Treatment of Acute Venous Thromboembolism With Dabigatran or Warfarin and Pooled Analysis

Schulman, Sam; Kakkar, Ajay K.; Goldhaber, Samuel Z.; Schellong, Sebastian; Eriksson, Henry; Mismetti, Patrick; Christiansen, Anita Vedel; Friedman, Jeffrey; Maulf, Florence Le; Peter, Nuala; Kearon, Clive

doi:10.1161/circulationaha.113.004450

Cited by 842 publications

(862 citation statements)

References 26 publications

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“…The safety and efficacy of dabigatran have been shown in Phase III trials in patients with non‐valvular atrial fibrillation (AF) and venous thromboembolism, and have also been evaluated in real‐world studies of patients with AF 3, 4, 5, 6, 7, 8. Despite the overall positive benefit–risk profile of dabigatran, life‐threatening bleeding in patients being treated with anticoagulant therapies remains an infrequent but real risk 9.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Norris

Ramael

Ikushima

et al. 2017

Brit J Clinical Pharma

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AimsIdarucizumab, a humanized monoclonal anti‐dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre‐existing and treatment‐emergent anti‐idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre‐existing and treatment‐emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab.MethodsData were pooled from three Phase I, randomized, double‐blind idarucizumab studies in healthy Caucasian subjects; elderly, renally impaired subjects; and healthy Japanese subjects. In plasma sampled before and after idarucizumab dosing, ADA were detected and titrated using a validated electrochemiluminescence method. ADA epitope specificities were examined using idarucizumab and two structurally related molecules. Idarucizumab PK/PD data were compared for subjects with and without pre‐existing ADA.ResultsPre‐existing ADA were found in 33 out of 283 individuals (11.7%), seven of whom had intermittent ADA. Titres of pre‐existing and treatment‐emergent ADA were low, estimated equivalent to <0.3% of circulating idarucizumab after a 5 g dose. Pre‐existing ADA had no impact on dose‐normalized idarucizumab maximum plasma levels and exposure and, although data were limited, no impact on the reversal of dabigatran‐induced anticoagulation by idarucizumab. Treatment‐emergent ADA were detected in 20 individuals (19 out of 224 treated [8.5%]; 1 out of 59 received placebo [1.7%]) and were transient in ten. The majority had specificity primarily toward the C‐terminus of idarucizumab. There were no adverse events indicative of immunogenic reactions.ConclusionPre‐existing and treatment‐emergent ADA were present at extremely low levels relative to the idarucizumab dosage under evaluation. The PK/PD of idarucizumab appeared to be unaffected by the presence of pre‐existing ADA.

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Section: Introductionmentioning

confidence: 99%

Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Norris

Ramael

Ikushima

et al. 2017

Brit J Clinical Pharma

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“…VTE‐BLEED was first derived from patients randomized to treatment with dabigatran in the RE‐COVER trials (Schulman et al , 2009, 2014). As the first validation step, the score was further evaluated in warfarin‐treated patients from the same trial programme.…”

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confidence: 99%

Predictive value of venous thromboembolism (VTE)‐BLEED to predict major bleeding and other adverse events in a practice‐based cohort of patients with VTE: results of the XALIA study

et al. 2018

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SummaryVenous thromboembolism (VTE)‐BLEED, a decision tool for predicting major bleeding during chronic anticoagulation for VTE has not yet been validated in practice‐based conditions. We calculated the prognostic indices of VTE‐BLEED for major bleeding after day 30 and day 90, as well as for recurrent VTE and all‐cause mortality, in 4457 patients enrolled in the international, prospective XALIA study. The median at‐risk time was 190 days (interquartile range 106–360). The crude hazard ratio (HR) for major bleeding after day 30 was 2·6 [95% confidence interval (CI) 1·3–5·2] and the treatment‐adjusted HR was 2·3 (95% CI 1·1–4·5) for VTE‐BLEED high (versus low) risk patients: the corresponding values for major bleeding after day 90 were 3·8 (95% CI 1·6–9·3) and 3·2 (95% CI 1·3–7·7), respectively. The predictive value of VTE‐BLEED was similar in selected patients with unprovoked VTE or those treated with rivaroxaban. High VTE‐BLEED score was associated with higher incidence of all‐cause mortality (treatment‐adjusted HR 11, 95% CI 4·8–23), but not evidently with recurrent VTE (treatment‐adjusted HR 1·5; 95% CI 0·85–2·7). These results confirm the predictive value of VTE‐BLEED in practice‐based data in patients treated with rivaroxaban or conventional anticoagulation, supporting the hypothesis that VTE‐BLEED may be useful for making management decisions on the duration of anticoagulant therapy.

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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%

“…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%

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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Treatment of Acute Venous Thromboembolism With Dabigatran or Warfarin and Pooled Analysis

Cited by 842 publications

References 26 publications

Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Predictive value of venous thromboembolism (VTE)‐BLEED to predict major bleeding and other adverse events in a practice‐based cohort of patients with VTE: results of the XALIA 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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