartment.…”

Section: Discussionsupporting

confidence: 52%

“…The same dosing schedule for DE was repeated on day 8 and ended on day 11 to examine the efficacy of idarucizumab to reverse the anticoagulant activity of DE. This dose of DE was selected to cover peak plasma concentration levels in the RE‐LY trial where plasma concentration around 2‐hour post‐dose achieved was 184 ng/mL20 and corresponded with the dosing schedule of the phase I trial in Caucasian subjects (males)19 (NCT identifier, NCT01688830). At this dosage, the C max of dabigatran at steady state covers the C max of dabigatran after administration of 150 mg bid to the patient population in the phase III global study conducted in patients with nonvalvular atrial fibrillation including Japanese individuals (unpublished data).…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

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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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“…We examined the proportion of patients with peak plasma concentrations of apixaban, dabigatran, and rivaroxaban falling below the median trough level for the respective drug as obtained from population pharmacokinetic (PK) studies in non‐obese patients 14, 15, 16, 17. In other words, in cases of such a low peak concentration, it would be very likely that the exposure to the drug is inadequate during most of the dosing interval.…”

Section: Methodsmentioning

confidence: 99%

Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: A retrospective study

Piran

Traquair

Chan

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundDue to a paucity of data on the efficacy and safety of direct oral anticoagulants (DOACs) in patients with a body mass index >40 kg/m2 or a weight >120 kg, the use of DOACs in this group is not recommended.ObjectivesTo determine the proportion of obese patients with body weight >120 kg with a peak plasma concentration of DOACs lower than the expected median trough level derived from population pharmacokinetic studies for each DOAC.MethodsPatients with body weight >120 kg taking DOACs for any indication underwent a peak drug concentration measurement at steady state.Results38 patients were included in the analysis. The mean age was 64 ± 11 years, and 30 (79%) were males. The median body weight was 132.5 kg (interquartile range [IQR] 127‐146.5). The median peak concentrations (IQR) were 148 ng/mL (138‐240), 138 ng/mL (123‐156.5), 215 ng/mL (181‐249) for apixaban, dabigatran, and rivaroxaban, respectively. Two patients (5%, 95% confidence interval [CI]: 0.5%‐18%) had a peak plasma concentration lower than the median trough and eight (21%, 95% CI: 11%‐37%) had a peak plasma concentration below the fifth percentile (10th percentile for dabigatran) peak concentration.ConclusionsMost patients in our study had peak plasma concentration higher than the median trough level for each of the three DOACs. However, 21% had a peak plasma concentration that was below the usual on‐therapy range of peak concentration for the corresponding DOAC.

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“…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%

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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The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients

Cited by 742 publications

References 17 publications

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

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

Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: A retrospective study

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

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