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Patterns of Benzodiazepine Use and Excess Risk of All-Cause Mortality in the Elderly: A Nationwide Cohort Study

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Abstract

Introduction

Despite the risks associated with their use, benzodiazepines remain used more widely than wisely. In this context, a better understanding of how their patterns of use can be associated with an increased risk of death appears essential. Indeed, the studies that investigated this association so far are inconsistent and question the influence of potential biases.

Objective

The objective of this study was to investigate the association of various patterns of benzodiazepine use with all-cause mortality.

Methods

A nationwide cohort of non-prevalent benzodiazepine users aged ≥ 65 years was identified using French healthcare insurance system claims databases. Exposure to benzodiazepines considered short-term, chronic (defined as a cumulated ≥ 6-month period over the previous 12 months), ongoing, and discontinued use. Using a Cox model, adjusted hazard ratios for all-cause mortality were estimated according to benzodiazepine patterns of use; exposure and confounders were treated as time-dependent variables.

Results

In the cohort of 54,958 individuals aged ≥ 65 years, adjusted hazard ratios for all-cause mortality and benzodiazepines were 2.26 (95% confidence interval 1.96–2.61) for short-term use, 3.86 (3.04–4.90) for chronic use—discontinued, and 3.05 (2.17–4.29) for chronic use—ongoing. At age 80 years, these were 1.62 (1.48–1.79), 2.00 (1.82–2.19) and 1.13 (1.02–1.26), respectively. Adjusted hazard ratios show similar decreases with age for all patterns of benzodiazepine use.

Conclusions

These findings confirm the existence of an excess risk of mortality associated with benzodiazepine use and provide pattern- and age-specific estimates. Higher risks were observed for patients aged < 80 years, short-term use, or chronic use recently interrupted. If the two latter can relate to an indication bias, the associations found for ongoing chronic use and short-term use conversely support a potential causal hypothesis.

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Author information

Authors and Affiliations

  1. Univ. Bordeaux, INSERM, BPH, U1219, Team Pharmacoepidemiology, Univ. Bordeaux, F-33000, Bordeaux, France

    Clément Mathieu, Bernard Bégaud & Antoine Pariente

  2. Univ. Bordeaux, INSERM, BPH, U1219, Team Biostatistics, Univ. Bordeaux, F-33000, Bordeaux, France

    Pierre Joly, Hélène Jacqmin-Gadda & Mathilde Wanneveich

  3. CHU Bordeaux, Pôle de Santé Publique, Centre de Pharmacovigilance de Bordeaux, Service de Pharmacologie Médicale, 33000, Bordeaux, France

    Bernard Bégaud & Antoine Pariente

Authors
  1. Clément Mathieu
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  2. Pierre Joly
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  3. Hélène Jacqmin-Gadda
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  4. Mathilde Wanneveich
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  5. Bernard Bégaud
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  6. Antoine Pariente
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Corresponding author

Correspondence to Antoine Pariente.

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Funding

Antoine Pariente coordinated the DRUGS Systematised Assessment in real-liFe Environment (DRUGS-SAFE) program funded by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). The present study was included in the DRUGS-SAFE program. This program aimed at providing an integrated system to allow the concomitant monitoring of drug use and safety in France. The potential impact of drugs, frailty of populations, and seriousness of risks drove the research program. The funding sources played no role in the design and interpretation of this study. This publication represents the views of the authors and does not necessarily represent the opinion of ANSM.

Conflict of Interest

Clément Mathieu, Pierre Joly, Hélène Jacqmin-Gadda, Mathilde Wanneveich, Bernard Bégaud, and Antoine Pariente have no conflicts of interest that are directly relevant to the content of this study.

Ethics Approval

Not applicable.

Consent to Participate

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Consent for Publication

Not applicable.

Data Availability

Publicly sharing EGB data is forbidden by law according to The French National Data Protection Agency (Commission Nationale de l’Informatique et des LIbertés, CNIL); regulatory decisions AT/CPZ/SVT/JB/DP/CR05222O of 14 June, 2005 and DP/CR071761 of 28 August, 2007. To request data access, please contact The National Institute for Health Data (Institut National des Données de Santé, INDS).

Code Availability

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Author Contributions

CM had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to the conceptualization and design of the study and to the interpretation of the results. CM drafted the manuscript. PJ, HJG, MW, BB, and AP revised the manuscript for important intellectual content. All authors gave final approval of the article. AP supervised the study.

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Mathieu, C., Joly, P., Jacqmin-Gadda, H. et al. Patterns of Benzodiazepine Use and Excess Risk of All-Cause Mortality in the Elderly: A Nationwide Cohort Study. Drug Saf 44, 53–62 (2021). https://doi.org/10.1007/s40264-020-00992-7

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