Ferran Barbé

Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial.

CONTEXT Continuous positive airway pressure (CPAP) is the first-line treatment for patients with symptomatic obstructive sleep apnea (OSA). However, its indication for all patients with sleep-disordered breathing, regardless of daytime symptoms, is unclear. OBJECTIVE To evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in a cohort of nonsleepy patients with OSA. DESIGN, SETTING, AND PATIENTS Multicenter, parallel-group, randomized controlled trial in 14 teaching hospitals in Spain. Between May 2004 and May 2006, 725 consecutive patients were enrolled who had an apnea-hypopnea index of 20 h(-1) or greater and an Epworth Sleepiness Scale score of 10 or less (scores range from 0-24, with values <10 suggesting no daytime sleepiness). Exclusion criteria were previous cardiovascular event, physical or psychological incapacity, chronic disease, or drug or alcohol addiction. Follow-up ended in May 2009. INTERVENTION Patients were allocated to receive CPAP treatment or no active intervention. All participants received dietary counseling and sleep hygiene advice. MAIN OUTCOME MEASURES Incidence of either systemic hypertension (taking antihypertensive medication or blood pressure greater than 140/90 mm Hg) or cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for unstable angina or arrhythmia, heart failure, or cardiovascular death). RESULTS Seven hundred twenty-three patients underwent follow-up for a median of 4 (interquartile range, 2.7-4.4) years (1 patient from each group did not receive allocated treatment); 357 in the CPAP group and 366 in the control group were included in the analysis. In the CPAP group there were 68 patients with new hypertension and 28 cardiovascular events (17 unstable angina or arrhythmia, 3 nonfatal stroke, 3 heart failure, 2 nonfatal myocardial infarction, 2 transient ischemic attack, 1 cardiovascular death). In the control group there were 79 patients with new hypertension and 31 cardiovascular events (11 unstable angina or arrhythmia, 8 nonfatal myocardial infarction, 5 transient ischemic attack, 5 heart failure, 2 nonfatal stroke). The hypertension or cardiovascular event incidence density rate was 9.20 per 100 person-years (95% CI, 7.36-11.04) in the CPAP group and 11.02 per 100 person-years (95% CI, 8.96-13.08) in the control group. The incidence density ratio was 0.83 (95% CI, 0.63-1.1; P = .20). CONCLUSIONS In patients with OSA without daytime sleepiness, the prescription of CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events. However, the study may have had limited power to detect a significant difference. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00127348.

CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea

BACKGROUND Obstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain. METHODS After a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood. RESULTS Most of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood. CONCLUSIONS Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).

Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea.

RATIONALE Continuous positive airway pressure (CPAP) is the current treatment for patients with symptomatic obstructive sleep apnea (OSA). Its use for all subjects with sleep-disordered breathing, regardless of daytime symptoms, is unclear. OBJECTIVES This multicenter controlled trial assesses the effects of 1 year of CPAP treatment on blood pressure (BP) in nonsymptomatic, hypertensive patients with OSA. METHODS We evaluated 359 patients with OSA. Inclusion criteria consisted of an apnea-hypopnea index (AHI) greater than 19 hour(-1), an Epworth Sleepiness Scale score less than 11, and one of the following: under antihypertensive treatment or systolic blood pressure greater than 140 or diastolic blood pressure greater than 90 mm Hg. Patients were randomized to CPAP (n = 178) or to conservative treatment (n = 181). BP was evaluated at baseline and at 3, 6, and 12 months of follow-up. MEASUREMENTS AND MAIN RESULTS Mean (SD) values were as follows: age, 56 +/- 10 years; body mass index (BMI), 32 +/- 5 kg x m(-2); AHI, 45 +/- 20 hour(-1); and Epworth Sleepiness Scale score, 7 +/- 3. After adjusting for follow-up time, baseline blood pressure values, AHI, time with arterial oxygen saturation less than 90%, and BMI, together with the change in BMI at follow-up, CPAP treatment decreased systolic blood pressure by 1.89 mm Hg (95% confidence interval: -3.90, 0.11 mm Hg; P = 0.0654), and diastolic blood pressure by 2.19 mm Hg (95% confidence interval: -3.46, -0.93 mm Hg; P = 0.0008). The most significant reduction in BP was in patients who used CPAP for more than 5.6 hours per night. CPAP compliance was related to AHI and the decrease in Epworth Sleepiness Scale score. CONCLUSIONS In nonsleepy hypertensive patients with OSA, CPAP treatment for 1 year is associated with a small decrease in BP. This effect is evident only in patients who use CPAP for more than 5.6 hours per night. Clinical trial registered with www.clinicaltrials.gov (NCT00127348).

Effect of CPAP on Blood Pressure in Patients With Obstructive Sleep Apnea and Resistant Hypertension The HIPARCO Randomized Clinical Trial

IMPORTANCE More than 70% of patients with resistant hypertension have obstructive sleep apnea (OSA). However, there is little evidence about the effect of continuous positive airway pressure (CPAP) treatment on blood pressure in patients with resistant hypertension. OBJECTIVE To assess the effect of CPAP treatment on blood pressure values and nocturnal blood pressure patterns in patients with resistant hypertension and OSA. DESIGN, SETTING, AND PARTICIPANTS Open-label, randomized, multicenter clinical trial of parallel groups with blinded end point design conducted in 24 teaching hospitals in Spain involving 194 patients with resistant hypertension and an apnea-hypopnea index (AHI) of 15 or higher. Data were collected from June 2009 to October 2011. INTERVENTIONS CPAP or no therapy while maintaining usual blood pressure control medication. MAIN OUTCOMES AND MEASURES The primary end point was the change in 24-hour mean blood pressure after 12 weeks. Secondary end points included changes in other blood pressure values and changes in nocturnal blood pressure patterns. Both intention-to-treat (ITT) and per-protocol analyses were performed. RESULTS A total of 194 patients were randomly assigned to receive CPAP (n = 98) or no CPAP (control; n = 96). The mean AHI was 40.4 (SD, 18.9) and an average of 3.8 antihypertensive drugs were taken per patient. Baseline 24-hour mean blood pressure was 103.4 mm Hg; systolic blood pressure (SBP), 144.2 mm Hg; and diastolic blood pressure (DBP), 83 mm Hg. At baseline, 25.8% of patients displayed a dipper pattern (a decrease of at least 10% in the average nighttime blood pressure compared with the average daytime blood pressure). The percentage of patients using CPAP for 4 or more hours per day was 72.4%. When the changes in blood pressure over the study period were compared between groups by ITT, the CPAP group achieved a greater decrease in 24-hour mean blood pressure (3.1 mm Hg [95% CI, 0.6 to 5.6]; P = .02) and 24-hour DBP (3.2 mm Hg [95% CI, 1.0 to 5.4]; P = .005), but not in 24-hour SBP (3.1 mm Hg [95% CI, -0.6 to 6.7]; P = .10) compared with the control group. Moreover, the percentage of patients displaying a nocturnal blood pressure dipper pattern at the 12-week follow-up was greater in the CPAP group than in the control group (35.9% vs 21.6%; adjusted odds ratio [OR], 2.4 [95% CI, 1.2 to 5.1]; P = .02). There was a significant positive correlation between hours of CPAP use and the decrease in 24-hour mean blood pressure (r = 0.29, P = .006), SBP (r = 0.25; P = .02), and DBP (r = 0.30, P = .005). CONCLUSIONS AND RELEVANCE Among patients with OSA and resistant hypertension, CPAP treatment for 12 weeks compared with control resulted in a decrease in 24-hour mean and diastolic blood pressure and an improvement in the nocturnal blood pressure pattern. Further research is warranted to assess longer-term health outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00616265.

Noninvasive ventilatory support does not facilitate recovery from acute respiratory failure in chronic obstructive pulmonary disease

This investigation evaluates, in a prospective, randomized and controlled manner, whether noninvasive ventilatory support (NIVS) with bilevel positive airway pressure (BiPAP) facilitates recovery from acute respiratory failure (ARF) in patients with chronic obstructive pulmonary disease (COPD). Twenty four patients (mean age (+/-SEM) 68 +/- 2 yrs) with COPD (forced expiratory volume in one second (FEV1) at discharge 33 +/- 2% predicted), who attended the emergency room because of ARF (pH 7.33 +/- 0.01; arterial oxygen tension (Pa,O2) 6.0 +/- 0.2 kPa; arterial carbon dioxide tension (Pa,CO2) 7.9 +/- 0.3 kPa), were initially randomized. Four out of the 14 patients (29%) allocated to received NIVS did not tolerate it. Of the remaining 20 patients, 10 received NIVS with BiPAP in a conventional hospital ward during the first 3 days of hospitalization (two daytime sessions of 3 h duration each). All 20 subjects were treated with oxygen, bronchodilators and steroids. On the first and third hospitalization days, before and 30 min after withdrawing oxygen therapy and/or BiPAP ventilatory support, we measured peak expiratory flow, arterial blood gas values, ventilatory pattern, occlusion pressure (P0.1), and maximal inspiratory (MIP) and maximal expiratory (MEP) pressures. All patients were discharged without requiring tracheal intubation and mechanical ventilation. Hospitalization time was similar in both groups (11.3 +/- 1.3 vs 10.6 +/- 0.9 days, control vs BiPAP, respectively). Arterial oxygenation, respiratory acidosis and airflow obstruction improved significantly throughout hospitalization in both groups. By contrast, the ventilatory pattern, P0.1, MIP and MEP did not change. NIVS with BiPAP did not cause any significant difference between groups. We conclude that noninvasive ventilatory support with bilevel positive airway pressure does not facilitate recovery from acute respiratory failure in patients with chronic obstructive pulmonary disease. Furthermore, a substantial proportion of patients (29%) do not tolerate noninvasive ventilatory support under these circumstances. From these results, we cannot recommend the use of noninvasive ventilatory support with bilevel positive airway pressure in the routine management of chronic obstructive pulmonary disease patients recovering from acute respiratory failure.

Obstructive sleep apnoea and cardiovascular disease

Obstructive sleep apnoea (OSA) is a common health concern caused by repeated episodes of collapse of the upper airway during sleep. The events associated with OSA lead to brain arousal, intrathoracic pressure changes, and intermittent episodes of hypoxaemia and reoxygenation. These events activate pathways such as oxidative stress, sympathetic activation, inflammation, hypercoagulability, endothelial dysfunction, and metabolic dysregulation that predispose patients with OSA to hypertension and atherosclerosis. OSA is a common cause of systemic hypertension and should be suspected in hypertensive individuals, especially those with resistant hypertension. In patients with OSA, continuous positive airway pressure (CPAP) treatment reduces blood pressure, and its effects are related to compliance and baseline blood pressure. Evidence suggests that OSA is a risk factor for stroke and heart failure. An association between coronary heart disease and OSA seems to be limited to middle-aged men (30-70 years). Cardiac rhythm disorders occur in about half of patients with OSA, but their clinical relevance is still unknown. The association of OSA with cardiovascular risk is mainly based on studies in men, and an association has yet to be established in women. Data on older patients is similarly scarce. Currently, there is not enough evidence to support treatment with CPAP for primary or secondary prevention of cardiovascular disease.

Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial

Objective To assess the effect of continuous positive airway pressure (CPAP) on 24 hour ambulatory blood pressure monitoring values in a large number of patients with untreated systemic hypertension of new onset and obstructive sleep apnoea. Design Multicentre, double blind, randomised, placebo controlled trial. Setting Eleven general hospitals in Spain between 2004 and 2007. Participants 340 patients recently diagnosed as having systemic hypertension by a general practitioner (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or both) and an apnoea-hypopnoea index per hour of sleep of >15 events/hour. Intervention Patients were assigned to CPAP (n=169) or sham CPAP (n=171) for three months. Main outcome measurements Net changes in the different 24 hour ambulatory blood pressure monitoring values from baseline to three months of optimal or sham CPAP. Results 277 (81%) of the 340 patients randomised were men; the patients had a mean age of 52.4 (SD 10.5) years, a body mass index of 31.9 (5.7), an Epworth sleepiness scale score of 10.1 (4.3), an apnoea-hypopnoea index of 43.5 (24.5). No differences between groups were seen at baseline. Compared with placebo and analysed by intention to treat, the mean 24 hour ambulatory blood pressure of the CPAP group decreased by 1.5 (95% confidence interval: 0.4 to 2.7) mm Hg (P=0.01). The mean 24 hour ambulatory blood pressure monitoring measures decreased by 2.1 mm Hg (0.4 to 3.7) mm Hg (P=0.01) for systolic pressure and 1.3 (0.2 to 2.3) mm Hg (P=0.02) for diastolic blood pressure. Mean nocturnal blood pressure decreased by 2.1 (0.5 to 3.6) mm Hg (P=0.01). Conclusions CPAP produced a statistically significant reduction in blood pressure in patients with systemic hypertension and obstructive sleep apnoea. This reduction is small and did not achieve the 3 mm Hg drop in mean 24 hour ambulatory blood pressure that the trial was powered to detect. Consequently, these results may have uncertain clinical relevance. However, taking into account the prevalence of hypertension and the likelihood of comorbidities, the decrease in blood pressure, although minimal, may be beneficial. Trial registration Clinical trials NCT00202527.

Antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment

The episodes of hypoxia/re-oxygenation associated with the respiratory disturbances observed in patients with obstructive sleep apnoea syndrome (OSAS) may induce the generation of oxygen free radicals. Indeed, several studies suggest that OSAS is associated with oxidative stress. The present study tested the hypothesis that patients with OSAS have an alteration in antioxidant defences. The plasma levels of total antioxidant status (TAS), glutathione peroxidase (GPX), γ-glutamyltransferase (GGT), vitamins A, E, B12 and folate, and homocysteine were determined in 47 patients with OSAS and 37 healthy subjects. Of these, 27 patients who used continuous positive airway pressure (CPAP) for >4 h·night−1 were re-examined 12 months later. Patients with OSAS had lower TAS (1.4±0.16 versus 1.50±0.10 mmol·L−1), vitamin A (64±19 versus 74±17 μg·dL−1) and vitamin E levels (1,525±499 versus 1,774±503 μg·dL−1), and increased values of GGT (42±22 versus 32±16 U·L−1) than controls. There was no difference between groups in GPX, homocysteine, vitamin B12 and folate plasma levels. CPAP treatment normalised the levels of TAS (1.50±0.13 mmol·L−1) and the activity of GGT (30±14 U·L−1) without any influence on vitamins levels. In conclusion, the results indicate that patients with obstructive sleep apnoea syndrome have a decreased antioxidant capacity that is partially reversed by continuous positive airway pressure treatment.

Association between Obstructive Sleep Apnea and Cancer Incidence in a Large Multicenter Spanish Cohort

RATIONALE Obstructive sleep apnea (OSA) has been associated with increased cancer mortality, but whether it is also associated with cancer incidence is unknown. OBJECTIVES To investigate whether OSA is associated with increased cancer incidence in a large clinical cohort. METHODS A multicenter, clinical cohort study including consecutive patients investigated for suspected OSA between 2003 and 2007 in seven Spanish teaching hospitals. Apnea-hypopnea index (AHI) and percent nighttime with oxygen saturation less than 90% (TSat(90)) were used as surrogates of OSA severity, both as continuous variables and categorized by tertiles. Cox proportional hazards regression analyses were used to calculate hazard ratio (HR) and 95% confidence interval (CI) for cancer incidence after adjusting for confounding variables. MEASUREMENTS AND MAIN RESULTS A total of 4,910 patients were analyzed (median follow-up, 4.5 yr; interquartile range, 3.4-5.2). Compared with the lower TSat(90) category (<1.2%), the adjusted hazards (95% CI) of cancer incidence for increasing categories were 1.58 (1.07-2.34) for TSat(90) 1.2-12% and 2.33 (1.57-3.46) for TSat(90) greater than 12%. Continuous TSat(90) was also associated with cancer incidence (adjusted HR, 1.07 [1.02-1.13] per 10-unit increase in TSat(90)). In stratified analyses, TSat(90) was associated with cancer incidence in patients younger than 65 years (adjusted HR, 1.13 [95% CI, 1.06-1.21] per 10-unit increase in TSat(90)) and males (adjusted HR, 1.11 [95% CI, 1.04-1.17] per 10-unit increase in TSat(90)). AHI was not associated with cancer incidence in the adjusted analyses, except for patients younger than 65 years (adjusted HR for AHI >43 vs. <18.7, 1.66; 95% CI, 1.04-2.64). CONCLUSIONS Increased overnight hypoxia as a surrogate of OSA severity was associated with increased cancer incidence. This association seems to be limited to men and patients younger than 65 years of age.

Daytime sleepiness and polysomnographic variables in sleep apnoea patients

Excessive daytime sleepiness (EDS) is not invariably present in patients with obstructive sleep apnoea syndrome (OSAS). The aim of the present study was to investigate polysomnographic determinants of EDS in patients with OSAS. EDS was assessed using the Epworth Sleepiness Scale (ESS) and the multiple sleep latency test (MSLT). Patients showed EDS whenever the ESS score was >10 and the MSLT score <5 min. Absence of EDS was defined as having an ESS score of <10 and an MSLT score of >10 min. In total, 23 male patients with EDS (mean±sd ESS and MSLT score 17±3 and 4±1 min, respectively) and 17 without EDS (ESS and MSLT score 5±2 and 16±3 min, respectively), were studied. Both groups exhibited a similar apnoea/hypopnoea index (62±18 versus 60±20 events·h−1). Patients with EDS exhibited shorter sleep latency (11±16 versus 18±18 min) and greater sleep efficiency (90±7 versus 82±13%) than those without EDS. Patients with EDS showed lower oxygenation (lowest arterial oxygen saturation 69±12 versus 79±8%; mean arterial oxygen saturation 87±6 versus 90±5%). Sleep stage distribution and arousal index did not differ between the groups. Patients with obstructive sleep apnoea syndrome and excessive daytime sleepiness are characterised by shorter sleep latency, increased sleep efficiency and worse nocturnal oxygenation than those without excessive daytime sleepiness. Nocturnal hypoxaemia can be a major determinant of excessive daytime sleepiness in patients with obstructive sleep apnoea syndrome.