pharmacoepidemiology and drug safety 2015; 24: 779–783 Published online 17 February 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.3745
BRIEF REPORT
Hypnotics and mortality—partial confounding by disease, substance abuse and socioeconomic factors? Margit Kriegbaum1,2*, Carsten Hendriksen1,2, Mikkel Vass1,2, Erik Lykke Mortensen1,2 and Merete Osler1,3 1
Department of Public Health, University of Copenhagen, Denmark Centre for Healthy Aging, University of Copenhagen, Denmark 3 Research Centre for Prevention and Health, Glostrup University Hospital, Denmark 2
ABSTRACT Purpose The aim of this Cohort study of 10 527 Danish men was to investigate the extent to which the association between hypnotics and mortality is confounded by several markers of disease and living conditions. Methods Exposure was purchases of hypnotics 1995–1999 (“low users” (150 or less defined daily dose (DDD)) or “high users” (151 or more DDD)). Follow-up for all-cause mortality was from 1 Jan 2000 to 19 June 2010. Cox proportional hazard models were used to study the association. Covariates were entered one at a time and simultaneously. Results were reported using hazard ratio (HR) and 95% confidence intervals (CI). Results When covariates were entered one at a time, the changes in HR estimates showed that psychiatric disease, socioeconomic position and substance abuse reduced the excess risk by 17–36% in the low user group and by 45–52% in the high user group. Somatic disease, intelligence score and cohabitation reduced the excess risk by 2–11% in the low user group and 8–24% in the high user group. When adjusting for all covariates, the HR was reduced to 1.22 95% CI (0.97–1.54) in the low user group and 1.43 95% CI (1.11–1.85) in the high user group. Conclusions The results of this study point at psychiatric disease, substance abuse and socioeconomic position as potential confounding factors partly explaining the association between use of hypnotics and all-cause mortality. Copyright © 2015 John Wiley & Sons, Ltd. key words—hypnotics; mortality; socioeconomic position; co-morbidity; pharmacoepidemiology Received 28 November 2013; Revised 24 November 2014; Accepted 8 December 2014
INTRODUCTION A large proportion of the general population use hypnotics. Hypnotics are prescribed by general practitioners to a wide range of patients with both somatic and psychiatric diseases, including sleep disorders. However, some studies have raised concern about the possible hazards associated with the use of hypnotics 1–4 whereas some studies reported no association.5 The strength of the association between hypnotics and mortality depends on the definition of hypnotics and on the included covariates. Hypnotics are more frequently used by individuals from lower social classes, by people with co-morbidities and by individuals with mental health problems or substance abuse.6–10 In addition, *Correspondence to: K. Margit, Institute of Public Health, Øster Farimagsgade 5, 1014 Copenhagen, Denmark. E-mail: [email protected]
Copyright © 2015 John Wiley & Sons, Ltd.
intelligence has been linked with all-cause mortality and with health behaviors 11 and may contribute to explain the association between hypnotics and mortality. These factors should be considered when judging the hazards of hypnotics. Previous studies of the association between hypnotics and mortality have frequently adjusted for somatic conditions and health behaviors, and in some cases measures of socioeconomic position and depression have been included. However, other psychiatric conditions and substance abuse have rarely been analyzed as potential confounders of the association between hypnotics and mortality.12 Hence, it is an important methodological issue to evaluate the extent to which these factors confound the association between hypnotics and mortality. The aim of the study was to investigate the association between hypnotics and mortality and to analyze the extent to which the association is confounded by
780
m. kriegbaum et al.
socioeconomic position, intelligence, cohabitation, psychiatric and somatic disease and substance abuse. METHODS The study population was the Metropolit Cohort which comprises all boys born in Greater Copenhagen in 1953 and living in Denmark in 1968. The population was linked to data from the conscript board examination, to register data from Statistics Denmark on socioeconomic conditions in 1994 and to the Danish National Patient Register, the Danish Psychiatric Central Register and to the Danish National Prescription Registry. Vital status was retrieved from the Danish Civil Registration System (CRS) until July 2010. The present study was limited to individuals living in Denmark on 1 Jan 1996 of whom 98.6% (n = 10 334) had complete records of information on all covariates. The included cohort members all appeared before the draft board. Individuals with Down’s syndrome and other severe mental handicaps are exempted from draft board examination,13 and therefore the present study cohort consists of men who were relatively healthy during late adolescence. The Metropolit Project was approved by the Danish Data Protection Agency (protocol nr 2001-41-1547).
ICD10 codes and ATC-codes see supplementary material in appendix 1. The conscript board intelligence score was coded in tertiles with the highest tertile as reference group. Information on socioeconomic position and cohabitation was retrieved from the social registers in 1994. Socioeconomic position was coded as ‘employed manager, professional, or skilled worker’, ‘employed unskilled or semi-skilled worker’, ‘unemployed’, ‘pre-retirement pensioner’ and ‘other’. Cohabitation was coded as ‘cohabiting’ vs ‘not cohabiting’. Outcome and statistical methods Outcome was all-cause mortality between 1 Jan 1996 and 19 Jul 2010. Associations between hypnotics and mortality were analyzed using Cox’s proportional hazard regression model. Relative differences between groups are reported in hazard ratio (HR) and a 95% confidence interval (CI). Follow-up time ended at the date of death (n = 758), emigration (n = 133), disappearance (n = 7) or 19 Jul 2010 whichever came first. Proportionality assumptions were assessed by inspection of cumulative incident plots, and there was no evidence of any violation. RESULTS
Exposure variable Use of hypnotics was defined as one or more purchases of anatomical therapeutic classification (ATC) group NO5C medications (disregarding melatonin, meprobamate and scopolamine) during the period 1 Jan 1995 to 31 Dec 1999. The exposure variable was categorized into ‘no use’, ‘low users’: 1–150 defined daily doses (DDD) and ‘high users’: 151 or more DDD. The limit between low and high use corresponds to an average of 30 DDD per year which is equivalent to 1 package of 30 pills or 3 packages of 10 pills which are the most frequently sold package sizes in Denmark. Covariates Information on psychiatric and somatic disease, and substance abuse was obtained from register data on hospitalizations and prescription medicine. Somatic disease was coded as ‘none’ vs. ‘any’. Psychiatric disease was coded as ‘none’ vs. ‘admission to a psychiatric ward’, ‘other indication of psychiatric disease’ (use of antipsychotics (N05A) or antidepressants (N06) in 1995 or psychiatric diagnosis as a sidediagnosis from a somatic ward, but no admission to a psychiatric ward). Substance abuse was coded as ‘none’ and ‘any indication’. For detailed description of ICD-8 (International Classification of Diseases) and Copyright © 2015 John Wiley & Sons, Ltd.
Between 1995 and 1999, 982 (9.3%) used hypnotics. Among the users, 670 used 1 to 150 DDD and 312 used 151 DDD or more. Most commonly used hypnotics were Nitrazepam, Zopiclone, Flunitrazepam, Zolipidem, Triazolam and Estazolam (listed according to the total number of prescriptions). During follow-up 758 died. The crude HR (model 1) for all-cause mortality was HR 2.27 95% CI (1.82–2.83) for ‘low users’ and HR 4.75 95% CI (3.76–5.99) for ‘high users’. Adjusting for each of the potential confounders entered one at a time showed that psychiatric disease, socioeconomic position and substance abuse reduced the excess risk by 17–36% in the low user group and by 45–52% in the high user group. Somatic disease, intelligence score and cohabitation reduced the excess risk by 2–11% in the low user group and 8–24% in the high user group. Changes in estimates by including one covariate at a time are shown in Table 1 (model 2–7). In the fully adjusted model (model 8) the HR was reduced to 1.22 95% CI (0.97–1.54) and 1.43 95% CI (1.11–1.85) for low and high users, respectively. DISCUSSION We found an association between use of hypnotics and all-cause mortality which was substantially attenuated Pharmacoepidemiology and Drug Safety, 2015; 24: 779–783 DOI: 10.1002/pds
Copyright © 2015 John Wiley & Sons, Ltd.
547
211
9609
725
321
437
7072
3262
97
516
77
687
160
296
4907
569
128
3655
371
Model 1
4.75 (3.76–5.99)
1 (ref) 2.27 (1.82–2.83)
Model 1: Unadjusted model Model 2: Adjusted for psychiatric disease Model 3: Adjusted for somatic disease Model 4: Adjusted for substance abuse Model 5: Adjusted for IQ Model 6: Adjusted for socioeconomic position Model 7: Adjusted for cohabitation Model 8: Adjusted for all covariates
Lived with partner 1994 Did not live with partner 1994
4 pre-retirement pensioners 5 Other
1 employed higher qualifications 2 employed lower qualifications 3 unemployed
3796
459 299
7890 2444
IQ low
227
989
161 226
119
779
3340 3198
412
81
586 91
Cases
8566
312
IQ high IQ mid
No psychiatric disease Other indication of psychiatric disease Admission to a psychiatric ward No somatic disease One or more somatic comorbidities No indication of substance abuse Substance abuse
High use
9352 670
Total number
4.57 (3.85–5.43)
2.89 (2.34–3.57)
1 (ref)
2.26 (1.79–2.89)
1 (ref) 1.46 (1.16–1.84)
Model 2:
1 (ref) 1.98 (1.71–2.29)
4.09 (3.23–5.17)
1 (ref) 2.07 (1.66–2.58)
Model 3
Model 4
4.82 (4.06–5.72)
1 (ref)
2.59 (2.02–3.31)
1 (ref) 1.66 (1.33–2.09)
Use of hypnotics 1995–1999 and risk of all-cause mortality between 2000 and 2010 HR 95% CI
No hypnotics Low use
Table 1.
1.95 (1.62–2.35)
1 (ref) 1.48 (1.21–1.81)
4.38 (3.47–5.53)
1 (ref) 2.23 (1.79–2.79)
Model 5
5.36 (4.11–6.99)
7.60 (5.97–9.67)
3.23 (2.43–4.28)
1.76 (1.43–2.16)
1 (ref)
2.47 (1.93–3.15)
1 (ref) 1.88 (1.50–2.35)
Model 6
2.85 (2.46–3.29)
1 (ref)
3.62 (2.86–4.58)
1 (ref) 2.02 (1.62–2.52)
Model 7
1.75 (1.48–2.06)
1.46 (1.18–1.82) 2.01 (1.49–2.71) 2.76 (2.06–3.69) 2.63 (1.96–3.52) 1 (ref)
2.34 (1.94–2.83) 1 (ref) 1.09 (0.88–1.34) 1.12 (0.92–1.37) 1 (ref)
1 (ref)
1.56 (1.25–1.96) 1.84 (1.49–2.26) 1 (ref) 1.80 (1.55–2.09)
1 (ref) 1.22 (0.97–1.54) 1.43 (1.11–1.85) 1 (ref)
Model 8
hypnotics and mortality 781
Pharmacoepidemiology and Drug Safety, 2015; 24: 779–783 DOI: 10.1002/pds
782
m. kriegbaum et al.
after inclusion of all covariates. Psychiatric disease, substance abuse and socioeconomic position explained most of the association between use of hypnotics and all-cause mortality. However, the association between high use and mortality remained statistically significant in the model including all potential confounders. There was no statistically significant association between low use and mortality. However, the sample size was relatively small, and an association between hypnotics and mortality in the low user group cannot be ruled out on the basis of the present study. The present study is a population-based cohort study which includes all boys born in Greater Copenhagen, corresponding to about one third of all boys born in Denmark in 1953. Data on socioeconomic position in childhood, IQ and other covariates were collected prospectively from birth to midlife. Register based information provides almost complete follow-up on participants and eliminates recall-bias and has complete coverage of prescription medications purchased at Danish pharmacies. Information on covariates was also retrieved from national registers. The register-based design lacks information on minor mental disorders, physical activity, smoking, alcohol consumption and impaired sleep which is associated with mortality and with use of hypnotics and may confound the association between hypnotics and mortality. However, Mallon et al. 20093 found that sleep quality did not explain the association between hypnotics and mortality. In a sub cohort with information on health behaviors, we found that adding smoking, alcohol consumption and physical activity to the existing covariates reduced the HR by 3%, and if self-reported sleep problems were included in addition to health behaviours, the HR was reduced by 7%. It is, however, a strength that individuals with severe mental illness and substance abusers are included by using register data since these individual are usually underrepresented in surveys of the general population. We did not have access to data on causes of death for the entire follow-up period; however, between 2000 and 2009 the most common causes of death were cancers (all types) (28%), cardiovascular disease (17%) and alcoholic cirrhosis of the liver (9%) alcohol abuse/alcohol addiction (9%) (own calculations on causes of death of the study cohort). Further, our register data did not include information on actual intake of medicine. This study was limited to men, and the association with mortality may be different for women, who generally are more likely to use hypnotics.9 Use of hypnotics was measured between 1995 and 1999 and all confounders were measured before 1995. However, Copyright © 2015 John Wiley & Sons, Ltd.
use of hypnotics prior to 1995 may have affected socioeconomic position, cohabitation, somatic and mental disease and substance abuse, while it is unlikely that use of hypnotics influenced IQ, which was measured in late adolescence. This study did not have access to data to study if hypnotics used before 1995 influenced any of the confounders. The prevalence of hypnotic use and confounders change with age, and this may influence the degree to which confounders explain the association between hypnotics and mortality. Hence, our findings may not apply to other age groups. Future studies should ideally include information on both use of hypnotics and disease, socioeconomic position and comorbidities at several follow-up points, in both men and women and in different age groups. In conclusion, this study points at psychiatric disease, substance abuse and socioeconomic position as potential confounding factors influencing the association between use of hypnotics and all cause mortality. CONFLICT OF INTEREST The authors declare that they have no conflicts of interest. FUNDING This work was supported by a grant from the Center for Healthy Aging, University of Copenhagen, sponsored by The Nordea Foundation. KEY POINTS This study contributes to the knowledge about potential confounding of the association between hypnotics and mortality • Controlling for a range of disease indicators and socioeconomic position substantially reduced the association between hypnotics and all-cause mortality. However, an excess risk was found for those who purchased more than 30 DDD/year. • Psychiatric disease, substance abuse and socioeconomic position explain much of the excess mortality risk among users of hypnotics
•
ACKNOWLEDGEMENTS The authors thank K Svalastoga, E Høgh, P Wolf, T Rishøj, G Strande-Sørensen, E Manniche, B Holten, I A Weibull and A Ortmann who established the data between 1965 and 1983. Pharmacoepidemiology and Drug Safety, 2015; 24: 779–783 DOI: 10.1002/pds
hypnotics and mortality
PREVIOUS PRESENTATION OF RESULTS Preliminary results were presented at the Gerontological Society of America 65th Annual Scientific Meeting AUTHOR CONTRIBUTIONS Margit Kriegbaum drafted the paper and did the statistical analyses. Merete Osler, Mikkel Vass, Carsten Hendriksen and Erik Lykke Mortensen contributed to the design of the study, interpretation of results and critical revisal of the paper. REFERENCES 1. 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(8): 913–18. 2. Kripke DF, Langer RD, Kline LE. Hypnotics’ association with mortality or cancer: a matched cohort study. BMJ Open 2012; 2: e000850. doi:10.1136/ bmjopen-2012-000850 3. Mallon L, Broman JE, Hetta J. Is usage of hypnotics associated with mortality? Sleep Med 2009; 10(3): 279–86. 4. Belleville G. Mortality hazard associated with anxiolytic and hypnotic drug use in the National Population Health Survey. Can J Psychiatry 2010; 55(9): 558–67. 5. Rumble R, Morgan K. Hypnotics, sleep, and mortality in elderly people. J Am Geriatr Soc 1992; 40(8): 787–91.
Copyright © 2015 John Wiley & Sons, Ltd.
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6. Isacson D. Long-term benzodiazepine use: factors of importance and the development of individual use patterns over time—a 13-year follow-up in a Swedish community. Soc Sci Med 1997; 44(12): 1871–80. 7. Nielsen MW, Hansen EH, Rasmussen NK. Patterns of psychotropic medicine use and related diseases across educational groups: national cross-sectional survey. Eur J Clin Pharmacol 2004; 60(3): 199–204. 8. Sundquist J, Ekedahl A, Johansson SE. Sales of tranquillizers, hypnotics/sedatives and antidepressants and their relationship with underprivileged area score and mortality and suicide rates. Eur J Clin Pharmacol 1996; 51(2): 105–9. 9. Allgulander C, Nasman P. Regular hypnotic drug treatment in a sample of 32,679 Swedes: associations with somatic and mental health, inpatient psychiatric diagnoses and suicide, derived with automated record-linkage. Psychosom Med 1991; 53(1): 101–8. 10. Skurtveit S, Rosvold EO, Furu K. Use of psychotropic drugs in an urban adolescent population: the impact of health-related variables, lifestyle and sociodemographic factors—The Oslo Health Study 2000–2001. Pharmaco epidemiol Drug Saf 2005; 14(4): 277–83. 11. Calvin CM, Deary IJ, Fenton C, et al. Intelligence in youth and all-causemortality: systematic review with meta-analysis. Int J Epidemiol 2011; 40(3): 626–44. 12. Weich S, Pearce HL, Croft P, et al. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study. BMJ 2014; 348: g1996. doi: http://dx.doi.org/10.1136/bmj.g1996 (Published 19 March 2014). 13. Green A. The Danish Conscription Registry: a resource for epidemiological research. Dan Med Bull 1996; 43(5): 464–67.
SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article at the publisher’s web site.
Pharmacoepidemiology and Drug Safety, 2015; 24: 779–783 DOI: 10.1002/pds
BRIEF REPORT
Hypnotics and mortality—partial confounding by disease, substance abuse and socioeconomic factors? Margit Kriegbaum1,2*, Carsten Hendriksen1,2, Mikkel Vass1,2, Erik Lykke Mortensen1,2 and Merete Osler1,3 1
Department of Public Health, University of Copenhagen, Denmark Centre for Healthy Aging, University of Copenhagen, Denmark 3 Research Centre for Prevention and Health, Glostrup University Hospital, Denmark 2
ABSTRACT Purpose The aim of this Cohort study of 10 527 Danish men was to investigate the extent to which the association between hypnotics and mortality is confounded by several markers of disease and living conditions. Methods Exposure was purchases of hypnotics 1995–1999 (“low users” (150 or less defined daily dose (DDD)) or “high users” (151 or more DDD)). Follow-up for all-cause mortality was from 1 Jan 2000 to 19 June 2010. Cox proportional hazard models were used to study the association. Covariates were entered one at a time and simultaneously. Results were reported using hazard ratio (HR) and 95% confidence intervals (CI). Results When covariates were entered one at a time, the changes in HR estimates showed that psychiatric disease, socioeconomic position and substance abuse reduced the excess risk by 17–36% in the low user group and by 45–52% in the high user group. Somatic disease, intelligence score and cohabitation reduced the excess risk by 2–11% in the low user group and 8–24% in the high user group. When adjusting for all covariates, the HR was reduced to 1.22 95% CI (0.97–1.54) in the low user group and 1.43 95% CI (1.11–1.85) in the high user group. Conclusions The results of this study point at psychiatric disease, substance abuse and socioeconomic position as potential confounding factors partly explaining the association between use of hypnotics and all-cause mortality. Copyright © 2015 John Wiley & Sons, Ltd. key words—hypnotics; mortality; socioeconomic position; co-morbidity; pharmacoepidemiology Received 28 November 2013; Revised 24 November 2014; Accepted 8 December 2014
INTRODUCTION A large proportion of the general population use hypnotics. Hypnotics are prescribed by general practitioners to a wide range of patients with both somatic and psychiatric diseases, including sleep disorders. However, some studies have raised concern about the possible hazards associated with the use of hypnotics 1–4 whereas some studies reported no association.5 The strength of the association between hypnotics and mortality depends on the definition of hypnotics and on the included covariates. Hypnotics are more frequently used by individuals from lower social classes, by people with co-morbidities and by individuals with mental health problems or substance abuse.6–10 In addition, *Correspondence to: K. Margit, Institute of Public Health, Øster Farimagsgade 5, 1014 Copenhagen, Denmark. E-mail: [email protected]
Copyright © 2015 John Wiley & Sons, Ltd.
intelligence has been linked with all-cause mortality and with health behaviors 11 and may contribute to explain the association between hypnotics and mortality. These factors should be considered when judging the hazards of hypnotics. Previous studies of the association between hypnotics and mortality have frequently adjusted for somatic conditions and health behaviors, and in some cases measures of socioeconomic position and depression have been included. However, other psychiatric conditions and substance abuse have rarely been analyzed as potential confounders of the association between hypnotics and mortality.12 Hence, it is an important methodological issue to evaluate the extent to which these factors confound the association between hypnotics and mortality. The aim of the study was to investigate the association between hypnotics and mortality and to analyze the extent to which the association is confounded by
780
m. kriegbaum et al.
socioeconomic position, intelligence, cohabitation, psychiatric and somatic disease and substance abuse. METHODS The study population was the Metropolit Cohort which comprises all boys born in Greater Copenhagen in 1953 and living in Denmark in 1968. The population was linked to data from the conscript board examination, to register data from Statistics Denmark on socioeconomic conditions in 1994 and to the Danish National Patient Register, the Danish Psychiatric Central Register and to the Danish National Prescription Registry. Vital status was retrieved from the Danish Civil Registration System (CRS) until July 2010. The present study was limited to individuals living in Denmark on 1 Jan 1996 of whom 98.6% (n = 10 334) had complete records of information on all covariates. The included cohort members all appeared before the draft board. Individuals with Down’s syndrome and other severe mental handicaps are exempted from draft board examination,13 and therefore the present study cohort consists of men who were relatively healthy during late adolescence. The Metropolit Project was approved by the Danish Data Protection Agency (protocol nr 2001-41-1547).
ICD10 codes and ATC-codes see supplementary material in appendix 1. The conscript board intelligence score was coded in tertiles with the highest tertile as reference group. Information on socioeconomic position and cohabitation was retrieved from the social registers in 1994. Socioeconomic position was coded as ‘employed manager, professional, or skilled worker’, ‘employed unskilled or semi-skilled worker’, ‘unemployed’, ‘pre-retirement pensioner’ and ‘other’. Cohabitation was coded as ‘cohabiting’ vs ‘not cohabiting’. Outcome and statistical methods Outcome was all-cause mortality between 1 Jan 1996 and 19 Jul 2010. Associations between hypnotics and mortality were analyzed using Cox’s proportional hazard regression model. Relative differences between groups are reported in hazard ratio (HR) and a 95% confidence interval (CI). Follow-up time ended at the date of death (n = 758), emigration (n = 133), disappearance (n = 7) or 19 Jul 2010 whichever came first. Proportionality assumptions were assessed by inspection of cumulative incident plots, and there was no evidence of any violation. RESULTS
Exposure variable Use of hypnotics was defined as one or more purchases of anatomical therapeutic classification (ATC) group NO5C medications (disregarding melatonin, meprobamate and scopolamine) during the period 1 Jan 1995 to 31 Dec 1999. The exposure variable was categorized into ‘no use’, ‘low users’: 1–150 defined daily doses (DDD) and ‘high users’: 151 or more DDD. The limit between low and high use corresponds to an average of 30 DDD per year which is equivalent to 1 package of 30 pills or 3 packages of 10 pills which are the most frequently sold package sizes in Denmark. Covariates Information on psychiatric and somatic disease, and substance abuse was obtained from register data on hospitalizations and prescription medicine. Somatic disease was coded as ‘none’ vs. ‘any’. Psychiatric disease was coded as ‘none’ vs. ‘admission to a psychiatric ward’, ‘other indication of psychiatric disease’ (use of antipsychotics (N05A) or antidepressants (N06) in 1995 or psychiatric diagnosis as a sidediagnosis from a somatic ward, but no admission to a psychiatric ward). Substance abuse was coded as ‘none’ and ‘any indication’. For detailed description of ICD-8 (International Classification of Diseases) and Copyright © 2015 John Wiley & Sons, Ltd.
Between 1995 and 1999, 982 (9.3%) used hypnotics. Among the users, 670 used 1 to 150 DDD and 312 used 151 DDD or more. Most commonly used hypnotics were Nitrazepam, Zopiclone, Flunitrazepam, Zolipidem, Triazolam and Estazolam (listed according to the total number of prescriptions). During follow-up 758 died. The crude HR (model 1) for all-cause mortality was HR 2.27 95% CI (1.82–2.83) for ‘low users’ and HR 4.75 95% CI (3.76–5.99) for ‘high users’. Adjusting for each of the potential confounders entered one at a time showed that psychiatric disease, socioeconomic position and substance abuse reduced the excess risk by 17–36% in the low user group and by 45–52% in the high user group. Somatic disease, intelligence score and cohabitation reduced the excess risk by 2–11% in the low user group and 8–24% in the high user group. Changes in estimates by including one covariate at a time are shown in Table 1 (model 2–7). In the fully adjusted model (model 8) the HR was reduced to 1.22 95% CI (0.97–1.54) and 1.43 95% CI (1.11–1.85) for low and high users, respectively. DISCUSSION We found an association between use of hypnotics and all-cause mortality which was substantially attenuated Pharmacoepidemiology and Drug Safety, 2015; 24: 779–783 DOI: 10.1002/pds
Copyright © 2015 John Wiley & Sons, Ltd.
547
211
9609
725
321
437
7072
3262
97
516
77
687
160
296
4907
569
128
3655
371
Model 1
4.75 (3.76–5.99)
1 (ref) 2.27 (1.82–2.83)
Model 1: Unadjusted model Model 2: Adjusted for psychiatric disease Model 3: Adjusted for somatic disease Model 4: Adjusted for substance abuse Model 5: Adjusted for IQ Model 6: Adjusted for socioeconomic position Model 7: Adjusted for cohabitation Model 8: Adjusted for all covariates
Lived with partner 1994 Did not live with partner 1994
4 pre-retirement pensioners 5 Other
1 employed higher qualifications 2 employed lower qualifications 3 unemployed
3796
459 299
7890 2444
IQ low
227
989
161 226
119
779
3340 3198
412
81
586 91
Cases
8566
312
IQ high IQ mid
No psychiatric disease Other indication of psychiatric disease Admission to a psychiatric ward No somatic disease One or more somatic comorbidities No indication of substance abuse Substance abuse
High use
9352 670
Total number
4.57 (3.85–5.43)
2.89 (2.34–3.57)
1 (ref)
2.26 (1.79–2.89)
1 (ref) 1.46 (1.16–1.84)
Model 2:
1 (ref) 1.98 (1.71–2.29)
4.09 (3.23–5.17)
1 (ref) 2.07 (1.66–2.58)
Model 3
Model 4
4.82 (4.06–5.72)
1 (ref)
2.59 (2.02–3.31)
1 (ref) 1.66 (1.33–2.09)
Use of hypnotics 1995–1999 and risk of all-cause mortality between 2000 and 2010 HR 95% CI
No hypnotics Low use
Table 1.
1.95 (1.62–2.35)
1 (ref) 1.48 (1.21–1.81)
4.38 (3.47–5.53)
1 (ref) 2.23 (1.79–2.79)
Model 5
5.36 (4.11–6.99)
7.60 (5.97–9.67)
3.23 (2.43–4.28)
1.76 (1.43–2.16)
1 (ref)
2.47 (1.93–3.15)
1 (ref) 1.88 (1.50–2.35)
Model 6
2.85 (2.46–3.29)
1 (ref)
3.62 (2.86–4.58)
1 (ref) 2.02 (1.62–2.52)
Model 7
1.75 (1.48–2.06)
1.46 (1.18–1.82) 2.01 (1.49–2.71) 2.76 (2.06–3.69) 2.63 (1.96–3.52) 1 (ref)
2.34 (1.94–2.83) 1 (ref) 1.09 (0.88–1.34) 1.12 (0.92–1.37) 1 (ref)
1 (ref)
1.56 (1.25–1.96) 1.84 (1.49–2.26) 1 (ref) 1.80 (1.55–2.09)
1 (ref) 1.22 (0.97–1.54) 1.43 (1.11–1.85) 1 (ref)
Model 8
hypnotics and mortality 781
Pharmacoepidemiology and Drug Safety, 2015; 24: 779–783 DOI: 10.1002/pds
782
m. kriegbaum et al.
after inclusion of all covariates. Psychiatric disease, substance abuse and socioeconomic position explained most of the association between use of hypnotics and all-cause mortality. However, the association between high use and mortality remained statistically significant in the model including all potential confounders. There was no statistically significant association between low use and mortality. However, the sample size was relatively small, and an association between hypnotics and mortality in the low user group cannot be ruled out on the basis of the present study. The present study is a population-based cohort study which includes all boys born in Greater Copenhagen, corresponding to about one third of all boys born in Denmark in 1953. Data on socioeconomic position in childhood, IQ and other covariates were collected prospectively from birth to midlife. Register based information provides almost complete follow-up on participants and eliminates recall-bias and has complete coverage of prescription medications purchased at Danish pharmacies. Information on covariates was also retrieved from national registers. The register-based design lacks information on minor mental disorders, physical activity, smoking, alcohol consumption and impaired sleep which is associated with mortality and with use of hypnotics and may confound the association between hypnotics and mortality. However, Mallon et al. 20093 found that sleep quality did not explain the association between hypnotics and mortality. In a sub cohort with information on health behaviors, we found that adding smoking, alcohol consumption and physical activity to the existing covariates reduced the HR by 3%, and if self-reported sleep problems were included in addition to health behaviours, the HR was reduced by 7%. It is, however, a strength that individuals with severe mental illness and substance abusers are included by using register data since these individual are usually underrepresented in surveys of the general population. We did not have access to data on causes of death for the entire follow-up period; however, between 2000 and 2009 the most common causes of death were cancers (all types) (28%), cardiovascular disease (17%) and alcoholic cirrhosis of the liver (9%) alcohol abuse/alcohol addiction (9%) (own calculations on causes of death of the study cohort). Further, our register data did not include information on actual intake of medicine. This study was limited to men, and the association with mortality may be different for women, who generally are more likely to use hypnotics.9 Use of hypnotics was measured between 1995 and 1999 and all confounders were measured before 1995. However, Copyright © 2015 John Wiley & Sons, Ltd.
use of hypnotics prior to 1995 may have affected socioeconomic position, cohabitation, somatic and mental disease and substance abuse, while it is unlikely that use of hypnotics influenced IQ, which was measured in late adolescence. This study did not have access to data to study if hypnotics used before 1995 influenced any of the confounders. The prevalence of hypnotic use and confounders change with age, and this may influence the degree to which confounders explain the association between hypnotics and mortality. Hence, our findings may not apply to other age groups. Future studies should ideally include information on both use of hypnotics and disease, socioeconomic position and comorbidities at several follow-up points, in both men and women and in different age groups. In conclusion, this study points at psychiatric disease, substance abuse and socioeconomic position as potential confounding factors influencing the association between use of hypnotics and all cause mortality. CONFLICT OF INTEREST The authors declare that they have no conflicts of interest. FUNDING This work was supported by a grant from the Center for Healthy Aging, University of Copenhagen, sponsored by The Nordea Foundation. KEY POINTS This study contributes to the knowledge about potential confounding of the association between hypnotics and mortality • Controlling for a range of disease indicators and socioeconomic position substantially reduced the association between hypnotics and all-cause mortality. However, an excess risk was found for those who purchased more than 30 DDD/year. • Psychiatric disease, substance abuse and socioeconomic position explain much of the excess mortality risk among users of hypnotics
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ACKNOWLEDGEMENTS The authors thank K Svalastoga, E Høgh, P Wolf, T Rishøj, G Strande-Sørensen, E Manniche, B Holten, I A Weibull and A Ortmann who established the data between 1965 and 1983. Pharmacoepidemiology and Drug Safety, 2015; 24: 779–783 DOI: 10.1002/pds
hypnotics and mortality
PREVIOUS PRESENTATION OF RESULTS Preliminary results were presented at the Gerontological Society of America 65th Annual Scientific Meeting AUTHOR CONTRIBUTIONS Margit Kriegbaum drafted the paper and did the statistical analyses. Merete Osler, Mikkel Vass, Carsten Hendriksen and Erik Lykke Mortensen contributed to the design of the study, interpretation of results and critical revisal of the paper. REFERENCES 1. 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(8): 913–18. 2. Kripke DF, Langer RD, Kline LE. Hypnotics’ association with mortality or cancer: a matched cohort study. BMJ Open 2012; 2: e000850. doi:10.1136/ bmjopen-2012-000850 3. Mallon L, Broman JE, Hetta J. Is usage of hypnotics associated with mortality? Sleep Med 2009; 10(3): 279–86. 4. Belleville G. Mortality hazard associated with anxiolytic and hypnotic drug use in the National Population Health Survey. Can J Psychiatry 2010; 55(9): 558–67. 5. Rumble R, Morgan K. Hypnotics, sleep, and mortality in elderly people. J Am Geriatr Soc 1992; 40(8): 787–91.
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Pharmacoepidemiology and Drug Safety, 2015; 24: 779–783 DOI: 10.1002/pds
