Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study

Background

Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20?mg once-daily.

Methods

EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20?mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18?years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3?months with the option to continue treatment in 3-month increments, up to a total of 12?months. However, based on most common current practice, children younger than 2?years with catheter-related thrombosis will have a main treatment period of 1?month with the option to prolong treatment in 1-month increments, up to a total of 3?months.

Conclusions

EINSTEIN-Jr will compare previously established 20?mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials.

Trial registration

Clinicaltrials.gov NCT02234843, registered on 9 September 2014.

     

Dietary Salt Intake and Discretionary Salt Use in Two General Population Samples in Australia: 2011 and 2014

The limited Australian measures to reduce population sodium intake through national initiatives targeting sodium in the food supply have not been evaluated. The aim was, thus, to assess if there has been a change in salt intake and discretionary salt use between 2011 and 2014 in the state of Victoria, Australia. Adults drawn from a population sample provided 24 h urine collections and reported discretionary salt use in 2011 and 2014. The final sample included 307 subjects who participated in both surveys, 291 who participated in 2011 only, and 135 subjects who participated in 2014 only. Analysis included adjustment for age, gender, metropolitan area, weekend collection and participation in both surveys, where appropriate. In 2011, 598 participants: 53% female, age 57.1(12.0)(SD) years and in 2014, 442 participants: 53% female, age 61.2(10.7) years provided valid urine collections, with no difference in the mean urinary salt excretion between 2011: 7.9 (7.6, 8.2) (95% CI) g/salt/day and 2014: 7.8 (7.5, 8.1) g/salt/day (p = 0.589), and no difference in discretionary salt use: 35% (2011) and 36% (2014) reported adding salt sometimes or often/always at the table (p = 0.76). Those that sometimes or often/always added salt at the table and when cooking had 0.7 (0.7, 0.8) g/salt/day (p = 0.0016) higher salt excretion. There is no indication over this 3-year period that national salt reduction initiatives targeting the food supply have resulted in a population reduction in salt intake. More concerted efforts are required to reduce the salt content of manufactured foods, together with a consumer education campaign targeting the use of discretionary salt.     

Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma

CD19 chimeric antigen receptor T (CAR T)-cell therapy with axicabtagene ciloleucel (axi-cel) for relapsed or refractory (R/R) large B-cell lymphoma (LBCL) may lead to durable remissions, however, prolonged cytopenias and infections may occur. In this single center retrospective study of 85 patients, we characterized immune reconstitution and infections for patients remaining in remission after axi-cel for LBCL. Prolonged cytopenias (those occurring at or after day 30 following infusion) were common with ≥grade 3 neutropenia seen in 21 of 70 (30%) patients at day 30 and persisting in 3 of 31 (9.7%) patients at 1 year. B cells were undetectable in 30 of 34 (88.2%) patients at day 30, but were detected in 11 of 19 (57.9%) at 1 year. Median immunoglobulin G levels levels reached a nadir at day 180. By contrast, CD4 T cells decreased from baseline and were persistently low with a median CD4 count of 155 cells/mL at 1 year after axi-cel (n=19, range: 33– 269). In total, 23 of 85 (27.1%) patients received intravenous immunoglobulins after axi-cel, and 34 of 85 (40%) received granulocyte-colony stimulating factor. Infections in the first 30 days occurred in 31 of 85 (36.5%) patients, of which 11 of 85 (12.9%) required intravenous antibiotics or hospitalization (“severe”) and were associated with cytokine release syndrome, neurotoxicity, tocilizumab use, corticosteroid use, and bridging therapy on univariate analyses. After day 30, seven severe infections occurred, with no late deaths due to infection. Prolonged cytopenias are common following axi-cel therapy for LBCL and typically recover with time. Most patients experience profound and prolonged CD4 T-cell immunosuppression without severe infection.     

Right Ventricular Longitudinal Strain Predicts Survival in Patients With Functional Tricuspid Regurgitation

BackgroundFunctional tricuspid regurgitation (TR) is a frequent finding in echocardiography. Despite general consent that right ventricular (RV) dysfunction impacts outcome of patients with TR, it is still unknown which echocardiographic parameters most accurately reflect prognosis. In this study we aimed to evaluate the prevalence of RV dysfunction and its prognostic value in patients with TR.MethodsData from 1089 consecutive patients were analysed. Tricuspid annular plane systolic excursion (TAPSE), fractional area change, and right ventricular free wall longitudinal strain (RV strain) were used to define RV dysfunction. Patients were followed for 2-year all-cause mortality. For prediction of survival, reclassification and C statistics of RV functional parameters using TR grade as reference model were performed.ResultsAmong the patients studied, 13.9% showed no TR, 61.2% had mild TR, 19.6% had moderate TR, and 5.3% had severe TR. The TR grade was associated with increased mortality (log rank, P < 0.001). Impaired RV strain and TAPSE were independent predictors for mortality (RV: hazard ratio [HR], 1.130; 95% confidence interval [CI], 1.099-1.160; P < 0.001; TAPSE: HR, 1.131; 95% CI, 1.085-1.175; P < 0.001). Both RV strain and TAPSE improved the reference model for survival prediction (RV: integrated discrimination improvement [IDI], 0.184; 95% CI, 0.146-0.221; P < 0.001; TAPSE: IDI, 0.057; 95% CI, 0.037-0.077; P < 0.001).ConclusionsEchocardiographic evaluation of RV function appears to useful for patients with TR. Assessment of RV strain provides additional value for prediction of 2-year mortality.     

Does hand involvement in systemic sclerosis limit completion of patient-reported outcome measures?

Clinical Rheumatology - The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM) completion...     

A patient-reported outcome measure for patients with pituitary adenoma undergoing transsphenoidal surgery

Pituitary - Pituitary adenomas affect patients’ quality-of-life (QoL) across several domains, with long-term implications even following gross-total resection or disease remission. While...