Article

Hypnotics' association with mortality or cancer: A matched cohort study

Scripps Clinic Viterbi Family Sleep Center, La Jolla, California, USA.
BMJ Open (Impact Factor: 2.06). 01/2012; 2(1):e000850. DOI: 10.1136/bmjopen-2012-000850
Source: PubMed

ABSTRACT An estimated 6%-10% of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality.
A large integrated health system in the USA.
Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis.
Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between January 2002 and January 2007.
Data were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Hazard ratios (HRs) for death were computed from Cox proportional hazards models controlled for risk factors and using up to 116 strata, which exactly matched cases and controls by 12 classes of comorbidity.
As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4-18, 18-132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose-response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease.
Receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used hypnotics and for newer shorter-acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.

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    • "Further limitations, characteristic of many large-scale longitudinal investigations, were reliance upon self-reported diagnoses (versus clinician-recorded); lack of assessment of other sleep disorders (e.g. sleep apnea and circadian rhythm sleep disorders); and absence of data on medication use, particularly sedative hypnotics, which have also been associated with adverse health effects (Kripke et al., 2012). Given the recent articulation by Vgontzas et al. (2013), emphasizing that insomnia with objective short sleep duration is the most biologically severe insomnia 'phenotype'—strongly connected with adverse health outcomes—it will be important to incorporate polysomnographic evaluations into future study designs with a view to teasing out the role of objective sleep. "
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