Sleep Disorders and Increased Risk of Subsequent Acute Coronary Syndrome in Individuals without Sleep Apnea: A Nationwide Population-Based Cohort Study
Wei-Sheng Chung, MD, PhD1,2; Cheng-Li Lin, MSc3; Yung-Fu Chen, PhD2; John Y. Chiang, PhD4; Fung-Chang Sung, PhD3,5; Yen-Jung Chang, PhD3,6;
Chia-Hung Kao, MD7,8
1Department of Internal Medicine, Taichung Hospital, Department of Health, Executive Yuan, Taichung, Taiwan; 2Department of Healthcare
Administration, Central Taiwan University of Science and Technology, Taichung, Taiwan;
3Management Office for Health Data, China Medical
University Hospital, Taichung, Taiwan; 4Department of Computer Science and Engineering, National Sun Yat-Sen University, Taiwan; 5Institute of
Public Health, College of Public Health, China Medical University, Taichung, Taiwan; 6Department of Health Promotion and Health Education,
National Taiwan Normal University, Taipei, Taiwan; 7Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine,
China Medical University, Taichung, Taiwan; 8Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
INTRODUCTION
Insomnia is a common complaint in the general population.1-3 Insomnia or sleep disturbance is the most prevalent sleep disorder.
Insomnia is defined as difficulty in falling asleep, remaining asleep, and early final awakening. The association is clear
between sleep disorders and comorbidities such as prior psychiatric disorders, circulatory diseases, and gastrointestinal diseases.3 Conversely, insomnia may predispose patients to cardiovascular and cerebrovascular risk factors. More than 50% of stroke patients have sleep disordered breathing, mostly in the form of obstructive sleep apnea, which is recognized as an independent
risk factor for cardiovascular diseases (CVDs) and cerebrovascular diseases (CVAs).4,5 However, studies investigating the
possibility that nonapnea sleep disorders may increase acute coronary syndromes (ACSs) are scant. Vgontzas et al.6 showed that
insomnia with short sleep duration is associated with increased
risk of hypertension in a cross-sectional study. The longitudinal study by Fernandez-Mendoza et al.7 further demonstrated that
the risk of incident hypertension was significantly increased in insomnia with objective short sleep duration. Recent studies have also shown insomnia to be associated with atherosclerosis risk.8 ACS types, including unstable angina and myocardial infarction with or without ST-segment elevation, are life-threatening disorders that retain high morbidity and mortality despite
advances in treatment.9 Grandner et al.10 showed the association between sleep disorders and increased risk of myocardial
infarction. However, this study did not objectively assess
sleep apnea and, therefore, could not control for its contribution to the increased risk of myocardial infarction. We evaluate sleep disorders other than sleep apnea in association with the development of ACS in Taiwan. The study results are from a
nationwide population-based cohort study assessing the possibilities of increased risk of ACS among patients with nonapnea
sleep disorders. The original data were derived from Taiwan’s National Health Insurance Research Database (NHIRD).
MATERIALS AND METHODS Data Sources
The National Health Insurance (NHI) program in Taiwan is a universal insurance system established by the Bureau of National Health Insurance in the Department of Health and was implemented in 1995. The insurance program provides healthcare
to 99% of the 23.74 million people in Taiwan, and has a contract with 97% of Taiwan hospitals and clinics.11 The National
Health Research Institute (NHRI) possesses the registration and claims data of 1 million persons, systematically selected from all insurants. The NHRI in Taiwan manages the NHI data bank. The NHI dataset includes information on medical facility registries, details of inpatient orders, ambulatory care, dental services, prescribed drugs, physicians providing services, and
contains registration files with encrypted identification. Diagnoses are coded according to the International Classification of
Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
This cohort study was approved by the Ethics Review Board of China Medical University (CMU-REC-101-012).
Study Participants
We selected patients with newly identified sleep disorders other than sleep apnea as the nonapnea sleep disorders cohort, including nonorganic sleep disorders and sleep disturbances diagnosed by physicians (ICD-9-CM codes 307.4 and 780.5) from January 1997 to December 2001. The date of nonapnea sleep disorder diagnosis was used as the index date. We excluded patients who had sleep apnea syndrome (ICD-9-CM codes 780.51, 780.53, and 780.57) and patients with a history of ACS before the index date. Nonapnea sleep disorders were classified into insomnia (ICD-9-CM code 780.52), sleep disturbance
(ICD-9-CM code 780.5), unspecified sleep disturbance (ICD- 9-CM code 780.50), unspecified hypersomnia (ICD-9-CM code 780.54), unspecified disruptions of 24-h sleep-wake cycle (ICD- 9-CM code 780.55), dysfunctions associated with sleep stages or arousal from sleep (ICD-9-CM code 780.56), unspecified sleep related movement disorder (ICD-9-CM code 780.58), and other (ICD-9-CM code 780.59), and other sleep disorders including specific disorders of sleep of nonorganic origin (ICD- 9-CM code 307.4). The comparison cohort comprised randomly selected patients without a history of sleep disorders, sleep apnea, and ACS, frequency matched by sex, age, and index date.
Two participants were selected for the comparison cohort for each nonapnea sleep disorder participant.
Outcome Measures
The person-y of follow-up were estimated for
study patients from the index date to ACS diagnoses, including acute myocardial infarction and
unstable angina (ICD-9-CM codes 410 and 411.1), censoring caused by death during hospitalization, loss to follow-up, withdrawal from the insurance
system, or the end of December 31, 2010. Comorbidities included in our study were hypertension
(ICD-9-CM codes 401-405), DM (ICD-9-CM code 250), hyperlipidemia (ICD-9-CM code 272), CVA (ICD-9-CM codes 430-438), depression (ICD- 9-CM codes 296.2, 296.3, 300.4, and 311), and chronic obstructive pulmonary disease (COPD;
ICD-9-CM codes 490-496).
Statistical Analysis
All statistical analyses were performed using SAS 9.2 (SAS Institute Inc., Cary, NC, USA). The
proportionate distribution of demographic characteristics and comorbidities between the cohorts of
nonapnea sleep disorders and nonsleep disorders were compared and tested using the χ2 test. The mean age between both cohorts was measured and tested using the t test. We assessed the overall, sex- and age-specific incidences of ACS for both nonapnea sleep disorder and nonsleep disorder cohorts, and used Cox proportional hazard regression analysis to estimate the hazard ratios
(HRs) with 95% confidence intervals (CIs) of ACS development in the nonapnea sleep disorder cohort, and compared with the nonsleep disorder cohort. The Cox proportion hazard regression models were used to assess the effects of nonapnea sleep disorders on the risk of ACS after adjusting for variables that the χ2 analyses showed to have a significant association. We
also measured the incidence associated with a specific comorbidity for both cohorts, and the HR for those with the comorbidity
compared with those without the comorbidity. To assess
the difference in the ACS-free rates between the two cohorts, we applied Kaplan-Meier analysis and the log-rank test.
RESULTS
The prevalence of nonapnea sleep disorder patients from 1997 to 2001 was 0.47% in 1997, 0.93% in 1998, 2.2% in 1999, 3.37% in 2000, and 4.1% in 2001. During 1997-2001, we identified 49,099 patients for the nonapnea sleep disorder cohort and
98,198 patients for the nonsleep disorder cohort. Almost half of the patients were 41-65 y of age, and 63.7% were women. The distribution of age and sex was similar between the two cohorts.
The nonapnea sleep disorder cohort was more prevalent with hypertension, DM, hyperlipidemia, CVA, COPD, and heart
failure than the nonsleep disorder cohort (P < 0.0001) (Table 1).
During the follow-up period, the overall incidence of ACS was almost twofold higher in patients with nonapnea sleep disorders than in patients with nonsleep disorders (14.6 versus 7.66 per 10,000 person-y) (Table 2). After adjusting for the covariates, the risk of developing ACS remained significant for patients
with nonapnea sleep disorders (HR = 1.43; 95% CI = 1.29-1.60). Men had a higher incidence of ACS in both cohorts and a 57%
increase of ACS risk, compared with women. The incidence of ACS increased with age in both cohorts. The age-specific crude relative risk of ACS for patients with nonapnea sleep disorders was higher in young adults than in middle-aged and older adults (age 40 y or younger, crude HR = 2.91, 95% CI = 1.63-5.19;
41-65 y of age, crude HR = 2.06, 95% CI = 1.77-2.40; older than 65 y, crude HR = 1.69, 95% CI = 1.46-1.95, respectively).
However, the adjusted HR was 5.02 (95% CI = 3.37-6.76) for middle-aged adults and 8.90 (95% CI = 6.56-12.10) for older adults compared with young adults (age 40 y or younger). The incidence of ACS increased with increased numbers of comorbidities in both cohorts. After adjusting for sex and age, patients
with more than three comorbidities had a 5.09-fold risk of developing ACS compared with those without comorbidities (Table 2).
However, the effect of nonapnea sleep disorders on the risk of ACS development decreased if only one comorbidity was
considered (Table 3). The multivariable Cox model showed that hypertension, DM, and hyperlipidemia were also significant
factors associated with the increased risk of ACS. We also observed the interactions between nonapnea sleep disorders and certain comorbidities including DM, CVA, and hyperlipidemia.
We further examined the association between ACS risk and different subgroups of nonapnea sleep disorder, and we determined the adjusted HRs to be 1.28 for insomnia, 1.51 for sleep disturbance, and 1.71 for other sleep disorders (Table 4).
Figure 1 shows the Kaplan-Meier curves of freedom from ACS in both cohorts. A significant difference exists in ACS occurrence between the nonapnea sleep disorders cohort and the nonsleep disorders cohort (log-rank test, P < 0.0001).
DISCUSSION
ACS includes life-threatening diseases that possess high morbidity and mortality despite advances in treatment.9 The ACS risk factors are similar to those for stroke, and include older age, hypertension, hyperlipidemia, DM, cigarette smoking, and lack of physical activity. Obstructive sleep apnea is associated with an increased risk of CVD and stroke, and is also strongly associated with obesity, insulin resistance, dyslipidemia, and hypertension.12,13 Screening for and treating obstructive sleep apnea in patients with coronary artery disease who may undergo percutaneous coronary intervention may result in a decreased risk of cardiac death.14 A previous study, by Grandner et al.,10 demonstrated an association between sleep disorders and increased risk
of myocardial infarction. However, this study did not objectively
assess sleep apnea and, therefore, could not control for its contribution to the increased risk of myocardial infarction.
Several cohort studies have observed that insomnia symptoms are associated with a moderately increased risk of CVD.15-17 Nonetheless, these studies did not exclude participants with obstructive sleep apnea, which may accentuate the association.
Studies addressing the association between nonapnea sleep disorders and CVD are scant. According to our research, this study is
the first to provide epidemiologic data for the Asian population to address the association between nonapnea sleep disorders and ACS. The yearly prevalence rate of nonapnea sleep disorders in this study increased from 0.47% in 1997 to 4.1% in 2001, which may explain why the participants sought medical treatment for their sleep disorders in increasingly greater numbers. However, the prevalence was lower than in previous studies conducted in other countries, ranging from 10-40%.16,18-21 Patients with
insomnia have been observed to rarely visit a physician to discuss their sleep problems, and four of 10 patients self-medicated with nonprescription medication or with alcohol.22 Most patients with nonapnea sleep disorder were middle-aged adults, signifying a possible association with psychological stress.23 A significant association was observed in our study between nonapnea sleep
disorders and comorbidities such as hypertension, DM, hyperlipidemia, CVA, COPD, and heart failure, a finding that is consistent
with those of previous studies.7,8,24,25
Most patients in the nonapnea sleep disorders cohort in our study were women. Numerous studies have observed a female preponderance of insomnia; the meta-analysis of Zhang and Wing26 and other studies27,28 also confirmed a high female insomnia risk. After adjusting for age and other comorbidities, we observed that men with nonapnea sleep disorders had a higher risk of developing ACS than did women, which is consistent with findings of previous studies.29,30 However, it is not supported by the study by Laugsand et al.,16 who reported that women have a slightly higher risk of acute myocardial infarction than men because of difficulties in initiating sleep, and cumulative insomnia symptoms. In addition, the agespecific crude relative risk showed that the effect of nonapnea
sleep disorders on ACS risk was higher among young adults than middle-aged and older adults. However, the risk of ACS increased with age after adjusting for sex and comorbidities.
This might be because older adults have a higher proportion of comorbidities interacting with nonapnea sleep disorders,
leading to development of ACS. This epiphenomenon can be explained by ACS risk having increased when the patients had more comorbidities in addition to nonapnea sleep disorders.
Conversely, the effect of nonapnea sleep disorders on the risk of ACS development decreased if only one comorbidity was considered. This phenomenon can be explained by effect modification. We observed the interactions between nonapnea sleep disorders and certain comorbidities including DM, CVA, and hyperlipidemia. Comorbidities such as hypertension, DM, and hyperlipidemia also increased the risk of ACS in our study.
Patients with nonapnea sleep disorder with more than three comorbidities had a 5.09-fold risk of developing ACS compared to those without comorbidities.
The nonapnea sleep disorders cohort in the current study had a 1.43-fold increased risk of subsequent ACS compared with the nonsleep disorders cohort after controlling for age, sex, and comorbidities. The results were relatively robust in different
multivariable models. Studies have found inconsistent cardiovascular effects of insomnia by using questionnaires or other
methods,6,31-35 which differs from our study population based on
physician diagnoses. We further examined the subgroup effects of nonapnea sleep disorders on ACS risk and determined the adjusted HRs to be 1.28 for insomnia, 1.51 for sleep disturbance, and 1.71 for other sleep disorders. Although there are several potential mechanisms, the nature of the association between nonapnea sleep disorders and ACS remains unclear.36,37 A recent study by Fernandez-Mendoza et al.7 showed that insomnia with short sleep duration increased the risk of incident hypertension.
Objective short sleep duration in insomnia may serve as a useful predictor of the biological severity of incident hypertension.7 Our study also showed that a significantly higher proportion of hypertension and hyperlipidemia existed in the nonapnea sleep disorder cohort than in the nonsleep disorder cohort. Nakazaki et al.8 observed that insomnia and short sleep duration were
associated with atherosclerosis risk leading to CVD. Atherosclerosis and incident hypertension may predispose patients
to sudden reduced or occluded blood flow of the coronary arteries, which may explain why the patients in our study with nonapnea sleep disorders were shown to have a higher risk of developing ACS. We conducted further mediation analysis and found that the inclusion of hypertension and hyperlipidemia in the multivariable models attenuated the effect of nonapnea sleep disorders on the risk of ACS (the adjusted HR decreased from 1.59 to 1.41 after adding hypertension to the multivariable model that included sex, age, DM, CVA, COPD, and depression, to 1.55 after adding hyperlipidemia, and to 1.43 after
controlling for hypertension and hyperlipidemia together).
To evaluate the contribution of more specific sleep disorders, the sleep disorder diagnoses associated with ACS incidence were further analyzed. Results showed that 40.2% of sleep disorders had been diagnosed as insomnia, 37.2% as sleep disturbance, and 22.6% as others. The incidence rates of ACS were 14.3, 13.5, and 17.0 per 10,000 person-y, with adjusted HRs of 1.28 (95% CI = 1.10-1.47), 1.52 (95% CI = 1.31-1.76), and 1.61 (95% CI = 1.36-1.90), respectively.
However, our study has limitations. First, the NHIRD does not provide detailed patient information such as smoking habits, alcohol consumption, body mass index, physical
activity, socioeconomic status, and family history, which all are potential confounding factors in this study. However, these factors may be randomly distributed in these two large cohorts.
Second, the evidence derived from a retrospective cohort study is of lower methodological quality than that from randomized trials because a retrospective cohort study design is subject to certain biases related to confounder adjustments. Third, the lack of data on objective sleep measurement or other mental health conditions highly comorbid with sleep disorders and a history of medication is a critical limitation. In addition, a possible
survival effect may be another limitation. Despite these limitations, the strength of this study is in providing a nationwide
population-based cohort longitudinal study for the Asian
population regarding the link between nonapnea sleep disorders and the risk of subsequent ACS events. Our findings may
benefit from further analyses regarding specific sleep disorders contributing to ACS incidence in future studies. In summary, we found that patients with nonapnea sleep disorders are at a higher risk of developing ACS, and this risk increases with age.
Because the number of patients with nonapnea sleep disorders is increasing, enhancing sleep disorder management may be vital for ACS prevention.
