Dabigatran for Treatment and Secondary Prevention of Venous Thromboembolism in Pediatric Congenital Heart Disease.

Background: Congenital heart disease (CHD) is common in children and associated with greater risk of thrombotic complications. Management of these complications with standard-of-care treatment is suboptimal for these children.

Methods And Results: The effectiveness and safety of dabigatran were demonstrated in pivotal pediatric studies for the treatment of acute venous thromboembolism (VTE; NCT01895777) and secondary VTE prevention (NCT02197416).

Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia.

In the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm, phase 3, secondary VTE prevention study, up to 12 months dabigatran use was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications.

Anticoagulant Effects of Dabigatran on Coagulation Laboratory Parameters in Pediatric Patients: Combined Data from Five Pediatric Clinical Trials.

Background:  Dabigatran etexilate, a direct oral thrombin inhibitor, is approved to treat venous thromboembolism (VTE) in both adults and children.

Objectives:  This population analysis characterized relationships between dabigatran total plasma concentrations and coagulation laboratory parameters (activated partial thromboplastin time [aPTT]; diluted thrombin time [dTT]; ecarin clotting time [ECT]).

Methods:  Data from three phase 2a and one single-arm and one randomized, comparative phase 2b/3 pediatric studies (measurements: aPTT 2,925 [ = 358]; dTT 2,348 [ = 324]; ECT 2,929 [ = 357]) were compared with adult data (5,740 aPTT, 3,472 dTT, 3,817 ECT measurements;  = 1,978).

Outcome of patients with relapsed or progressive Ewing sarcoma enrolled on cooperative group phase 2 clinical trials: A report from the Children's Oncology Group.

SevenChildren's Oncology Group phase 2 trials for patients with relapsed/progressive solid tumors were analyzed to estimate the event-free survival (EFS) for relapsed/progressive Ewing sarcoma. One hundred twenty-eight Ewing sarcoma patients were enrolled and 124 events occurred. The 6-month EFS was 12.

Pharmacokinetic modeling and simulation support for age- and weight-adjusted dosing of dabigatran etexilate in children with venous thromboembolism.

Background: Dabigatran etexilate (DE), a direct oral thrombin inhibitor, has been evaluated in children with venous thromboembolism (VTE) using oral solution, pellets, or capsules.

Objectives: This study evaluated DE pharmacokinetics (PK) in children with VTE and the appropriateness of a DE pediatric age- and weight-based dosing algorithm.

Patients/methods: A population PK model was fitted to data from four single-arm and one randomized, comparative pediatric VTE studies (358 children aged birth to <18 years; 2748 PK observations) and one healthy-adult study (32 males aged <40 years; 1523 PK observations) using nonlinear mixed-effects modeling.

Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial.

Background: Dabigatran etexilate is a direct oral anticoagulant with potential to overcome the limitations of standard of care in children with venous thromboembolism. The aims of this clinical trial were to study the appropriateness of a paediatric dabigatran dosing algorithm, and the efficacy and safety of dabigatran dosed according to that algorithm versus standard of care in treating children with venous thromboembolism.

Methods: DIVERSITY is a randomised, controlled, open-label, parallel-group, phase 2b/3 non-inferiority trial done in 65 centres in 26 countries.

Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children.

This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to <18 years (age stratum 1), 2 to <12 years (stratum 2), and >3 months to <2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ≥3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved.

The Population Pharmacokinetics of High-Dose Methotrexate in Infants with Acute Lymphoblastic Leukemia Highlight the Need for Bedside Individualized Dose Adjustment: A Report from the Children's Oncology Group.

Background: Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate may have reduced methotrexate clearance (CL) due to renal immaturity, which may predispose them to toxicity.

Objective: The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL.

Methods: A total of 672 methotrexate plasma concentrations were obtained from 71 infants enrolled in the Children's Oncology Group (COG) Clinical Trial P9407.

Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials.

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

Background: Anticoagulant 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.

Objectives: To 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.

Design and rationale for the DIVERSITY study: An open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism.

Background: The current standard of care (SOC) for pediatric venous thromboembolism (VTE) comprises unfractionated heparin (UFH), or low-molecular-weight heparin (LMWH) followed by LMWH or vitamin K antagonists, all of which have limitations. Dabigatran etexilate (DE) has demonstrated efficacy and safety for adult VTE and has the potential to overcome some of the limitations of the current SOC. Pediatric trials are needed to establish dosing in children and to confirm that results obtained in adults are applicable in the pediatric setting.

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

Unlabelled: 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.

Antithrombotic Therapy in a Prospective Trial of a Pediatric Ventricular Assist Device.

Efficacious ventricular assist device (VAD) support in pediatric patients depends on successful antithrombotic management. The experience with antithrombotic management for the EXCOR Pediatric VAD Investigational Device Exemption (IDE) study is described. All 68 children in North America enrolled in the IDE study from May 9, 2007 to December 10, 2010 are included.

Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children's Cancer Group, Pediatric Oncology Group, and Children's Oncology Group: Learning From the Past to Move Forward.

Purpose: The use of radiographic response as the primary end point in phase II osteosarcoma trials may limit optimal detection of treatment response because of the calcified tumor matrix. We performed this study to determine if time to progression could be used as an end point for subsequent studies.

Patients And Methods: We performed a retrospective analysis of outcome for patients with recurrent/refractory osteosarcoma enrolled in one of seven phase II trials conducted by the Children's Oncology Group and predecessor groups from 1997 to 2007.

Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency.

Severe congenital protein C (PC) deficiency (SCPCD) is associated with disseminated intravascular coagulation (DIC), purpura fulminans (PF), and vascular thromboembolic events (TE), often leading to organ failure and death. PC replacement therapy offers a safe, effective treatment for thromboembolic complications of SCPCD and secondary prophylaxis for recurrent DIC, PF, and TEs. A prospective, multi-centre, open-label, phase 2/3 study was conducted to demonstrate the safety and efficacy of protein C concentrate for treatment of PF and acute TEs.

Age-based difference in activation markers of coagulation and fibrinolysis in extracorporeal membrane oxygenation.

Objective: Coagulation system activation in extracorporeal membrane oxygenation results in hemostatic derangements. Thrombin generation markers like prothrombin fragment 1+2 and thrombin-antithrombin complex are sensitive markers of hypercoagulability. Plasmin-antiplasmin complex is a sensitive marker for fibrinolysis.

Response to warfarin therapy in obese pediatric patients dosed according to institutional guidelines.

Background: Current warfarin dosing guidelines for pediatric patients do not account for obesity. Published data from adults suggest that obesity may affect warfarin dosing requirements. Obesity is prevalent in the pediatric population, and current warfarin dosing methods should be evaluated in obese pediatric patients.

Anticoagulation therapy trends in children supported by ventricular assist devices: a multi-institutional study.

Ventricular assist device (VAD) use in children has increased dramatically. There are currently few data regarding trends in anticoagulation management for pediatric VADs. A retrospective cohort study was conducted for patients with an International Classification of Diseases, Ninth Revision (ICD-9) code for VAD implantation from 2000 to 2011 from the Pediatric Health Information System database.

Readmissions for warfarin-related bleeding in pediatric patients after hospital discharge.

Background: Warfarin therapy in pediatric patients can be difficult to manage with bleeding as a primary adverse event. Therapy initiation can be difficult as doses to achieve therapeutic outcomes are being determined. Evaluation of readmission for bleeding in pediatric patients discharged on warfarin therapy may be useful to prevent adverse events.

Comparison of anti-Xa levels in obese and non-obese pediatric patients receiving treatment doses of enoxaparin.

Objective: To determine if using actual body weight to dose enoxaparin in obese pediatric patients results in higher anti-Xa levels compared with non-obese pediatric patients.

Study Design: This was a retrospective case-matched study of obese and non-obese pediatric patients receiving treatment doses of enoxaparin in a tertiary care children's hospital. Patients were included if they were initiated on treatment doses of enoxaparin, had appropriate anti-Xa levels drawn, and were between 2 and 18 years of age.

Prospective trial of a pediatric ventricular assist device.

Background: Options for mechanical circulatory support as a bridge to heart transplantation in children with severe heart failure are limited.

Methods: We conducted a prospective, single-group trial of a ventricular assist device designed specifically for children as a bridge to heart transplantation. Patients 16 years of age or younger were divided into two cohorts according to body-surface area (cohort 1, <0.

Risk factors for elevated INR values during warfarin therapy in hospitalized pediatric patients.

Background: There are currently no data describing the incidence of or risk factors for elevated International Normalized Ratio (INR) values in patients receiving warfarin at a tertiary care pediatric hospital. By minimizing risk factors for elevated INR values patient morbidity may be minimized.

Procedures: A 6-year retrospective chart review of inpatient admissions at our institution that received warfarin was performed.

Pilot study of the effect of romiplostim on child health-related quality of life (HRQoL) and parental burden in immune thrombocytopenia (ITP).

Background: Childhood ITP can have a negative impact on the child and his/her family even though it is typically a benign disorder with low risk of serious bleeding. In adults and now children, romiplostim increases the platelet count without significant adverse effects. In this study, the impact of romiplostim treatment on the HRQoL of children with chronic ITP was assessed using the Kid's ITP Tools (KIT).

A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.

Romiplostim, a thrombopoietin-mimetic peptibody, increases and maintains platelet counts in adults with immune thrombocytopenia (ITP). In this first study of a thrombopoietic agent in children, patients with ITP of ≥ 6 months' duration were stratified by age 1:2:2 (12 months-< 3 years; 3-< 12 years; 12-< 18 years). Children received subcutaneous injections of romiplostim (n = 17) or placebo (n = 5) weekly for 12 weeks, with dose adjustments to maintain platelet counts between 50 × 10(9)/L and 250 × 10(9)/L.

Development of factor V and thrombin inhibitors in children following bovine thrombin exposure during cardiac surgery: a report of three cases.

Factor V and thrombin inhibitors may develop following exposure to bovine thrombin preparations. In patient populations where exposure to bovine thrombin is common, such as children undergoing cardiovascular surgery, the development of such inhibitors should be considered in the evaluation of prolonged prothrombin times. We present three cases of children developing factor V and thrombin inhibitors following repeated exposure during cardiac surgical procedures.