Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study OPEN ACCESS

Objective To test the hypothesis that people taking anxiolytic and hypnotic drugs are at increased risk of premature mortality, using primary care prescription records and after adjusting for a wide range of potential confounders. Design Retrospective cohort study. Setting 273 UK primary care practices contributing data to the General Practice Research Database. Participants 34 727 patients aged 16 years and older first prescribed anxiolytic or hypnotic drugs, or both, between 1998 and 2001, and 69 418 patients with no prescriptions for such drugs (controls) matched by age, sex, and practice. Patients were followed-up for a mean of 7.6 years (range 0.1-13.4 years). Main outcome All cause mortality ascertained from practice records. Results Physical and psychiatric comorbidities and prescribing of non-study drugs were significantly more prevalent among those prescribed study drugs than among controls. The age adjusted hazard ratio for mortality during the whole follow-up period for use of any study drug in the first year after recruitment was 3.46 (95% confidence interval 3.34 to 3.59) and 3.32 (3.19 to 3.45) after adjusting for other potential confounders. Dose-response associations were found for all three classes of study drugs (benzodiazepines, Z drugs (zaleplon, zolpidem, and zopiclone), and other drugs). After excluding deaths in the first year, there were approximately four excess deaths linked to drug use per 100 people followed for an average of 7.6 years after their first prescription. Conclusions In this large cohort of patients attending UK primary care, anxiolytic and hypnotic drugs were associated with significantly increased risk of mortality over a seven year period, after adjusting for a range of potential confounders. As with all observational findings, however, these results are prone to bias arising from unmeasured and residual confounding. Introduction Prescribing of hypnotic and anxiolytic drugs is common and increasing in places. In 2011-12 more than 16 million prescriptions for these drugs were written in general practice in England at a cost of over £60m ($100m; €73m) per annum. Benzodiazepines currently account for 62% and Z drugs (zaleplon, zolpidem, and zopiclone) 32% of total prescriptions for hypnotics and anxiolytics in primary care in England. 4 Evidence of adverse effects including increased risk of dementia and other psychomotor impairments (daytime fatigue, ataxia, falls, and road traffic incidents), cancer, pneumonia, and other infections has increased concerns of an association with premature mortality. Until recently evidence for this was based on a small number of studies, which varied in setting, sample (especially age distribution), length of follow-up, source of drug usage data, type of drug, and the extent of control for confounding (especially from physical and psychiatric comorbidity, co-prescribing, socioeconomic status, smoking, and drug and alcohol misuse). 22 23 Although two studies in older populations did not report a statistically significant association between benzodiazepine use andmortality after adjusting for confounders, 25 four others (in younger samples) found evidence of significantly increased mortality. 20 22 23 26 A study in people with schizophrenia reported associations with suicide and with all cause mortality. Adjusted hazard ratios have varied substantially, ranging from 1.14 to 4.56. 23 27 A recent study found that the mortality risk extended to those with low levels of use, was greater in younger people, and that heavy use of hypnotics increased the Correspondence to: S Weich [email protected] Open Access: Reuse allowed Subscribe: http://www.bmj.com/subscribe BMJ 2014;348:g1996 doi: 10.1136/bmj.g1996 (Published 19 March 2014) Page 1 of 12