Benefit-Risk Assessment of Off-Label Drug Use in Children: The Bravo Framework.

A drug is granted a license for use after a thorough assessment of risks and benefits based on high-quality scientific proof of its efficacy and safety. Many drugs that are relevant to children are not licensed for use in this population implying that a thorough assessment of risks and benefits in the pediatric population has not been made at all, implying a negative risk-benefit balance in children, or implying insufficient information to establish the risk-benefit balance. Use of drugs without positive assessment of risks and benefits exposes children to potential lack of efficacy, unknown toxicity, and harm. To aid guideline committees and individual prescribers, we here present a tutorial of the Benefit and Risk Assessment for Off-label use (BRAvO) decision framework. This pragmatic framework offers a structured assessment of benefits and risks of off-label drug use, including a clinical pharmacological based approach to age-appropriate dose selection. As proof of concept and to illustrate the practical use, we have applied the framework to assess benefits and risks of off-label use of ondansetron for gastroenteritis-induced nausea and vomiting. The framework could also guide decisions on off-label use in other special populations (e.g., pregnant women, elderly, obese, or critically ill patients) where off-label drug use is frequent, thereby contributing to effective and safe pharmacotherapy.

3D gait analysis, haemophilia joint health score, leg muscle laterality and biomarkers of joint damage: A cross-sectional comparative assessment of haemophilic arthropathy.

INTRODUCTION: 3D gait analysis has been proposed as a reproducible and valid method to assess abnormal gait patterns and to monitor disease progression in patients with haemophilia (PWH). AIM: This study aimed at comparing Gait Deviation Index (GDI) between adult PWH and healthy controls, and at assessing the agreement between outcome measures of haemophilic arthropathy. METHODS: Male PWH aged 18-49 years (prespecified subgroups: 18-25 vs 26-49 years) on prophylactic replacement therapy, and male healthy age-matched controls passed through a cross-sectional assessment panel. Besides the 3D gait analysis derived GDI, secondary outcomes included kinematic, kinetic and spatio-temporal gait parameters, the Haemophilia Joint Health Score (HJHS), electric impedance derived leg muscle laterality and inflammatory biomarkers. RESULTS: Patients with haemophilia (n = 18) walked slower, in shorter steps and accordingly with less functional range of motion in the hips and ankles, as compared to healthy controls (n = 24). Overall, PWH did not differ significantly in GDI and specific gait parameters. PWH had a higher mean HJHS (18.8 vs 2.6, P = .000) and leg muscle laterality (4.3% vs 1.5%, P = .004). A subgroup analysis revealed progressed gait pathology in PWH aged 26-49 years (not statistically significant). Leg muscle laterality was strongly correlated with HJHS (r = .76, P = .000), whereas GDI just moderately (r = -.39, P = .110). PWH had higher levels of the inflammatory markers CRP and IL-6. CONCLUSION: Progressed gait pathology was found in PWH, mainly those aged 26-49 years. Leg muscle laterality correlated strongly with HJHS and was identified as a promising tool for detecting progression and physiological consequences of haemophilic joint arthropathy.

The clinical significance of anti-prothrombin antibodies for risk assessment of thromboembolism in patients with lupus anticoagulant.

INTRODUCTION: Thromboembolism is a common manifestation of lupus anticoagulant (LA), however only a subgroup of LA-patients is affected by thrombosis. Study objective was to investigate whether anti-prothrombin antibodies can identify LA-patients at increased risk for thrombosis. MATERIALS AND METHODS: In total 79 patients, 50 with (42 men/8 women) and 29 without thrombosis (21 men/8 women), were investigated for their presence of anti-prothrombin IgG and IgM antibodies using assays from two different manufacturers (Aeskulisa=assay I, CoaChrom=assay II). RESULTS: The prevalence of elevated levels of anti-prothrombin IgG, IgM as well as IgG and/or IgM antibodies was 66% [assayI] (36% [assayII]), 38% (24%) and 72% (50%) in patients with thrombosis and 55% (24%), 28% (28%) and 66% (41%) in patients without thrombosis, respectively. Neither anti-prothrombin IgG or IgM nor IgG and/or IgM antibodies were found to indicate an increased risk for thrombosis. In the subgroup of patients with arterial or venous thrombosis there was also no association between anti-prothrombin antibodies and thrombosis. The comparison of median levels of IgG and IgM anti-prothrombin antibodies between patients with and without thrombosis yielded a borderline statistically significant difference only for anti-prothrombin IgG antibodies by using assay II (p=0.033), all other comparisons were not statistically significant. CONCLUSIONS: In conclusion, presence of anti-prothrombin antibodies was not associated with thromboembolism in LA-patients.