Hypnotics and mortality in an elderly general population: a 12-year prospective study

  • Isabelle Jaussent1, 2,

    Affiliated with

    • Marie-Laure Ancelin1, 2,

      Affiliated with

      • Claudine Berr1, 2,

        Affiliated with

        • Karine Pérès3, 4,

          Affiliated with

          • Jacqueline Scali1,

            Affiliated with

            • Alain Besset1, 2,

              Affiliated with

              • Karen Ritchie1, 2, 5 and

                Affiliated with

                • Yves Dauvilliers1, 2, 6, 7Email author

                  Affiliated with

                  BMC Medicine201311:212

                  DOI: 10.1186/1741-7015-11-212

                  Received: 25 July 2013

                  Accepted: 9 September 2013

                  Published: 26 September 2013

                  Abstract

                  Background

                  Hypnotics are widely used by the elderly, and their impact on mortality remains controversial. The inconsistent findings could be due to methodological limitations, notably the lack of control for underlying sleep symptoms or illness associated with hypnotic use, for example, insomnia symptoms and excessive daytime sleepiness, depression and anxiety. Our objective was to examine the association between the use of hypnotics and mortality risk in a large cohort of community-dwelling elderly, taking into account a wide range of potential competing risks including sociodemographic characteristics, lifestyle, and chronic disorders as well as underlying psychiatric disorders and sleep complaints.

                  Methods

                  Analyses were carried out on 6,696 participants aged 65 years or older randomly recruited from three French cities and free of dementia at baseline. Adjusted Cox proportional hazards models with delayed entry, and age of the participants as the time scale, were used to determine the association between hypnotic use and 12-year survival.

                  Results

                  At baseline, 21.7% of the participants regularly used at least one hypnotic. During follow-up, 1,307 persons died, 480 from cancer and 344 from cardiovascular disease. Analyses adjusted for study center, age and gender showed a significantly greater risk of all-cause and cardiovascular-related mortality with hypnotics, particularly benzodiazepines, and this increased with the number of hypnotics used. None of these associations were significant in models adjusting for sociodemographic and lifestyle characteristics, chronic disorders including cardiovascular pathologies, sleep and psychiatric disorders. Results remained unchanged when duration of past hypnotic intake or persistent versus intermittent use during follow-up were taken into account.

                  Conclusions

                  When controlling for a large range of potential confounders, the risk of mortality was not significantly associated with hypnotic use regardless of the type and duration. Underlying psychiatric disorders appear to be the principal confounders of the observed association.

                  Keywords

                  Cohort studies Elderly Hypnotics Mortality Sleep disorders

                  Background

                  Sleep changes with advancing age; however, the high prevalence of insomnia in the older adult population is often due to associated age-related medical and psychosocial comorbidities and the frequent use of medications that may impact sleep per se[1]. Insomnia symptoms in older adults are frequently associated with daytime fatigue, excessive daytime sleepiness (EDS), and hypnotics use [24]. Insomnia and EDS are also frequently comorbid with other pathologies, notably cardiovascular diseases (CVD) [5, 6] and psychiatric disorder, for example, anxiety and depression [2, 4, 7].

                  Hypnotics are indicated for treating insomnia symptoms, including those associated with anxiety and depression, and may also be used together with antidepressant treatment. The current use of hypnotics in the general population is estimated to range between 3.5% and 11.7%, doubling in elderly populations [811]. Hypnotics may produce residual daytime sleepiness and impairment of psychomotor, attention and memory performances the day after bedtime administration, especially with the high dose and long half-life durations [12]. Moreover, the use of hypnotics seems to be associated with excess risk of accidents such as falls and car accidents [12] and may increase mortality risk, especially in elderly people with increased pharmacodynamic alterations.

                  However, the high rate of insomnia, EDS complaints, and psychiatric disorder in the elderly, their frequent comorbidity, and the potential risk of mortality associated with both sleep disorders [13] and psychiatric disorders [14, 15] may override hypnotics as the cause of increased mortality, independently of the underlying burden of illness.

                  Overall, evidence suggesting an association between hypnotics consumption and mortality in the elderly remains controversial. Four observational studies in young adults [16, 17] and elderly people [18, 19] found no significant associations between hypnotics and all-cause mortality. Other studies reported a significant association with excessive all-cause deaths in adults [2022]. Two large studies with very wide age ranges from young adult to older elderly people [2325] found significant associations in all age groups, including the elderly. Most of the above studies controlled for sociodemographic characteristics, lifestyle, and some chronic disorders but rarely or not at all for the underlying medical conditions associated with hypnotic prescription, that is depression, antidepressant use, anxiety, insomnia, and EDS. Finally, no studies examined the cumulative effect of hypnotics or the impact of their long-term use on mortality risk in an elderly population specifically. Several methodological issues may contribute to the observed inconsistencies, including the design of the study (retrospective or prospective); the duration of follow-up (between 2.5 and 20 years); the heterogeneity in sample size and age range; the type and duration of hypnotic prescription; and the lack of control for psychiatric and sleep disorders (prescription/indication biases).

                  The aim of the present study is to examine the associations between the use of hypnotics and 12-year mortality risk (all-causes, cancer and CVD) in a large cohort of community-dwelling elderly people, taking into account a wide range of potential competing risks including sociodemographic characteristics, lifestyle, and chronic disorders as well as underlying psychiatric disorders, EDS, and insomnia complaints. The impact of duration and type of hypnotic treatment were also evaluated.

                  Methods

                  Study population

                  Participants were recruited as part of the Three-City Study, an ongoing multi-site longitudinal study involving three French cities: Bordeaux, Dijon and Montpellier [26]. Briefly, non-institutionalized participants aged 65 years or over were randomly selected from electoral rolls between 1999 and 2001. The acceptance rate was 37%, yielding a sample of 9,294 individuals.

                  The study protocol was approved by the ethical committee of the University Hospital of Kremlin-Bicêtre and CPP Sud Méditérannée III, and written informed consent was obtained from each participant. The participants were administered standardized questionnaires and underwent clinical examinations at baseline and after 2, 4, 8, 10 and 12 years.

                  Mortality

                  The exact date of death of the participants was obtained from death registries. The causes of death were collected by the local study centers from medical records and interviews with family physicians, clinicians and other non-medical informants (relatives or caregivers) [27]. A validation committee used all information to classify the cause of death using the tenth revision of International Classification of Diseases (ICD-10) [28] as follows: cancer (ICD-10: C00 to C97 and D37 to D48), coronary heart disease and stroke (ICD-10: I00 to I99 and R960 to R961), respiratory (ICD-10: J00 to J99), and ill-defined causes (ICD-10: R00 to R99).

                  Sociodemographic and clinical variables at baseline

                  The standardized interview included questions on demographic characteristics, level of education, living alone, and on health behaviors (for example, consumption of alcohol and smoking status). Information on the health of the participants was obtained through detailed medical questionnaires. Case-level depressive symptoms were defined as a score above the 16-point cut-off on the Center for Epidemiological Studies-Depression Scale [29]. Anxiety trait symptoms were measured using the Spielberger’s State-Trait Anxiety Inventory [30]. In the absence of a validated cut-off score in elderly populations, the state score was divided into tertiles with the highest tertile (higher level of anxiety) being compared to the two lowest tertiles. Global cognitive function was assessed by the Mini-Mental State Examination [31] and participants scoring less than 26 were classified as cognitively impaired. Confinement was defined as social restriction (confinement to bed, home or outings restricted to the neighborhood) [32]. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m2). The presence of hypertension was defined by measured systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥95 mmHg or current antihypertensive treatment. Diabetes was defined as fasting glucose level ≥7.0 mmol/l or treatment for diabetes. Hypercholesterolemia was defined as total cholesterol level ≥6.2 mmol/L or treatment with lipid-lowering agents. Detailed medical questionnaires included past history of respiratory and thyroid disorders, and cardio-cerebrovascular disease (angina pectoris, myocardial infarction, cardiovascular surgery, arteritis, and stroke) established according to standardized questions.

                  Sleep complaints at baseline

                  Sleep complaints were assessed at baseline as part of the clinical interview, followed by the completion of a specific sleep questionnaire [33]. The participants self-rated as ‘never, rarely, frequently, or often’ occurrence of being excessively sleepy during the day (EDS), having difficulties in initiating sleep (DIS), having several awakenings during the night (difficulties in maintaining sleep; DMS), having early morning awakening (EMA) without being able to go back to sleep, and snoring loudly. In this analysis, EDS was defined as reporting frequently or often being excessively sleepy. Insomnia complaints based on DIS, DMS, and EMA were dichotomized as frequently/often versus never/rarely and summed up to obtain a number of insomnia complaints ranging from 0 to 3. The risk of obstructive sleep apnea syndrome (OSAS) was defined clinically as being obese (BMI ≥30 kg/m2), with frequent/often EDS, and frequent/often loud snoring.

                  Medications and hypnotic use

                  At baseline and at 2, 4, and 8-year follow-up, an inventory of all prescriptions and over-the-counter drugs used during the preceding month was included in a standardized interview. Medical prescriptions and the medications themselves were checked by the interviewer, thus minimizing exposure misclassification. Current use of antidepressants and hypnotics were coded according to the World Health Organization’s Anatomical Therapeutic Chemical Classification [34]. Hypnotics were classified as; benzodiazepines (BZD), BZD-like compounds (zolpidem, zopiclone), and miscellaneous medications (including barbiturates, antihistamines, and other pharmacological categories such as neuroleptics). At baseline, the participants currently taking hypnotics were also requested to report the duration of hypnotic intake.

                  Statistical analyses

                  Logistic regression models were used to compare the characteristics of participants according to the use of hypnotics at baseline after adjustment for study center, age, and gender. To analyze the associations between hypnotic use and risk of mortality, Cox proportional hazard models with delayed entry and age of the participants as the time scale were used to estimate hazard ratios (HR) and their 95% confidence intervals (CI). This method gives better adjustment for age and is therefore preferable for a sample of elderly individuals over the standard model that uses study time as the time scale, because the covariates are strongly associated with age (for example, chronic diseases) [35, 36]. Multivariate models included covariates that were associated with mortality at a conservative level of P <0.15. Model 1 was adjusted for study center, age, and gender. Model 2 was further adjusted for education, alcohol intake, smoking status, BMI, confinement, respiratory disorder, cognitive impairment, history of CVD, hypertension, and diabetes. Two other models were adjusted for diseases associated with hypnotic use to take into account possible prescription bias, for example, number of insomnia complaints and EDS (model 3); and anxiety, depressive symptomatology, and antidepressant use (model 4). The multivariate model 5 was adjusted for all possible confounders. All-cause mortality was the principal outcome defined for the analysis. In secondary analyses, cause-specific mortality due to CVD and cancer was analyzed for separate end points. If both CVD and cancer were reported as cause of death, both causes were considered in the analysis. In all final models, significance level was set at P <0.05. Analyses were performed using SAS statistical software (version 9.2; SAS Inc, Cary, NC, USA).

                  Results

                  Study population

                  As shown in the study diagram (Figure  1), the study sample included 6,696 participants free of dementia (58.7% women) with a median age of 72.8 years (range, 65.0 to 95.0 years). The 2,382 participants free of dementia excluded from the study were significantly more likely to be older, have a lower education level, were more frequently female and living alone, with confinement, hypertension, diabetes, respiratory disease, hypercholesterolemia, depressive and anxiety symptoms, cognitive impairment, past history of cardio-cerebrovascular disease, and taking more hypnotics (P <0.05 for all comparisons). They were also more likely to have died during the follow-up period (P <0.0001).
                  http://static-content.springer.com/image/art%3A10.1186%2F1741-7015-11-212/MediaObjects/12916_2013_847_Fig1_HTML.jpg
                  Figure 1

                  Flow diagram. (1) For 41 participants, the cause of death was related to both cardiovascular and cancerb.

                  At baseline, 21.7% of the participants (n = 1,454) were taking at least one hypnotic, 6.9% (n = 464) had three insomnia complaints, and 3.9% (n = 260) had no insomnia complaints. More than 3% (n = 212) reported taking two or more hypnotics. Regarding the main classes of hypnotics, 16% (n = 1070) took BZD, 4.8% (n = 321) BZD-like compounds, and 3.0% (n = 204) miscellaneous medications (of whom 54.4% took antihistamines, 25.0% non-BZD anxiolytics, 18.6% barbiturates, and 4.4% neuroleptics). With regard to duration, 4.8% (n = 304) had been taking hypnotics for less than 5 years, 3.9% (n = 244) between 5 and 10 years, 2.0% (n = 127) between 10 and 20 years, and 6.0% (n = 378) for more than 20 years.

                  Baseline sociodemographic and clinical characteristics of the participants according to hypnotic use are described in Table  1. An analysis adjusted for study center, age, and gender showed that participants taking hypnotics had a lower education level; were more likely to be confined to home; had more symptoms of depression, anxiety, and cognitive impairment; more frequently had a past history of chronic disease (CVD, thyroid disease, diabetes, hypercholesterolemia); consumed less caffeine; and reported more insomnia complaints and EDS (P <0.05 for all comparisons).
                  Table 1

                  Sociodemographic and clinical characteristics of participants according to hypnotic use at baseline

                    

                  Hypnotic use

                    

                  No N = 5,242

                  Yes N = 1,454

                  Variable

                   

                  n

                  %

                  n

                  %

                  Odds ratio [95% CI]a

                  P

                  High level of educationb

                  No

                  4,136

                  78.90

                  1,245

                  85.63

                  1

                  0.0006

                   

                  Yes

                  1,106

                  21.10

                  209

                  14.37

                  0.75 [0.63;0.88]

                   

                  Living alone

                  Yes

                  1,610

                  30.71

                  605

                  41.61

                  1

                  0.06

                   

                  No

                  3,632

                  69.29

                  849

                  58.39

                  0.88 [0.77;1.01]

                   

                  Confinement

                  No

                  5,025

                  95.86

                  1,314

                  90.37

                  1

                  <0.0001

                   

                  Yes

                  217

                  4.14

                  140

                  9.63

                  1.90 [1.51;2.40]

                   

                  Alcohol intake (g/day)

                  <12

                  955

                  18.22

                  349

                  24.00

                  1

                  0.14

                   

                  12 to 36

                  3,799

                  72.47

                  1,012

                  69.60

                  0.86 [0.75;1.00]

                   
                   

                  >36

                  488

                  9.31

                  93

                  6.40

                  0.92 [0.70;1.22]

                   

                  Caffeine intake (mg/day)

                  ≤125

                  1,310

                  24.99

                  423

                  29.09

                  1

                  0.007

                   

                  125 to 375

                  3,103

                  59.19

                  836

                  57.50

                  0.83 [0.73;0.95]

                   
                   

                  >375

                  829

                  15.81

                  195

                  13.41

                  0.76 [0.62;0.92]

                   

                  Smoking status

                  Never

                  3,033

                  57.86

                  969

                  66.64

                  1

                  0.38

                   

                  Past

                  1,901

                  36.26

                  402

                  27.65

                  0.99 [0.85;1.15]

                   
                   

                  Current

                  308

                  5.88

                  83

                  5.71

                  1.19 [0.92;1.55]

                   

                  History of cardiovascular diseasec

                  No

                  3,902

                  74.44

                  945

                  64.99

                  1

                  <0.0001

                   

                  Yes

                  1,340

                  25.56

                  509

                  35.01

                  1.59 [1.40;1.81]

                   

                  Respiratory disease

                  No

                  4,945

                  94.33

                  1,364

                  93.81

                  1

                  0.35

                   

                  Yes

                  297

                  5.67

                  90

                  6.19

                  1.13 [0.88;1.44]

                   

                  Thyroid disease

                  No

                  4,823

                  92.01

                  1,286

                  88.45

                  1

                  0.009

                   

                  Yes

                  419

                  7.99

                  168

                  11.55

                  1.29 [1.07;1.57]

                   

                  Depressive symptomatology

                  No

                  4,295

                  81.93

                  897

                  61.69

                  1

                  <0.0001

                   

                  Yes

                  947

                  18.07

                  557

                  38.31

                  2.76 [2.41;3.15]

                   

                  Antidepressants intake

                  No

                  5,081

                  96.93

                  1,196

                  82.26

                  1

                  <0.0001

                   

                  Yes

                  161

                  3.07

                  258

                  17.74

                  6.32 [5.12;7.81]

                   

                  Spielberger trait anxiety

                  <43

                  3,688

                  70.35

                  715

                  49.17

                  1

                  <0.0001

                   

                  ≥43

                  1,554

                  29.65

                  739

                  50.83

                  2.33 [2.06;2.64]

                   

                  Mini Mental State Examination Score

                  ≥ 26

                  4,559

                  86.97

                  1,190

                  81.84

                  1

                  <0.0001

                   

                  <26

                  683

                  13.03

                  264

                  18.16

                  1.40 [1.20;1.65]

                   

                  Body mass index (kg/m2)

                  Normal (<25)

                  2,477

                  47.25

                  747

                  51.38

                  1

                  0.41

                   

                  Overweight (25 to 29)

                  2,106

                  40.18

                  515

                  35.42

                  0.92 [0.81;1.05]

                   
                   

                  Obese (≥30)

                  659

                  12.57

                  192

                  13.20

                  1.00 [0.83;1.20]

                   

                  Hypertension

                  No

                  2,175

                  41.49

                  538

                  37.00

                  1

                  0.08

                   

                  Yes

                  3,067

                  58.51

                  916

                  63.00

                  1.12 [0.99;1.27]

                   

                  Diabetes mellitus

                  No

                  4,777

                  91.13

                  1,314

                  90.37

                  1

                  0.03

                   

                  Yes

                  465

                  8.87

                  140

                  9.63

                  1.25 [1.02;1.54]

                   

                  Hypercholesterolemia

                  No

                  3,349

                  63.89

                  859

                  59.08

                  1

                  0.005

                   

                  Yes

                  1,893

                  36.11

                  595

                  40.92

                  1.19 [1.05;1.34]

                   

                  Snoring loudly (n = 5,972)

                  Never/Rarely

                  3,021

                  64.30

                  863

                  67.74

                  1

                  0.63

                   

                  Frequently/Often

                  1,677

                  35.70

                  411

                  32.26

                  0.97 [0.84;1.11]

                   

                  Difficulties in initiating sleep

                  Never/Rarely

                  3,760

                  71.73

                  641

                  44.09

                  1

                  <0.0001

                   

                  Frequently/Often

                  1,482

                  28.27

                  813

                  55.91

                  2.85 [2.51;3.24]

                   

                  Difficulties in maintaining sleep

                  Never/Rarely

                  2,029

                  38.71

                  455

                  31.29

                  1

                  <0.0001

                   

                  Frequently/Often

                  3,213

                  61.29

                  999

                  68.71

                  1.29 [1.14;1.47]

                   

                  Early morning awakening

                  Never/Rarely

                  3,565

                  68.01

                  740

                  50.89

                  1

                  <0.0001

                   

                  Frequently/Often

                  1,677

                  31.99

                  714

                  49.11

                  1.85 [1.64;2.09]

                   

                  Number of insomnia complaintsd

                  0

                  1,586

                  30.26

                  260

                  17.88

                  1

                  <0.0001

                   

                  1

                  1,729

                  32.98

                  326

                  22.42

                  1.15 [0.96;1.38]

                   
                   

                  2

                  1,138

                  21.71

                  404

                  27.79

                  2.02 [1.70;2.41]

                   
                   

                  3

                  789

                  15.05

                  464

                  31.91

                  3.07 [2.56;3.68]

                   

                  Excessive daytime sleepiness

                  Never/Rarely

                  4,384

                  83.63

                  1,165

                  80.12

                  1

                  0.005

                   

                  Frequently/Often

                  858

                  16.37

                  289

                  19.88

                  1.25 [1.07;1.47]

                   

                  aAdjustment for center study, age and gender; buniversity level; chistory of cardiovascular disease (stroke or coronary heart disease); dnumber of insomnia complaints: difficulties in initiating sleep + difficulties in maintaining sleep + early morning awakening. CI, confidence interval.

                  Association between hypnotic use and 12-year mortality

                  The median follow-up time for the study was 8.9 years with a range of 0.06 to 11.7 years. During this period, 1,307 (19.5%) deaths were observed. They were particularly related to CVD (26.3%), cancer (36.8%), and co-morbid CVD and cancer (3.1%). A substantial number of deaths were due to ill-defined causes (21.6%) as the result of multiple pathologies associated with frailty, and 10.2% died from respiratory diseases.

                  Baseline sociodemographic and clinical characteristics in relation to follow-up mortality (all causes) are given in Table  2. Participants who died during follow-up were more frequently confined to home, obese, past or current smoker, consuming less alcohol, had hypertension, diabetes mellitus, a past history of CVD, respiratory disease, poorer cognitive performance, EDS, depressive symptoms, or were taking antidepressants. They also tended to have a lower level of education, and more frequently reported insomnia and anxiety symptoms (P <0.15). Subsequent analyses were adjusted for these factors. A significant association was also found for participants at risk of OSAS (n = 133; HR = 1.76; 95% CI = 1.31, 2.36; P = 0.0002).
                  Table 2

                  Baseline predictors of deaths from all causes during follow-up

                    

                  Deaths-all causes

                    
                    

                  No N = 5,389

                  Yes N = 1,307

                    

                  Variable

                   

                  n

                  %

                  n

                  %

                  Hazard ratio [95% CI]a

                  P a

                  High level of educationb

                  No

                  4,337

                  80.48

                  1,044

                  79.88

                  1

                  0.06

                   

                  Yes

                  1,052

                  19.52

                  263

                  20.12

                  0.87 [0.76;1.00]

                   

                  Living alone

                  Yes

                  1,782

                  33.07

                  433

                  33.13

                  1

                  0.84

                   

                  No

                  3,607

                  66.93

                  874

                  66.87

                  1.01 [0.89;1.15]

                   

                  Confinement

                  No

                  5,181

                  96.14

                  1,158

                  88.60

                  1

                  0.0001

                   

                  Yes

                  208

                  3.86

                  149

                  11.40

                  1.78 [1.49;2.13]

                   

                  Alcohol intake (g/day)

                  <12

                  1,062

                  19.71

                  242

                  18.52

                  1.23 [1.06;1.42]

                  0.01

                   

                  12 to 36

                  3,900

                  72.37

                  911

                  69.70

                  1

                   
                   

                  >36

                  427

                  7.92

                  154

                  11.78

                  1.14 [0.96;1.36]

                   

                  Caffeine intake (mg/day)

                  ≤125

                  1,362

                  25.27

                  371

                  28.39

                  1

                  0.86

                   

                  125 to 375

                  3,164

                  58.71

                  775

                  59.30

                  0.97 [0.85;1.09]

                   
                   

                  >375

                  863

                  16.01

                  161

                  12.32

                  0.97 [0.81;1.17]

                   

                  Smoking status

                  Never

                  3,368

                  62.50

                  634

                  48.51

                  1

                  <0.0001

                   

                  Past

                  1,740

                  32.29

                  563

                  43.08

                  1.22 [1.07;1.40]

                   
                   

                  Current

                  281

                  5.21

                  110

                  8.42

                  1.73 [1.41;2.14]

                   

                  History of cardiovascular diseasec

                  No

                  4,079

                  75.69

                  768

                  58.76

                  1

                  0.0001

                   

                  Yes

                  1,310

                  24.31

                  539

                  41.24

                  1.49 [1.33;1.67]

                   

                  Respiratory disease

                  No

                  5,121

                  95.03

                  1,188

                  90.90

                  1

                  0.0001

                   

                  Yes

                  268

                  4.97

                  119

                  9.10

                  1.64 [1.36;1.98]

                   

                  Thyroid disease

                  No

                  4,890

                  90.74

                  1,219

                  93.27

                  1

                  0.19

                   

                  Yes

                  499

                  9.26

                  88

                  6.73

                  1.16 [0.93;1.45]

                   

                  Depressive symptomatology

                  No

                  4,209

                  78.10

                  983

                  75.21

                  1

                  0.0005

                   

                  Yes

                  1,180

                  21.90

                  324

                  24.79

                  1.26 [1.11;1.43]

                   

                  Antidepressant use

                  No

                  5,072

                  94.12

                  1,205

                  92.20

                  1

                  0.0002

                   

                  Yes

                  317

                  5.88

                  102

                  7.80

                  1.47 [1.20;1.80]

                   

                  Spielberger trait anxiety

                  <43

                  3,509

                  65.11

                  894

                  68.40

                  1

                  0.13

                   

                  ≥43

                  1,880

                  34.89

                  413

                  31.60

                  1.10 [0.97;1.23]

                   

                  Mini Mental State Examination Score

                  ≥ 26

                  4,666

                  86.58

                  1,083

                  82.86

                  1

                  0.005

                   

                  <26

                  723

                  13.42

                  224

                  17.14

                  1.23 [1.07;1.43]

                   

                  Body mass index (kg/m2)

                  Normal (<25)

                  2,611

                  48.45

                  613

                  46.90

                  1

                  0.0007

                   

                  Overweight (25 to 29)

                  2,118

                  39.30

                  503

                  38.49

                  1.01 [0.90;1.14]

                   
                   

                  Obese (≥30)

                  660

                  12.25

                  191

                  14.61

                  1.36 [1.15;1.60]

                   

                  Hypertension

                  No

                  2,313

                  42.92

                  400

                  30.60

                  1

                  0.002

                   

                  Yes

                  3,076

                  57.08

                  907

                  69.40

                  1.21 [1.07;1.36]

                   

                  Diabetes mellitus

                  No

                  4,965

                  92.13

                  1,126

                  86.15

                  1

                  0.0001

                   

                  Yes

                  424

                  7.87

                  181

                  13.85

                  1.58 [1.35;1.85]

                   

                  Hypercholesterolemia

                  No

                  3,333

                  61.85

                  875

                  66.95

                  1

                  0.99

                   

                  Yes

                  2,056

                  38.15

                  432

                  33.05

                  1.00 [0.89;1.12]

                   

                  Snoring loudly (n = 5,972)

                  Never/Rarely

                  3,114

                  64.93

                  770

                  65.48

                  1

                  0.90

                   

                  Frequently/Often

                  1,682

                  35.07

                  406

                  34.52

                  1.01 [0.89;1.14]

                   

                  Difficulties in initiating sleep

                  Never/Rarely

                  3,506

                  65.06

                  895

                  68.48

                  1

                  0.20

                   

                  Frequently/Often

                  1,883

                  34.94

                  412

                  31.52

                  0.92 [0.81;1.04]

                   

                  Difficulties in maintaining sleep

                  Never/Rarely

                  2,055

                  38.13

                  429

                  32.82

                  1

                  0.26

                   

                  Frequently/Often

                  3,334

                  61.87

                  878

                  67.18

                  1.07 [0.95;1.20]

                   

                  Early morning awakening

                  Never/Rarely

                  3,434

                  63.72

                  871

                  66.64

                  1

                  0.12

                   

                  Frequently/Often

                  1,955

                  36.28

                  436

                  33.36

                  0.91 [0.81;1.02]

                   

                  Number of insomnia complaintsd

                  0

                  1,526

                  28.32

                  320

                  24.48

                  1

                  0.07

                   

                  1

                  1,595

                  29.60

                  460

                  35.20

                  1.14 [0.99;1.31]

                   
                   

                  2

                  1,227

                  22.77

                  315

                  24.10

                  1.08 [0.92;1.26]

                   
                   

                  3

                  1,041

                  19.32

                  212

                  16.22

                  0.92 [0.77;1.11]

                   

                  Excessive daytime sleepiness

                  Never/Rarely

                  4,555

                  84.52

                  994

                  76.05

                  1

                  0.003

                   

                  Frequently/Often

                  834

                  15.48

                  313

                  23.95

                  1.23 [1.07;1.40]

                   

                  aAdjusted for center study, gender and age; buniversity level; chistory of cardiovascular disease (stroke or coronary heart disease; dnumber of insomnia complaints: difficulties in initiating sleep + difficulties in maintaining sleep + early morning awakening.

                  Table  3 shows the associations between hypnotic use at baseline and all-cause mortality over the 12-year follow-up. After adjustment for age, gender, and study center, the risk of all-cause mortality increased significantly with the use of any hypnotic, the number of hypnotics, and alone for BZD (P <0.01 for all comparisons, model 1). When potential lifestyle and chronic disorder confounders were entered into the model (model 2), the HR were reduced and failed to be significant except for BZD (P = 0.05) and this was unchanged when further adjusting for sleep complaints (model 3). When adjusting for anxiety and depressive symptomatology (model 4), the associations were not significant even for BZD (P = 0.22) and this was also the case for the complete multivariate model adjusted for all potential confounders (model 5). BZD-like compounds, and miscellaneous medications intake were not associated with all-cause mortality even in the minimally adjusted model 1. No significant interaction was found for mortality between hypnotic use and EDS, number of insomnia complaints, antidepressant use, chronic diseases, or being at risk for OSAS.
                  Table 3

                  Risks of death from all causes over 12-year according to hypnotic use

                   

                  All-cause death

                       
                   

                  No

                  Yes

                  Model 1a

                  Model 2b

                  Model 3c

                  Model 4d

                  Model 5e

                  N = 5,389

                  N = 1,307

                  Variable

                  n

                  %

                  n

                  %

                  HR [95% CI]

                  P

                  HR [95% CI]

                  P

                  HR [95% CI]

                  P

                  HR [95% CI]

                  P

                  HR [95% CI]

                  P

                  Hypnotic use

                   No

                  4,261

                  79.07

                  981

                  75.06

                  1

                  0.007

                  1

                  0.16

                  1

                  0.12

                  1

                  0.50

                  1

                  0.43

                   Yes

                  1,128

                  20.93

                  326

                  24.94

                  1.19 [1.05;1.36]

                   

                  1.10 [0.96;1.25]

                   

                  1.12 [0.97;1.29]

                   

                  1.05 [0.92;1.20]

                   

                  1.06 [0.92;1.23]

                   

                  Number of hypnotics

                   0

                  4,261

                  79.07

                  981

                  75.06

                  1

                  0.003

                  1

                  0.13

                  1

                  0.13

                  1

                  0.44

                  1

                  0.47

                   1

                  970

                  18.00

                  272

                  20.81

                  1.14 [0.99;1.31]

                   

                  1.06 [0.93;1.22]

                   

                  1.09 [0.94;1.26]

                   

                  1.02 [0.89;1.18]

                   

                  1.04 [0.89;1.21]

                   

                   ≥2

                  158

                  2.93

                  54

                  4.13

                  1.53 [1.16;2.01]

                   

                  1.32 [1.00;1.74]

                   

                  1.33 [0.98;1.81]

                   

                  1.20 [0.90;1.60]

                   

                  1.21 [0.88;1.65]

                   

                  BZD

                   No

                  4,557

                  84.56

                  1069

                  81.79

                  1

                  0.003

                  1

                  0.05

                  1

                  0.05

                  1

                  0.22

                  1

                  0.21

                   Yes

                  832

                  15.44

                  238

                  18.21

                  1.24 [1.08;1.44]

                   

                  1.15 [1.00;1.33]

                   

                  1.17 [1.00;1.37]

                   

                  1.10 [0.95;1.28]

                   

                  1.11 [0.94;1.30]

                   

                  BZD-like compounds

                   No

                  5,135

                  95.29

                  1240

                  94.87

                  1

                  0.93

                  1

                  0.56

                  1

                  0.76

                  1

                  0.40

                  1

                  0.55

                   Yes

                  254

                  4.71

                  67

                  5.13

                  1.01 [0.79;1.29]

                   

                  0.93 [0.72;1.19]

                   

                  0.96 [0.74;1.25]

                   

                  0.90 [0.70;1.15]

                   

                  0.92 [0.71;1.20]

                   

                  Miscellaneous medications

                   No

                  5,241

                  97.25

                  1251

                  95.72

                  1

                  0.15

                  1

                  0.30

                  1

                  0.32

                  1

                  0.49

                  1

                  0.49

                   Yes

                  148

                  2.75

                  56

                  4.28

                  1.22 [0.93;1.60]

                   

                  1.15 [0.88;1.51]

                   

                  1.16 [0.87;1.55]

                   

                  1.10 [0.84;1.45]

                   

                  1.11 [0.83;1.48]

                   

                  aAdjusted for age, study center, and gender; badjusted for age, study center, gender, level of education, confinement, alcohol intake, smoking status, history of cardio and cerebrovascular disease, respiratory disease, Mini Mental State Examination score, body mass index, hypertension, and diabetes mellitus; cadjusted for all the covariates in model 2, plus excessive daytime sleepiness and number of insomnia complaints; dadjusted for all the covariates in model 2, plus depressive symptoms, antidepressant use and Spielberger trait anxiety score; eadjusted for all the covariates in model 3 plus depressive symptoms, antidepressants use and Spielberger trait anxiety score. BZD, benzodiazepines; CI, confidence interval; HR, hazard ratios.

                  The relationship between hypnotic intake and the risk of mortality remained unchanged after exclusion of the participants who died during the first two years of follow-up (n = 134), the follow-up rate at two years being 88%. With regard to specific causes of death, the use of hypnotics and BZD as well as number of hypnotics were associated with a significantly increased risk of CVD-related death in model 1, but not in the complete multivariate model adjusted for all potential confounders (Table  4). There was no significant association between hypnotics and cancer-related death regardless of covariates, even in the minimally-adjusted model 1 (P = 0.38).
                  Table 4

                  Risks of cardiovascular disease and cancer as causes of death over 12 years according hypnotic use

                   

                  Cardiovascular disease deaths

                  Cancer deaths

                   

                  No n = 6,311

                  Yes N = 385

                  Model 1a

                  Model 2b

                  No n = 6,174

                  Yes N = 522

                  Model 1a

                  Model 2b

                  Variable

                  n

                  %

                  n

                  %

                  HR [95% CI]

                  P

                  HR [95% CI]

                  P

                  n

                  %

                  n

                  %

                  HR [95% CI]

                  P

                  HR [95% CI]

                  P

                  Hypnotic use

                   No

                  4,962

                  78.62

                  280

                  72.73

                  1

                  0.02

                  1

                  0.56

                  4,818

                  78.04

                  424

                  81.23

                  1

                  0.38

                  1

                  0.73

                   Yes

                  1,349

                  21.38

                  105

                  27.27

                  1.32 [1.04;1.66]

                   

                  0.92 [0.71;1.20]

                   

                  1,356

                  21.96

                  98

                  18.77

                  0.90 [0.72;1.13]

                   

                  0.96 [0.74;1.23]

                   

                  Number of hypnotics

                   0

                  4,962

                  78.62

                  280

                  72.73

                  1

                  0.03

                  1

                  0.78

                  4,818

                  78.04

                  424

                  81.23

                  1

                  0.67

                  1

                  0.94

                   1

                  1,154

                  18.29

                  88

                  22.86

                  1.26 [0.99;1.61]

                   

                  0.94 [0.72;1.23]

                   

                  1,157

                  18.74

                  85

                  16.28

                  0.91 [0.72;1.15]

                   

                  0.96 [0.74;1.25]

                   

                   ≥2

                  195

                  3.09

                  17

                  4.42

                  1.69 [1.03;2.76]

                   

                  0.83 [0.45;1.52]

                   

                  199

                  3.22

                  13

                  2.49

                  0.89 [0.51;1.54]

                   

                  0.93 [0.50;1.72]

                   

                  BZD

                   No

                  5,321

                  84.31

                  305

                  79.22

                  1

                  0.004

                  1

                  0.60

                  5,170

                  83.74

                  456

                  87.36

                  1

                  0.27

                  1

                  0.42

                   Yes

                  990

                  15.69

                  80

                  20.78

                  1.45 [1.13;1.87]

                   

                  1.08 [0.81;1.43]

                   

                  1,004

                  16.26

                  66

                  12.64

                  0.86 [0.66;1.12]

                   

                  0.89 [0.66;1.19]

                   

                  BZD-like compounds

                   No

                  6,008

                  95.20

                  367

                  95.32

                  1

                  0.65

                  1

                  0.12

                  5,879

                  95.22

                  496

                  95.02

                  1

                  0.78

                  1

                  0.44

                   Yes

                  303

                  4.80

                  18

                  4.68

                  0.90 [0.56;1.44]

                   

                  0.67 [0.40;1.11]

                   

                  295

                  4.78

                  26

                  4.98

                  1.06 [0.71;1.57]

                   

                  1.18 [0.77;1.82]

                   

                  Miscellaneous medications

                   No

                  6,123

                  97.02

                  369

                  95.84

                  1

                  0.64

                  1

                  0.43

                  5,986

                  96.95

                  506

                  96.93

                  1

                  0.88

                  1

                  0.95

                   Yes

                  188

                  2.98

                  16

                  4.16

                  1.13 [0.68;1.87]

                   

                  0.80 [0.45;1.41]

                   

                  188

                  3.05

                  16

                  3.07

                  0.96 [0.58;1.59]

                   

                  1.02 [0.59;1.74]

                   

                  aAdjusted for age, study center, and gender; badjusted for all covariates in model 1 plus high level of education, confinement, alcohol intake, smoking status, history of cardio-cerebrovascular disease, respiratory disease, Mini Mental State Examination score, body mass index, hypertension and diabetes mellitus, depressive symptoms, antidepressants use, Spielberger trait anxiety score, excessive daytime sleepiness, and number of insomnia complaints. BZD, benzodiazepines; CI, confidence interval; HR, hazard ratios.

                  Duration of hypnotic use and mortality

                  Sensitivity analyses were performed to examine the relationship between persistent use of hypnotics during the initial 4 years and all-cause mortality. A total of 3,496 participants (65.9%) did not report hypnotic use at baseline or at follow-up examination, 773 (14.5%) reported use both at baseline and at the first two follow-ups (persistent users) and 1,040 (19.6%) were taking hypnotics at one of two time points (intermittent users). The risk of mortality for the next 8 years was not significantly associated with the persistent use of hypnotics (when compared with non-users, HR = 1.03, 95% CI = 0.84, 1.28 for intermittent users; HR = 1.11, 95% CI = 0.88, 1.39 for persistent users; multivariate model 5). Similar results were obtained when the analyses focused on persistent BZD users in comparison to non persistent BZD users or non BZD users.

                  We also examined the impact of past hypnotic intake duration and compared participants who were not taking sleep medication at baseline with those having previously reported taking sleep medications for less than 5 years, between 5 and 10 years, between 10 and 20 years, and for more than 20 years. No significant association was observed between duration of hypnotic intake and all-cause mortality, the global P-value ranging from 0.18 (model 1) to 0.76 (model 5) (data not shown).

                  Discussion

                  This study examined associations between hypnotic intake and risk of excess mortality (all-causes and specific causes) over a 12-year period in a large elderly cohort, taking into account a wide range of potential confounding factors. As in several previous studies we observed significant associations between hypnotic use, notably BZDs, and mortality; however, these associations became non-significant after adjustment for all potential confounding factors, notably psychiatric disorder. These findings persisted even after taking into account up to 20 years duration of past hypnotic intake or persistent versus intermittent use.

                  Previous studies have been inconsistent, with some studies observing significant relationships between hypnotic prescriptions and mortality [16, 2025, 37] and others not [1619]. Our findings suggest that these differences are probably largely due to failure to take into account confounding associations, notably common affective symptoms and sleep complaints, although other factors such as study design, participant age, and class of hypnotics probably also influence study outcome.

                  Insomnia symptoms often lead to the use of hypnotics, a condition frequently associated with EDS, anxiety, and mood disorders. Depression and anxiety are also risk factors for mortality [14, 15]. Depressive symptomatology and insomnia are both common in the elderly and in France there are no official guidelines for management, so antidepressants are often used to treat sleep disorder and hypnotics to treat depression, especially where sleep disturbance is one of the presenting symptoms [2]. EDS is also of multifactorial origin, and commonly associated with depression [7], cognitive decline [38], physical illness (particularly CVD), and mortality in older adults [5, 6, 13]. Thus, all these conditions may increase the risk of mortality in elderly patients through pathways independently of hypnotics. However, few previous studies have controlled for psychological status [17, 18, 22, 23] and in studies where depressive symptoms have been considered, antidepressant use has not been necessarily taken into account. This is important because antidepressant use may relieve depressive symptomatology, but the underlying biological risk factors associated with increased mortality may still be operating. No previous studies have controlled for anxiety or simultaneously for insomnia and EDS symptoms as potential independent confounding factors. To our knowledge, our study is the first one controlling for such a large range of potential confounding factors, especially the underlying diseases associated with hypnotic use, such as anxiety and depressive symptomatology and antidepressant use, as well as EDS and insomnia complaints. Our finding that psychiatric disorder could be a principal determinant driving the association between hypnotics and mortality risk explains previous inconsistencies.

                  Chronic use of hypnotic drugs, particularly BZD, may be associated with the risk of addiction and insomnia-rebound after withdrawal, psychomotor impairment and cognitive problems, OSAS, EDS, and car accidents [12, 39, 40]. In our sample, only one participant died from a car accident, and this person did not use hypnotics. We did not find any interaction between individuals clinically at risk for OSAS, hypnotics intake, and mortality, suggesting that if hypnotics trigger or aggravate OSAS they do not impact on mortality risk. The use of BZD may also favor falls and hip fractures and thus increase the risk for disability and death especially in the elderly [41, 42]. However some studies have suggested that nighttime sleep problems may also be significant risk factors for falls in the elderly, independently of hypnotic use [4345]. In our study, the associations between hypnotic use and all-causes or CVD-related death became non-significant after adjustment for health behavior and status variables, plus EDS and insomnia complaints.

                  An increased incidence risk for cancer was also reported in individuals using hypnotics in some studies [21, 22, 24], even in infrequent hypnotic users [22]. Our study did not report any association between hypnotic use and cancer-related death. Again, differences in adjustment of underlying co-morbid conditions frequently associated with the chronic use of hypnotics appear to explain previous findings.

                  The present study has some limitations. Unfortunately, data related to hypnotic dose were not available. Bias could have been introduced by the low participation rate at baseline and the non-random exclusion of participants with missing data at baseline – these participants were older, were more commonly hypnotics users, and more often had psychiatric and other chronic disorders that may limit the generalizability of our findings. Although unlikely, the possibility of overadjusment can not be excluded: potential confounding variables should be intermediate variables in the causal pathway between hypnotics intake and mortality. Finally, the absence of significant association between the use of hypnotics and mortality (all-causes, and CVD) after adjustments for covariates should be interpreted with caution regarding the small number of events per predictor variable.

                  Our prospective study based on a large community sample has several strengths, including the duration of the follow-up and adjustment for a wide range of possible confounding factors including sociodemographic and lifestyle factors, chronic disorders, and sleep complaints as well as depression and anxiety disorders that were found as key confounding factors in this study. Prescriptions and medications themselves were checked by the interviewer and the causes of death were established by an independent committee. Finally, excluding participants who died during the first two years of follow-up did not modify the main results, suggesting a modest confounding effect of severe undiagnosed conditions in relation to hypnotic use and death.

                  Conclusions

                  Our findings suggest that the use of hypnotics is not independently associated with an increased risk of mortality in the elderly, and that previous findings may be largely attributable to failure to take into account confounding variables, notably clinical co-morbidity, which is frequent at higher ages, particularly psychiatric disorders. Use of hypnotics might be a marker underlying more complex health issues.

                  Abbreviations

                  BMI: 

                  Body mass index

                  BZD: 

                  Benzodiazepines

                  CI: 

                  Confidence interval

                  CVD: 

                  Cardiovascular diseases

                  DIS: 

                  Difficulties in initiating sleep

                  DMS: 

                  Difficulties in maintaining sleep

                  EDS: 

                  Excessive daytime sleepiness

                  EMA: 

                  Early morning awakening

                  HR: 

                  Hazard ratios

                  ICD-10: 

                  International classification of diseases

                  OSAS: 

                  Obstructive sleep apnea syndrome.

                  Declarations

                  Acknowledgements

                  The 3C Study is conducted under a partnership agreement between Inserm, the Victor Segalen – Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and first phase of the study. The 3C-Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Regional Governments of Aquitaine, Bourgogne and Languedoc-Roussillon and, the Fondation de France, the Ministry of Research-Inserm Programme “Cohorts and collection of biological material”. The Lille Génopôle received an unconditional grant from Eisai. Part of this project is financed by grants from the Agence Nationale de la Recherche and Fondation Plan Alzheimer. None of the sponsors had any further involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

                  Authors’ Affiliations

                  (1)
                  Inserm, U1061
                  (2)
                  Université Montpellier 1
                  (3)
                  Inserm, Centre Inserm U897
                  (4)
                  ISPED, Centre Inserm U897, Université Bordeaux
                  (5)
                  Faculty of Medicine, Imperial College
                  (6)
                  CHU Montpellier, Service de Neurologie, Unité des Troubles du Sommeil, Hôpital Gui-de-Chauliac
                  (7)
                  Service de Neurologie, Hôpital Gui-de-Chauliac

                  References

                  1. Bloom HG, Ahmed I, Alessi CA, Ancoli-Israel S, Buysse DJ, Kryger MH, Phillips BA, Thorpy MJ, Vitiello MV, Zee PC: Evidence-based recommendations for the assessment and management of sleep disorders in older persons. J Am Geriatr Soc 2009, 57:761–789.PubMedView Article
                  2. Morin CM, Benca R: Chronic insomnia. Lancet 2012, 379:1129–1141.PubMedView Article
                  3. Morin CM, LeBlanc M, Daley M, Gregoire JP, Merette C: Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep Med 2006, 7:123–130.PubMedView Article
                  4. Ohayon MM, Dauvilliers Y, Reynolds CF 3rd: Operational definitions and algorithms for excessive sleepiness in the general population: implications for DSM-5 nosology. Arch Gen Psychiatry 2012, 69:71–79.PubMedView Article
                  5. Blachier M, Dauvilliers Y, Jaussent I, Helmer C, Ritchie K, Jouven X, Tzourio C, Amouyel P, Besset A, Ducimetiere P, Empana JP: Excessive daytime sleepiness and vascular events: the Three City Study. Ann Neurol 2012, 71:661–667.PubMedView Article
                  6. Jaussent I, Empana JP, Ancelin ML, Besset A, Helmer C, Tzourio C, Ritchie K, Bouyer J, Dauvilliers Y: Insomnia, daytime sleepiness and cardio-cerebrovascular diseases in the elderly: a 6-year prospective study. PLoS One 2013, 8:e56048.PubMedView Article
                  7. Jaussent I, Bouyer J, Ancelin ML, Akbaraly T, Peres K, Ritchie K, Besset A, Dauvilliers Y: Insomnia and daytime sleepiness are risk factors for depressive symptoms in the elderly. Sleep 2011, 34:1103–1110.PubMed
                  8. Mellinger GD, Balter MB, Uhlenhuth EH: Insomnia and its treatment. Prevalence and correlates. Arch Gen Psychiatry 1985, 42:225–232.PubMedView Article
                  9. Ohayon MM, Caulet M: Psychotropic medication and insomnia complaints in two epidemiological studies. Can J Psychiatry 1996, 41:457–464.PubMed
                  10. Ohayon MM, Caulet M, Priest RG, Guilleminault C: Psychotropic medication consumption patterns in the UK general population. J Clin Epidemiol 1998, 51:273–283.PubMedView Article
                  11. Quera-Salva MA, Orluc A, Goldenberg F, Guilleminault C: Insomnia and use of hypnotics: study of a French population. Sleep 1991, 14:386–391.PubMed
                  12. Vermeeren A: Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs 2004, 18:297–328.PubMedView Article
                  13. Empana JP, Dauvilliers Y, Dartigues JF, Ritchie K, Gariepy J, Jouven X, Tzourio C, Amouyel P, Besset A, Ducimetiere P: Excessive daytime sleepiness is an independent risk indicator for cardiovascular mortality in community-dwelling elderly: the three city study. Stroke 2009, 40:1219–1224.PubMedView Article
                  14. Carrière I, Ryan J, Norton J, Scali J, Stewart R, Ritchie K, Ancelin M: Anxiety and risk of death in the elderly: the Esprit study. Br J Psychiatry 2013. in press
                  15. Ryan J, Carriere I, Ritchie K, Stewart R, Toulemonde G, Dartigues JF, Tzourio C, Ancelin ML: Late-life depression and mortality: influence of gender and antidepressant use. Br J Psychiatry 2008, 192:12–18.PubMedView Article
                  16. Kojima M, Wakai K, Kawamura T, Tamakoshi A, Aoki R, Lin Y, Nakayama T, Horibe H, Aoki N, Ohno Y: Sleep patterns and total mortality: a 12-year follow-up study in Japan. J Epidemiol 2000, 10:87–93.PubMedView Article
                  17. Phillips B, Mannino DM: Does insomnia kill? Sleep 2005, 28:965–971.PubMed
                  18. Hays JC, Blazer DG, Foley DJ: Risk of napping: excessive daytime sleepiness and mortality in an older community population. J Am Geriatr Soc 1996, 44:693–698.PubMed
                  19. Rumble R, Morgan K: Hypnotics, sleep, and mortality in elderly people. J Am Geriatr Soc 1992, 40:787–791.PubMed
                  20. Hausken AM, Skurtveit S, Tverdal A: Use of anxiolytic or hypnotic drugs and total mortality in a general middle-aged population. Pharmacoepidemiol Drug Saf 2007, 16:913–918.PubMedView Article
                  21. Kripke DF, Langer RD, Kline LE: Hypnotics’ association with mortality or cancer: a matched cohort study. BMJ Open 2012, 2:e000850.PubMedView Article
                  22. Mallon L, Broman JE, Hetta J: Is usage of hypnotics associated with mortality? Sleep Med 2009, 10:279–286.PubMedView Article
                  23. Belleville G: Mortality hazard associated with anxiolytic and hypnotic drug use in the national population health survey. Can J Psychiatry 2010, 55:558–567.PubMed
                  24. Kripke DF, Garfinkel L, Wingard DL, Klauber MR, Marler MR: Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry 2002, 59:131–136.PubMedView Article
                  25. Kripke DF, Klauber MR, Wingard DL, Fell RL, Assmus JD, Garfinkel L: Mortality hazard associated with prescription hypnotics. Biol Psychiatry 1998, 43:687–693.PubMedView Article
                  26. 3C Study Group: Vascular factors and risk of dementia: design of the three-city study and baseline characteristics of the study population. Neuroepidemiol 2003, 22:316–325.View Article
                  27. Alperovitch A, Bertrand M, Jougla E, Vidal JS, Ducimetiere P, Helmer C, Ritchie K, Pavillon G, Tzourio C: Do we really know the cause of death of the very old? Comparison between official mortality statistics and cohort study classification. Eur J Epidemiol 2009, 24:669–675.PubMedView Article
                  28. World Health Organization: International Statistical Classification of Diseases and Related Health Problems. 10th edition. Geneva; Switzerland: WHO; 1992.
                  29. Radloff LS: The CES-D Scale: a self-report depression scale for research in the general population. App Psychol Measure 1977, 1:385–401.View Article
                  30. Spielberger C: Manual for the State-Trait Anxiety Inventory (Form Y). Palo Alto, CA: Consulting Psychologists Press; 1983.
                  31. Folstein MF, Folstein SE, McHugh PR: Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975, 12:189–198.PubMedView Article
                  32. World Health Organization: International Classification of Functioning, Disability and Health. Geneva, Switzerland: WHO; 2001.
                  33. Jaussent I, Dauvilliers Y, Ancelin ML, Dartigues JF, Tavernier B, Touchon J, Ritchie K, Besset A: Insomnia symptoms in older adults: associated factors and gender differences. Am J Geriatr Psychiatry 2011, 19:88–97.PubMedView Article
                  34. World Health Organization: World Health Organization Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC Classification and DDD Assignment. Oslo, Norway: WHO; 2000.
                  35. Commenges D, Letenneur L, Joly P, Alioum A, Dartigues JF: Modelling age-specific risk: application to dementia. Stat Med 1998, 17:1973–1988.PubMedView Article
                  36. Thiebaut AC, Benichou J: Choice of time-scale in Cox’s model analysis of epidemiologic cohort data: a simulation study. Stat Med 2004, 23:3803–3820.PubMedView Article
                  37. Hublin C, Partinen M, Koskenvuo M, Kaprio J: Sleep and mortality: a population-based 22-year follow-up study. Sleep 2007, 30:1245–1253.PubMed
                  38. Jaussent I, Bouyer J, Ancelin ML, Berr C, Foubert-Samier A, Ritchie K, Ohayon MM, Besset A, Dauvilliers Y: Excessive sleepiness is predictive of cognitive decline in the elderly. Sleep 2012, 35:1201–1207.PubMed
                  39. Billioti De Gage S, Begaud B, Bazin F, Verdoux H, Dartigues JF, Peres K, Kurth T, Pariente A: Benzodiazepine use and risk of dementia: prospective population based study. BMJ 2012, 345:e6231.PubMedView Article
                  40. Guilleminault C: Benzodiazepines, breathing, and sleep. Am J Med 1990, 88:25S-28S.PubMedView Article
                  41. MacDonald JB, MacDonald ET: Nocturnal femoral fracture and continuing widespread use of barbiturate hypnotics. Br Med J 1977, 2:483–485.PubMedView Article
                  42. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ 3rd: Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987, 316:363–369.PubMedView Article
                  43. Avidan AY, Fries BE, James ML, Szafara KL, Wright GT, Chervin RD: Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005, 53:955–962.PubMedView Article
                  44. Brassington GS, King AC, Bliwise DL: Sleep problems as a risk factor for falls in a sample of community-dwelling adults aged 64–99 years. J Am Geriatr Soc 2000, 48:1234–1240.PubMed
                  45. Stone KL, Ancoli-Israel S, Blackwell T, Ensrud KE, Cauley JA, Redline S, Hillier TA, Schneider J, Claman D, Cummings SR: Actigraphy-measured sleep characteristics and risk of falls in older women. Arch Intern Med 2008, 168:1768–1775.PubMedView Article
                  46. Pre-publication history

                    1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1741-7015/​11/​212/​prepub

                  Copyright

                  © Jaussent et al.; licensee BioMed Central Ltd. 2013

                  This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.