Polysomnographic Assessment of Sleep Disturbances in Cancer Development: A Historical Multicenter Clinical Cohort Study.

BACKGROUND: Many cellular processes are controlled by sleep. Therefore, alterations in sleep might be expected to stress biological systems that could influence malignancy risk. RESEARCH QUESTION: What is the association between polysomnographic measures of sleep disturbances and incident cancer, and what is the validity of cluster analysis in identifying polysomnography phenotypes? STUDY DESIGN AND METHODS: We conducted a retrospective multicenter cohort study using linked clinical and provincial health administrative data on consecutive adults free of cancer at baseline with polysomnography data collected between 1994 and 2017 in four academic hospitals in Ontario, Canada. Cancer status was derived from registry records. Polysomnography phenotypes were identified by k-means cluster analysis. A combination of validation statistics and distinguishing polysomnographic features was used to select clusters. Cox cause-specific regressions were used to assess the relationship between identified clusters and incident cancer. RESULTS: Among 29,907 individuals, 2,514 (8.4%) received a diagnosis of cancer over a median of 8.0 years (interquartile range, 4.2-13.5 years). Five clusters were identified: mild (mildly abnormal polysomnography findings), poor sleep, severe OSA or sleep fragmentation, severe desaturations, and periodic limb movements of sleep (PLMS). The associations between cancer and all clusters compared with the mild cluster were significant while controlling for clinic and year of polysomnography. When additionally controlling for age and sex, the effect remained significant only for PLMS (adjusted hazard ratio [aHR], 1.26; 95% CI, 1.06-1.50) and severe desaturations (aHR, 1.32; 95% CI, 1.04-1.66). Further controlling for confounders, the effect remained significant for PLMS, but was attenuated for severe desaturations. INTERPRETATION: In a large cohort, we confirmed the importance of polysomnographic phenotypes and highlighted the role that PLMS and oxygenation desaturation may play in cancer. Using this study's findings, we also developed an Excel (Microsoft) spreadsheet (polysomnography cluster classifier) that can be used to validate the identified clusters on new data or to identify which cluster a patient belongs to. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT03383354 and NCT03834792; URL: www. CLINICALTRIALS: gov.

Polysomnographic Markers of Obstructive Sleep Apnea Severity and Cancer-related Mortality: A Large Retrospective Multicenter Clinical Cohort Study.

Rationale: The evidence for an association between cancer survival and obstructive sleep apnea (OSA) remains underexplored. Objectives: To evaluate an association between markers of OSA severity (respiratory disturbances, hypoxemia, and sleep fragmentation) and cancer-related mortality in individuals with previously diagnosed cancer. Methods: We conducted a multicenter retrospective cohort study using linked clinical and provincial health administrative data on consecutive adults who underwent a diagnostic sleep study between 1994 and 2017 in four Canadian academic hospitals and were previously diagnosed with cancer through the Ontario Cancer Registry. Multivariable cause-specific Cox regressions were used to address the research objective. Results: We included 2,222 subjects. Over a median follow-up time of 5.6 years (interquartile range [IQR], 2.7-9.1 years), 261/2,222 (11.7%) individuals with prevalent cancer died from cancer-related causes, which accounted for 44.2% (261/590) of all-cause death. Controlling for age, sex, alcohol use disorder, prior heart failure, chronic obstructive pulmonary disease, hypertension, diabetes, treatment for OSA, clinic site, year of the sleep study, and time since the cancer diagnosis, measures of hypoxemia and sleep fragmentation, but not apnea-hypopnea index, were significantly associated with the cancer-specific mortality: percentage of time spent with arterial oxygen saturation (SaO2) < 90% (hazard ratio [HR] per 5% increase, 1.05; 95% confidence interval, 1.01-1.09); mean SaO2 (HR per 3% increase, 0.79; 0.68-0.92); and percentage of stage 1 sleep (HR per 16% increase, 1.27; 1.07-1.51). Conclusions: In a large clinical cohort of adults with suspected OSA and previously diagnosed cancer, measures of nocturnal hypoxemia and sleep fragmentation as markers of OSA severity were significantly associated with cancer-related mortality, suggesting the need for more targeted risk awareness.

The relationship between opioid use and obstructive sleep apnea: A systematic review and meta-analysis.

We conducted a systematic review to address limited evidence suggesting that opioids may induce or aggravate obstructive sleep apnea (OSA). All clinical trials or observational studies on adults from 1946 to 2018 found through MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane Databases were eligible. We assessed the quality of the studies using published guidelines. Fifteen studies (six clinical trials and nine observational) with only two of good quality were included. Fourteen studies investigated the impact of opioids on the presence or severity of OSA, four addressed the effects of treatment for OSA  in opioid users, and none explored the consequences of opioid use in individuals with OSA. Eight of 14 studies found no significant relationship between opioid use or dose and apnea-hypopnea index (AHI) or degree of nocturnal desaturation. A random-effects meta-analysis (n = 10) determined the pooled mean change in AHI associated with opioid use of 1.47/h (-2.63-5.57; I2 = 65%). Three of the four studies found that continuous positive airway pressure (CPAP) therapy reduced AHI by 17-30/h in opioid users with OSA. Bilevel therapy with a back-up rate and adaptive servo-ventilation (ASV) without mandatory pressure support successfully normalized AHI (≤5) in opioid users. Limited by a paucity of good-quality studies, our review did not show a significant relationship between opioid use and the severity of OSA. There was some evidence that CPAP, Bilevel therapy, and ASV alleviate OSA for opioid users, with higher failure rates observed in patients on CPAP in opioid users.

Obstructive Sleep Apnea and Incident Cancer: A Large Retrospective Multicenter Clinical Cohort Study.

BACKGROUND: To examine the association between the severity of obstructive sleep apnea (OSA) and nocturnal hypoxemia with incident cancer. METHODS: This was a multicenter retrospective clinical cohort study using linked clinical and provincial health administrative data on consecutive adults who underwent a diagnostic sleep study between 1994 and 2017 in four academic hospitals (Canada) who were free of cancer at baseline. Cancer status was derived from the Ontario Cancer Registry. Cox cause-specific regressions were utilized to address the objective and to calculate the 10-year absolute risk difference (ARD) in the marginal probability of incident cancer and the number needed to harm (NNH). RESULTS: Of 33,997 individuals considered, 33,711 with no missing OSA severity were included: median age, 50 years; 58% male; and 23% with severe OSA (apnea-hypopnea index >30). Of the 18,458 individuals with information on sleep time spent with oxygen saturation (SaO2) <90%, 5% spent >30% of sleep with SaO2 <90% (severe nocturnal hypoxemia). Over a median of 7 years, 2,498 of 33,711 (7%) individuals developed cancer, with an incidence rate of 10.3 (10.0-10.8) per 1,000 person-years. Controlling for confounders, severe OSA was associated with a 15% increased hazard of developing cancer compared with no OSA (HR = 1.15, 1.02-1.30; ARD = 1.28%, 0.20-2.37; and NNH = 78). Severe hypoxemia was associated with about 30% increased hazard (HR = 1.32, 1.08-1.61; ARD = 2.38%, 0.47-4.31; and NNH = 42). CONCLUSIONS: In a large cohort of individuals with suspected OSA free of cancer at baseline, the severity of OSA and nocturnal hypoxemia was independently associated with incident cancer. IMPACT: These findings suggest the need for more targeted cancer risk awareness in individuals with OSA.

Cardiovascular consequences of obstructive sleep apnea in women: a historical cohort study.

OBJECTIVE/BACKGROUND: Evidence on sex differences in the association between obstructive sleep apnea (OSA) and cardiovascular outcomes is limited and controversial. We conducted a historical cohort study to investigate this relationship. PATIENTS/METHODS: Clinical data on adults who underwent sleep study at a large urban academic hospital (Toronto, Canada) between 1994 and 2010 were linked to provincial health administrative data from 1991 to 2015. We fit Cox regressions to investigate the association between OSA severity and a cardiovascular composite outcome (all-cause mortality or hospitalization due to myocardial infarction, stroke, heart failure or atrial fibrillation), controlling for risk factors and stratifying by sex. RESULTS: A total of 10,149 subjects were included: median age of 49 years, 38% women. Over a median of 9.3 years, 1782 (18%) participants developed an outcome. The association between percentage of sleep time spent with oxygen saturation <90% and outcome was stronger for women (HR for IQR, 3 vs 0% = 1.30, 1.19-1.42) than for men (HR for IQR = 1.13, 1.06-1.21) (p for interaction = 0.01) in the adjusted model. Stratifying by sex, oxygen desaturations and heart rate in sleep were significant predictors in both men and women, while presence of daytime sleepiness, sleep efficiency and periodic leg movements in sleep were predictive in women but not in men. CONCLUSIONS: In a large clinical cohort with suspected OSA, the impact of OSA as measured by the degree of nocturnal oxygen desaturation on the composite outcome was found to be greater in women than in men. We also found a different predictive ability of OSA-related factors by sex.

Cardiovascular Outcomes and All-Cause Mortality in Patients with Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease (Overlap Syndrome).

RATIONALE: The combined impact of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) on cardiovascular outcomes remains controversial. OBJECTIVES: We determined whether the combined presence of COPD and severe OSA defined by the apnea-hypopnea index (AHI) or degree of nocturnal hypoxemia is associated with increased hazards of cardiovascular events and mortality. METHODS: Prospectively collected data from adults with suspected OSA who underwent sleep study between 1994 and 2010 were linked to provincial administrative data to determine a presence of COPD and composite outcome. Exposures of interest were: 1) AHI greater than 30, and 2) 10 or more minutes of sleep time spent with oxygen saturation (SaO2) less than 90%. The primary outcome was a composite of hospitalization due to myocardial infarction, stroke, congestive heart failure, cardiac revascularization procedures, or death from any cause. Using Cox regression and controlling for confounders, hazards were compared between four groups: AHI greater than 30 with COPD, AHI greater than 30 without COPD, AHI less than or equal to 30 with COPD, and AHI less than or equal to 30 without COPD (reference). A similar approach was used for the degree of nocturnal hypoxemia. Relative excess risk due to interaction (RERI) was calculated. To adjust for the effect of positive airway pressure treatment, given that information on its acceptance, but not adherence, was available, a separate analysis was conducted only on untreated individuals who never claimed a positive airway pressure device. RESULTS: Among 10,149 participants, 30% had AHI greater than 30, 25% spent at least 10 minutes of sleep with SaO2 less than 90%, and 12% had COPD. Over a median of 9.4 years, 16.4% developed an outcome. In the total sample, a greater hazard of outcome was observed in individuals with COPD who spent at least 10 minutes of sleep with SaO2 less than 90% (hazard ratio, 1.91; 95% confidence interval [CI], 1.60 to 2.28) but not with AHI greater than 30; a synergistic effect was found in women (RERI, 1.18; 95% CI, 0.05 to 2.30), but not men (RERI, -0.08; 95% CI, -0.47 to 0.32). The highest hazard of outcome was associated with the co-occurrence of AHI greater than 30 and COPD in untreated individuals (hazard ratio, 2.01; 95% CI, 1.55 to 2.62); a synergistic effect was not found. CONCLUSIONS: In adults with suspected OSA, the co-occurrence of nocturnal hypoxemia and COPD was associated with an increased hazard of cardiovascular events and mortality with a synergistic effect found only in women.

Sleep Apnea Increases the Risk of New Hospitalized Atrial Fibrillation: A Historical Cohort Study.

OBJECTIVES: This study examined the relationship between newly diagnosed OSA and incident hospitalized atrial fibrillation (AF) over the subsequent 10 years in a large arrhythmia-free cohort. METHODS: Adults referred between 1994 and 2010 to a large academic hospital with suspected OSA who were arrhythmia-free at the time of the first diagnostic sleep study were included. Clinical data were linked to provincial health administrative data to define outcome. Cox regressions were used to investigate the relationship between severity of OSA as measured by the apnea-hypopnea index (AHI) and degree of nocturnal hypoxemia, and incident hospitalized AF. RESULTS: In total, 8,256 subjects were included in this study. Their median age was 47 years, 62% were men; 28% had an AHI > 30 events per hour, and 6% spent > 30% of sleep time with oxygen saturation < 90%. Over a median follow-up of 10 years (interquartile range, 7-13 years), 173 participants (2.1%) were hospitalized with AF. Controlling for age, sex, alcohol consumption, smoking status, previous heart failure, COPD, and pulmonary embolism, nocturnal hypoxemia (but not AHI) was a significant predictor of incident AF: hazard ratio, 2.47 (95% CI, 1.64-3.71). After further controlling for BMI and hypertension, this association was attenuated but remained significant (hazard ratio, 1.77 [95% CI, 1.15-2.74]). CONCLUSIONS: In a large arrhythmia-free clinical cohort with suspected OSA, nocturnal hypoxemia was independently associated with a 77% increased hazard of incident hospitalized AF. These findings further support a relationship between OSA, nocturnal hypoxemia, and new-onset AF, and they may be used to enhance AF prevention in patients with OSA and severe nocturnal hypoxemia.

Distinct Patterns of Hyperpnea During Cheyne-Stokes Respiration: Implication for Cardiac Function in Patients With Heart Failure.

STUDY OBJECTIVES: In heart failure (HF), we observed two patterns of hyperpnea during Cheyne-Stokes respiration with central sleep apnea (CSR-CSA): a positive pattern where end-expiratory lung volume remains at or above functional residual capacity, and a negative pattern where it falls below functional residual capacity. We hypothesized the negative pattern is associated with worse HF. METHODS: Patients with HF underwent polysomnography. During CSR-CSA, hyperpnea, apnea-hyperpnea cycle, and lung to finger circulation times (LFCT) were measured. Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration and left ventricular ejection fraction (LVEF) were assessed. RESULTS: Of 33 patients with CSR-CSA (31 men, mean age 68 years), 9 had a negative hyperpnea pattern. There was no difference in age, body mass index, and apnea-hypopnea index between groups. Patients with a negative pattern had longer hyperpnea time (39.5 ± 6.4 versus 25.8 ± 5.9 seconds, P < .01), longer cycle time (67.8 ± 15.9 versus 51.7 ± 9.9 seconds, P < .01), higher NT-proBNP concentrations (2740 [6769] versus 570 [864] pg/ml, P = .01), and worse New York Heart Association class (P = .02) than those with a positive pattern. LFCT and LVEF did not differ between groups. CONCLUSIONS: Patients with HF and a negative CSR-CSA pattern have evidence of worse cardiac function than those with a positive pattern. Greater positive expiratory pressure during hyperpnea is likely generated during the negative pattern and might support stroke volume in patients with worse cardiac function. COMMENTARY: A commentary on this article appears in this issue on page 1227. CLINICAL TRIAL REGISTRATION: The trial is registered with Current Controlled Trials (www.controlled-trials.com; ISRCTN67500535) and Clinical Trials (www.clinicaltrials.gov; NCT01128816).

Obstructive sleep apnoea is not a risk factor for incident hospitalised depression: a historical cohort study.

We evaluated whether obstructive sleep apnoea (OSA) was related to the incidence of hospitalisation for depression, a robust end-point that is unlikely to result from misdiagnosis.All adults referred with suspected OSA who underwent a diagnostic sleep study at a large urban academic hospital between 1994 and 2010 and were linked to provincial health administrative data between 1991 and 2015 were included. Cox regression analysis was used to investigate the association between OSA symptoms and severity and incident hospitalised depression, the primary outcome.Over a median follow-up of 9.7 years, 136 (1.3%) out of 10 149 participants were hospitalised for depression. A significant crude effect of OSA symptoms (waking unrefreshed and impact on memory and concentration) on hospitalised depression became nonsignificant after controlling for confounders. Apnoea-hypopnoea index was not significantly associated with the outcome: adjusted hazard ratio (33 versus 6 events·h-1) 1.13 (95% CI 0.91-1.40). Factors associated with hospitalised depression were female sex, younger age, use of hypnotics, alcoholism and unemployment.In a large clinical cohort with suspected OSA, controlling for confounders, OSA symptoms and severity were not related to the risk of hospitalisation for depression, suggesting that previously reported links between OSA and depression may be due to overlapping diagnostic criteria. However, our findings cannot exclude a potential link between OSA and milder depression.

Design of the effect of adaptive servo-ventilation on survival and cardiovascular hospital admissions in patients with heart failure and sleep apnoea: the ADVENT-HF trial.

INTRODUCTION: Both types of sleep-disordered breathing (SDB), obstructive and central sleep apnoea (OSA and CSA, respectively), are common in patients with heart failure and reduced ejection fraction (HFrEF). In such patients, SDB is associated with increased cardiovascular morbidity and mortality but it remains uncertain whether treating SDB by adaptive servo-ventilation (ASV) in such patients reduces morbidity and mortality. AIM: ADVENT-HF is designed to assess the effects of treating SDB with ASV on morbidity and mortality in patients with HFrEF. METHODS: ADVENT-HF is a multicentre, multinational, randomized, parallel-group, open-label trial with blinded assessment of endpoints of standard medical therapy for HFrEF alone vs. with the addition of ASV in patients with HFrEF and SDB. Patients with a history of HFrEF undergo echocardiography and polysomnography. Those with a left ventricular ejection fraction ≤45% and SDB (apnoea-hypopnoea index ≥15) are eligible. SDB is stratified into OSA with ≥50% of events obstructive or CSA with >50% of events central. Those with OSA must not have excessive daytime sleepiness (Epworth score of ≤10). Patients are then randomized to receive or not receive ASV. The primary outcome is the composite of all-cause mortality, cardiovascular hospital admissions, new-onset atrial fibrillation requiring anti-coagulation but not hospitalization, and delivery of an appropriate discharge from an implantable cardioverter-defibrillator not resulting in hospitalization during a maximum follow-up time of 5 years. CONCLUSION: The ADVENT-HF trial will help to determine whether treating SDB by ASV in patients with HFrEF improves morbidity and mortality.

The Interaction of Obesity and Nocturnal Hypoxemia on Cardiovascular Consequences in Adults with Suspected Obstructive Sleep Apnea. A Historical Observational Study.

RATIONALE: The interrelationships between obstructive sleep apnea (OSA) and obesity are complex and bidirectional; however, current evidence regarding their combined effect on cardiovascular risk is limited and conflicting. Animal studies suggest that obesity may exacerbate the cardiovascular consequences of intermittent hypoxemia. OBJECTIVES: In this historical observational study, we investigated whether obesity increases the effect of nocturnal hypoxemia on the incidence of cardiovascular events in adults with suspected OSA. METHODS: All adults with suspected OSA who underwent diagnostic polysomnography at a large academic hospital between 1994 and 2010 were linked to provincial health administrative data to determine a composite cardiovascular outcome (hospitalization due to heart failure, myocardial infarction, stroke, or revascularization procedures). Using a competing-risk model and controlling for confounders, hazards were compared between four groups: group 1 comprised obese patients (body mass index >30 kg/m2) with oxygen desaturation (>9 min of sleep spent with SaO2 <90%); group 2 comprised obese patients without desaturation; group 3 comprised nonobese patients with desaturation; and group 4 comprised nonobese patients without desaturation. Interaction was measured using the relative excess risk due to interaction. MEASUREMENTS AND MAIN RESULTS: A total of 10,149 participants were followed, with 17%, 25%, 8%, and 50% in groups 1-4, respectively. Over a median of 7.8 years, 896 (8.8%) first cardiovascular events occurred. Group 1 was associated with the highest hazard compared with the other groups, using group 4 as a reference (hazard ratio [HR] for group 1, 1.84; 95% confidence interval [CI], 1.46-2.32; HR for group 2, 1.59, 95% CI, 1.29-1.95; HR for group 3, 1.51; 95% CI, 1.15-1.98). The relative excess risk due to interaction was -0.25 (95% CI, -0.78 to 0.27), indicating no interaction. CONCLUSIONS: In adults with suspected OSA, the highest cardiovascular risk was found in obese patients with nocturnal oxygen desaturation; however, the effect of these two factors together does not exceed the effect of each factor considered individually.

The Effect of Patient Neighborhood Income Level on the Purchase of Continuous Positive Airway Pressure Treatment among Patients with Sleep Apnea.

RATIONALE: The cost of continuous positive airway pressure (CPAP) treatment for patients with low socioeconomic status may be an important barrier to successful treatment of obstructive sleep apnea under a copayment health care system. OBJECTIVES: We evaluated an association between patient neighborhood income level and the purchase of a CPAP device under a cost-sharing health care insurance system. METHODS: All adults who underwent a first diagnostic sleep study at St. Michael's Hospital (Toronto, ON, Canada) between 2004 and 2010 were included. Severity of obstructive sleep apnea was determined by the apnea-hypopnea index (AHI) and level of daytime sleepiness (by the Epworth Sleepiness Scale). Patient data were linked to provincial health administrative data from 1991 to 2013 to determine the purchase of CPAP equipment, comorbidities, neighborhood income, and rural status at baseline. Neighborhood income was categorized into quintiles, ranked from poorest (Q1) to wealthiest (Q5). Assuming that the majority of participants with severe obstructive sleep apnea (AHI > 30 events/h) and excessive daytime sleepiness (Epworth Sleepiness Scale ≥ 10) would have been strongly recommended CPAP, we evaluated the association between patient neighborhood income and purchase of a CPAP device in this group via multivariable Cox regressions. MEASUREMENTS AND MAIN RESULTS: Of the 695 participants with severe obstructive sleep apnea and excessive daytime sleepiness, 400 (58%) purchased a CPAP device. Patients who accepted CPAP were more likely to live in a higher-income neighborhood. Cumulative incidence of CPAP acceptance at 6 months was 43% for individuals in a low-income neighborhood (Q1) and 52% in combined higher-income neighborhoods (Q2-5) (P = 0.05). Controlling for sex and age, living in higher-income neighborhoods was associated with a 27% increased chance of accepting CPAP compared with the lowest-income neighborhood (hazard ratio Q2-5 vs. Q1, 1.27; 95% confidence interval, 0.98-1.64; P = 0.07). CONCLUSIONS: Living in an unfavorable neighborhood is not an obstacle to CPAP treatment among symptomatic patients with severe obstructive sleep apnea under a copayment health care system. However, a potential 27% improvement in CPAP acceptance associated with higher neighborhood income is not inconsequential. Also, the overall CPAP acceptance rate was relatively low, suggesting that obstacles other than finances are primarily responsible.

Obstructive sleep apnea and the prevalence and incidence of cancer.

BACKGROUND: A link between obstructive sleep apnea and cancer development or progression has been suggested, possibly through chronic hypoxemia, but supporting evidence is limited. We examined the association between the severity of obstructive sleep apnea and prevalent and incident cancer, controlling for known risk factors for cancer development. METHODS: We included all adults referred with possible obstructive sleep apnea who underwent a first diagnostic sleep study at a single large academic hospital between 1994 and 2010. We linked patient data with data from Ontario health administrative databases from 1991 to 2013. Cancer diagnosis was derived from the Ontario Cancer Registry. We assessed the cross-sectional association between obstructive sleep apnea and prevalent cancer at the time of the sleep study (baseline) using logistic regression analysis. Cox regression models were used to investigate the association between obstructive sleep apnea and incident cancer among patients free of cancer at baseline. RESULTS: Of 10 149 patients who underwent a sleep study, 520 (5.1%) had a cancer diagnosis at baseline. Over a median follow-up of 7.8 years, 627 (6.5%) of the 9629 patients who were free of cancer at baseline had incident cancer. In multivariable regression models, the severity of sleep apnea was not significantly associated with either prevalent or incident cancer after adjustment for age, sex, body mass index and smoking status at baseline (apnea-hypopnea index > 30 v. < 5: adjusted odds ratio [OR] 0.96, 95% confidence interval [CI] 0.71-1.30, for prevalent cancer, and adjusted hazard ratio [HR] 1.02, 95% CI 0.80-1.31, for incident cancer; sleep time spent with oxygen saturation < 90%, per 10-minute increase: adjusted OR 1.01, 95% CI 1.00-1.03, for prevalent cancer, and adjusted HR 1.00, 95% CI 0.99-1.02, for incident cancer). INTERPRETATION: In a large cohort, the severity of obstructive sleep apnea was not independently associated with either prevalent or incident cancer. Additional studies are needed to elucidate whether there is an independent association with specific types of cancer.

Obstructive sleep apnea and incident diabetes. A historical cohort study.

RATIONALE: Despite emerging evidence that obstructive sleep apnea (OSA) may cause metabolic disturbances independently of other known risk factors, it remains unclear whether OSA is associated with incident diabetes. OBJECTIVES: To evaluate whether risk of incident diabetes was related to the severity and physiologic consequences of OSA. METHODS: A historical cohort study was conducted using clinical and provincial health administrative data. All adults without previous diabetes referred with suspected OSA who underwent a diagnostic sleep study at St. Michael's Hospital (Toronto, Canada) between 1994 and 2010 were followed through health administrative data until May 2011 to examine the occurrence of diabetes. All OSA-related variables collected from the sleep study were examined as predictors in Cox regression models, controlling for sex, age, body mass index, smoking status, comorbidities, and income. MEASUREMENTS AND MAIN RESULTS: Over a median follow-up of 67 months, 1,017 (11.7%) of 8,678 patients developed diabetes, giving a cumulative incidence at 5 years of 9.1% (95% confidence interval, 8.4-9.8%). In fully adjusted models, patients with apnea-hypopnea index (AHI) greater than 30 had a 30% higher hazard of developing diabetes than those with AHI less than 5. Among other OSA-related variables, AHI in rapid eye movement sleep and time spent with oxygen saturation less than 90% were associated with incident diabetes, as were heart rate, neck circumference, and sleep time. CONCLUSIONS: Among people with OSA, and controlling for multiple confounders, initial OSA severity and its physiologic consequences predicted subsequent risk for incident diabetes.

Obstructive sleep apnea and risk of cardiovascular events and all-cause mortality: a decade-long historical cohort study.

BACKGROUND: Obstructive sleep apnea (OSA) has been reported to be a risk factor for cardiovascular (CV) disease. Although the apnea-hypopnea index (AHI) is the most commonly used measure of OSA, other less well studied OSA-related variables may be more pathophysiologically relevant and offer better prediction. The objective of this study was to evaluate the relationship between OSA-related variables and risk of CV events. METHODS AND FINDINGS: A historical cohort study was conducted using clinical database and health administrative data. Adults referred for suspected OSA who underwent diagnostic polysomnography at the sleep laboratory at St Michael's Hospital (Toronto, Canada) between 1994 and 2010 were followed through provincial health administrative data (Ontario, Canada) until May 2011 to examine the occurrence of a composite outcome (myocardial infarction, stroke, congestive heart failure, revascularization procedures, or death from any cause). Cox regression models were used to investigate the association between baseline OSA-related variables and composite outcome controlling for traditional risk factors. The results were expressed as hazard ratios (HRs) and 95% CIs; for continuous variables, HRs compare the 75th and 25th percentiles. Over a median follow-up of 68 months, 1,172 (11.5%) of 10,149 participants experienced our composite outcome. In a fully adjusted model, other than AHI OSA-related variables were significant independent predictors: time spent with oxygen saturation <90% (9 minutes versus 0; HR = 1.50, 95% CI 1.25-1.79), sleep time (4.9 versus 6.4 hours; HR = 1.20, 95% CI 1.12-1.27), awakenings (35 versus 18; HR = 1.06, 95% CI 1.02-1.10), periodic leg movements (13 versus 0/hour; HR = 1.05, 95% CI 1.03-1.07), heart rate (70 versus 56 beats per minute [bpm]; HR = 1.28, 95% CI 1.19-1.37), and daytime sleepiness (HR = 1.13, 95% CI 1.01-1.28).The main study limitation was lack of information about continuous positive airway pressure (CPAP) adherence. CONCLUSION: OSA-related factors other than AHI were shown as important predictors of composite CV outcome and should be considered in future studies and clinical practice.

Untreated obstructive sleep apnea and the risk for serious long-term adverse outcomes: a systematic review.

BACKGROUND: Reports on the association between obstructive sleep apnea (OSA) and risk of death, cardiovascular (CV) events, diabetes and depression have been inconsistent. METHODS: We conducted a systematic review of the prognostic value of clinical and polysomnographic (PSG) characteristics of OSA for adverse long-term outcomes of untreated OSA in adult patients. A comprehensive search strategy for prognosis studies, OSA, CV events, mortality, depression and diabetes was developed in collaboration with a medical information specialist. All English language studies, from Jan 1999 to Dec 2011, with longitudinal design in adults with OSA diagnosed by PSG recording, found through Medline, Embase and bibliographies of identified articles, were considered eligible. Quality was assessed using published guidelines. RESULTS: Among 26 articles, ten evaluated the association of OSA with mortality, 9 with a composite CV outcome, 4 with stroke, 2 with diabetes and 1 with depression. Significant relationships between the apnea-hypopnea index (AHI) and outcomes of interest were reported in 18 studies: seven for all-cause mortality, six for composite CV events, three for stroke, one for diabetes and one for depression. The effect of AHI was attenuated by female gender, older age, absence of daytime sleepiness and higher body mass index. Due to clinical heterogeneity between studies, meta-analyses were not performed. CONCLUSION: Evidence exists in men for a relationship between OSA and all-cause mortality and a composite CV outcome. Associations between OSA and other outcomes remain uncertain. Among OSA-specific markers, only AHI was a consistent predictor. Other consistent predictors were traditional CV risk factors. Research is required to identify effect modifiers and the predictive ability of various AHI threshold values and hypopnea definitions. An enhanced set of OSA-specific predictors will allow better risk stratification to guide OSA treatment.

Evaluation of the measurement properties of the Epworth sleepiness scale: a systematic review.

OBJECTIVE: To examine published evidence on the psychometric properties of the Epworth sleepiness scale (ESS) for describing the level of daytime sleepiness (DS) in adults. METHODS: Articles were located on MEDLINE and EMBASE. Psychometric properties were appraised using the COnsensus-based Standards for the selection of health status Measurement Instruments (COSMIN) checklist. RESULTS: We found thirty-five studies evaluating psychometric properties of the ESS in adults. Of these, 27 studies examined construct validity, 14 - known-group validity, 8 - internal consistency and 4 - test-retest reliability. Study quality ranged from excellent to poor the majority being fair. Internal consistency by Cronbach's alphas was good (0.73-0.86). There is little available evidence on test-retest reliability. Pooled correlations of the ESS with other constructs varied: from moderate (the maintenance of wakefulness test; ρ = -0.43), to weak (the multiple sleep latency test; ρ = -0.27, and sleep apnea-related variables; ρ from 0.11 to 0.23). Although ESS scores varied significantly across groups of subjects with known differences in DS, not all differences were clinically important. CONCLUSION: There have been relatively few high quality studies on the ESS psychometric properties. The internal consistency of the ESS suggests that this instrument can be recommended for group but not individual-level comparisons. Correlations with other measures of DS were stronger than with sleep apnea-related or general health measures, but still lower than expected. Further studies are required in the areas of test-retest reliability of the ESS.