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.

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 (Sa_O2) < 90% (hazard ratio [HR] per 5% increase, 1.05; 95% confidence interval, 1.01-1.09); mean Sa_O2 (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.

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.

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.