Introduction

Obstructive sleep apnea (OSA) is characterized by repetitive upper airway collapse during sleep, resulting in intermittent pauses (apneas) or decrements (hypopneas) in breathing. These events cause episodic hypoxia and arousals from sleep. OSA is highly prevalent in the general population, affecting approximately 34% of men and 17% of women.¹ The most important risk factors for OSA are increasing age, male gender, and obesity. Excessive daytime sleepiness and snoring are common symptoms of OSA; a history of nocturnal choking or gasping is less frequent, but more specific for the presence of OSA. The severity of sleep apnea is usually quantified by the apnea-hypopnea index (AHI), defined as the number of apneas and hypopneas per hour of sleep. OSA is defined as the presence of an AHI of ≥5 predominantly obstructive events/hour. OSA is considered to be mild when AHI is ≥5 and <15 events/hour, moderate when AHI is ≥15 and <30 events/hour, and severe when AHI exceeds 30 events/hour of sleep.

Association Between OSA, Cardiovascular Risk Factors, and CVD

Cross-sectional studies link OSA to cardiovascular risk factors including insulin resistance, dyslipidemia, hypertension, and inflammation.² An independent association with incident diabetes has also been demonstrated.³ Data about the association between OSA and incident hypertension are conflicting.^4-7 More reliable evidence of the causal effect of OSA on blood pressure is derived from randomized clinical trials, which demonstrate a reduction in BP with continuous positive airway pressure (CPAP). Although the average effect size is small (reduction of ~2 mmHg), it may be greater in resistant hypertension.^8,9

OSA is associated with an increased risk for CVD, including coronary artery disease, stroke, and atrial fibrillation.¹⁰ Untreated severe OSA has been associated with an increased risk of all-cause mortality compared with individuals without OSA. In men but not in women, OSA is a predictor of incident heart failure (HF).¹¹

Pathophysiology of Cardiovascular Disease in OSA

Mechanisms linking OSA to cardiovascular disease (CVD) are incompletely understood. Obstructive events are associated with marked sympathetic activation, causing increased heart rate and blood pressure. Arousal from sleep terminates the asphyxia event with restoration of airflow and re-oxygenation, but further increases sympathetic tone. Of note, sympathetic activation persists beyond the apneic event, "carrying over" to daytime wakefulness.⁶ Whereas hypoxia-mediated chemoreceptor activation is thought to play a role in sympathetic activation in OSA, hypoxia alone does not explain the effect of OSA on blood pressure.⁸ Intermittent hypoxia may also induce oxidative stress and the production of reactive oxygen species. OSA is associated with increased circulating inflammatory cytokines and metabolic dysregulation (with abnormalities in both fat and glucose metabolism). However, data regarding the impact of CPAP on inflammatory markers in OSA patients are conflicting.^8,12,13 Similarly, at present, there is insufficient clinical evidence to establish a causal role for OSA in the development of insulin resistance and/or dyslipidemia in humans.

The inspiratory effort against a closed upper airway causes an increase in negative intra-thoracic pressure. This transiently increases the left ventricular (LV) transmural pressure gradient (increasing LV afterload) and increases systemic venous return (and hence RV preload), but the clinical significance of these transient alterations in cardiovascular hemodynamics remain unclear.

Role of Obesity

Obesity and OSA are strongly associated. Like OSA, obesity is linked to insulin resistance, dyslipidemia, hypertension, and inflammation. The causal relation of OSA versus obesity to these abnormalities cannot be confidently discerned in observational studies. A randomized trial assigned 181 obese adults with moderate-to-severe OSA who had high C-reactive protein levels (CRP) to either: 1) weight loss therapy; 2) CPAP therapy, or; 3) combined therapy with weight loss and CPAP, for 24 weeks.¹³ The trial evaluated the incremental effect of combination therapy with CPAP and weight loss over each therapy alone on various cardiovascular risk factors. Weight loss alone significantly reduced CRP, insulin resistance, dyslipidemia, and blood pressure. In contrast, there was not a significant effect of CPAP on CRP, insulin sensitivity, or dyslipidemia, even among the subsample of subjects who adhered to CPAP therapy. Weight loss was significantly more effective than CPAP in reducing CRP, with a trend for superiority of combined therapy over CPAP alone. Similarly, reductions in insulin resistance and serum triglycerides were greater in the combined-intervention group than in CPAP-only group, but there were no significant differences in these values between the combined-intervention group and the weight loss only group. These results argue against an independent causal relationship between OSA and these cardiovascular risk factors. Interestingly, both CPAP and weight loss significantly reduced blood pressure. Among compliant subjects, the combined intervention resulted in a larger reduction in blood pressure than did either CPAP or weight loss alone. Overall, this trial indicates that CPAP alone is not an effective therapy to reduce the CV risk factor burden and that weight loss should be a central component of strategies to improve the risk factor profile in this population. Further research is needed to enhance the delivery of effective and affordable weight loss interventions for these patients.

The Sleep Apnea Cardiovascular Endpoints (SAVE) trial

The SAVE trial is a large multicenter, randomized trial that examined the effect of CPAP therapy on the secondary prevention of cardiovascular events.¹⁴ In this trial, 2717 adults aged 45-75 years with moderate-to- severe OSA and coronary or cerebrovascular disease were randomized to CPAP plus usual care (CPAP group) or usual care alone (usual-care group) in a parallel-group, open-label, blinded end-point design. The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Patients were excluded from the trial if they reported severe daytime sleepiness, if they were considered to have an increased risk of an accident from falling asleep, or if they had exhibited severe hypoxemia or a pattern of Cheyne-Stokes respiration. A minimum level of adherence to CPAP therapy (at least 3 hours/night, during a 1-week run-in period in which CPAP was prescribed at sub-therapeutic pressure) was required prior to randomization. Most of the participants were males, had moderate-to-severe obstructive sleep apnea at baseline, and reported minimal sleepiness (Epworth Sleepiness Scale score=7). Mean body mass index was 29 kg/m². CPAP reduced the apnea-hypopnea index from 29 to 3.7 events/hour during use, but the mean adherence to CPAP was only 3.3±2.3 hours/night. After a mean follow-up of 3.7 years, CPAP was not associated with a significant reduction in the primary endpoint, which occurred in 17% of subjects in the CPAP arm and 15.4% of subjects in the usual care arm (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, as well as work productivity.

In pre-specified analyses in which subjects who adhered to CPAP therapy (those who used CPAP for ≥4 hours per night) were compared with propensity-score matched subjects in the usual-care group, the primary end-point occurred in 15.3% of subjects in the CPAP group and 17.5% of subjects in the usual-care group (hazard ratio = 0.80; 95% CI = 0.60 to 1.07; P = 0.13). In these analyses, patients who were adherent to CPAP therapy had a lower risk of stroke than those in the usual-care group (hazard ratio, 0.56; 95% CI = 0.32 to 1.00; P = 0.05), as well as a lower risk of the non-pre-specified composite end point of cerebral events (hazard ratio, 0.52; 95% CI = 0.30 to 0.90; P = 0.02). These results from the compliant subgroup should be interpreted cautiously, given the potential for additional confounding and the lack of correction for multiple comparisons.

This trial demonstrates the lack of clinical efficacy of CPAP for the secondary prevention of cardiovascular events. There are, however, some important considerations. The trial excluded patients with excessive daytime sleepiness, patients at high risk of an accident, and patients with severe hypoxemia. Although the mean adherence to CPAP was low (mean was 3.3 hours per night), it is representative of what may be expected in clinical practice. It should be considered that CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood. Although these effects may prompt consideration of CPAP therapy in various clinical scenarios, this intervention should not be expected to reduce CV risk in the average patient with established cardiovascular disease. More comprehensive strategies for CV risk reduction in this population should be implemented.

Conclusions

Available evidence indicates that moderate to severe OSA is independently associated with various forms of CVD. Whereas there is strong evidence of causality for elevated BP, the effect is small. Solid proof for causality for other cardiovascular risk factors and for clinical cardiovascular disease is lacking. Insufficient RCT data are available regarding the role of CPAP for the primary prevention of cardiovascular disease. Available data suggests that for this purpose, a comprehensive clinical strategy is required. It is important to note that many patients with OSA are obese, and that addressing obesity via weight loss interventions markedly improves the cardiometabolic risk factor profile in obese patients with OSA, whereas CPAP in the absence of weight loss has little effect. Weight loss should therefore be considered an essential component of CV risk reduction strategies in patients with OSA.

The role of CPAP therapy for the secondary prevention of CVD also remains uncertain. The recent SAVE trial demonstrated that CPAP does not reduce the incidence of CV events in patients with established CVD, but the limited compliance with CPAP therapy in this trial (which is also an expected problem in clinical practice) should be considered in the interpretation of this study. More research is required to assess the role of CPAP to reduce recurrence rates after restoration of sinus rhythm in patients with atrial fibrillation.

References

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Keywords: Airway Obstruction, Angina, Unstable, Asphyxia, Atrial Fibrillation, Blood Pressure, Body Mass Index, C-Reactive Protein, Cardiovascular Diseases, Cheyne-Stokes Respiration, Continuous Positive Airway Pressure, Coronary Artery Disease, Diabetes Mellitus, Dyslipidemias, Heart Failure, Heart Rate, Hypertension, Ischemic Attack, Transient, Myocardial Infarction, Obesity, Oxidative Stress, Primary Prevention, Reactive Oxygen Species, Risk Factors, Secondary Prevention, Sleep Apnea, Obstructive, Snoring, Stroke, Weight Loss, Wakefulness

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