Dataset Information

History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study.

ABSTRACT: Previous estimates of whether long-term exposure to benzodiazepines increases dementia risk are conflicting and are compromised by the difficulty of controlling for confounders and by reverse causation. We investigated how estimates for the association between benzodiazepine use and later dementia incidence varied based on study design choices, using a case-control study nested within the United Kingdom's Clinical Practice Research Datalink. A total of 40,770 dementia cases diagnosed between April 2006 and July 2015 were matched on age, sex, available data history, and deprivation to 283,933 control subjects. Benzodiazepines and Z-drug prescriptions were ascertained in a drug-exposure period 4-20 years before dementia diagnosis. Estimates varied with the inclusion of new or prevalent users, with the timing of covariate ascertainment, and with varying time between exposure and outcome. There was no association between any new prescription of benzodiazepines and dementia (adjusted odds ratio (OR) = 1.03, 95% confidence interval (CI): 1.00, 1.07), whereas an inverse association was observed among prevalent users (adjusted OR = 0.91, 95% CI: 0.87, 0.95), although this was likely induced by unintentional adjustment for colliders. By considering the choice of confounders and timing of exposure and covariate measurement, our findings overall are consistent with no causal effect of benzodiazepines or Z-drugs on dementia incidence.

SUBMITTER: Richardson K

PROVIDER: S-EPMC6601519 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study.

Richardson Kathryn K Mattishent Katharina K Loke Yoon K YK Steel Nicholas N Fox Chris C Grossi Carlota M CM Bennett Kathleen K Maidment Ian I Boustani Malaz M Matthews Fiona E FE Myint Phyo K PK Campbell Noll L NL Brayne Carol C Robinson Louise L Savva George M GM

American journal of epidemiology 20190701 7

Previous estimates of whether long-term exposure to benzodiazepines increases dementia risk are conflicting and are compromised by the difficulty of controlling for confounders and by reverse causation. We investigated how estimates for the association between benzodiazepine use and later dementia incidence varied based on study design choices, using a case-control study nested within the United Kingdom's Clinical Practice Research Datalink. A total of 40,770 dementia cases diagnosed between Apr ...[more]

PMID: 31111865

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Project description:PurposeIn studies of effects of time-varying drug exposures, adequate adjustment for time-varying covariates is often necessary to properly control for confounding. However, the granularity of the available covariate data may not be sufficiently fine, for example when covariates are measured for participants only when their exposure levels change.MethodsTo illustrate the impact of choices regarding the frequency of measuring time-varying covariates, we simulated data for a large target trial and for large observational studies, varying in covariate measurement design. Covariates were measured never, on a fixed-interval basis, or each time the exposure level switched. For the analysis, it was assumed that covariates remain constant in periods of no measurement. Cumulative survival probabilities for continuous exposure and non-exposure were estimated using inverse probability weighting to adjust for time-varying confounding, with special emphasis on the difference between 5-year event risks.ResultsWith monthly covariate measurements, estimates based on observational data coincided with trial-based estimates, with 5-year risk differences being zero. Without measurement of baseline or post-baseline covariates, this risk difference was estimated to be 49% based on the available observational data. With measurements on a fixed-interval basis only, 5-year risk differences deviated from the null, to 29% for 6-monthly measurements, and with magnitude increasing up to 35% as the interval length increased. Risk difference estimates diverged from the null to as low as -18% when covariates were measured depending on exposure level switching.ConclusionOur simulations highlight the need for careful consideration of time-varying covariates in designing studies on time-varying exposures. We caution against implementing designs with long intervals between measurements. The maximum length required will depend on the rates at which treatments and covariates change, with higher rates requiring shorter measurement intervals.

Project description:ImportanceThe receipt of overlapping opioid and benzodiazepine prescriptions is associated with increased overdose risk. It is unknown whether this increase in risk varies when overlapping prescriptions are written by multiple prescribers vs 1 prescriber.ObjectiveTo evaluate the association between receipt of overlapping opioid and benzodiazepine prescriptions from multiple prescribers and overdose risk.Design, setting, and participantsThis cohort study was conducted using 2017 to 2018 claims from the Optum deidentified Clinformatics Data Mart. Participants were patients with private insurance or Medicare Advantage aged 12 years or older with overlapping opioid and benzodiazepine prescriptions. Data were analyzed from March through November 2020.ExposuresFor each patient, person-days on which opioid and benzodiazepine prescriptions overlapped were identified. The exposure was whether these prescriptions were written by multiple prescribers vs 1 prescriber.Main outcomes and measuresThe outcome was a treated overdose, defined as the occurrence of 1 or more claims containing a diagnosis code for opioid or benzodiazepine poisoning on a person-day of opioid-benzodiazepine overlap. The association between exposure and outcome at the person-day level was estimated using logistic regression, controlling for opioid and benzodiazepine prescribing patterns, demographics, and comorbidities. The average marginal effect (AME) of the exposure, defined as the absolute difference in the probability of a treated overdose if all person-days of overlap involved prescriptions from multiple prescribers vs 1 prescriber, was calculated.ResultsAmong 529 053 patients, the mean (SD) age was 61.2 (15.6) years and 350 857 (66.3%) were female patients. Mean (SD) follow-up was 198.7 (249.8) days. During follow-up, overdose occurred on 1 or more person-days of opioid-benzodiazepine overlap for 2288 patients (0.4%, or 1 in 231 patients). There were 52 989 316 person-days of opioid-benzodiazepine overlap. Among 19 895 457 person-days (37.5%) involving prescriptions from multiple prescribers, there were 1390 overdoses (7.0 per 100 000 person-days), and among 33 093 859 person-days (62.5%) involving prescriptions from 1 prescriber, there were 1302 overdoses (3.9 per 100 000 person-days). Overdose risk was increased 1.8-fold (95% CI, 1.6-1.9) on person-days of overlap involving prescriptions from multiple prescribers vs 1 prescriber. The association between multiple prescribers and increased risk of overdose persisted in adjusted analyses (adjusted odds ratio, 1.20; 95% CI, 1.10-1.31; AME, 0.91 per 100 000 person-days of overlap; 95% CI, 0.46-1.37).Conclusions and relevanceThis study found that among patients already at increased risk of overdose owing to concurrent treatment with opioids and benzodiazepines, overdose risk was increased further when multiple prescribers were responsible for this treatment regimen compared with 1 prescriber. This increased risk was not fully accounted for by differences in prescribing patterns, demographics, or comorbidities. This finding suggests that other factors, such as poor care coordination, may be associated with the increase in risk.

Dataset Information

History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study.

Publications

History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study.

Similar Datasets

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