Positive Airway Pressure Adherence, Mortality, and Cardiovascular Events in Patients with Sleep Apnea.

Rationale: Randomized controlled trials showed no effect of positive airway pressure (PAP) therapy for obstructive sleep apnea (OSA) on cardiovascular (CV) risk. However, patient selection and low PAP adherence preclude the generalization of their data to clinical samples. Objectives: To evaluate the association between hours of PAP use, mortality, and CV morbidity in real-life conditions. Methods: Data from the Pays de la Loire Cohort were linked to health administrative data to identify incident major adverse cardiovascular events (MACEs; a composite outcome of mortality, stroke, and cardiac diseases) in patients with OSA who were prescribed PAP. Cox proportional hazards analyses were conducted to evaluate the association between MACEs and quartiles of average daily PAP use over the study period. Measurements and Main Results: After a median follow-up of 6.6 years, 961 of 5,138 patients experienced MACEs. Considering nonadherent patients (0-4 h/night) as the reference group, adjusted hazard ratios (95% confidence intervals) for MACEs were 0.87 (0.73-1.04) for the 4-6 h/night group, 0.75 (0.62-0.92) for the 6-7 h/night group, and 0.78 (0.65-0.93) for the ⩾7 h/night group (P = 0.0130). Sensitivity analyses using causal inference approaches confirmed the association of PAP use with MACEs. The association was stronger in male patients (P value for interaction = 0.0004), patients without overt CV disease at diagnosis (P < 0.0001), and those belonging to the excessively sleepy symptom subtype (P = 0.060). Conclusions: These real-life clinical data demonstrate a dose-response relationship between PAP adherence and incident MACEs in OSA. Patient support programs may help improve PAP adherence and CV outcomes in patients with OSA.

Cancer risk in patients with sleep apnoea following adherent 5-year CPAP therapy.

BACKGROUND: Increasing evidence suggests that obstructive sleep apnoea (OSA) contributes to cancer risk; however, limited data are available on the impact of continuous positive airway pressure (CPAP) therapy on cancer incidence. We aimed to determine whether adherence to CPAP therapy is associated with a reduction in all-cancer incidence compared with nonadherent patients with OSA. METHODS: The study relied on data collected by the multicentre Pays de la Loire Sleep Cohort study, linked to health administrative data, so as to identify new-onset cancer. We included patients who were prescribed CPAP for OSA, with no history of cancer before the diagnostic sleep study or during the first year of CPAP. Patients with documented CPAP use for ≥4 h per night were defined as adherent. Those who discontinued or used CPAP <4 h per night constituted the nonadherent group. A propensity score inverse probability of treatment weighting analysis was performed to assess the effect of CPAP adherence on cancer risk. RESULTS: After a median (interquartile range) follow-up of 5.4 (3.1-8.0) years, 437 (9.7%) out of 4499 patients developed cancer: 194 (10.7%) in the nonadherent group (n=1817) and 243 (9.1%) in adherent patients (n=2682). The final weighted model showed no significant impact of CPAP adherence on all-cause cancer risk (subdistribution hazard ratio 0.94, 95% CI 0.78-1.14). CONCLUSIONS: Adherence to CPAP therapy in OSA patients was not associated with a reduction in all-cancer incidence. Whether adherent CPAP therapy of OSA might reduce the risk of specific cancer sites should be further evaluated.

Obstructive sleep apnea, chronic obstructive pulmonary disease and NAFLD: an individual participant data meta-analysis.

RATIONALE: Chronic intermittent hypoxia occurring in obstructive sleep apnea (OSA) is independently associated with nonalcoholic fatty liver disease (NAFLD). Chronic obstructive pulmonary disease (COPD) has also been suggested to be linked with liver disease. OBJECTIVE: In this individual participant data meta-analysis, we investigated the association between liver damage and OSA and COPD severity. METHODS AND MEASUREMENTS: Patients suspected of OSA underwent polysomnography (PSG) or home sleep apnea testing (HSAT). Non-invasive tests were used to evaluate liver steatosis (Hepatic Steatosis Index) and fibrosis (Fibrotest or FibroMeter). An individual participant data meta-analysis approach was used to determine if the severity of OSA/COPD affects the type and severity of liver disease. Results were confirmed by multivariate and causal mediation analysis. Sub-group analyses were performed to investigate specific populations. MAIN RESULTS: Among 2120 patients, 1584 had steatosis (75%). In multivariable analysis, risk factors for steatosis were an apnea-hypopnea index (AHI) > 5/h, body mass index (BMI) > 26 kg/m2, age, type 2 diabetes (all p-values <0.01) and male gender (p = 0.02). Concerning fibrosis, among 2218 patients 397 had fibrosis (18%). Risk factors associated with fibrosis were BMI>26 kg/m2, age, male gender, and type 2 diabetes (all p-values <0.01). AHI severity was not associated with fibrosis. A combination of AHI >30/h and COPD stage 1 was associated with an increased risk of steatosis. CONCLUSION: This meta-analysis confirms the strong association between steatosis and the severity of OSA. The relation between OSA and fibrosis is mainly due to BMI as shown by causal mediation analysis.

A CPAP data-based algorithm for automatic early prediction of therapy adherence.

OBJECTIVE: Adherence is a critical issue in the treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP). Approximately 40% of patients treated with CPAP are at risk of discontinuation or insufficient use (< 4 h/night). Assuming that the first few days on CPAP are critical for continued treatment, we tested the predictive value at day 14 (D14) of the Philips Adherence Profiler™ (AP) algorithm for adherence at 3 months (D90). METHOD: The AP™ algorithm uses CPAP machine data hosted in the database of EncoreAnywhere™. This retrospective study involved 457 patients (66% men, 60.0 ± 11.9 years; BMI = 31.2 ± 5.9 kg/m2; AHI = 37.8 ± 19.2; Epworth score = 10.0 ± 4.8) from the Pays de la Loire Sleep Cohort. At D90, 88% of the patients were adherent as defined by a mean daily CPAP use of ≥ 4 h. RESULTS: In a univariate analysis, the factors significantly associated with CPAP adherence at D90 were older age, lower BMI, CPAP adherence (≥ 4 h/night) at D14, and AP™ prediction at D14. In a multivariate analysis, only older age (OR 2.10 [1.29-3.41], p = 0.003) and the AP™ prediction at D14 (OR 16.99 [7.26-39.75], p < 0.0001) were significant predictors. CPAP adherence at D90 was not associated with device-derived residual events, nor with the levels of pressure or leakage except in the case of very significant leakage when it persisted for 90 days. CONCLUSION: Automatic telemonitoring algorithms are relevant tools for early prediction of CPAP therapy adherence and may make it possible to focus therapeutic follow-up efforts on patients who are at risk of non-adherence.

Association Between Nocturnal Hypoxemia and Cancer Incidence in Patients Investigated for OSA: Data From a Large Multicenter French Cohort.

BACKGROUND: Previous studies have yielded inconsistent findings regarding the association between OSA and cancer in humans. RESEARCH QUESTION: Is there an association between indexes of sleep-disordered breathing severity and cancer incidence in patients investigated for suspected OSA? STUDY DESIGN AND METHODS: Data from a large multicenter cohort of cancer-free patients investigated for OSA were linked to health administrative data to identify new-onset cancer. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the association of cancer incidence with OSA severity and nocturnal hypoxemia. RESULTS: After a median follow-up period of 5.8 years (interquartile range, 3.8-7.8), 718 of 8,748 patients (8.2%) had received a diagnosis of cancer. On unadjusted Kaplan-Meier survival analyses, cancer incidence was associated with increasing severity of OSA (log-rank test, P < .0005) and nocturnal hypoxemia (log-rank test, P < .0001 for both oxygen desaturation index and percent night time with oxygen saturation < 90% [T90]). After adjustment for anthropomorphic data, smoking and alcohol consumption, comorbid cardiac, metabolic, and respiratory diseases, marital status, type of sleep study, and study site, only T90 was associated with cancer incidence (adjusted hazard ratio, 1.33; 95% CI, 1.05-1.68 for T90 ≥ 13% vs < 0.01%; P = .02). On stratified analyses, the association between T90 and cancer appeared stronger in older patients with obesity and no adequate OSA therapy. Among the most frequent cancer sites, nocturnal hypoxemia was associated with lung and breast malignancies. INTERPRETATION: Nocturnal hypoxemia was associated with all-cancer incidence in patients investigated for OSA. Whether OSA therapy might reduce the risk of cancer needs further evaluation.

Association Between Severity of Obstructive Sleep Apnea and Blood Markers of Liver Injury.

Obstructive sleep apnea (OSA) may contribute to the development of nonalcoholic fatty liver disease. We performed a multisite cross-sectional study to evaluate the association between the severity of OSA and blood markers of liver steatosis (using the hepatic steatosis index), cytolysis (based on alanine aminotransferase activity), and significant liver fibrosis (based on the FibroMeter [Echosens] nonalcoholic fatty liver disease score) in 1285 patients with suspected OSA in France. After adjusting for confounders including central obesity, the risk of liver steatosis increased with the severity of OSA (P for trend < .0001) and sleep-related hypoxemia (P for trend < .0003 for mean oxygen saturation). Decreasing mean oxygen saturation during sleep also was associated independently with a higher risk of liver cytolysis (P for trend < .0048). Severe OSA conferred an approximate 2.5-fold increase in risk for significant liver fibrosis compared with patients without OSA, but the association between OSA severity and liver fibrosis was not maintained after adjusting for confounders.

Renal insufficiency is the leading cause of double maintenance (bevacizumab and pemetrexed) discontinuation for toxicity to advanced non-small cell lung cancer in real world setting.

OBJECTIVES: In advanced non-small cell lung cancer (NSCLC), maintenance therapy has emerged as a novel therapeutic reference for patients with non-progressive disease after platinum-based induction chemotherapy. However, the use of double maintenance (DM) with pemetrexed and bevacizumab is still being evaluated in terms of its clinical benefits and safety profile. The objective of this retrospective study was to describe the reasons for DM discontinuation in a real-world setting. MATERIALS AND METHODS: Patients with advanced non-squamous NSCLC were eligible if they had received at least 4 cycles of induction chemotherapy, followed by at least 1 cycle of DM. They were identified by using the oncology pharmacy database of 17 French centers. RESULTS: Eighty-one patients who began a DM after induction chemotherapy were identified from September 2009 to April 2013. Among the 78 patients who had stopped DM at the time of the analysis, the main reasons for discontinuation were disease progression (42%), adverse events (33%), and personal preference (8%). The most frequent toxicity responsible for DM discontinuation was renal insufficiency (54%). CONCLUSION: For patients with advanced NSCLC eligible for DM therapy, a particular attention should be paid to potential renal failure. Kidney function should be monitored carefully before and during DM to detect and manage early this adverse event.

Association between obstructive sleep apnea severity and glucose control in patients with untreated versus treated diabetes.

The purpose of this study was to determine whether the association between obstructive sleep apnea severity and glucose control differs between patients with newly diagnosed and untreated type 2 diabetes, and patients with known and treated type 2 diabetes. This multicentre cross-sectional study included 762 patients investigated by sleep recording for suspected obstructive sleep apnea, 497 of whom were previously diagnosed and treated for type 2 diabetes (treated diabetic patients), while 265 had no medical history of diabetes but had fasting blood glucose ≥126 mg dL(-1) and/or glycated haemoglobin (HbA1c ) ≥6.5% consistent with newly diagnosed type 2 diabetes (untreated diabetic patients). Multivariate regression analyses were performed to evaluate the independent association between HbA1c and obstructive sleep apnea severity in treated and untreated patients with diabetes. In untreated diabetic patients, HbA1c was positively associated with apnea-hypopnea index (P = 0.0007) and 3% oxygen desaturation index (P = 0.0016) after adjustment for age, gender, body mass index, alcohol habits, metabolic dyslipidaemia, hypertension, statin use and study site. The adjusted mean value of HbA1c increased from 6.68% in the lowest quartile of the apnea-hypopnea index (<17) to 7.20% in the highest quartile of the apnea-hypopnea index (>61; P = 0.033 for linear trend). In treated patients with diabetes, HbA1c was associated with non-sleep variables, including age, metabolic dyslipidaemia and insulin use, but not with obstructive sleep apnea severity. Obstructive sleep apnea may adversely affect glucose control in patients with newly diagnosed and untreated type 2 diabetes, but may have a limited impact in patients with overt type 2 diabetes receiving anti-diabetic medications.

Cumulative association of obstructive sleep apnea severity and short sleep duration with the risk for hypertension.

Obstructive sleep apnea (OSA) and short sleep duration are individually associated with an increased risk for hypertension (HTN). The aim of this multicenter cross-sectional study was to test the hypothesis of a cumulative association of OSA severity and short sleep duration with the risk for prevalent HTN. Among 1,499 patients undergoing polysomnography for suspected OSA, 410 (27.3%) previously diagnosed as hypertensive and taking antihypertensive medication were considered as having HTN. Patients with total sleep time (TST) <6 h were considered to be short sleepers. Logistic regression procedures were performed to determine the independent association of HTN with OSA and sleep duration. Considering normal sleepers (TST ≥6 h) without OSA as the reference group, the odds ratio (OR) (95% confidence intervals) for having HTN was 2.51 (1.35-4.68) in normal sleepers with OSA and 4.37 (2.18-8.78) in short sleepers with OSA after adjustment for age, gender, obesity, diabetes, depression, current smoking, use of thyroid hormones, daytime sleepiness, poor sleep complaint, time in bed, sleep architecture and fragmentation, and study site. The risk for HTN appeared to present a cumulative association with OSA severity and short sleep duration (p<0.0001 for linear trend). The higher risk for HTN was observed in short sleepers with severe OSA (AHI ≥30) (OR, 4.29 [2.03-9.07]). In patients investigated for suspected OSA, sleep-disordered breathing severity and short sleep duration have a cumulative association with the risk for prevalent HTN. Further studies are required to determine whether interventions to optimize sleep may contribute to lower BP in patients with OSA.

Feasibility and clinical impact of re-biopsy in advanced non small-cell lung cancer: a prospective multicenter study in a real-world setting (GFPC study 12-01).

OBJECTIVES: When advanced non-small-cell lung cancer (NSCLC) progresses during first-line treatment, re-biopsy may be indicated to detect a possible new biological profile (comparison to initial status, emergence of resistance biomarkers, or assessment of new biomarkers). The aim of this pragmatic prospective multicenter study was to assess the feasibility and clinical utility of re-biopsy in advanced NSCLC in a real-world setting. METHODS: The main inclusion criteria were advanced NSCLC with an indication for repeat biopsy identified by the patient's clinician. The primary outcome was the percentage of successful procedures. Secondary outcomes were the type of procedure, new biological status, tolerability of the procedure, and clinical utility (treatment modification). RESULTS: From May 2012 to May 2013, 18 centers enrolled 100 patients (males: 44%; median age: 64.8 years; PS 0/1: 88%; adenocarcinoma: 89%; EGFR mutated: 50%; no initial biological profile: 16.4%). Re-biopsy was not possible in 19.5% of cases and provided no or too few tumor cells in 25.6% of cases. Repeat biopsy was useful for guiding treatment in 30.4% (25/82) of cases. Complications were infrequent (2 cases of moderate bleeding and 1 case of pneumothorax). CONCLUSION: Re-biopsy of advanced NSCLC is feasible in the real-world setting, with acceptable adverse events. Guidelines are needed on the indications of re-biopsy, the choice of procedure, the sampling site, and laboratory analysis.

Depressive symptoms before and after long-term CPAP therapy in patients with sleep apnea.

BACKGROUND: The outcome of depressive symptoms under CPAP therapy for OSA-hypopnea syndrome (OSAHS) has been poorly evaluated. In this multicenter, prospective cohort study, we evaluated the prevalence and correlates of persistent depressive symptoms after long-term CPAP therapy for OSAHS. METHODS: This study included 300 patients with OSAHS and depressive symptoms (13-item, self-rated Pichot depression scale [QD2A] ≥ 7) at diagnosis. The primary dependent variable was persistent depressive symptoms after ≥ 1 year of CPAP therapy. Multivariate regression analyses were performed to determine variables independently associated with the persistence of depressive symptoms. RESULTS: After an average of 529 days (range, 365-1,569 days) of CPAP therapy, the mean (SD) QD2A score decreased from 9.2 (2.0) to 5.4 (4.0) (P < .0001), but 125 patients (41.7%) presented persistent depressive symptoms. The persistence of depressive symptoms was independently associated with persistent excessive daytime sleepiness (EDS) (OR, 2.72; 95% CI, 1.33-5.61), comorbid cardiovascular disease (OR, 1.76; 95% CI, 1.02-3.00), and female sex (OR, 1.53; 95% CI, 1.09-2.13). A positive linear trend was observed for the adjusted OR of persistent depressive symptoms with decreasing CPAP effect on the Epworth sleepiness scale (P < .0001). CONCLUSIONS: CPAP therapy does not resolve depressive symptoms in many patients with OSAHS. Persistent depressive symptoms are strongly associated with EDS. Active monitoring of depressive symptoms is needed in patients with OSAHS who are treated with CPAP. Interventional trials are required to evaluate the impact of antidepressants, cognitive behavioral therapy, or both on comorbid depression in patients with OSAHS.

Independent association between nocturnal intermittent hypoxemia and metabolic dyslipidemia.

BACKGROUND: There is growing evidence from animal models that intermittent hypoxemia (IH) may induce dyslipidemia. Altered lipid metabolism may contribute to the increased cardiovascular risk observed in obstructive sleep apnea (OSA). In this multisite, cross-sectional study, we tested the hypothesis that there is an independent association between nocturnal IH and dyslipidemia in OSA. METHODS: Fasting serum lipid levels were measured in 2,081 patients (638 women) undergoing nocturnal recording for clinical suspicion of OSA. Multivariate regression analyses were performed to evaluate the independent associations between oxygen desaturation index (ODI) and lipid profile after adjustment for potential confounders, including components of the metabolic syndrome (MS) or the MS itself. Adjusted OR for metabolic dyslipidemia (triglycerides [TG] ≥ 150 mg/dL and high-density lipoprotein cholesterol [HDL-C] ≤ 50 mg/dL for women and ≤ 40 mg/dL for men) according to quartiles of ODI were determined by logistic regression. RESULTS: Total cholesterol and low-density lipoprotein cholesterol were not associated with ODI. In contrast, nocturnal IH and OSA severity were associated with higher TG levels and lower HDL-C levels after adjustment for confounding factors. The association between ODI and TG and HDL-C levels was independent of the MS. Adjusted OR (95% CIs) for metabolic dyslipidemia were 1 (reference), 1.56 (1.24-1.96), 1.72 (1.29-2.29), and 1.93 (1.55-2.41) for ODI ≤ 7, > 7 to ≤ 18, > 18 to ≤ 38, and > 38, respectively (P < .0001 for linear trend). CONCLUSIONS: Nocturnal IH is independently associated with metabolic dyslipidemia, which may predispose patients with OSA to a higher risk of cardiovascular disease.

Independent association between obstructive sleep apnea severity and glycated hemoglobin in adults without diabetes.

OBJECTIVE: We tested the hypothesis of an independent cross-sectional association between obstructive sleep apnea (OSA) severity and glycated hemoglobin (HbA(1c)) in adults without known diabetes. RESEARCH DESIGN AND METHODS: HbA(1c) was measured in whole-blood samples from 2,139 patients undergoing nocturnal recording for suspected OSA. Participants with self-reported diabetes, use of diabetes medication, or HbA(1c) value ≥6.5% were excluded from this study. Our final sample size comprised 1,599 patients. RESULTS: A dose-response relationship was observed between apnea-hypopnea index (AHI) and the percentage of patients with HbA(1c) >6.0%, ranging from 10.8% for AHI <5 to 34.2% for AHI ≥50. After adjustment for age, sex, smoking habits, BMI, waist circumference, cardiovascular morbidity, daytime sleepiness, depression, insomnia, sleep duration, and study site, odds ratios (95% CIs) for HbA(1c) >6.0% were 1 (reference), 1.40 (0.84-2.32), 1.80 (1.19-2.72), 2.02 (1.31-3.14), and 2.96 (1.58-5.54) for AHI values <5, 5 to <15, 15 to <30, 30 to <50, and ≥50, respectively. Increasing hypoxemia during sleep was also independently associated with the odds of HbA(1c) >6.0%. CONCLUSIONS: Among adults without known diabetes, increasing OSA severity is independently associated with impaired glucose metabolism, as assessed by higher HbA(1c) values, which may expose them to higher risks of diabetes and cardiovascular disease.

Influence of marital status and employment status on long-term adherence with continuous positive airway pressure in sleep apnea patients.

BACKGROUND: Long-term adherence is a major issue in patients receiving home continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea-hypopnea syndrome (OSAHS). In a multicenter prospective cohort (the Institut de Recherche en Santé Respiratoire des Pays de la Loire [IRSR] sleep cohort) of consecutive OSAHS patients in whom CPAP had been prescribed for at least 90 days, we studied the impact on long-term treatment adherence of socioeconomic factors, patients and disease characteristics prior to CPAP initiation. METHODS AND PRINCIPAL FINDINGS: Among 1,141 patients in whom CPAP had been prescribed for an average of 504±251 days (range: 91 to 1035), 674 (59%) were adherent with a mean daily use of CPAP≥4 h (mean: 6.42±1.35 h). Stepwise regression analysis identified 4 independent factors of CPAP adherence including apnea-hypopnea index (AHI) (OR: 1.549, 95%CI 1.163 to 2.062 for AHI≥30 vs. AHI<30; p = 0.003), body mass index (BMI) (OR: 1.786, 95%CI 1.131 to 2.822 for BMI≥25 and <30 kg/m(2), p = 0.01; OR: 1.768, 95%CI 1.145-2.731 for BMI≥30 kg/m(2), p = 0.01 vs. BMI<25 kg/m(2)), employment status (OR: 1.414, 95%CI 1.097-1.821 for retired vs. employed; p = 0.007) and marital status (OR: 1.482, 95%CI 1.088-2.019 for married or living as a couple vs. living alone; p = 0.01). Age, gender, Epworth sleepiness scale, depressive syndrome, associated cardiovascular morbidities, educational attainment and occupation category did not influence CPAP adherence. CONCLUSIONS: Marital status and employment status are independent factors of CPAP adherence in addition to BMI and disease severity. Patients living alone and/or working patients are at greater risk of non-adherence, whereas adherence is higher in married and retired patients. These findings suggest that the social context of daily life should be taken into account in risk screening for CPAP non-adherence. Future interventional studies targeting at-risk patients should be designed to address social motivating factors and work-related barriers to CPAP adherence.