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

Daniel F Kripke, Robert D Langer, Lawrence E Kline, Daniel F Kripke, Robert D Langer, Lawrence E Kline

Abstract

Objectives: 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.

Setting: A large integrated health system in the USA.

Design: Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis.

Subjects: 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.

Main outcome measures: 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.

Results: 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.

Conclusions: 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.

Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form. DFK reports long-term criticism of hypnotic drugs at his non-profit web site. DFK reports a family interest in an investment corporation, which has a small percentage of its assets in stock of Sanofi-Aventis and Johnson & Johnson. RDL and LEK report no competing interests.

Figures

Figure 1
Figure 1
Survival curves for patients prescribed no hypnotic are compared with survival curves for patients prescribed hypnotics, divided into four age groups (age at commencement of period of observation). These curves were derived from a special Cox proportional hazards model in which those taking and not taking hypnotics in the four age groups were coded as eight categories of an independent predictor variable. The curves represent the fraction of patients surviving over the increasing years of observation until censored (died, lost to follow-up or end of observation). Those censored

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