Z-drugs and risk of falls and fractures: A systematic review and metaanalysis

Transcription

1 Originally submitted to academic advisory board: February 2015 Revised: September 2017 Z-drugs and risk of falls and fractures: A systematic review and metaanalysis - Protocol Nir Treves, Amichai Perlman, Lital Kolenberg Geron, Angham asaly, Ilan Matok Objectives: To analyze the risk of falls and of fractures during treatment with Z-drugs. Search methods: We plan to search the "Embase", "PubMed" and "clinicaltrials.gov" databases according to pre-selected key words. Key words: Benzodiazepines (BZ) (See Appendix 1), hypnotic agent, benzodiazepine derivatives (Embase's index term for all BZs, including Z- drugs), Z-drugs, Falling, falls, fracture, hip fracture (See Appendix 1 for further detail). Conditions being studied: Falls and fractures occurring during treatment with Z-drugs. Study population: Adult patients receiving Z-drugs. Exposures: Atypical benzodiazepine receptor ligands (Z-drugs). Comparators: Adult patients not treated with Z-drugs. Types of studies to be included: Randomized controlled trials (RCTs) and observational studies adjusted for potential confounders.

2 Inclusion criteria: RCTs Observational studies (cohort, case control) Patients over 18 years old Exclusion criteria Reviews, case reports, studies without control, etc. Studies with in-extractable data due to limited access to study manuscript Study manuscript reported in languages other than English or French. Outcomes: Primary - Falls Secondary - Fractures, injuries, incident disability, death Data extraction: Data will be extracted by a single reviewer using a standard protocol. The data will subsequently be evaluated by two independent reviewers. Disagreements will be resolved through consensus or referral to a third reviewer where necessary. References in retrieved articles will be scanned for additional relevant articles. We will search our results for duplicate articles in order to ensure every article is counted only once. From the selected studies we will extract data regarding the patients included (age, gender, concomitant medications, and community dwelling status) details about the study (study design, location, year, number of participants, and outcomes) and exposure details (drug studied, doses, timing and treatment duration).

3 Risk of bias (quality) assessment: For randomized clinical trials, we will use the "Cochrane Collaboration's Tool for Assessing Risk of Bias". This tool assesses for selection bias, performance bias, detection bias, attrition bias, and reporting bias. For observational studies, we will use the "Newcastle-Ottawa Scale". Sub group analysis: Evaluation of risks in different Z-drugs. Strategy for data synthesis: Data synthesis: We will perform the analysis using Review Manager 5 software (RevMan 2012). Assessment of heterogeneity using fixed and random effect methods and the I² statistic. Reporting bias will assessed by "Funnel plot". Sensitivity analysis - We will perform sensitivity analysis to assess the robustness of our findings, by repeating the analyses while restricting them to studies of high quality according to our quality assessment tools. Planned subgroup analysis: Sensitivity analysis Analysis by study quality score of Newcastle-Ottawa Quality Assessment scale" (NOS). Evaluation of risks in specific Z-drugs Post hoc analysis in fractures outcome (added July 2017):

4 Insomnia sub analysis Gender sub analysis Age sub analysis Subanalysis estimating the risks by specific fractures. Subanalysis estimating the risks in the community vs. inpatients. Sensitivity analysis based on study quality score of Newcastle-Ottawa Quality Assessment scale"(nos), ROBANS and ROBINS-I tools.

5 Appendix 1 Systematic review will follow the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) framework guidelines, and include MEDLINE, EMBASE and "clinicaltrials.gov" databases according to preselected keywords, as well as published systematic reviews, reviews, and original articles. No language or date restrictions will be applied in these searches. Search will include terms related to benzodiazepines and z-drugs. Records will be evaluated separately for z-drugs and for benzodiazepines which will thereafter be analyzed separately. Generic syntax: bretazenil or brotizolam or cinolazepam or etizolam or midazolam or oxazepam or triazolam or bromazepam or chlordiazepoxide or clobazam or clorazepate or cloxazolam or clonazepam or delorazepam or diazepam or diclazepam or ethyl and loflazepate or flubromazepam or flunitrazepam or flurazepam or flutoprazepam or halazepam or ketazolam or medazepam or nimetazepam or nitrazepam or nordazepam or phenazepam or pinazepam or prazepam or pyrazolam or quazepam or tetrazepam or alprazolam or clotiazepam or estazolam or loprazolam or lorazepam or lormetazepam or temazepam or eszopiclone or zolpidem or zaleplon or zopiclone or benzodiazepines or 'hypnotic agent' or 'benzodiazepine derivative' and (falling or falls or fracture or 'hip fracture') To