SDB/OSA can be effectively and safety treated using positive airway pressure (PAP) therapies. PAP is delivered nasally, using either a nasal mask or prongs, or a full face mask. Millions of patients worldwide already receive this therapy, which is typically delivered at a pressure of approximately 10 cm H
2O (or about 1% of atmospheric pressure). Furthermore, screening for SDB, its definitive diagnosis, and initiation of treatment can be cost effective and easy using home-based diagnosis and automated CPAP treatment, with optimal mask fitting done by a trained respiratory technician or nurse [
92‐
94]. Since its introduction 25 years ago, CPAP has changed lives for the better in over 10 million patients worldwide.
There are few published randomised trials on the effects of treatment on disease progression because ethical considerations preclude randomization of OSA patients to no therapy for long periods in a clinical trial setting, but there are many observational studies demonstrating the benefits of CPAP therapy. Therefore, there is a considerable and growing body of evidence suggesting that effective treatment of SDB/OSA with CPAP also attenuates some of the negative consequences of untreated sleep apnea and the rate of progression of many comorbid conditions [
34,
133‐
135,
137,
95‐
104]. Furthermore, it has been shown that patients compliant with PAP treatment are much less likely to use inpatient and outpatient services, resulting in substantial cost savings for the healthcare system [
105‐
110].
Arterial hypertension
In the most recent meta-analysis of published data, which included 32 randomized controlled trials, mean reductions in daytime systolic and diastolic blood pressure (BP) with CPAP versus no treatment were 2.6 and 2.0 mmHg, respectively; corresponding night-time reductions were 3.8 and 1.8 mmHg (p < 0.001) [
111]. While these effects are modest, most patients in these studies had well-controlled hypertension before CPAP was initiated. Therefore, BP reductions during CPAP were additional to those associated with antihypertensive drug therapy, and were of a magnitude that was at least half of that achieved with drug therapy alone in similar analyses. The meta-analysis also showed a link between baseline OSA severity and the beneficial effects of CPAP on BP, with the greatest reductions seen in those with more severe OSA (β ± standard error, 0.08 ± 0.04) [
111]. The most substantial reductions in BP during CPAP therapy have been seen in patients with drug-resistant hypertension [
53]. A meta-analysis of five randomized clinical trials of CPAP in patients with OSA and resistant hypertension reported pooled reductions of 4.78 and 2.95 mmHg in 24-h ambulatory systolic and diastolic BP, respectively [
100].
Based on combined data from three randomized trials, increases in mean office and home systolic BP after CPAP was stopped were 5.4 and 9.0 mmHg, respectively (p < 0.003 and p < 0.001 vs on CPAP, respectively). Corresponding increases in mean diastolic BP were 5.0 and 7.8 mmHg (both p < 0.001). The changes were described as clinically relevant by authors of the analysis [
112]. In addition, there was a significant association between OSA severity and the extent of BP increase in response to CPAP withdrawal [
112].
Congestive heart failure
Two randomized trials evaluating the effect of CPAP therapy in patients with OSA and HF showed significant improvements in left ventricular ejection fraction (LVEF) after 1 and 3 months and improved quality of life [
98,
101]. A Japanese cohort study documented a positive effect of CPAP treatment on survival in HF patients with OSA, and also highlighted the importance of compliance with therapy in achieving beneficial outcomes [
99]. Treating OSA in patients with HF
pEF has been shown to improve left ventricular diastolic function [
95]. The 2010 Heart Failure Society of America Comprehensive Heart Failure guidelines [
113] and the 2013 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines [
114] recommend that HF patients with OSA should receive treatment for sleep apnea to improve their HF status.
CPAP has limited ability to treat CSA/CSR in patients with HF [
115‐
118], and the Canadian Positive Airway Pressure (CANPAP) study, which investigated the effect of CPAP therapy on CSA/CSR on transplantation-free survival in patients with stable HF, did not show a positive effect of therapy on either transplant-free survival or hospitalization [
119]. Adaptive servo-ventilation (ASV) is a PAP therapy designed specifically to treat CSA/CSR, and is the most effective treatment for this type of SDB in HF patients [
120‐
123].
Smaller trials of ASV have documented improvements in AHI, sleep quality, quality of life, LVEF, New York Heart Association class, oxygen uptake, natriuretic peptide levels, inflammatory markers and exercise capacity [
124‐
127], with these results being consolidated in a recent meta-analysis [
128]. The effect of ASV treatment on morbidity and mortality was investigated in the SERVE-HF study (NCT00733343) [
129], which enrolled 1325 patients with chronic stable HF
rEF and CSA/CSR, and finished in mid-2015 [
130]. The effects of using ASV in HF
rEF patients overall was disappointing, and patients with the most severe disease (LVEF <30 and >50% CSR) randomized to ASV had a higher mortality rate than those in the control group [
130]. Conversely, patients with an LVEF ≥ 30% appeared to fare better when randomized to ASV [
130]. On the basis of these results, ASV is contraindicated in patients with HF
rEF and LVEF ≤ 45%. However, ASV still has a role in a number of other indications, including HF
pEF.
The cardiovascular improvements with minute ventilation-targeted ASV therapy in heart failure (CAT-HF) study (NCT01953874) compared the effects of targeted ASV added to optimized medical therapy compared with medical therapy alone in patients with acute decompensated HF [
131]. The primary endpoint (a global rank score based on a hierarchy of death, cardiovascular hospitalizations and percent changes in 6-min walk distance at 6 months) did not differ significantly between the ASV and control groups (p = 0.92), and there was no significant interaction between treatment and LVEF. However, a subgroup analysis suggested that ASV may improve outcomes in patients with HF
pEF, and sleep apnea parameters were significantly improved by ASV in all patients [
131].
Arrhythmias
The effectiveness of antiarrhythmic drugs and ablation interventions for the treatment of AF is reduced in patients with severe OSA [
132]. Treatment of OSA with CPAP significantly reduces the risk of AF recurrence after ablation therapy [
133], with one small study finding that the 1-year arrhythmia recurrence rate after successful cardioversion was halved when OSA was treated with CPAP [
134]. In a larger study (n = 426), CPAP therapy was associated with a higher AF-free survival rate (71.9 vs 36.7% in untreated patients; p = 0.01) in patients with OSA and AF undergoing pulmonary vein isolation. The proportion of patients who were free of AF without drug treatment or repeat ablation was also significantly higher in CPAP users versus non-users [
135]. Co-existing HF and SDB increases the risk of developing malignant ventricular arrhythmias [
136], but this can be reduced by treating CSR with ASV [
137]. Effective treatment of OSA is recommended by the electrophysiological societies of Europe and North America [
138].
Coronary artery disease
Treatment of OSA with CPAP has been shown to have a beneficial effect on cardiovascular event rates and mortality in patients with coronary artery disease. In one study the risk of fatal and nonfatal cardiovascular events in OSA patients treated with CPAP was 36% lower than in untreated patients, a finding that has been repeated in studies with longer follow-up durations [
96,
97,
102,
104]. However, the results of the international, multicenter sleep apnea cardiovascular endpoints (SAVE) study, conducted in non-sleepy patients with OSA and existing coronary or cerebrovascular disease, were neutral [
139]. The rate of the primary endpoint (a composite of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure or transient ischemic attack) was similar in patients treated with CPAP + usual care and usual care alone (HR 1.10, 95% CI 0.91–1.32; p = 0.34). Thus, the addition of CPAP to usual care did not reduce cardiovascular events when used as a secondary prevention intervention in OSA patients with coronary or cerebrovascular disease in this study. However, average CPAP usage was only 3.3 h/night, a level most clinicians would define as inadequate treatment. Even with usage levels this low, the CPAP group showed significantly improved daytime alertness, mood, and quality of life, and the number of self-reported work days lost due to ill-health was reduced. This is the first large sleep apnea study demonstrate that treatment with CPAP has a positive impact on depressive symptoms.
Ongoing studies (ISAACC [
140] and TEAM-ASV) will determine the role of early PAP therapy after acute coronary syndrome, based on documented associations between SDB and infarct size/myocardial salvage [
141] and right heart enlargement [
142] after acute myocardial infarction.
Stroke
Use of CPAP in patients with stroke and OSA has been associated with improvements in subjective well-being, significant reductions in the AHI, and normalization of nocturnal BP and oxygen saturation [
143‐
145]. A reduction in 5-year mortality has been documented in stroke patients with an AHI of >20/h who tolerated CPAP compared with those who were untreated [
103]. The results of these studies show that there is an increasing body of evidence that OSA plays a significant role in the overall risk management of stroke patients and that CPAP therapy can improve outcomes.
Diabetes mellitus
Treatment of OSA with CPAP has the potential to lower fasting plasma glucose, post-prandial glucose and glycosylated hemoglobin levels to at least the same extent as oral hypoglycemic agents in patients with diabetes [
34]. Other beneficial effects of CPAP therapy in these patients include reductions in blood pressure, sympathetic nerve activity and arterial stiffness [
146], as well as improved quality of life [
147]. Reductions in cardiovascular risk seen in cohorts of OSA patients treated with CPAP would also be expected to be seen in those with diabetes. Screening and treatment of SDB is becoming incorporated in some care pathways for diabetes [
148,
149], but better recognition of SDB as an important comorbidity by endocrinologists is needed.
Chronic obstructive pulmonary disease
Treatment of OSA with CPAP in patients with COPD has been shown to have a number of beneficial effects. Most importantly, use of CPAP decreased mortality in overlap syndrome patients [
83,
150,
151], with greater reductions seen as device usage time increased [
151]. The rate of COPD exacerbations can also be reduced by CPAP treatment of OSA [
83].
Noninvasive ventilation (NIV) is the standard of care for treating severe acute exacerbations of COPD and is widely used. However, until recently, there was no positive study for the effect of NIV on long-term survival in chronic stable COPD patients. A landmark trial recently showed that stable hypercapnic COPD patients treated with NIV had a two-thirds reduction in mortality and improved quality of life compared to those not receiving NIV [
152]. The key point in this study was that NIV was targeted to markedly reduce hypercapnia. The benefits of NIV in patients with hypercapnic COPD were reinforced by the results of the HOT-HMV study, conducted in COPD patients with persistent hypercapnia at 2–4 weeks after an acute exacerbation [
153]. This randomized, controlled trial showed that the addition of home mechanical ventilation (HMV [NIV]) to home oxygen therapy (HOT) reduced the likelihood of readmission or death by almost 50%. In addition, the time to readmission or death was increased by >90 days. Overall, treatment of 6 patients with HMV was required to prevent 1 readmission or death. These results are consistent with the effects of NIV on other chronic diseases causing respiratory failure, and are expected to lead to significantly increased chronic use of NIV in COPD.