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

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.

SUBMITTER: Kripke DF

PROVIDER: S-EPMC3293137 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Kripke Daniel F DF Langer Robert D RD Kline Lawrence E LE

BMJ open 20120227 1

<h4>Objectives</h4>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.<h4>Setting</h4>A large integrated health system in the USA.<h4>Design</h4>Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis.<h4>Subjects</h4>Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypn ...[more]

PMID: 22371848

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Project description:ObjectivesTo assess the risk of mortality in primary care patients, multimorbid (?2 chronic conditions) or not, prescribed hypnotics/anxiolytics.DesignA longitudinal cohort study SETTING: Primary healthcare in the Reykjavik area.Participants114 084 individuals (aged 10-79 years, average 38.5, SD 18.4) contacting general practitioners during 2009-2012 (mortality follow-up to 31 December 2016). Of those, the reference group comprised 58 560 persons who were neither multimorbid nor had redeemed prescriptions for hypnotics/anxiolytics. Participants (16 108) redeeming prescriptions for hypnotics/anxiolytics on a regular basis for 3 consecutive years were considered as consistent, long-term users. They were subdivided into low-dose (1-300 defined daily doses (DDD)/3 years), medium-dose (301-1095 DDDs/3 years) and high-dose users (>1095 DDDs/3 years). All six groups taking these drugs were compared with the reference group.Main outcome measuresAll-cause mortality.ResultsHRs were calculated with the no multimorbidity-no drug group as a reference, using Cox proportional hazards regression model adjusting for age, sex and the number of chronic conditions (n=111 767), patients with cancer excluded. During follow-up, 516 358 person-years in total, 1926 persons died. Mean follow-up was 1685 days (4.6 years), range 1-1826 days (5.0 years). For all multimorbid patients who took no drugs the HR was 1.14 (95% CI 1.00 to 1.30) compared with those without multimorbidity. HRs in the non-multimorbid participants varied from 1.49 to 3.35 (95% CI ranging from 1.03 to 4.11) with increasing doses of hypnotics/anxiolytics, and correspondingly from 1.55 to 3.52 (1.18 to 4.29) in multimorbid patients.ConclusionsMortality increased in a dose-dependent manner among both multimorbid and non-multimorbid patients taking hypnotics/anxiolytics. This increase was clearly associated with prescribing of these drugs. Their use should be limited to the recommended period of 2-4 up to 6 weeks; long-term use may incur increased risk and should be re-examined.

Project description:BackgroundBenzodiazepine hypnotics and the related nonbenzodiazepine hypnotics (z-drugs) are among the most frequently prescribed medications for older adults. Both can depress respiration, which could have fatal cardiorespiratory effects, particularly among patients with concurrent opioid use. Trazodone, frequently prescribed in low doses for insomnia, has minimal respiratory effects, and, consequently, may be a safer hypnotic for older patients. Thus, for patients beginning treatment with benzodiazepine hypnotics or z-drugs, we compared deaths during periods of current hypnotic use, without or with concurrent opioids, to those for comparable patients receiving trazodone in doses up to 100 mg.Methods and findingsThe retrospective cohort study in the United States included 400,924 Medicare beneficiaries 65 years of age or older without severe illness or evidence of substance use disorder initiating study hypnotic therapy from January 2014 through September 2015. Study endpoints were out-of-hospital (primary) and total mortality. Hazard ratios (HRs) were adjusted for demographic characteristics, psychiatric and neurologic disorders, cardiovascular and renal conditions, respiratory diseases, pain-related diagnoses and medications, measures of frailty, and medical care utilization in a time-dependent propensity score-stratified analysis. Patients without concurrent opioids had 32,388 person-years of current use, 260 (8.0/1,000 person-years) out-of-hospital and 418 (12.9/1,000) total deaths for benzodiazepines; 26,497 person-years,150 (5.7/1,000) out-of-hospital and 227 (8.6/1,000) total deaths for z-drugs; and 16,177 person-years,156 (9.6/1,000) out-of-hospital and 256 (15.8/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (respective HRs: 0.99 [95% confidence interval, 0.81 to 1.22, p = 0.954] and 0.95 [0.82 to 1.14, p = 0.513] and z-drugs (HRs: 0.96 [0.76 to 1.23], p = 0.767 and 0.87 [0.72 to 1.05], p = 0.153) did not differ significantly from that for trazodone. Patients with concurrent opioids had 4,278 person-years of current use, 90 (21.0/1,000) out-of-hospital and 127 (29.7/1,000) total deaths for benzodiazepines; 3,541 person-years, 40 (11.3/1,000) out-of-hospital and 64 (18.1/1,000) total deaths for z-drugs; and 2,347 person-years, 19 (8.1/1,000) out-of-hospital and 36 (15.3/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (HRs: 3.02 [1.83 to 4.97], p < 0.001 and 2.21 [1.52 to 3.20], p < 0.001) and z-drugs (HRs: 1.98 [1.14 to 3.44], p = 0.015 and 1.65 [1.09 to 2.49], p = 0.018) were significantly increased relative to trazodone; findings were similar with exclusion of overdose deaths or restriction to those with cardiovascular causes. Limitations included composition of the study cohort and potential confounding by unmeasured variables.ConclusionsIn US Medicare beneficiaries 65 years of age or older without concurrent opioids who initiated treatment with benzodiazepine hypnotics, z-drugs, or low-dose trazodone, study hypnotics were not associated with mortality. With concurrent opioids, benzodiazepines and z-drugs were associated with increased out-of-hospital and total mortality. These findings indicate that the dangers of benzodiazepine-opioid coadministration go beyond the documented association with overdose death and suggest that in combination with opioids, the z-drugs may be more hazardous than previously thought.

Project description:BackgroundCancer in patients with chronic kidney disease (CKD) is an added burden to their overall morbidity and mortality. Cancer can be a cause or an effect of CKD. In CKD patients, a better understanding of cancer distribution and associations can aid in the proper planning of renal replacement therapy (RRT) and in the choice of chemotherapeutic agents, many of which are precluded in more advanced CKD. This study aims to investigate the distribution and the association of cancer with mortality, renal progression and RRT assignment in a non-dialysis dependent CKD cohort, few studies have investigated this in the past.MethodsThe study was carried out on 2952 patients registered in the Salford Kidney Study (SKS) between October 2002 and December 2016. A comparative analysis was performed between 339 patients with a history of cancer (previous and current) and 2613 patients without cancer at recruitment. A propensity score matched cohort of 337 patients was derived from each group and used for analysis. Cox-regression models and Kaplan-Meier estimates were used to compare the association of cancer with mortality and end-stage renal disease (ESRD) outcomes. Linear regression analysis was applied to generate the annual rate of decline in estimated glomerular filtration rate (delta eGFR).ResultsOf our cohort, 13.3% had a history of cancer at recruitment and the annual rate of de novo cancers in the non-cancer patients was 1.6%. Urogenital cancers including kidney and bladder, and prostate and testicle in males, ovary and uterus in females, were the most prevalent cancers (46%), as expected from the anatomical or physiological roles of these organs and relationship to nephrology. Over a median follow-up of 48 months, 1084 (36.7%) of patients died. All-cause mortality was higher in the previous and current cancer group (49.6% vs 35%, p < 0.001), primarily because of cancer-specific mortality. Multivariate Cox regression analysis showed a strong association of cancer with all-cause mortality (HR:1.41; 95%CI: 1.12-1.78; p = 0.004). There was no difference between the groups regarding reaching end-stage renal disease (26% in both groups) or the rate of decline in eGFR (- 0.97 for cancer vs - 0.93 mL/min/year for non-cancer, p = 0.93). RRT uptake was similar between the groups (17.2% vs 19.3%, p = 0.49).ConclusionsCancer status proved to be an added burden and an independent risk factor for all-cause mortality but not for renal progression. CKD patients with a previous or current history of cancer should be assessed on a case by case basis in planning for renal replacement therapy options, and the presence of cancer should not be a limitation for RRT provision including transplantation.

Dataset Information

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

Publications

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

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