- •Quantifying the effect of benzodiazepines on mortality is not straightforward.
- •Immortal time bias threatens the validity of benzodiazepine effect estimates.
- •A process of cloning, weighting, and censoring is used to avoid immortal time bias.
- •The observed benzodiazepine-related 30-day mortality was largely due to confounding.
Background and Objectives
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Study Funding: This work is was funded by the NIH (Award number NIA 1 R01 AG073410-01).
Conflicts of interest: The authors declare no conflict of interest.
CRediT author statement: Dr Lidia Moura: conceptualization, methodology, formal analysis, data curation, writing–original draft, writing–review & editing, funding acquisition, supervision. Dr Maria A Donahue: writing–original draft, writing–review & editing, visualization, project administration. Zhiyu Yan: software, validation, formal analysis, data curation, visualization. Louisa Smith: validation, formal analysis, writing–review & editing. Dr Hsu: writing–review & editing. Dr Schwamm: writing–review & editing. Dr Newhouse: writing–review & editing. Drs Haneuse: conceptualization, methodology, formal analysis, writing–review & editing. Dr Blacker: conceptualization, methodology, writing–review & editing. Dr Hernandez-Diaz: conceptualization, methodology, formal analysis, writing–review & editing, and supervision.
Sponsor's role: This work was done as part of the fulfillment of Dr Moura's doctoral degree in Population Health Sciences (Epidemiology) at the Harvard T.H. Chan School of Public Health.
Financial disclosures: L.M.V.R.M.: Support from the Centers for Diseases Control and Prevention (U48DP006377), the National Institutes of Health (NIH-NIA 5K08AG053380-02, NIH-NIA 5R01AG062282-02, NIH-NIA 2P01AG032952-11, NIH- NIA 3R01AG062282-03S1), and the Epilepsy Foundation of America and reports no conflict of interest. Z.Y., M.A.D. and L.H.S.: have no conflict of interest to disclose. J.P.N. receives funding from NIH (2P01- AG032952, T32-AG51108) and reports being a director of Aetna until May 2018 and holding equity in Aetna until November 2018. L.H.S.: Scientific consultant regarding trial design and conduct on late window thrombolysis and member of steering committee for Genentech (TIMELESS NCT03785678); user interface design and usability to LifeImage; stroke systems of care to the Massachusetts Dept of Public Health; member of a Data Safety Monitoring Board for Penumbra (MIND NCT03342664); Diffusion Pharma (PHAST-TSC NCT03763929); principal investigator, multicenter trial of stroke prevention for Medtronic (Stroke AF NCT02700945); principal investigator, StrokeNet Network NINDS (New England Regional Coordinating Center U24NS107243). J.H.: Support from the NIH (1R01AG062282-012, P01AG032952). J.P.N.: receives funding from NIH (2P01- AG032952, T32-AG51108) and reports being a director of Aetna until May 2018 and holding equity in Aetna until November 2018. S.H.: Support from the NIH (R01HD098421, R01NS104143, P50CA244433, 1R01DK128150-01, R01DK107972) and Gates Foundation (INV-003612) reports no conflict of interest. D.B.: Support from the NIH (5P30 AG062421-03, 2P01AG036694-11, 5U01AG032984-12, 1U24NS100591-04, 1R01AG058063-04, R01AG063975-03, 5R01AG062282-04, 3R01AG062282-03S1, 5R01AG066793-02, 1U19AG062682-03, 2P01AG032952-11, 2T32MH017119-34 Billing Agreement 010,289.0001, 3P01AG032952-12S3, 1U01AG068221-01, 1U01AG076478-01, 5R01AG048351-05) and 747,021.Blacker.2019 from President and Fellows of Harvard College reports no conflict of interest. S.H.D. receives funding from NIH (5R01HD088393-02) and reports grants to her institution from Takeda, and consulting for Bayer and UCB, all outside the submitted work.