Safety of Levetiracetam in paediatrics: a systematic review

Objective To identify adverse events (AEs) associated with Levetiracetam (LEV) in children. Methods Databases EMBASE (1974-February 2015) and Medline (1946-February 2015) were searched for articles in which paediatric patients (≤18 years) received LEV treatment for epilepsy. All studies with reports on safety were included. Studies involving adults, mixed age population (i.e. children and adults) in which the paediatric subpopulation was not sufficiently described, were excluded. A meta-analysis of the RCTs was carried out and association between the commonly reported AEs or treatment discontinuation and the type of regimen (polytherapy or monotherapy) was determined using Chi2 analysis. Results Sixty seven articles involving 3,174 paediatric patients were identified. A total of 1,913 AEs were reported across studies. The most common AEs were behavioural problems and somnolence, which accounted for 10.9% and 8.4% of all AEs in prospective studies. 21 prospective studies involving 1120 children stated the number of children experiencing AEs. 47% of these children experienced AEs. Significantly more children experienced AEs with polytherapy (64%) than monotherapy (22%) (p<0.001). Levetiracetam was discontinued in 4.5% of all children on polytherapy and 0.9% on monotherapy (p<0.001), the majority were due to behavioural problems. Conclusion Behavioural problems and somnolence were the most prevalent adverse events to LEV and the most common causes of treatment discontinuation. Children on polytherapy have a greater risk of adverse events than those receiving monotherapy

Br J Clin Pharmacol

BACKGROUND: We compared the 1-year safety and effectiveness of dabigatran 110 mg (D110) or 150 mg (D150) to vitamin K antagonists (VKA) in patients with non-valvular atrial fibrillation (NVAF), METHODS: New user cohort study of patients dispensed D110 or D150 vs. VKA in 2013 for NVAF, followed 1 year in the French Systeme National des Donnees de Sante (SNDS, 66 million persons). D110 and D150 users were matched 1:1 with VKA users on sex, age, date of first drug dispensing, and high-dimensional propensity score (hdPS). Hazard ratios (HR [95% confidence intervals]) for stroke and systemic embolism (SSE), major bleeding (MB), and death were computed using Cox proportional hazards or Fine and Gray models during exposure. RESULTS: In 14,442 matched D110 and VKA patients, mean age 79, 49% male, 91% with CHA2 DS2 -VASc >/=2 and 8% with HAS-BLED >3, incidence rates of SSE were 1.9% and 2.6% person-years (HR 0.69 [0.56-0.84]), MB 1.8% and 2.9% (0.62 [0.51-0.76]), death 7.2% and 8.6% (0.84 [0.76-0.94]). In 8,389 matched D150 and VKA patients, mean age 67, 67% male, 65% with CHA2 DS2 -VASC >/= 2; 3, incidence rates were for SSE 1.4% and 1.9% (0.76 [0.56-1.04]), MB 0.6 % and 1.9% (0.30 [0.20-0.46]), death 1.6% and 3.6% (0.46 [0.35-0.59]). Numbers needed to treat to observe one fewer death were 78 for D110, 88 for D150 CONCLUSION: In real life D110 and D150 were at least as effective and safer than VKA

Am J Cardiovasc Drugs

Background Clinical trials have indicated that the direct-acting oral anticoagulants dabigatran and rivaroxaban have better risk/benefit profiles than do vitamin K antagonists (VKAs) for stroke prevention in non-valvular atrial fibrillation (NVAF). Objective Our objective was to compare the 1-year real-life risk of major clinical events with dabigatran or rivaroxaban versus VKAs for NVAF. Methods This was a high-dimensional propensity score (hdPS)-matched cohort study of new users of dabigatran, rivaroxaban or VKAs for NVAF in the French national healthcare systems database in 2013 followed-up for 1 year [22]. Hazard ratios (HRs) with 95% confidence intervals (CIs) for clinical events and death were determined during exposure. Results In 2013, a total of 103,101 new anticoagulant users had definite NVAF: 44,653 VKA, 27,060 dabigatran, and 31,388 rivaroxaban. In matched populations, HRs were as follows for dabigatran versus VKAs (20,489 per group): stroke and systemic embolism (SSE) 0.75 (95% CI 0.63–0.88), clinically relevant bleeding (CRB) 0.58 (95% CI 0.51–0.66), hemorrhagic stroke (HS) 0.22 (95% CI 0.14–0.36), gastrointestinal bleeding (GIB) 0.98 (95% CI 0.80–1.19), acute coronary syndrome (ACS) 0.79 (95% CI 0.65–0.95), death 0.74 (95% CI 0.67–0.82), composite (any of the above) 0.71 (95% CI 0.66–0.76). For matched rivaroxaban versus VKA (23,053 per group) HRs were as follows: SSE 0.98 (95% CI 0.85–1.14), CRB 0.83 (95% CI 0.75–0.92), HS 0.65 (95% CI 0.49–0.87), GIB 1.08 (95% CI 0.90–1.30), ACS 0.84 (95% CI 0.71–1.00), death 0.77 (95% CI 0.71–0.84), composite 0.84 (95% CI 0.79–0.89). Numbers needed to treat to observe one fewer death were 49 ± 0.05 with dabigatran or rivaroxaban versus VKAs. Conclusion Consistent with results from clinical trials and other observational studies, dabigatran and rivaroxaban were at least as effective and safer than VKAs for the prevention of thromboembolic events in NVAF over 1 year in the French population

Clin Pharmacol Ther

Dabigatran and rivaroxaban at standard (SD) or reduced doses (RD) have been compared to warfarin in non-valvular atrial fibrillation (NVAF), but not to each other. This was a new user study of SD and RD dabigatran or rivaroxaban for NVAF in the French healthcare database, matched on gender, age, date of first dispensing, and high-dimensional propensity score, followed 2 years. Hazard ratios [95% Confidence Intervals] of stroke or systemic embolism (SSE), major bleeding (MB) or death, were computed. In matched SD patients (8,290 per arm), mean age 67, HR for dabigatran vs. rivaroxaban were SSE 0.92 [0.67-1.26], MB 0.59 [0.39-0.90], death 0.84 [0.65-1.11]. In RD patients (7639 per arm), mean age 80, HR for dabigatran vs. rivaroxaban were SSE 0.73 [0.59-0.94], MB 0.74 [0.57-0.96], death 0.95 [0.83-1.09]. In conclusion, at either dose dabigatran had similar or better effectiveness than rivaroxaban, but lower bleeding risk. Death rates were not different. This article is protected by copyright. All rights reserved

Europace

Aims The real-life benefits and risks of the non-vitamin K antagonist oral anticoagulants for stroke prevention in very elderly patients with atrial fibrillation (AF) are still debated. Methods and results Cohorts of new users of rivaroxaban 15 mg, dabigatran 110 mg, or vitamin K antagonists (VKA) for AF ≥85 years old in 2013 or 2014 were identified in the nationwide French claims database and followed-up for 1 year. Cohorts were compared after 1:1 matching using high-dimensional propensity score. Compared to VKA use and considering 1-year cumulative incidences, risk of stroke, and systemic embolism was not different with rivaroxaban use [hazard ratio 1.14, 95% confidence interval (CI): 0.93–1.40] and lower with dabigatran use (0.77, 95% CI: 0.60–0.99), risk of major bleeding was not different with rivaroxaban use (0.91, 95% CI: 0.74–1.11) and with dabigatran use (0.81, 95% CI: 0.64–1.03), risk of all-cause death was borderline to significance lower with rivaroxaban use (0.91, 95% CI: 0.83–1.00), and lower with dabigatran use (0.87, 95% CI: 0.78–0.97). The risk for a composite of all events above was not different with rivaroxaban use (0.96, 95% CI: 0.88–1.04) and lower with dabigatran use (0.87, 95% CI: 0.79–0.96) as compared with VKA use. The risk for the composite of all events was not different with rivaroxaban use as compared with dabigatran use (1.09, 95% CI: 0.97–1.23). Conclusion This study shows for the first time in more than 25 000 new real-life anticoagulant users for AF aged ≥85 years a neutral overall benefit-risk of rivaroxaban 15 mg vs. VKA and a favourable overall benefit-risk of dabigatran 110 mg vs. VKA on relevant clinical events

Eur Arch Psychiatry Clin Neurosci

Benzodiazepines and z-drugs are primarily indicated for the treatment of sleep disorders and anxiety symptoms. Their frequent long-term use contrasts with the international guidelines that limit treatment duration to a maximum of 4 weeks. The objective of this study was to assess the frequency of their use that was not in accordance with guidelines in the French general population between 2007 and 2012 and associated characteristics. A cohort of 67,550 benzodiazepine new users was set up in an exhaustive database for health-care reimbursements and representative of the French population. Benzodiazepine use not in accordance with guidelines was defined as the concomitant dispensation of several benzodiazepines, the dispensation of treatment over a period longer than recommended, or a new dispensing within the 2 months following the end of a previous treatment of maximum recommended duration, considering that French recommendations distinguish between hypnotic (4 weeks) and anxiolytic benzodiazepines (12 weeks). Benzodiazepine use not in accordance with guidelines was high, in about 30% of new hypnotic users and 20% of new anxiolytic users. Its frequency was stable over the study period. Associated characteristics were similar for new hypnotic or anxiolytic users, i.e.. older age, treatment initiation by a psychiatrist, presence of a chronic disease, hospitalization, or another psychotropic treatment. These findings provide a solid basis for establishing a public health policy to reduce benzodiazepine use not compliant with guidelines. They should be further explored in patients most at risk in the present study, e.g., patients treated by a psychiatrist