European Journal of Clinical Pharmacology

, Volume 74, Issue 11, pp 1475–1484 | Cite as

Use of benzodiazepines and cardiovascular mortality in a cohort of women aged over 50 years

  • Sylvie Mesrine
  • Gaëlle Gusto
  • Françoise Clavel-Chapelon
  • Marie-Christine Boutron-Ruault
  • Agnès FournierEmail author
Pharmacoepidemiology and Prescription



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.


Anxiolytics 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.

Sponsor’s role

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.

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.

Supplementary material

228_2018_2515_MOESM1_ESM.docx (91 kb)
ESM 1 (DOCX 91 kb)


  1. 1.
    Olfson M, King M, Schoenbaum M (2015) Benzodiazepine use in the United States. JAMA Psychiatry 72:136–142. CrossRefPubMedGoogle Scholar
  2. 2.
    Grandner MA, Alfonso-Miller P, Fernandez-Mendoza J, Shetty S, Shenoy S, Combs D (2016) Sleep: important considerations for the prevention of cardiovascular disease. Curr Opin Cardiol 31:551–565. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corrà U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Løchen ML, Löllgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp H, van Dis I, Verschuren WMM, Binno S, ESC Scientific Document Group (2016) 2016 European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 37:2315–2381. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Piña IL, Di Palo KE, Ventura HO (2018) Psychopharmacology and cardiovascular disease. J Am Coll Cardiol 71:2346–2359. CrossRefPubMedGoogle Scholar
  5. 5.
    Liu J, Wang LN, Ma X, Ji X (2016) Gamma aminobutyric acid (GABA) receptor agonists for acute stroke. Cochrane Database Syst Rev 10:CD009622PubMedGoogle Scholar
  6. 6.
    Sutton JA, Clauss RP (2017) A review of the evidence of zolpidem efficacy in neurological disability after brain damage due to stroke, trauma and hypoxia: a justification of further clinical trials. Brain Inj 31:1019–1027. CrossRefPubMedGoogle Scholar
  7. 7.
    Bosone D, Fogari R, Zoppi A, D'Angelo A, Ghiotto N, Perini G, Ramusino MC, Costa A (2018) Effect of flunitrazepam as an oral hypnotic on 24-hour blood pressure in healthy volunteers. Eur J Clin Pharmacol. CrossRefGoogle Scholar
  8. 8.
    Mendelson N, Gontmacher B, Vodonos A, Novack V, Abu-AjAj M, Wolak A, Shalev H, Wolak T (2018) Benzodiazepine consumption is associated with lower blood pressure in ambulatory blood pressure monitoring (ABPM): retrospective analysis of 4938 ABPMs. Am J Hypertens 31:431–437. CrossRefPubMedGoogle Scholar
  9. 9.
    Parsaik AK, Mascarenhas SS, Khosh-Chashm D, Hashmi A, John V, Okusaga O, Singh B (2016) Mortality associated with anxiolytic and hypnotic drugs—a systematic review and meta-analysis. Aust N Z J Psychiatry 50:520–533. CrossRefPubMedGoogle Scholar
  10. 10.
    Wu CK, Huang YT, Lee JK, Jimmy Juang JM, Tsai CT, Lai LP, Hwang JJ, Chiang FT, Lin JL, Chen PC, Lin LY (2014) Anti-anxiety drugs use and cardiovascular outcomes in patients with myocardial infarction: a national wide assessment. Atherosclerosis 235:496–502. CrossRefPubMedGoogle Scholar
  11. 11.
    Lan TY, Zeng YF, Tang GJ, Kao HC, Chiu HJ, Lan TH, Ho HF (2015) The use of hypnotics and mortality—a population-based retrospective cohort study. PLoS One 10:e0145271. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Honkola J, Hookana E, Malinen S, Kaikkonen KS, Junttila MJ, Isohanni M, Kortelainen ML, Huikuri HV (2012) Psychotropic medications and the risk of sudden cardiac death during an acute coronary event. Eur Heart J 33:745–751. CrossRefPubMedGoogle Scholar
  13. 13.
    Chen HC, Su TP, Chou P (2013) A nine-year follow-up study of sleep patterns and mortality in community-dwelling older adults in Taiwan. Sleep 36:1187–1198. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Diez-Quevedo C, Lupon J, Gonzalez B et al (2013) Depression, antidepressants, and long-term mortality in heart failure. Int J Cardiol 167:1217–1225. CrossRefPubMedGoogle Scholar
  15. 15.
    Jaussent I, Ancelin ML, Berr C, Pérès K, Scali J, Besset A, Ritchie K, Dauvilliers Y (2013) Hypnotics and mortality in an elderly general population: a 12-year prospective study. BMC Med 11(212).
  16. 16.
    Thorogood M, Cowen P, Mann J, Murphy M, Vessey M (1992) Fatal myocardial infarction and use of psychotropic drugs in young women. Lancet 340:1067–1068CrossRefGoogle Scholar
  17. 17.
    Mallon L, Broman JE, Hetta J (2009) Is usage of hypnotics associated with mortality? Sleep Med 10:279–286. CrossRefPubMedGoogle Scholar
  18. 18.
    Rod NH, Vahtera J, Westerlund H, Kivimaki M, Zins M, Goldberg M, Lange T (2011) Sleep disturbances and cause-specific mortality: results from the GAZEL cohort study. Am J Epidemiol 173:300–309. CrossRefPubMedGoogle Scholar
  19. 19.
    Tiihonen J, Mittendorfer-Rutz E, Torniainen M, Alexanderson K, Tanskanen A (2016) Mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepines in patients with schizophrenia: an observational follow-up study. Am J Psychiatry 173:600–606. CrossRefPubMedGoogle Scholar
  20. 20.
    Neutel CI, Johansen HL (2015) Association between hypnotics use and increased mortality: causation or confounding? Eur J Clin Pharmacol 71:637–642. CrossRefPubMedGoogle Scholar
  21. 21.
    Davidson PM, Phillips JL, Dennison-Himmelfarb C, Thompson SC, Luckett T, Currow DC (2016) Providing palliative care for cardiovascular disease from a perspective of sociocultural diversity: a global view. Curr Opin Support Palliat Care 10:11–17. CrossRefPubMedGoogle Scholar
  22. 22.
    Kelly PT, McCulloch J (1983) The effects of the GABAergic agonist muscimol upon the relationship between local cerebral blood flow and glucose utilization. Brain Res 258:338–342CrossRefGoogle Scholar
  23. 23.
    Chi OZ, Hunter C, Liu X, Chi Y, Weiss HR (2011) Effects of GABA(a) receptor blockade on regional cerebral blood flow and blood–brain barrier disruption in focal cerebral ischemia. J Neurol Sci 301:66–70. CrossRefPubMedGoogle Scholar
  24. 24.
    Johnson CF, Barnsdale LR, McAuley A (2016) Investigating the role of benzodiazepines in drug-related mortality—a systematic review undertaken on behalf of the Scottish National Forum on drug-related deaths. NHS Health Scotland, EdinburghGoogle Scholar
  25. 25.
    Clavel-Chapelon F, E3N Study Group (2015) Cohort profile: the French E3N cohort study. Int J Epidemiol 44:801–809. Questionnaires available at CrossRefGoogle Scholar
  26. 26.
    Lamarche-Vadel A, Pavillon G, Aouba A, Johansson LA, Meyer L, Jougla E, Rey G (2014) Automated comparison of last hospital main diagnosis and underlying cause of death ICD10 codes, France, 2008−2009. BMC Med Inform Decis Mak 14(44).
  27. 27.
    WHO Collaborating Centre for Drug Statistics Methodology: DDD: definition and general considerations. Accessed November 23, 2017
  28. 28.
    Fuhrer R, Rouillon F (1989) The French version of the Center for Epidemiologic Studies–Depression Scale [in French]. Psychiatr Psychobiol 4:163–166Google Scholar
  29. 29.
    Suissa S (2008) Immeasurable time bias in observational studies of drug effects on mortality. Am J Epidemiol 168:329–335. CrossRefPubMedGoogle Scholar
  30. 30.
    Agence Nationale de Sécurité du Médicament et des produits de santé (2013) État des lieux de la consommation des benzodiazépines en France. Accessed November 23, 2017
  31. 31.
    Mikkelsen L, Phillips DE, AbouZahr C, Setel PW, de Savigny D, Lozano R, Lopez AD (2015) A global assessment of civil registration and vital statistics systems: monitoring data quality and progress. Lancet 386:1395–1406. CrossRefPubMedGoogle Scholar
  32. 32.
    Smoller JW, Allison M, Cochrane BB, Curb JD, Perlis RH, Robinson JG, Rosal MC, Wenger NK, Wassertheil-Smoller S (2009) Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the Women’s Health Initiative study. Arch Intern Med 169:2128–2139. CrossRefPubMedGoogle Scholar
  33. 33.
    Whang W, Kubzansky LD, Kawachi I, Rexrode KM, Kroenke CH, Glynn RJ, Garan H, Albert CM (2009) Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses’ Health Study. J Am Coll Cardiol 53:950–958. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Biffi A, Scotti L, Corrao G (2017) Use of antidepressants and the risk of cardiovascular and cerebrovascular disease: a meta-analysis of observational studies. Eur J Clin Pharmacol 73:487–497. CrossRefPubMedGoogle Scholar
  35. 35.
    Hiance-Delahaye A, de Schongor FM, Lechowski L, Teillet L, Arvieu JJ, Robine JM, Ankri J, Herr M (2017) Potentially inappropriate prescription of antidepressants in old people: characteristics, associated factors, and impact on mortality. Int Psychogeriatr 30:715–726. CrossRefPubMedGoogle Scholar
  36. 36.
    Bachhuber MA, Hennessy S, Cunningham CO, Starrels JL (2016) Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996–2013. Am J Public Health 106:686–688. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.CESP, Fac. de médecine—Univ. Paris-Sud, Fac. de médecine—UVSQ, INSERMUniversité Paris-SaclayVillejuifFrance
  2. 2.Gustave RoussyVillejuifFrance
  3. 3.Inserm, CESP “Generations and Health” TeamGustave RoussyVillejuif cedexFrance

Personalised recommendations