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. Primary end points included VTE recurrence, bleeding events, and mortality at 6 and 12 months. Overall, 203 children received dabigatran, with median exposure being 36.3 weeks (range, 0-57 weeks); 171 of 203 (84.2%) and 32 of 203 (15.8%) took capsules and pellets, respectively. Overall, 2 of 203 children (1.0%) experienced on-treatment VTE recurrence, and 3 of 203 (1.5%) experienced major bleeding events, with 2 (1.0%) reporting clinically relevant nonmajor bleeding events, and 37 (18.2%) minor bleeding events. There were no on-treatment deaths. On-treatment postthrombotic syndrome was reported for 2 of 162 children (1.2%) who had deep vein thrombosis or central-line thrombosis as their most recent VTE. Pharmacokinetic/pharmacodynamic relationships of dabigatran were similar to those in adult VTE patients. In summary, dabigatran showed a favorable safety profile for secondary VTE prevention in children aged from >3 months to <18 years with persistent VTE risk factor(s). This trial was registered at www.clinicaltrials.gov as #NCT02197416.

Increased plasminogen activator inhibitor results in a hypofibrinolytic state in adolescents with obesity: in vivo and ex vivo evidence.

Obesity in adolescents increases their risk for deep vein thrombosis. The objectives of this study were to determine potential mechanisms for thrombotic risk by investigating the fibrinolytic pathway in a sample of adolescents with and without obesity. Thirty-seven adolescents with obesity and 16 normal weight age-matched controls were recruited. Plasma levels of components of the fibrinolytic system were measured in addition to a Global Haemostasis Potential assay (GHP), which assesses plasma capacity to generate and lyse a fibrin clot. Levels of plasminogen activator inhibitor (PAI) and tissue plasminogen activator (tPA)/PAI complexes were increased in adolescents with obesity when compared to normal weight controls. There was a significant inverse association of increasing PAI with a decrease in plasmin-antiplasmin complexes. The GHP in obese adolescents displayed a hypofibrinolytic response with a markedly increased t½ clot lysis time, as well as an increase in fibrin clot density as indicated by increased absorbance at maximum peak height. In the obese group, immunodepletion of PAI decreased both t½ lysis time and absorbance at maximum peak height. We have shown in vivo and ex vivo there is a hypofibrinolytic state in obese adolescents and have established the hypofibrinolytic state is due to increased PAI levels.

Evaluation of the interpretation of serial ultrasound examinations in the diagnosis of deep venous thrombosis in children: a retrospective cohort study.

PURPOSE: To assess ultrasound intrascan variability and the potential error rate of serial ultrasounds in the diagnosis of deep venous thrombosis in children. METHODS: A retrospective cohort review of imaging results of children having at least 3 serial ultrasound examinations of the same region within a 2-month period. The results were interpreted as either (1) inadequately visualized or (2) the absence or presence of deep venous thrombosis, and were categorized by location. Serial imaging findings then were further categorized based on results and clinical information. RESULTS: Sixty-four patients and 157 vessel segments were included in the study. Deep venous thrombosis was documented in 58 patients. Concordant results were observed in 26 patients (40.1%), clot resolution in 17 patients (26.6%), clot formation in 12 patients (18.8%), and discordant results in 9 patients (14%). Twenty-one of 64 patients (32.8%) had at least 1 vessel inadequately imaged. CONCLUSIONS: The inconsistency of serial ultrasound results in up to 25% of patients calls attention to the potential inaccuracy of ultrasound for diagnosis and follow-up of deep venous thrombosis in children. The high proportion of patients with at least 1 inadequately visualized vessel also highlights the limitation of ultrasound in the diagnosis of pediatric deep venous thrombosis.

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). We report safety and efficacy outcomes from subgroup analyses of these studies for children with CHD (diagnosed according to local practice) and those without. In NCT01895777, 17/21 (81.0%) and 16/27 (59.3%) patients with CHD (including cyanotic) treated with dabigatran and standard of care, respectively, met the primary end point (complete thrombus resolution, freedom from recurrent VTE, and freedom from VTE-related death; odds ratio [OR], 0.34 [95% CI, 0.08-1.23]). In patients without CHD, 41.0% (n=64) versus 34.9% (n=22) achieved this end point with the respective treatments (OR, 0.77 [95% CI, 0.42-1.41]). Although numerical differences were observed, no heterogeneity in treatment effect of dabigatran on the composite primary end point was detected in patients with and without CHD (interaction P =0.2674). In NCT02197416, recurrent VTE at 12 months occurred in 0/17 patients with CHD versus 3/194 (1.5%) without. No patient with CHD experienced major or clinically relevant nonmajor bleeding events. CONCLUSIONS: Data on favorable anticoagulant alternatives for the unmet needs of children with CHD are emerging, and our exploratory results suggest that dabigatran could be an appropriate treatment choice, although challenging sample size limitations in pediatric studies require cautious interpretation of findings. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01895777, NCT02197416.

Apixaban versus no anticoagulation for the prevention of venous thromboembolism in children with newly diagnosed acute lymphoblastic leukaemia or lymphoma (PREVAPIX-ALL): a phase 3, open-label, randomised, controlled trial.

BACKGROUND: Paediatric patients with acute lymphoblastic leukaemia or lymphoma are at increased risk of venous thromboembolism resulting in increased mortality and morbidity. We hypothesised that apixaban, a direct oral anticoagulant, would safely reduce venous thromboembolism in this patient population. METHODS: PREVAPIX-ALL was a phase 3, open-label, randomised, controlled trial conducted in 74 paediatric hospitals in 9 countries. Participants aged 1 year or older to younger than 18 years with newly diagnosed acute lymphoblastic leukaemia (pre-B cell or T cell) or lymphoblastic lymphoma (B cell or T cell immunophenotype) and a central venous line in place throughout induction were randomly assigned 1:1 to standard of care (SOC, ie, no systemic anticoagulation) or weight-adjusted twice-daily apixaban during induction. Randomisation was performed centrally and stratified by age (those <10 years or those ≥10 years). Participants weighing 35 kg or less were administered 2·5 mg twice daily of apixaban as a 2·5 mg tablet, 0·5 mg tablets, or 0·4 mg/mL oral solution, while those weighing more than 35 kg were administered weight-adjusted prophylactic doses using 0·5 mg tablets or the 0·4 mg/mL oral solution twice daily. Primary outcomes were assessed by a blinded central adjudication committee. The primary efficacy outcome for the intention to treat population was the composite of symptomatic or clinically unsuspected venous thromboembolism, the primary safety outcome was major bleeding, and secondary safety outcomes included clinically relevant non-major (CRNM) bleeding. Patients were screened for venous thromboembolism by ultrasound and echocardiogram at the end of induction. The trial was registered with ClinicalTrials.gov (NCT02369653) and is now complete. FINDINGS: Between Oct 22, 2015, and June 4, 2021, 512 participants were randomly assigned and included in analyses (222 [43%] female and 290 [57%] male; 388 [76%] White, 52 [10%] Asian, 24 [5%] Black or African American, and 48 [9%] other races; and 122 [24%] Hispanic or Latino ethnicity). During a median follow-up period of 27 days (IQR 26-28), 31 (12%) of 256 patients on apixaban had a composite venous thromboembolism compared with 45 (18%) of 256 participants receiving SOC (relative risk [RR] 0·69, 95% CI 0·45-1·05; p=0·080). Two major bleeding events occurred in each group (RR 1·0, 95% CI 0·14-7·01; p=1·0). A higher incidence of CRNM bleeding, primarily grade 1 or 2 epistaxis, occurred in the apixaban group (11 [4%] of 256 participants) compared with the SOC group (3 [1%] of 256; RR 3·67, 95% CI 1·04-12·97, p=0·030). The most frequent grade 3-5 adverse events in both groups were thrombocytopenia (n=28 for the apixaban group and n=20 for the SOC group) or platelet count decreased (n=49 and n=45), anaemia (n=77 and n=74), febrile neutropenia (n=27 and n=20), and neutropenia (n=16 and n=17) or neutrophil count decreased (n=22 and n=25). Five deaths occurred, which were due to infection (n=3 in the SOC group), cardiac arrest (n=1 in apixaban group), and haemorrhagic cerebral sinus vein thrombosis (n=1 in the SOC group). There was one apixaban-related death (coagulopathy and haemorrhage after cardiac arrest of unknown cause). INTERPRETATION: PREVAPIX-ALL is, to our knowledge, the first trial assessing primary thromboprophylaxis using a direct oral anticoagulant in paediatric patients with acute lymphoblastic leukaemia or lymphoma. No statistically significant treatment benefit was identified in participants receiving apixaban. Major and CRNM bleeding were infrequent overall, but a higher incidence of CRNM bleeding (primarily epistaxis in younger children) occurred in participants receiving apixaban. For patients deemed to be at particularly high risk of thrombosis, PREVAPIX-ALL provides encouraging safety data for the use of apixaban in clinical settings in which the potential benefits are thought to outweigh the risk of bleeding. FUNDING: Bristol Myers Squibb-Pfizer Alliance.

In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes.

Anticoagulation with vitamin K antagonists (VKAs) is problematic because of difficulties in safely managing dosing. Polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase genes (VKORC1) have been shown to affect VKA dosing in adults. The association of these polymorphisms on VKA dosing in children has not been investigated. The objective of the study was to assess associations of CYP2C9 and VKORC1 polymorphisms and clinical variables on VKA dosing in children. A nonselected cohort of pediatric patients receiving VKA were tested for CYP2C9 and VKORC1 polymorphisms, and clinical data were collected. Multiple linear regression modeling was used to assess relationships of VKA dose with genetic and clinical variables. Fifty-nine patients were recruited; 55.9% were receiving warfarin, and 44.1% were on phenprocoumon. There was a negative association of age with VKA dose (P < .001). Comparing VKORC1 genotypes, the AA group required significantly lower daily doses than GG group (P = .011). In the full model including age, VKORC1 and CYP2C9 genotypes accounted for 38% of dose variation. Age explained 28.3% of VKA dose variations; VKORC1 and CYP2C9 explained only 3.7% and 0.4%, respectively. In children, the most critical factor in determining VKA dose is age. VKORC1/CYP2C9 genotypes only marginally explain dose variations.

Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study.

Among risk factors for developing thromboembolism (VTE) in children with acute lymphoblastic leukemia were Escherichia coli asparaginase, concomitant steroid use, presence of central venous lines, and thrombophilic abnormalities. Developing a predictive model for determining children at increased risk would be beneficial in targeting interventional studies to high-risk groups (HRGs). Predictive variables were incorporated into a risk assessment model, which was evaluated in 456 children and then validated in 339 patients. VTE risk by score was no greater than 2.5 for low-risk group (LRG) and greater than 2.5 for HRG. VTE rates at 3.5 months (validation cohorts) were 2.5% in LRG and 64.7% in HRG. In multivariate analysis adjusted for age, duration of asparaginase administration, enoxaparin prophylaxis, and T-immunophenotype, the HRG was significantly associated with VTE compared with the LRG (hazard/95% confidence interval [CI], 8.22/1.85-36.53). Model specificity was 96.2% and sensitivity was 63.2%. As secondary objective we investigated the use of enoxaparin for VTE prophylaxis in the HRG. HRG patients without enoxaparin prophylaxis showed a significantly reduced thrombosis-free survival compared with children on low-molecular-weight heparin (LMWH). On the basis of the high specificity, the model may identify children with leukemia at risk of VTE. LMWH may help prevent VTE in the HRG; this warrants assessment in larger cooperative clinical trials.

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. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in the DIVERSITY trial and safety in both studies. Thrombophilia types were similar between the DIVERSITY trial (total population) and secondary prevention studies: factor V Leiden, 42% vs 33%; prothrombin mutation (G20210A), 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; and antiphospholipid antibodies, 18% vs 20% of patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary end point (Mantel-Haenszel-weighted rate difference, -0.135; 95% confidence interval, -0.36 to 0.08; noninferiority P = .0014); comparable to the total DIVERSITY trial population (46% vs 42%) showing dabigatran noninferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia. These trials were registered at www.clinicaltrials.gov as #NCT01895777 and #NCT02197416.

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 [N = 358]; dTT 2,348 [N = 324]; ECT 2,929 [N = 357]) were compared with adult data (5,740 aPTT, 3,472 dTT, 3,817 ECT measurements; N = 1,978). Population models were fitted using nonlinear mixed-effects modeling. Covariates (e.g., sex, age) were assessed on baseline and drug-effect parameters, using a stepwise covariate model-building procedure. RESULTS: Overall, relationships between dabigatran, aPTT, dTT, and ECT were similar in children and adults. For children aged <6 months, a higher proportion of baseline samples were outside or close to the upper aPTT and ECT adult ranges. No age-related differences were detected for dTT. With increasing dabigatran concentration, aPTT rose nonlinearly (half the maximum effect at 368 ng/mL dabigatran) while dTT and ECT increased linearly (0.37 and 0.73% change per ng/mL dabigatran, respectively). Mean baseline aPTT (45 vs. 36 seconds) and ECT (40 vs. 36 seconds) were slightly increased for those aged <6 months versus older children. CONCLUSION: The similar relationships of laboratory parameters observed across pediatric age groups suggests that developmental changes in the hemostatic system may have little effect on response to dabigatran.

Outcome measures in interventional trials for prevention or treatment of venous thrombosis in the pediatric population.

Determining clinically relevant outcomes are one of the key issues in the design of clinical trials. Recently, a working group from the Perinatal and Pediatric Subcommittee of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis published a position article defining outcomes in interventional trials for prevention and treatment of deep vein thrombosis (DVT) in children. For these studies the primary efficacy outcomes are DVT and the primary safety outcomes are bleeding. The exact definitions for these outcomes are included in this review article. This article expands on these recommendations by summarizing and reviewing the current literature in pediatric anticoagulation studies; discussing the relationship of choice of outcomes to specific clinical trial design; providing a more detailed discussion on the rationale for the defined outcomes in pediatric anticoagulation trials, as well as a detailed examination of secondary and tertiary outcomes. With a growing interest in multicenter, multinational pediatric anticoagulation clinical trials, establishment of standardized outcome measures that are applied uniformly over all studies is critically important. Agreement from the international academic community on these outcomes is an important step in assuring well-designed clinical trials, which are implemented to optimize the prevention and treatment of DVT in children.

Safety and efficacy of low molecular weight heparins in children: a systematic review of the literature and meta-analysis of single-arm studies.

Within the last two decades low molecular weight heparins (LMWH) have gained increasing widespread use as anticoagulants in children. The use of LMWH has been implemented into clinical care even though there is a lack of firm evidence on the efficacy and safety of LMWH in this population due to the absence of sufficiently powered randomized controlled trials. In the absence of clinical trials, we performed a meta-analysis of available single-arm studies using LMWH in children. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1980 to 2010 was conducted using keywords in combination both as MeSH terms and text words. Two authors independently screened citations and those meeting a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients, ethnicity, venous thromboembolic events type, and frequency of recurrence and major bleedings were abstracted. Pooled incidence rates (IR) including 95% confidence intervals (95% CIs) on efficacy and safety data of LMWH administration on primary prophylaxis, as well as on secondary prophylaxis in children following symptomatic thromboembolism (TE) were shown. We included 2251 pediatric patients derived from 35 single-arm studies from 12 study countries who were eligible for analysis in the present systematic review. Pooled incidence rates (95% CI) to develop first TE on primary prophylaxis, further TE event on LMWH secondary prophylaxis, or a major bleeding event on LMWH were 0.047 (0.023 to 0.091), 0.052 (0.037 to 0.073) for efficacy, and 0.054 (0.039 to 0.074) for safety (treatment data only), respectively. Efficacy and safety data are comparable with adult data. The present systematic review suggests that use of LMWH in children as primary prophylaxis and in treatment of symptomatic thrombosis is effective and safe. However, properly designed randomized controlled trials are needed.

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. A stepwise, covariate, model-building procedure evaluated the influence of covariates (e.g., age, body weight, body surface area [BSA]-normalized renal function, and sex). The final model was used to evaluate the pediatric dosing algorithm, with simulations comparing pediatric trough exposure with reference exposure defined for the pediatric studies. RESULTS: The population PK of dabigatran was adequately described by a two-compartment model with first-order elimination and absorption. Age, weight, BSA-normalized renal function, and sex were statistically significant covariates (all P < .05). Apparent clearance increased with age (independently of body weight), diminished with decreasing BSA-normalized renal function, and was lower in females than males. All disposition parameters increased with body weight escalation (allometric scaling). Simulations confirmed that for all DE formulations, the final pediatric dosing algorithms achieved reference exposure without dose adjustment. CONCLUSIONS: Using a population PK model of DE for children with VTE, simulations showed that the final dosing algorithms were appropriate for all DE formulations; no dose titration was needed.

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. Standard of care (low-molecular-weight heparins, unfractionated heparin, vitamin K antagonists or fondaparinux) was compared with a paediatric oral dabigatran dosing regimen (an age-adjusted and weight-adjusted nomogram) in children younger than 18 years with acute venous thromboembolism initially treated (5-21 days) with parenteral anticoagulation, requiring anticoagulation therapy for at least 3 months. Patients were randomised 1:2 (standard of care:dabigatran) and stratified by age (12 to <18 years, 2 to <12 years, and birth to <2 years) via interactive response technology. The primary composite efficacy endpoint (intention-to-treat analysis) was the proportion of children with complete thrombus resolution, and freedom from recurrent venous thromboembolism and venous thromboembolism-related death. A non-inferiority margin of absolute differences of 20% was used. Secondary endpoints included safety (determined by major bleeding events [time-to-event analysis on the treated set]), and pharmacokinetic-pharmacodynamic relationships (descriptive analyses). This trial is registered with ClinicalTrials.gov, NCT01895777 and is completed. FINDINGS: 328 children were enrolled between Feb 18, 2014, and Nov 14, 2019. 267 were randomly assigned (90 [34%] to standard of care and 177 [66%] to dabigatran) and included in the analyses. Median exposure to standard of care was 85·0 days (IQR 80·0-90·0) and to dabigatran was 84·5 days (78·0-89·0). Similar proportions of children treated with standard of care and dabigatran met the composite efficacy endpoint (38 [42%] of 90 vs 81 [46%] of 177; Mantel-Haenszel weighted difference, -0·04; 90% CI -0·14 to 0·07; p<0·0001 for non-inferiority). On-treatment bleeding events were reported in 22 (24%) of 90 children receiving standard of care and 38 (22%) of 176 children receiving dabigatran (hazard ratio [HR] 1·15, 95% CI 0·68 to 1·94; p=0·61); major bleeding events were similar between the groups (two [2%] of 90 and four [2%] of 176; HR 0·94, 95% CI 0·17 to 5·16; p=0·95). Pharmacokinetic-pharmacodynamic curves showed a linear relationship between total dabigatran plasma concentration and diluted thrombin time and ecarin clotting time, and a non-linear relationship with activated partial thromboplastin time; curves were similar to those for adults. Serious adverse events were reported for 18 (20%) of 90 children receiving standard of care and 22 (13%) of 176 children receiving dabigatran. The most common severe adverse events were vascular disorders (standard of care three [3%] of 90, dabigatran two [1%] of 176), and gastrointestinal disorders (standard of care two [2%] of 90 and dabigatran five [3%] of 176). One on-treatment death occurred in the standard of care group (retroperitoneal bleeding, not considered treatment related by the study investigators). INTERPRETATION: An age-adjusted and weight-adjusted dabigatran dosing algorithm was appropriate in children aged birth to less than 18 years with venous thromboembolism. Dabigatran was non-inferior to standard of care in terms of efficacy, with similar pharmacokinetic-pharmacodynamic relationships as those seen in adults, and might be a suitable alternative to standard of care. FUNDING: Boehringer Ingelheim.

The effect of 1 month of therapy with midodrine, octreotide-LAR and albumin in refractory ascites: a pilot study.

BACKGROUND: The pathogenesis of refractory ascites (RA) is linked to splanchnic vasodilation. We hypothesized that a combination of midodrine, octreotide long-acting release (LAR) and albumin would result in increased natriuresis, better control of ascites and an improvement in renal function in patients with RA+/-Type 2 hepatorenal syndrome. METHODS: A prospective pilot study in patients with RA as defined by the International Ascites Club. Consecutive patients received an intramuscular injection of octreotide-LAR, 50 g of albumin three times per week and midodrine titrated to increase the systolic blood pressure for 1 month. RESULTS: Ten patients with RA were enrolled and eight with complete data to 1 month post-treatment were included in the analysis. There was no change in renal function but there was a trend towards a reduction in the volume of ascites removed by paracentesis (P=0.08) and a significant reduction in the plasma renin (P=0.01) and aldosterone concentrations (P=0.01). Interestingly, there was a transient worsening in the model for end-stage liver disease (MELD) score (P=0.01). The deterioration in MELD was completely reversible after discontinuation of therapy. CONCLUSIONS: To our knowledge, this is the first study of prolonged midodrine, octreotide and albumin therapy in RA. We observed a significant reduction in the plasma renin and aldosterone concentrations and a trend towards a reduction in the volume of ascites removed by paracentesis without an effect on renal function. The beneficial effects are at the expense of a reversible deterioration in the MELD score. Large controlled trials are needed before this therapy can be routinely recommended.

PREVAPIX-ALL: Apixaban Compared to Standard of Care for Prevention of Venous Thrombosis in Paediatric Acute Lymphoblastic Leukaemia (ALL)-Rationale and Design.

Venous thromboembolic (VTE) complications in children and adolescents with acute lymphoblastic leukaemia (ALL) and T or B cell lymphoblastic lymphoma (T/B cell LL) can result not only in life-threatening acute complications but also contribute to significant long-term sequelae. The PREVAPIX-ALL study is an open-label randomized controlled study comparing outcomes of treatment with prophylactic dose apixaban versus no anticoagulation (standard of care) in children and adolescents with ALL and T/B cell LL receiving standard induction chemotherapy with asparaginase and the presence of a central venous access device. On day 29 of induction, all patients undergo screening imaging with duplex ultrasonography and echocardiography. The primary efficacy endpoint of the study is a composite of symptomatic and asymptomatic VTE that includes deep vein thrombosis, pulmonary embolism, cerebral sinovenous thrombosis or VTE-related death. The primary safety outcome is major bleeding. Secondary outcomes are central line-associated infections, patency and line replacement, superficial thrombosis, arterial events and death. A planned sample size of 500 randomized paediatric patients enrolled over a period of 5 years is based on the estimation of VTE rates of 20 and 10% in the standard of care and apixaban groups, respectively. An optional biomarker study in 150 patients will examine predictors of increased VTE risk and study in vivo anticoagulant effects of apixaban in children by measuring specific biomarkers in the haemostatic system and inflammatory pathway. This study will provide valuable information for the safety and efficacy of apixaban in VTE prevention during induction in paediatric ALL.

Anticoagulant Effects of Dabigatran in Paediatric Patients Compared with Adults: Combined Data from Three Paediatric Clinical Trials.

BACKGROUND: Physiological age-related changes in the haemostatic and coagulation systems result in differing anticoagulant assay responses to standard anticoagulants. Therefore, we investigated the response of anticoagulant assays to dabigatran etexilate (DE) in children compared with adults. OBJECTIVE: This article assesses the relationship between plasma dabigatran concentration and coagulation assay results across age groups in children and adults. PATIENTS AND METHODS: Data from three clinical trials in which children received DE following standard of care for venous thromboembolism were compared with data from adult clinical trials. The effects of dabigatran concentration on diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) were analysed graphically and with modelling. RESULTS: The concentration-dTT relationships were consistent in children across all ages and adults in the graphical analysis. For ECT and aPTT, relationships based on ratios over baseline were similar across all ages; absolute clotting times showed that the same exposure resulted in longer clotting times in some of the children aged < 1 year versus adults. Modelling showed concentration-clotting time relationships for all three assays were largely comparable between adults and children, except in those aged < 2 months, in whom there was a slight upward shift in ECT and aPTT relative to adults. CONCLUSION: Results suggest that developmental haemostatic changes will have little impact on response to DE. However, further paediatric clinical trials assessing the relationship between coagulation assay responses and clinical outcomes will be needed to confirm this finding.

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. OBJECTIVES: To describe the design and rationale of a planned phase IIb/III trial that will evaluate a proposed dosing algorithm for DE and assess the safety and efficacy of DE versus SOC for pediatric VTE treatment. PATIENTS/METHODS: An open-label, randomized, parallel-group noninferiority study will be conducted in approximately 180 patients aged 0 to <18 years with VTE, who have received initial UFH or LMWH treatment and who are expected to require ≥3 months of anticoagulation therapy. Patients will receive DE or SOC for 3 months. DE will be administered twice daily as capsules, pellets, or an oral liquid formulation according to patient age. Initial doses will be calculated using a proposed dosing algorithm. RESULTS: There will be two coprimary endpoints: a composite efficacy endpoint comprising the proportion of patients with complete thrombus resolution, freedom from recurrent VTE and VTE-related mortality, and a safety endpoint: freedom from major bleeding events. CONCLUSION: Findings will provide valuable information regarding the efficacy and safety of DE for the treatment of pediatric VTE. ClinicalTrials.gov registration number: NCT01895777.

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. We report herein the rationale and design of the study. PATIENTS/METHODS: This 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. RESULTS: The 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. CONCLUSION: This 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.