Assessment of exposure to direct oral anticoagulants in elderly hospitalised patients.

It is unclear whether elderly patients established on direct oral anticoagulants (DOACs) have greater exposure to these drugs, which could subsequently increase their risk of bleeding. We assessed DOAC exposure and factors affecting it in a real-world elderly cohort of patients. For this, 151 medically stable hospital inpatients (76 established on apixaban, 61 on rivaroxaban, 14 on dabigatran) with a median [interquartile range (IQR)] age of 84 (78-89) years were recruited. Patients provided blood samples for measurement of peak and trough plasma DOAC concentrations. There was up to 48-fold and 13-fold variation in trough and peak plasma drug concentrations respectively. A significantly greater proportion of patients on apixaban had peak plasma drug concentrations within the reported ranges compared to those on either rivaroxaban or dabigatran (82·9% vs. 44·3% vs. 64·3% respectively; P < 0·001). A third of the variability in DOAC plasma concentrations was attributed to the influences of DOAC dosage, renal function and gender. To what extent the observed increases in DOAC exposure in the older patients is the cause of their increased risk of bleeding, which could potentially be ameliorated by dosing titration, requires further investigation.

PROTECT VIII Kids: BAY 94-9027 (PEGylated Recombinant Factor VIII) safety and efficacy in previously treated children with severe haemophilia A.

INTRODUCTION: BAY 94-9027, a site-specifically PEGylated, B-domain-deleted recombinant factor VIII (FVIII) with extended half-life, demonstrated efficacy for bleed prevention and treatment in previously treated adolescents and adults with severe haemophilia A. AIM: To assess BAY 94-9027 in children with severe haemophilia A. METHODS: In the two-part PROTECT VIII Kids study, boys <12 years with <1% FVIII and >50 exposure days (EDs) to FVIII were enrolled in two cohorts (<6 years; 6-<12 years) and treated with BAY 94-9027 prophylaxis twice-weekly, every 5 days, or every 7 days at physician discretion for ≥50 EDs (Part 1) or twice-weekly for 12-weeks (Part 2). Annualized bleeding rate (ABR) was a primary efficacy endpoint; FVIII inhibitor development was the primary safety variable. RESULTS: At study completion, 25 patients had been treated twice-weekly, 28 in the every-5-day group, and 8 in the every-7-day group. Median ABR for all bleeds was 2.9 (Part 1) and 2.4 (Part 2) and similar in younger and older patients; median ABR for joint bleeds was 0 for both cohorts. In the last 90 days' treatment, median ABR was 0 for younger and older patients (Part 1). Of 149 reported bleeds, 93% were treated with ≤2 infusions. Twelve patients, the majority <6 years (n = 11), discontinued due to apparent loss of efficacy or hypersensitivity. No FVIII inhibitors developed. CONCLUSIONS: In PROTECT VIII Kids, which allowed tailoring of prophylaxis to individual clinical response, BAY 94-9027 was efficacious for bleed prevention and treatment in previously treated children with severe haemophilia A.

Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development.