Biases in reporting of adverse effects in clinical trials, and potential impact on safety assessments in systematic reviews and therapy guidelines.

BACKGROUND: Clinical trials are an important source of adverse effects data, including analyses in systematic reviews and recommendations in therapy guidelines. Trial publication bias may have profound effects on safety perceptions. This MiniReview presents and discusses biases in reporting of safety data in clinical trials and the implications for systematic reviews and guidelines. OBJECTIVES: The objectives of this work are to analyse risk of gastrointestinal bleeding in systemic corticosteroid trials and to assess adverse effects reporting in a fluoxetine trial in depression (Treatment for Adolescents With Depression Study [TADS]) and descriptions of adverse effects in adolescent depression therapy guidelines. METHODS: We performed literature reviews and descriptive analyse of clinical trials with corticosteroids, and publications from the TADS trial. Risk of gastrointestinal bleeding from corticosteroids was analysed by meta-analysis. FINDINGS: Gastrointestinal bleeding definitions varied considerably between trials. The incidence was significantly increased in hospitalized, but not in ambulant, patients compared to placebo. We identified several biases concerning TADS safety reporting, including severity thresholds and nonpublication of most adverse effects data beyond the initial 12 weeks. Therapy guidelines on adolescent depression mentioned suicidality risk, but many failed to mention other adverse effects. CONCLUSIONS: We identified several pitfalls in adverse effects reporting in clinical trials. These include heterogeneous disease definitions, reporting thresholds, and incomplete reporting. Trial bias may have great impact on risk assessments in systematic reviews and meta-analyses.

Adverse effects information in clinical guidelines on pharmacological treatment of depression in children and adolescents: a systematic review.

OBJECTIVES: To analyse to what extent clinical practice guidelines on drug treatment of depression in children and adolescents mention the risk of adverse effects, to characterise the citations in the guidelines and to assess to what extent data from a major study (Treatment for Adolescents With Depression Study, TADS) was used as basis for information about adverse effects. DESIGN: Systematic review of clinical guidelines and clinical decision support tools. DATA SOURCES: PubMed, EMBASE, guideline collections, Health libraries. ELIGIBILITY CRITERIA: We included national guidelines on depression in children and adolescents from European and/or English-speaking countries, published in English, German, French or any Scandinavian language since 2008. We also included well-known, international clinical decision support tools. DATA EXTRACTION AND SYNTHESIS: Guidelines were examined by all authors to identify and classify information on adverse effects. Citations for statements on adverse effects were extracted and classified by category. The extent of citations about suicidality risk versus other adverse effects was assessed. RESULTS: 19 guidelines were assessed. All guidelines discussed risk of suicidal behaviour connected with use of antidepressants. Most guidelines mentioned some other psychiatric adverse effects. Several guidelines did not include information on well-known and common somatic adverse effects. Most references concerned risk of suicidality. Adverse effects identified in underlying studies were not always presented. The TADS study was referred to, directly or indirectly, by 18/19 guidelines, but some only referred to TADS with regard to suicidality without citing the study's findings of somatic adverse effects. No guideline commented on the lack of long-term adverse effects data from TADS. CONCLUSIONS: Guidelines for treatment of depression in children and adolescents vary widely regarding information on adverse effects. Many guidelines do not provide information on common somatic adverse effects. There is no consensus as to what extent risks of adverse effects connected with use of antidepressants should be described in guidelines.

Critical appraisal of adverse effects reporting in the 'Treatment for Adolescents With Depression Study (TADS)'.

OBJECTIVE: To identify all publications from the 'Treatment for Adolescents With Depression Study (TADS)' and assess the findings regarding occurrence of any adverse effects in the treatment groups both for the short-term and long-term study stages. DESIGN: Descriptive analysis of TADS publications with any information on adverse effects. RESULTS: We identified 48 publications describing various aspects of the TADS, in which 439 adolescent patients received treatment with fluoxetine, cognitive-behavioural therapy, cognitive-behavioural therapy plus fluoxetine or placebo. Eight publications were assessed as providing some data on adverse effects. Risk of suicidal behaviour was the only adverse effect that was addressed in all publications. Several psychiatric and physical adverse effects were reported during the first 12 weeks, but not mentioned in reports from later study stages. Common adverse effects of fluoxetine, such as weight changes or sexual problems, were not identified or mentioned in the publications. CONCLUSIONS: The TADS publications do not present a comprehensive assessment of treatment risk with fluoxetine in adolescents, especially for more than 12 weeks of treatment. Risk of suicidality was the only adverse effect that was reported over time. Reporting of adverse effects was incomplete with regard to the long-term safety profile of fluoxetine.

Characterization of gastrointestinal adverse effects reported in clinical studies of corticosteroid therapy.

OBJECTIVES: To examine whether 159 studies included in a previous meta-analysis reported on gastrointestinal bleeding or perforation in accordance with the CONSORT extension for reporting harms outcomes (CONSORT Harms recommendations checklist); whether differences were associated with funding source, journal, or publication year; and whether the CONSORT Harms checklist is a suitable tool for evaluation of adverse effects reporting. STUDY DESIGN AND SETTING: Articles were assessed for fulfillment of the CONSORT Harms recommendations, funding source, publication type, and year. Agreement between reviewers was assessed by comparing scores for each study. RESULTS: The mean CONSORT Harms score was 5.25 out of 10 (standard deviation ± 2.09). Most studies included information on participant withdrawals (133 studies, 83.6%), absolute risk of gastrointestinal bleeding or perforation (130 studies, 81.8%), and how harms-related information was collected (118 studies, 74.2%). Reporting of gastrointestinal bleeding or perforation increased with higher scores (odds ratio 1.173, P = 0.042). There was no significant association between CONSORT Harms score achieved and publication year or funding source, but there was a trend toward higher scores in studies published in the major medical journals (score difference 0.78, P = 0.052). Definitions of gastrointestinal bleeding differed between studies. Reviewer agreement was fair to moderate with large variations. CONCLUSION: Few studies in the systematic review received high scores using the CONSORT Harms criteria. Most studies reported on the most important criteria regarding risk of gastrointestinal bleeding or perforation. Reviewer agreement showed large variations due to imprecise texts and ambiguous criteria. Routine scoring according to fulfillment of the CONSORT Harms recommendations would be inadvisable without qualified judgment.

Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis.

OBJECTIVE: To assess whether corticosteroids are associated with increased risk of gastrointestinal bleeding or perforation. DESIGN: Systematic review and meta-analysis of randomised, double-blind, controlled trials comparing a corticosteroid to placebo for any medical condition or in healthy participants. Studies with steroids given either locally, as a single dose, or in crossover studies were excluded. DATA SOURCES: Literature search using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews between 1983 and 22 May 2013. OUTCOME MEASURE: Outcome measures were the occurrence of gastrointestinal bleeding or perforation. Predefined subgroup analyses were carried out for disease severity, use of non-steroidal anti-inflammatory drugs (NSAIDs) or gastroprotective drugs, and history of peptic ulcer. RESULTS: 159 studies (N=33 253) were included. In total, 804 (2.4%) patients had a gastrointestinal bleeding or perforation (2.9% and 2.0% for corticosteroids and placebo). Corticosteroids increased the risk of gastrointestinal bleeding or perforation by 40% (OR 1.43, 95% CI 1.22 to 1.66). The risk was increased for hospitalised patients (OR 1.42, 95% CI 1.22 to 1.66). For patients in ambulatory care, the increased risk was not statistically significant (OR 1.63, 95% CI 0.42 to 6.34). Only 11 gastrointestinal bleeds or perforations occurred among 8651 patients in ambulatory care (0.13%). Increased risk was still present in subgroup analyses (studies with NSAID use excluded; OR 1.44, 95% CI 1.20 to 1.71, peptic ulcer as an exclusion criterion excluded; OR 1.47, 95% CI 1.21 to 1.78, and use of gastroprotective drugs excluded; OR 1.42, 95% CI 1.21 to 1.67). CONCLUSIONS: Corticosteroid use was associated with increased risk of gastrointestinal bleeding and perforation. The increased risk was statistically significant for hospitalised patients only. For patients in ambulatory care, the total occurrence of bleeding or perforation was very low, and the increased risk was not statistically significant.

Probable topiramate-induced diarrhea in a 2-month-old breast-fed child - A case report.

An infant developed a severe condition of recurrent and persistent watery diarrhea at 40 days of age. The child had been partially breast-fed, and the mother used topiramate for epilepsy. Hospital examination excluded a viral or bacterial infection and failed to identify any other potential cause. After two weeks, topiramate exposure was suspected to be the cause, and breast-feeding was suspended. The diarrhea ceased within 2 days. Analysis of the breast milk showed a topiramate concentration of 15.7 µmol/L (5.3 µg/mL). There is little information on the use of topiramate in breast-feeding women. The potential effects on the children are not known. Topiramate passes into breast milk, and the concentration may equal the therapeutic plasma concentration. In this case, the infant may have ingested up to 40% of the mother's weight-adjusted dose. Diarrhea is a well-known adverse reaction to topiramate and has the potential to cause serious electrolyte disturbances in neonates and infants. The condition improved rapidly after suspension of breast-feeding. Topiramate in breast milk may reach levels that cause adverse effects in infants. Based on the adverse reaction profile of topiramate and the milk concentration, the diarrhea was assessed as a probable adverse drug reaction in the infant.

A question-answer pair (QAP) database integrated with websites to answer complex questions submitted to the Regional Medicines Information and Pharmacovigilance Centres in Norway (RELIS): a descriptive study.

OBJECTIVE: To assess a question-answer pair (QAP) database integrated with websites developed for drug information centres to answer complex questions effectively. DESIGN: Descriptive study with comparison of two subsequent 6-year periods (1995-2000 and 2001-2006). SETTING: The Regional Medicines Information and Pharmacovigilance Centres in Norway (RELIS). PARTICIPANTS: A randomised sample of QAPs from the RELIS database. PRIMARY OUTCOME MEASURE: Answer time in days compared with Mann-Whitney U test. SECONDARY OUTCOME MEASURE: Number of drugs involved (one, two, three or more), complexity (judgemental and/or patient-related or not) and literature search (none, simple or advanced) compared with χ(2) tests. RESULTS: 842 QAPs (312 from 1995 to 2000 and 530 from 2001 to 2006) were compared. The fraction of judgemental and patient-related questions increased (66%-75% and 54%-72%, respectively, p<0.01). Number of drugs and literature search (>50% advanced) was similar in the two periods, but the fraction of answers referring to the RELIS database increased (13%-31%, p<0.01). Median answer time was reduced from 2 days to 1 (p<0.01), although the fraction of complex questions increased from the first to the second period. Furthermore, the mean number of questions per employee per year increased from 66 to 89 from the first to the second period. CONCLUSIONS: The authors conclude that RELIS has a potential to efficiently answer complex questions. The model is of relevance for organisation of drug information centres.

[Post-exposure varicella prophylaxis]. / Profylaktisk behandling etter varicellaeksponering.

BACKGROUND: Varicella may have a serious and sometimes fatal course, especially in immunocompromised patients. Some patient groups may need prophylaxis after exposure to the varicella-zoster-virus. In this article we review the evidence for usefulness of prophylactic measures after such exposure. MATERIAL AND METHODS: The article is based on a non-systematic literature search in Medline, the Cochrane Library, UpToDate and Clinical Evidence. RESULTS: The effect of post-exposure varicella prophylaxis on disease rate and severity of varicella is only weakly documented. There is some evidence that passive immunisation with varicella-zoster immunoglobulin (VZIG) reduces the risk of serious disease when it is administered within 72-96 hours after exposure. Several studies of mostly healthy children have shown that prophylactic acyclovir is better than control treatment, but the studies are small and they are not properly designed. Post-exposure vaccination is shown to reduce disease rate and severity in otherwise healthy children. INTERPRETATION: We believe that acyclovir or valacyclovir can be used as post-exposure varicella prophylaxis in risk patients for whom the time window for VZIG-use has expired.

Dosage and formulation issues: oral vitamin E therapy in children.

PURPOSE: Oral vitamin E is used in several childhood diseases, but dosage recommendations differ. Few oral products have a marketing authorization for therapeutic use in children. Preliminary data indicate differences in bioavailability among the various vitamin E compounds. Our objective was to review published data on oral vitamin E therapy in neonates and children in order to establish dosage recommendations at a local level. METHODS: A literature search was conducted, including Medline Ovid, EMBASE (1980-Feb 2008), Cochrane databases, product monographs, handbooks, and textbooks. RESULTS: The main vitamin E compounds being used in children are alpha-tocopherol, alpha-tocopheryl acetate, and tocofersolan. The most data are available on tocopheryl acetate, both in neonates and older children. In children with malabsorption disorders, tocofersolan appears to have an increased bioavailability compared to tocopherol or tocopheryl acetate. Published data on pharmacokinetics and dosages for clinical use are few and heterogeneous. No pharmacokinetic studies were found for tocofersolan in neonates and infants. There are few comparative studies on pharmacokinetics, therapeutic use, and adverse drug reactions (ADRs) in children. Dosages used in clinical studies and dosage recommendations in handbooks differ considerably. CONCLUSIONS: The differences in dosing recommendations in children may be due to lack of systematic studies. Existing published data on oral vitamin E do not provide a basis for evaluation of dosage recommendations in children. Comparative clinical studies are required for scientific evaluation of pharmacokinetics, dosage regimens, and efficacy/ADR assessments in children.

Probable warfarin-simvastatin interaction.

OBJECTIVE: To report and discuss a case of fatal cerebral hemorrhage following a switch from atorvastatin to simvastatin in a patient taking warfarin. CASE SUMMARY: An 82-year-old white female was admitted to the hospital because of an international normalized ratio (INR) value greater than 8, which was detected at a routine follow-up visit to monitor warfarin therapy. Four weeks earlier her lipid-lowering therapy had been switched from atorvastatin 10 mg daily to simvastatin 10 mg daily. She had been treated with 2.5 mg of warfarin daily for almost 30 years due to episodes of deep venous thrombosis and lung embolism. Her INR had been stable within the treatment range (2.0-3.5) for more than 2 years before the INR increase. Upon hospitalization, she was given 5 mg of vitamin K orally. A few hours later she lost the feeling and movement of her right arm and a computed tomography scan showed major bleeding in the left cerebral hemisphere. She died the following day. DISCUSSION: One study has shown a lack of interaction between warfarin and atorvastatin. In comparison, 3 studies have shown significant increases (10-30%) in warfarin effect and/or reductions in dose requirement after starting concomitant simvastatin treatment. The interaction mechanism between simvastatin and warfarin is not known but is possibly associated with reduced elimination of warfarin. Use of the Naranjo probability scale showed that the likelihood of warfarin-induced INR increase following the switch to simvastatin was probable. CONCLUSIONS: Atorvastatin and simvastatin appear to differ in their potential to interact with warfarin. Clinicians should be aware of the interaction risk when starting simvastatin treatment in patients on warfarin therapy.

[Interaction risk with statin switch]. / Interaksjonsrisiko ved statinbytte.

BACKGROUND: The article is based upon two adverse drug reaction reports after switch from atorvastatin to simvastatin. Simvastatin interactions with warfarin and the cytochrome P450-3A4 inhibitor diltiazem were suspected as possible causes of the events (fatal intracranial haemorrhage with INR > 8 and myopathy). Relevant literature was examined to evaluate potential differences in atorvastatin and simvastatin interaction profiles. MATERIAL AND METHODS: Relevant interaction studies were identified through searches in the databases PubMed and ISI Web of Knowledge. Interaction databases referring to primary sources and product monographs were also examined. RESULTS: One interaction study was found for the warfarin-atorvastatin combination, but this showed no relevant changes in prothrombin time. Three interaction studies were identified for the combination warfarin-simvastatin and these showed consistently increased INR and/or reduced dose requirements for warfarin (10-30%) after starting treatment with simvastatin. Three studies had investigated the degree to which simvastatin and atorvastatin interact with a CYP3A4 inhibitor in the same population. In these studies, plasma concentrations of both statins increased, but the increases were several times greater for simvastatin than for atorvastatin. INTERPRETATION: Interaction studies show that atorvastatin and simvastatin display differences in interaction potential toward warfarin and drugs inhibiting CYP3A4 metabolism. It is important to consider the risk of interactions when switching to or starting simvastatin treatment.

[Vitamin E mixture for children--treatment with a blindfold?]. / Vitamin E-mikstur til barn--behandling i blinde?

BACKGROUND: Vitamin E is used in children with different diagnoses and conditions, including premature babies and infants. In Norway, there is no licensed vitamin E formulation designed for children. Consequently, extemporaneous production is carried out in pharmacies. Two formulation recipes are available, one for veterinary use and one intended for premature infants. MATERIAL AND METHODS: A questionnaire was sent to all Norwegian hospital pharmacies to examine what type of oral vitamin E drops that had been produced or procured after 1 January 2003. RESULTS: 27 (90%) of 30 hospital pharmacies replied. 18 (66.6%) had produced or procured vitamin E drops. 11 (40.7%) had produced or procured a product similar to Vitamin E 50 mg/ml drops for veterinary use. Nine (33.3 %) had produced or procured a product similar to the product called Vitamin E 50 IE/ml drops for premature infants. INTERPRETATION: Data on the various vitamin E formulations, concentrations, optimal dosing and toxicity lack consistency. Lack of data may cause sub-optimal treatment, adverse reactions, or overdosing.

[Paracetamol to preschool children--indications and cultural background]. / Paracetamol til førskolebarn--indikasjoner og kulturbakgrunn.

BACKGROUND: Immigrants may have a different attitude to the use of paracetamol (acetaminophen) than parents of western European or North American origin. The aim of this study was to examine under what conditions parents find treatment with paracetamol appropriate. MATERIAL AND METHOD: Parents at six public health centres were asked to select one or more among 26 indications for paracetamol treatment and to state the body temperature at which fever medication should be used. The indications were independently evaluated as appropriate, uncertain or inappropriate by the staff of the public health centres. RESULTS: 1563 (99%) parents participated in the study. 79% chose a fever threshold of 39 degrees C or above as appropriate for treatment with paracetamol. Fever, earache, influenza and headache were frequently chosen as appropriate indications by both parents and staff. On average, parents from non-western countries more frequently chose indications considered by the staff as uncertain or inappropriate and seemed to use paracetamol more frequently (odds ratio 2.35; 95% CI 1.26-4.40) and in larger doses than other parents did. INTERPRETATION: This study indicates that parents from non-western countries use paracetamol for their children on wider indications, to more of their children, and in larger doses than other parents do.

[The use of paracetamol and antibiotics among preschool children]. / Bruk av paracetamol og antibiotika blant førskolebarn.

BACKGROUND: Sales of paracetamol in paediatric formulations are increasing and antibiotics are frequently prescribed to children. Our aim was to study the use of paracetamol and antibiotics in different age groups among preschool children. MATERIAL AND METHODS: Parents of 1312 children (99% response rate) visiting public health centres were asked to state how often their child had been sick, used paracetamol, seen a doctor, or used antibiotics during the previous three months. If the child had used antibiotics, parents were asked to give the reason for treatment, the name of the drug used, and the duration of treatment. RESULTS: 71% of the children had been sick, 46% had received paracetamol, 36% had seen a doctor, and 12% had used antibiotics. The highest frequency of illness and paracetamol use was seen among children one to two years of age. Otitis was the main reason for using antibiotics in children of one to four years of age, and the duration of treatment was often longer than recommended. INTERPRETATION: Use of paracetamol is widespread among preschool children. Parents going back to work after maternity leave and more frequent fever resulting from exposure to infections may contribute to an increased use of paracetamol. Restrictive use of antibiotics for otitis and shorter treatment duration continue to be emphasised.