Efficacy and Safety of Infliximab in Pediatric Crohn Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Crohn disease is an inflammatory bowel disease with intermittent symptoms relating to damage to the gastrointestinal tract. Compared with adult-onset Crohn disease, the childhood-onset form is more likely to be severe. Infliximab has shown efficacy in adult patients. OBJECTIVE: To examine the efficacy and safety of infliximab in pediatric Crohn disease, by means of a systematic review. DATA SOURCES: Three databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials) and regulatory documents were searched from inception to December 2017. Clinical trial registries, conference abstracts, and reference lists were searched to March 2018. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials (RCTs) and prospective cohort studies that compared infliximab with active control were included in the analysis. Two reviewers independently performed screening, extracted data, and assessed risk of bias. The primary outcomes were induction and maintenance of endoscopic remission and severe adverse effects. DATA SYNTHESIS: Three eligible RCTs comparing different dose regimens, 16 prospective cohort studies comparing infliximab with other therapies (adalimumab, exclusive enteral nutrition, or standard of care), and 3 prospective cohort studies comparing different infliximab regimens were identified. Meta-analysis of the RCTs showed no significant difference between infliximab every 8 weeks compared with longer intervals for maintenance of clinical remission (risk ratio [RR] 1.76, 95% confidence interval [CI] 0.98-3.19). Meta-analyses of the prospective cohort studies showed no significant differences between infliximab and adalimumab for maintenance of endoscopic remission (RR 1.07, 95% CI 0.60-1.92), between infliximab and exclusive enteral nutrition for induction of clinical remission (RR 1.09, 95% CI 0.82-1.45), or between infliximab and standard of care for maintenance of clinical remission at 6 and 12 months (RR 1.12, 95% CI 0.58-2.17, and RR 1.24, 95% CI 0.84-1.84, respectively). CONCLUSIONS: Current evidence suggested comparable efficacy for infliximab and other therapies; however, the available literature was limited by risk of bias and small sample size. Further prospective studies are needed to confirm the efficacy and safety of this drug in pediatric Crohn disease.

CONTEXTE: La maladie de Crohn est une maladie inflammatoire de l'intestin, dont les symptômes intermittents sont liés à des lésions du tractus gastro-intestinal. Comparativement à la maladie de Crohn se déclarant à l'âge adulte, celle qui se déclare dans l'enfance risque d'être plus grave. L'infliximab s'est avéré efficace chez l'adulte. OBJECTIF: Étudier l'efficacité et l'innocuité de l'infliximab chez l'enfant atteint de la maladie de Crohn à l'aide d'une analyse systématique. SOURCES DES DONNÉES: Trois bases de données (MEDLINE, Embase, ainsi que le Registre central Cochrane des essais comparatifs) ont été interrogées et des documents réglementaires ont fait l'objet d'une recherche depuis leur création jusqu'en décembre 2017. Une consultation des registres d'essais cliniques, des résumés de conférences et des listes de références a eu lieu jusqu'en mars 2018. SÉLECTION DES ÉTUDES ET EXTRACTION DES DONNÉES: L'analyse a porté sur des essais cliniques à répartition aléatoire (ECRA) et des études de cohorte prospectives comparant l'infliximab au traitement actif. Deux examinateurs indépendants ont procédé à la sélection et à l'extraction des données ainsi qu'à l'évaluation des risques de biais. L'induction et le maintien d'une rémission endoscopique ainsi que les effets indésirables graves étaient les principaux paramètres d'évaluation. SYNTHÈSE DES DONNÉES: Trois ECRA admissibles comparant différents schémas posologiques, 16 études de cohorte prospectives comparant l'infliximab à d'autres traitements (l'adalimumab, une alimentation exclusivement entérale et les soins d'usage) et trois études de cohorte prospectives comparant différents schémas posologiques d'infliximab ont été sélectionnées. Une méta-analyse des ECRA ne montrait aucune différence significative entre un traitement à l'infliximab toutes les huit semaines comparativement à des intervalles plus longs pour le maintien d'une rémission clinique (risque relatif [RR] de 1,76, intervalle de confiance [IC] à 95 % de 0,98­3,19). Des méta-analyses des études de cohorte prospectives ne montraient aucune différence significative entre l'infliximab et l'adalimumab pour le maintien d'une rémission endoscopique (RR de 1,07, IC à 95 % de 0,60­1,92), aucune différence non plus entre l'infliximab et une alimentation exclusivement entérale pour l'induction d'une rémission clinique (RR de 1,09, IC à 95 % de 0,82­1,45) ni entre l'infliximab et les soins d'usage pour le maintien d'une rémission clinique à six et douze mois (respectivement : RR de 1,12, IC à 95 % de 0,58­2,17 et RR de 1,24, IC à 95 % de 0,84­1,84). CONCLUSIONS: Les données probantes actuelles laissaient entendre que l'efficacité de l'infliximab était comparable à celle des autres traitements; cependant, les articles disponibles étaient insuffisants en raison du risque de biais et de la faible taille de l'échantillon. De plus amples études prospectives sont nécessaires pour confirmer l'efficacité et l'innocuité de ce médicament chez l'enfant atteint de la maladie de Crohn.

Asenapine for the Treatment of Psychotic Disorders.

OBJECTIVE: A systematic review was conducted to examine the efficacy, tolerability, and acceptability of asenapine compared with other antipsychotics in the treatment of psychotic disorders. METHODS: Four databases, 8 trial registries, and conference presentations were searched for randomized clinical trials of asenapine versus any comparator for the treatment of any psychotic illness. Primary outcome measures were changes in the Positive and Negative Syndrome Scale (PANSS) total score and the incidence of withdrawal due to adverse effects. RESULTS: Eight randomized clinical trials, encompassing 3765 patients, that compared asenapine with placebo ( n = 5) and olanzapine ( n = 3) were included. No differences were found between asenapine and olanzapine in terms of changes to PANSS total or PANSS negative subscale scores. Patients taking asenapine were more likely to experience worsening schizophrenia and/or psychosis than were those taking olanzapine. No differences were found between asenapine and olanzapine in rates of discontinuation due to adverse drug reactions or lack of efficacy, but those taking asenapine had higher rates of withdrawal for any reason than those taking olanzapine. Asenapine caused less clinically significant weight gain or increases in triglycerides than olanzapine and was more likely to cause extrapyramidal symptoms than olanzapine. In comparison to placebo, either no difference or superiority was demonstrated in favour of asenapine on all efficacy measures. CONCLUSION: The current evidence is limited, as asenapine has been compared only with placebo or olanzapine. In the randomized clinical trials analysed, asenapine was similar or superior to placebo and similar or inferior to olanzapine on most efficacy outcomes. While asenapine demonstrated fewer adverse metabolic outcomes than olanzapine, rates of extrapyramidal symptom-related adverse effects were higher.

Prevention of necrotizing enterocolitis with probiotics: a systematic review and meta-analysis.

CONTEXT: Necrotizing enterocolitis (NEC) is the most frequent gastrointestinal emergency in neonates. The microbiome of the preterm gut may regulate the integrity of the intestinal mucosa. Probiotics may positively contribute to mucosal integrity, potentially reducing the risk of NEC in neonates. OBJECTIVE: To perform an updated systematic review and meta-analysis on the efficacy and safety of probiotics for the prevention of NEC in premature infants. DATA SOURCES: Structured searches were performed in: Medline, Embase, and the Cochrane Central Register of Controlled Trials (all via Ovid, from 2013 to January 2015). Clinical trial registries and electronically available conference materials were also searched. An updated search was conducted June 3, 2016. STUDY SELECTION: Randomized trials including infants less than 37 weeks gestational age or less than 2,500 g on probiotic vs. standard therapy. DATA EXTRACTION: Data extraction of the newly-identified trials with a double check of the previously-identified trials was performed using a standardized data collection tool. RESULTS: Thirteen additional trials (n = 5,033) were found. The incidence of severe NEC (RR 0.53 95% CI [0.42-0.66]) and all-cause mortality (RR 0.79 95% CI [0.68-0.93]) were reduced. No difference was shown in culture-proven sepsis RR 0.88 95% CI [0.77-1.00]. LIMITATIONS: Heterogeneity of organisms and dosing regimens studied prevent a species-specific treatment recommendation from being made. CONCLUSIONS: Preterm infants benefit from probiotics to prevent severe NEC and death.

Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study.

Current guidelines for heparin-induced thrombocytopenia (HIT) management recommend heparin cessation and switching to a nonheparin anticoagulant (ie, argatroban, danaparoid) upon clinical suspicion. Fondaparinux may be effective but information supporting its use is limited. We retrospectively evaluated 239 patients who received a nonheparin anticoagulant (fondaparinux = 133, danaparoid = 59, and argatroban = 47) for suspected or confirmed HIT. A propensity score was constructed based on age, gender, creatinine, 4T scores, and comorbidity index, and used to match 133 patients to 60 controls. Outcomes were thrombosis or thrombosis-related death and major bleeding. In the matched population there were 22 (16.5%) episodes of thromboses in the fondaparinux group and 13 (21.4%) in the control group (χ(2) P = .424). Bleeding was observed in 28 (21.1%) patients in the fondaparinux group compared with 12 (20%) in the control group (χ(2) P = .867). Survival analysis, and subgroup and unmatched analyses showed similar results. In the fondaparinux group, 60% of patients received prophylactic doses. Fondaparinux has similar effectiveness and safety as argatroban and danaparoid in patients with suspected HIT. Prophylactic fondaparinux doses seem to be effective if no indication for full anticoagulation exists.

Lacosamide adjunctive therapy for partial-onset seizures: a meta-analysis.

Background. The relative efficacy and safety of lacosamide as adjunctive therapy compared to other antiepileptic drugs has not been well established. Objective. To determine if lacosamide provides improved efficacy and safety, reduced length of hospital stay and improved quality of life compared with other anti-epileptic therapies for adults with partial-onset seizures. Data Sources. A systematic review of the medical literature using Medline (1946-Week 4, 2012), EMBASE (1980-Week 3, 2012), Cochrane Central Register of Controlled Trials (Issue 1 of 12, January 2012). Additional studies were identified (through to February 7, 2012) by searching bibliographies, the FDA drug approval files, clinical trial registries and major national and international neurology meeting abstracts. No restrictions on publication status or language were applied. Study Selection. Randomized controlled trials of lacosamide in adults with partial-onset seizures were included. Data Extraction. Study selection, extraction and risk of bias assessment were performed independently by two authors. Authors of studies were contacted for missing data. Data Synthesis. All pooled analyses used the random effects model. Results. Three trials (1311 patients) met inclusion criteria. Lacosamide increased the 50% responder rate compared to placebo (RR 1.68 [95% CI 1.36 to 2.08]; I(2) = 0%). Discontinuation due to adverse events was statistically significantly higher in the lacosamide arm (RR3.13 [95% CI 1.94 to 5.06]; I(2) = 0%). Individual adverse events (ataxia, dizziness, fatigue, and nausea) were also significantly higher in the lacosamide group. Limitations. All dosage arms from the included studies were pooled to make a single pair-wise comparison to placebo. Selective reporting of outcomes was found in all of the included RCTs. Conclusions. Lacosamide as adjunctive therapy in patients with partial-onset seizures increases the 50% responder rate but with significantly more adverse events compared to the placebo.

Mega-dose intravenous octreotide for the treatment of carcinoid crisis: a systematic review.

PURPOSE: Carcinoid crises are rare life-threatening events involving cardiac instability when carcinoid tumours release vasoactive peptides. Such events can occur in the perioperative setting. Octreotide, a somatostatin analogue, is administered as a bolus dose of 100-500 µg iv or by infusion to treat carcinoid crises. Due to the apparent low risk-to-benefit profile, a much higher dose is sometimes used in urgent situations. The purpose of this study was to assess the evidence for administering doses or hourly infusions of octreotide that exceeded 1,500 µg iv to treat carcinoid crises. We also sought to identify which patients may require large doses and to describe the adverse effects of such doses. SOURCE: We systematically searched Medline, EMBASE, and Cochrane databases and hand-searched reference lists of relevant articles in 2006 and again in 2010 and 2011. All study designs were included in our search. Resolution of crisis symptoms was the primary outcome. PRINCIPAL FINDINGS: Eighteen articles were included. No patient died during a carcinoid crisis. A retrospective chart review of 89 patients with carcinoid heart disease reported octreotide doses of 25-54,000 µg to treat carcinoid crises, although neither crisis symptoms nor outcomes were described. CONCLUSION: In the included case reports, carcinoid crises were managed effectively using octreotide 25-500 µg iv. Previous exposure to octreotide and carcinoid heart disease may warrant the need for higher doses. In addition to the low quality of the articles and the small sample size, inconsistent use of the term "carcinoid crisis" and paucity of reported outcomes were also limitations of this systematic review. These findings highlight the need for further investigation into dose-response relationships of octreotide for the treatment of carcinoid crisis.