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Research

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

BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j2941 (Published 06 July 2017) Cite this as: BMJ 2017;358:j2941
  1. Elisabetta Patorno, assistant professor,
  2. Robert J Glynn, professor,
  3. Raisa Levin, programmer,
  4. Moa P Lee, research specialist,
  5. Krista F Huybrechts, assistant professor
  1. Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02120, USA
  1. Correspondence to: E Patorno epatorno{at}bwh.harvard.edu
  • Accepted 4 June 2017

Abstract

Objectives To evaluate the risk of all cause mortality associated with initiating compared with not initiating benzodiazepines in adults, and to address potential treatment barriers and confounding related to the use of a non-active comparator group.

Design Retrospective cohort study.

Setting Large de-identified US commercial healthcare database (Optum Clinformatics Datamart).

Participants 1:1 high dimensional propensity score matched cohort of benzodiazepine initiators, and randomly selected benzodiazepine non-initiators with a medical visit within 14 days of the start of benzodiazepine treatment (n=1 252 988), between July 2004 and December 2013. To address treatment barriers and confounding, patients were required to have filled one or more prescriptions for any medication in the 90 days and 91-180 days before the index date (ie, the date of starting benzodiazepine treatment for initiators and the date of the selected medical visit for benzodiazepine non-initiators) and the high dimensional propensity score was estimated on the basis of more than 300 covariates.

Main outcome measure All cause mortality, determined by linkage with the Social Security Administration Death Master File.

Results Over a six month follow-up period, 5061 and 4691 deaths occurred among high dimensional propensity score matched benzodiazepine initiators versus non-initiators (9.3 v 9.4 events per 1000 person years; hazard ratio 1.00, 95% confidence interval 0.96 to 1.04). A 4% (95% confidence interval 1% to 8%) to 9% (2% to 7%) increase in mortality risk was observed associated with the start of benzodiazepine treatment for follow-ups of 12 and 48 months and in subgroups of younger patients and patients initiating short acting agents. In secondary analyses comparing 1:1 high dimensional propensity score matched patients initiating benzodiazepines with an active comparator, ie, patients starting treatment with selective serotonin reuptake inhibitor antidepressants, benzodiazepine use was associated with a 9% (95% confidence interval 3% to 16%) increased risk.

Conclusions This large population based cohort study suggests either no increase or at most a minor increase in risk of all cause mortality associated with benzodiazepine initiation. If a detrimental effect exists, it is likely to be much smaller than previously stated and to have uncertain clinical relevance. Residual confounding likely explains at least part of the small increase in mortality risk observed in selected analyses.

Footnotes

  • Contributors: EP and KFH were involved in all parts of the study. RL and MPL were involved in data analysis and revising the manuscript. RJG was involved in designing the study and revising the manuscript. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. EP and KFH are the guarantors.

  • Funding: This study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. KFH was supported by a career development grant (K01MH099141) from the National Institute of Mental Health. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: EP reports receiving research funding from GSK and Boehringer-Ingelheim, outside the submitted work; RJG reports grants from AstraZeneca and Novartis outside the submitted work; KFH reports grants from Eli Lilly, Pfizer, Boehringer-Ingelheim, and GSK outside the submitted work.

  • Ethical approval: The use of this dataset for research was approved by the institutional review board (No 2013P000573) of the Brigham and Women’s Hospital, Boston, MA and a data use agreement was in place.

  • Data sharing: No additional data available.

  • Transparency: The manuscript’s guarantors (EP and KFH) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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