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Benzodiazepines confer little to no increase in all-cause mortality risk

Stephen Padilla
14 Jul 2017

Benzodiazepine initiation is associated with either no increase or at most a small increase in the risk of all-cause mortality, results of a recent study based on an intention-to-treat approach suggest. If ever there is a detrimental effect on all-cause mortality, it is likely to be much lower than previously stated and to have uncertain clinical relevance.

“Residual confounding likely explains at least part of the small increase in mortality risk observed in selected analyses,” according to researchers.

A total of 5,061 deaths occurred among high dimensional propensity score-matched benzodiazepine initiators vs 4,691 deaths among noninitiators (9.3 vs 9.4 events per 1,000 person-years; hazard ratio, 1.00; 95 percent CI, 0.96 to 1.04) over a follow-up period of 6 months. [BMJ 2017;358:j2941]

There was a 4- (1 to 8 percent) to 9-percent (2 to 7 percent) increase in the risk of mortality related to the initiation of benzodiazepine treatment for follow-ups of 12 and 48 months and in subgroups of younger patients and those starting short acting agents.

Secondary analyses comparing 1:1 high dimensional propensity score-matched patients initiating benzodiazepines with an active comparator (ie, patients beginning treatment with selective serotonin reuptake inhibitor [SSRI] antidepressants) indicated that benzodiazepine use correlated with a 9-percent (3 to 16 percent) elevated risk.

“We observed small but statistically significant increases (owing to the large size of the cohort) in mortality risk associated with the initiation of benzodiazepines for follow-ups longer than 6 months, in younger patients, in patients initiating short acting drugs, and in the active comparison with selective serotonin reuptake inhibitor antidepressants,” researchers noted.

These findings do not dismiss the possibility of a modest detrimental effect related to benzodiazepines, but this effect is likely to be much lower than previously reported, they added. [BMJ Open 2012;358:e000850; BMJ 2014;358:g1996]

“Moreover, the direction and extent of the attenuation of the point estimates with high dimensional propensity score adjustment in both the comparisons with benzodiazepine noninitiators and SSRI initiators, and the tight confidence intervals driven by the large size of our study, suggest that residual confounding—rather than a true effect of benzodiazepine drugs—could drive the small increase in mortality risk observed in selected analyses,” researchers said.

In this retrospective cohort study, 1:1 high dimensional propensity score-matched cohort of benzodiazepine initiators and randomly selected noninitiators with a medical visit within 14 days of the start of benzodiazepine treatment (n=1,252,988) between July 2004 and December 2013 were included.

In addressing treatment barriers and confounding, patients filled one or more prescriptions for any medication in the 90 days and 91 to 180 days prior to the index date, and the high dimensional propensity score was measured on the bases of more than 300 covariates. The main outcome was all-cause mortality, determined by linkage with the Social Security Administration Death Master File.

“Benzodiazepines confer their effects through their action on γ-amino-butyric acid (GABA) type A receptors in the central nervous system, which are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity, and memory functions,” according to researchers. [Nature 1999;358:796-800]

The psychotropic action of benzodiazepines explains the study drug’s association with hypnotic-related side effects, including daytime sleepiness, impairment of psychomotor and cognitive functioning, increased risk of motor vehicle collisions, and increased risk of falls and fractures. [CNS Drugs 2004;358:297-328; Am J Public Health 2015;358:e64-9; Arch Intern Med 2004;358:1567-72; Pharmacoepidemiol Drug Saf 2016;358:66-78]

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