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To the Editor: Although benzodiazepines are indicated for only a limited number of psychiatric disorders, they are the most commonly prescribed psychotropic drugs in elderly individuals.¹ Use of benzodiazepines in this population has been related to poor outcomes such as hip fractures, motor vehicle crashes, and suicide,^2-4 but it remains unclear to what extent use of benzodiazepines increases the risk of mortality in elderly individuals.⁵ We investigated the relationship between benzodiazepine use and mortality in a prospective study among individuals aged 85 years or older.

Methods
The Leiden 85-plus Study is a prospective population-based study of all inhabitants of Leiden, the Netherlands, aged 85 years or older. Between September 1, 1997, and September 1, 1999, the study enrolled 599 participants (participation rate = 87%).⁶ Participants were visited annually at home for face-to-face interviews. The medical ethical committee of the Leiden University Medical Center approved the study and all participants provided oral informed consent.

All participants were followed up for mortality until September 1, 2002. Use of benzodiazepines was assessed annually from computerized pharmacy registries within a time frame of 3 months. Use of benzodiazepine was assumed if the prescription duration indicated that benzodiazepines were used in more than half of this period. Participants who did and who did not use benzodiazepines were compared using ² tests. Mortality risks were estimated as relative risks (RRs) in a Cox proportional hazards model using the annually observed use of benzodiazepine as the time-dependent covariate, adjusted for sex. In the full adjustment model, additional adjustments were made for level of education, chronic disease, marital status, living arrangements, annual assessment of depression, and annual assessment of cognitive impairment. This model assumes a temporal relationship between benzodiazepine use and mortality over a 1-year period, and incorporates continuation or discontinuation of benzodiazepines based on pharmacy registries. Specific causes of participant death were assessed shortly after death by a standardized interview with either the general practitioner or the nursing home physician.

Depression (defined as a score of 4 points on the 15-item Geriatric Depression Scale⁷) and cognitive impairment (defined as a score of 23 points on the Mini-Mental State Examination⁸) were assessed annually. Level of education was dichotomized at 6 years of schooling. Chronic disease was defined as a medical history of cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, arthritis, dementia, malignancy, or Parkinson disease.

Results
At baseline, 181 participants (30%) used benzodiazepines. The use of benzodiazepines was more frequent in women (36% vs 20%, P<.001), in participants with a low level of education (34% vs 24%, P = .01), and in depressed participants (41% vs 27%, P = .004), but was not significantly related to cognitive impairment, chronic disease, marital status, or living arrangements.

The overall prevalence of benzodiazepine use did not change during a mean follow-up of 3.0 years; we found a total of 465 person-years (26%) with benzodiazepine use and of 1339 person-years (74%) without benzodiazepine use. In total, 166 participants died. Table 1 presents the all-cause and fracture-related mortality risk adjusted for sex depending on the annually observed use of benzodiazepines. The risk of all-cause mortality was not increased for participants who used benzodiazepines compared with those who did not use benzodiazepines (RR, 0.77; 95% confidence interval [CI], 0.51-1.17). This estimate remained essentially unchanged after correcting for sex, level of education, chronic disease, marital status, living arrangments, depression, and cognitive impairment (RR, 0.68; 95% CI, 0.44-1.04).

View this table: [in this window] [in a new window] Table. Mortality Risk Depending on Use of Benzodiazepine

Six participants died from causes related to fracture. Mortality related to fracture was increased, although not significantly, for any benzodiazepine use, for use of more than 5 mg/d of diazepam equivalents, and for use of more than 1 benzodiazepine (Table 1). Risks of mortality from other causes of death were similar to the risk of all-cause mortality.

Comment
In this prospective study of community-dwelling elderly individuals, the use of benzodiazepines was assessed from computerized pharmacy registries. Use of benzodiazepines was observed in more than a quarter of the participants. During follow-up, use of benzodiazepines was not related to all-cause mortality. Similar to prior studies, however, we found an increase of mortality related to fracture in individuals who used benzodiazepines. The small number of deaths from fractures may explain the absence of statistical significance.

The use of benzodiazepines is common in individuals aged 85 years or older, although benzodiazepines are indicated only for a limited number of psychiatric disorders. In practice, clinicians should weigh the risks and benefits of benzodiazepine use. However, we did not find an increased risk of mortality related to benzodiazepine use.

Acknowledgment: This study was funded by unrestricted grants from the Netherlands Organisation of Scientific Research (ZonMw) and the Ministry of Health, Welfare, and Sports.

David J. Vinkers, MD, MA; Jacobijn Gussekloo, MD, PhD
Department of General Internal Medicine

Roos C. van der Mast, MD, PhD; Frans G. Zitman, MD, PhD
Department of Psychiatry

Rudi G. J. Westendorp, MD, PhD
Department of General Internal Medicine
Leiden University Medical Center
Leiden, the Netherlands

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Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2003;290:2942-2943.

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