Hip/femur fractures associated with the use of benzodiazepines (anxiolytics, hypnotics and related drugs): a methodological approach to assess consistencies across databases from the PROTECT‐EU project

Abstract

Background Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. Objectives The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. Methods To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. Results Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. Conclusions Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs.

Benzodiazepines and risk of all cause mortality in adults: cohort study

“…Benzodiazepines confer their effects through their action on γ-amino-butyric acid (GABA) type A receptors in the central nervous system, which are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity, and memory functions. 38 Because of their psychotropic action, benzodiazepines have been associated with hypnotic related side effects such as daytime sleepiness, impairment of psychomotor and cognitive functioning, increased risk of motor vehicle collisions, and increased risk of falls and fractures, [39][40][41][42] in particular among older patients, 31 and with possible greater risks for benzodiazepines with a longer half life. 32 33 Benzodiazepines have also been associated with an increased risk for development of dependence and misuse.…”

Risk of Hip Fracture in Older People Using Selective Serotonin Reuptake Inhibitors and Other Psychoactive Medicines Concurrently: A Matched Case–Control Study in Australia

“…Four case–control or cohort studies have assessed the risk of hip or hip/femur fracture as a result of concurrent use of psychoactive medicines defined in terms of current exposure [7–10]. An increased risk of hip or hip/femur fracture was found for current use of opioids with psychotropic medicines, current use of anxiolytics with hypnotics, and current use of benzodiazepines or zolpidem with potentially interacting medicines identified in drug information sources [7, 8, 10].…”

“…An increased risk of hip or hip/femur fracture was found for current use of opioids with psychotropic medicines, current use of anxiolytics with hypnotics, and current use of benzodiazepines or zolpidem with potentially interacting medicines identified in drug information sources [7, 8, 10]. For each combination of a benzodiazepine or zolpidem with interacting medicines, an assessment of additive interaction found that the risk estimate as a result of concurrent exposure was similar to the sum of the risk estimates due to individual exposures [8].…”

“…The former is less relevant to clinical practice [11–13]. Two of the four studies of concurrent use of psychoactive medicines and the risk of hip or hip/femur fracture did not assess interaction [7, 10]. Three past studies [7–9] of the risk of hip or hip/femur fracture as a result of concurrent use of psychoactive medicines were limited by the potential for survivor bias, as new medicine use was not assessed separately to continuous medicine use [14].…”

A methodological comparison of two European primary care databases and replication in a US claims database: inhaled long-acting beta-2-agonists and the risk of acute myocardial infarction

“…However, no relevant impact of considering such confounders on LABA-associated AMI risk estimates was found in other studies suggesting confounding by, e.g., lifestyle factors as already captured to a large extent by routinely collected confounders [37]. Similarly, for another drug-AE pair (benzodiazepines and hip/femur fractures) examined within the PROTECT project, consideration of additional lifestyle factors (e.g., alcohol, smoking) as part of a sensitivity analysis had no relevant impact on risk estimates in CPRD GOLD database [38]. However, we did include exposure information on several drugs prescribed for exacerbations (e.g., oral corticosteroids) as confounders in the sensitivity analysis, acting as a proxy for disease severity.…”