Use of benzodiazepines and cardiovascular mortality in a cohort of women aged over 50 years
To assess the association between use of benzodiazepines (including the Z-drugs zopiclone and zolpidem) and cardiovascular mortality in women aged over 50 years.
We used data from the E3N cohort. Data self-reported in biennial questionnaires was matched with drug reimbursement and vital status/causes of death data. In Cox models, exposure to benzodiazepines was fitted using time-varying variables, the reference category being women with no benzodiazepine delivery since January 2004.
Among 85,353 women born 1925–1950 and followed between 2004 and 2011, 506 cardiovascular deaths occurred. Exposure to benzodiazepines was associated with increased cardiovascular mortality when hazard ratios (HRs) were adjusted only for age (HRever use 1.65; 95% CI 1.39, 1.97), but not when further adjusted for antidepressant use (HRever use 1.15; 95% CI 0.94, 1.40), nor in the multivariable model (HRever use 0.93; 95% CI 0.75, 1.16). Exposure to hypnotic benzodiazepines remained associated with increased cardiovascular mortality (HRever use 1.23; 95% CI 1.01, 1.51), but with no consistent trend across duration/dose or time since last use, while exposure to anxiolytic benzodiazepines was not (HRever use 0.83; 95% CI 0.67, 1.02).
In our study, adjustment for antidepressant use strongly attenuated any benzodiazepine–cardiovascular mortality association. Whether the modest association observed with hypnotic benzodiazepines is due to residual confounding deserves further investigation.
KeywordsAnxiolytics Benzodiazepines Cardiovascular mortality Cohort Hypnotics Z-drugs
The authors are grateful to all members of the E3N-EPIC study group, particularly to Laureen Dartois, Marie Fangon, Pascale Gerbouin-Rérolle, Lyan Hoang, Céline Kernaleguen, Camille Laplanche, Maryvonne Niravong, and Maxime Valdenaire for their contribution to the acquisition of data. They are also indebted to the French National Service on Causes of Death (CépiDc).
A.F.: conducted the literature review, conceived and designed the study, supervised the statistical analyses, implemented the statistical analyses, and drafted the manuscript.
S.M.: conducted the literature review, conceived and designed the study, supervised the statistical analyses, and drafted the manuscript.
G.G.: implemented the statistical analyses.
F.C.-C.: set up the E3N study cohort and was responsible for data acquisition and maintenance.
All authors contributed substantially to analysis and interpretation of data, reviewed the manuscript, and approved the final version.
Funding sources had no involvement in the design and carrying out of the study, collection, management, analysis, and interpretation of data, or preparation, review, and approval of the manuscript.
This work was supported by a grant from the Agence nationale de sécurité du médicament et des produits de santé (ANSM; grant AAP-2012-032). It was carried out using data from the French National Institute of Health and Medical Research (Inserm) E3N cohort, which was established and maintained with the support of the Mutuelle Générale de l’Education Nationale (MGEN); the French League against Cancer (LNCC); Gustave Roussy; and the Agence Nationale de la Recherche (ANR; programme “Investissements d’avenir,” grant ANR-10-COHO-0006).
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
This article does not contain any studies with animals performed by any of the authors.
Informed consent was obtained from all individual participants included in the study.
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