Clinical trial NCT01587833: WEUKBRE5559: IMI PROTECT: Benzodiazepines & Fracture
Official title: WEUKBRE5559: IMI PROTECT (Work Package 2): Use of Benzodiazepines and Risk of Hip/Femur Fracture
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Anxiety Disorders
Keywords: Benzodiazepines
hip/femur fracture
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-04-30
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will consist of all patients included in the period of valid data collection from the following data bases: Bavarian, Mondriaan, National Databases (Denmark), GPRD, BIFAP and THIN. The study period will be defined from January 1, 2001 to December 31, 2009.

Brief summary: The studies described in this protocol are all performed within the framework of PROTECT (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium) Workpackage 2 and Workgroup 1. Primary aim of these studies is to develop, test and disseminate methodological standards for the design, conduct and analysis of Pharmacoepidemiological (PE) studies applicable to different safety issues and using different data sources. To achieve this, results from PE studies on five key adverse events (AEs) performed in different databases will be evaluated. Therefore, emphasis will be on the methodological aspects of the studies in this protocol and not on the clinical consequences of the association under investigation.

Benzodiazepines (BZDs) are one of the therapeutic groups most widely used, mainly indicated as hypnotics and anxiolytics. Guidelines recommend treatment courses not exceeding 4-6 weeks. However, long-term treatment is highly prevalent, particularly in older people with a prevalence ranging from 15 to 30%. However, treatment is often taken as needed.

Hip/femur fractures are a major cause of morbidity and mortality, impair quality of life and impose a considerable economic burden. Among people aged 50 years and older, a case-fatality rate of 20% is associated within the first year.

The relationship between benzodiazepines and hip fractures remains controversial. Psychotropic medication has been traditionally associated with hip fractures. Among psychotropic medication, long elimination half-life benzodiazepines were found to increase the risk of hip fractures in a case-control study published in the late eighties. Since then, several investigations have been performed, mostly in older patients focusing on the relationship between benzodiazepines and hip fractures, and between benzodiazepines and falls as a mechanism underlying this effect. A review performed in 2003, which included 11 epidemiological studies, reported that results were not always consistent. Seven out of eight cohort and population based case-control studies, found an association, but different results were reported according to benzodiazepines' half-life. In four hospital-based case-control studies no association between benzodiazepines use and hip fracture has been described. Data on dosing was only included in three of the studies, and once more results were not conclusive. Results ranged from no effect to an increased risk with high dose regimens. Results from subsequent succeeding studies have also shown contradictions, with no association reported in one of the studies, and an association described for the short-term use of short half-life, high-potency benzodiazepines.

Even though there is epidemiological evidence suggesting that the use of benzodiazepines increases the risk of hip fractures, problems rise with the definition of benzodiazepine exposure, or biases such as confounding by indication and the control for confounders. These remain unresolved topics that should be addressed in future studies. In the present protocol, it is proposed to further asses the risk of hip/femur fractures associated with benzodiazepines using different study designs in different primary databases, and to compare the results in order to evaluate the impact of design and population differences on the outcome of the study association.

The objective of this study is to assess the association between benzodiazepines use and hip/femur fracture with different study designs (descriptive, cohort, nested case-control, case crossover and self control case series) across different primary care databases (Bavarian, Mondriaan, National Databases (Denmark), General Practice Research Database (GPRD), Base de Datos para la Investigación Farmacoepidemiologica en Atencion Primaria (BIFAP) and The Health Improvement Network (THIN)) and to compare the results between databases, across designs to evaluate the impact of design/database/population differences on the outcome of the studied association.


Eligibility criteria: Inclusion Criteria:

* All patients who have at least one year of enrolment with the GP
* All patients who are at least 18 years of age
* All patients who have at least one benzodiazepine prescription

Exclusion Criteria:

* Patients with a benzodiazepine prescription within 6 months prior to study start
* Patients less than 18 years of age

Primary outcomes:
measure: Incident hip/femur fracture defined by ICPE-2 codes in BIFAP/Mondriaan, Read codes in GPRD/THIN and ICD-10 codes in Bavarian database
timeFrame: Up to nine years following drug exposure
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: