By Barbara Phillips, MD, MSPH

Professor of Medicine, University of Kentucky; Director, Sleep Disorder Center, Samaritan Hospital, Lexington

Dr. Phillips reports no financial relationships relevant to this field of study.

SYNOPSIS: In this large, multicenter, randomized, controlled trial, continuous positive airway pressure did not reduce incident cardiovascular events compared with usual care, but did reduce snoring and daytime sleepiness and improved health-related quality of life and mood.

SOURCE: McEvoy RD, Antic NA, Heely E, et al. CPAP for prevention of cardiovascular event in obstructive sleep apnea. N Engl J Med 2016;375:919-931.

The long-awaited Sleep Apnea Cardiovascular Endpoints (SAVE) trial was a mammoth undertaking, containing patients from 89 centers in seven countries. It was partly funded by industry (Respironics, makers of continuous positive airway pressure [CPAP] machines) and by the Australian government. The aim was to undertake a randomized, controlled trial of the effect of CPAP vs. usual care on cardiovascular endpoints in patients suffering from moderate-to-severe sleep apnea who already received a cardiovascular or cerebrovascular disease diagnosis. Obstructive sleep apnea was defined as an oxygen desaturation index (ODI) of at least 12 events per hour, which is an ethical and reproducible way to define sleep apnea, since the Apnea-Hypopnea Index (AHI) is a poorly reproducible, frequently changing metric.1 Of note, very sleepy (Epworth Sleepiness Scale score > 15) or very hypoxemic (SaO2 < 80% for > 10% of recording time) patients were excluded. Patients were randomized to CPAP or usual care, which was management of cardiovascular risk factors and advice on healthy sleep habits and “lifestyle changes to minimize obstructive sleep apnea,” which one would assume means weight loss.

CPAP pressures were set according to an analysis of data from autotitrating (or “smart”) CPAP machines. After a trial on autoPAP, the pressure on the CPAP machines was set at the 90th percentile (that is, the pressure at or below which the autotitrating or “smart” CPAP machine delivered 90% of the time, when used by the sleeping patient). Patients in both arms were followed at one, three, six, and 12 months and annually thereafter. The primary endpoint was a composite of death from any cardiovascular cause, myocardial infarction (including silent myocardial infarction), stroke, or hospitalization for heart failure, acute coronary syndrome (including unstable angina), or transient ischemic attack. Prespecified secondary cardiovascular endpoints included the individual components of the primary composite endpoint, other composites of cardiovascular events, revascularization procedures, new onset atrial fibrillation, new onset diabetes mellitus, and death from any cause. Other secondary endpoints included symptoms of obstructive sleep apnea, health-related quality of life, and mood.

Ultimately, 2,687 patients were included in the primary analysis. They were fairly typical advanced sleep apneics: 81% men, mean age 61 years, mean body mass index 29 kg/m2, mean ODI 28/hour, and mean Epworth score 7.4. The mean duration of follow-up was 3.7 years.

Among the participants in the CPAP group, the mean duration of adherence to CPAP therapy in the first month of treatment was 4.4 hours per night, but this fell to 3.5 hours per night by 12 months and remained relatively stable thereafter. The residual AHI during CPAP use, as measured by the CPAP machine (not the same thing as measured in a sleep lab, but close enough), averaged 3.7 events per hour, suggesting good control of sleep apnea. (This reviewer was unable to find data about the pressure settings in the paper or the online supplement but suspects that the pressures may have been too low). Of the 1,346 patients in the CPAP group, 566 (42%) demonstrated good adherence to treatment ( 4 hours per night) during follow-up.

No significant effect of CPAP was found in the adjusted analysis of data; a primary endpoint was observed in 17% of the CPAP group and 15.4% in the usual-care group (P = NS). There did not appear to be a difference in primary endpoints between propensity-matched patients with good CPAP adherence in the CPAP group compared with those in the usual care group, but for secondary endpoints, patients who were adherent to CPAP therapy demonstrated a lower risk of stroke and a lower risk of cerebral events than those in the usual care group.

The CPAP group also experienced greater reductions in sleepiness, other symptoms of obstructive sleep apnea (snoring and witnessed apneas), anxiety, and depression than the usual care group; the percentage of patients with clinically relevant depression scores was 25-30% lower in the CPAP group than in the usual care group by the end of follow-up. In addition, the CPAP group demonstrated greater improvement in scores on the physical and mental subscales of the 36-item Short Form Survey, as well as fewer days off from work because of poor health. The number of serious adverse events and the rate of traffic accidents and accidents causing injury did not differ significantly between the two groups.

COMMENTARY

This paper surprised and disappointed those of us who regularly manage sleep apnea, but perhaps it shouldn’t. Three other randomized trials have investigated the effect of CPAP on cardiovascular endpoints in patients presenting with obstructive sleep apnea.2-4 Two studies — a multicenter study conducted in Spain that compared CPAP with usual care in 725 patients with obstructive sleep apnea who did not have prior cardiovascular disease2 and a single-center study involving 224 patients with obstructive sleep apnea and coronary artery disease who had just undergone revascularization4 — did not find a difference in incident cardiovascular endpoints over several years of follow-up, although in adjusted analyses, both studies reported better outcomes among patients who used CPAP at least four hours per night than among patients who did not receive CPAP or who used CPAP less than four hours per night. The third study, which included 140 patients with recent ischemic stroke, showed no effect of CPAP on event-free survival over two years.3 In other words, CPAP appears to “work,” but the patient needs to use it. In the SAVE study, patients who were assigned to CPAP used the treatment for a mean of 3.3 hours per night over several years. Several studies, including those mentioned above, have indicated that this level of CPAP use is probably not enough to prevent or reduce cardiovascular damage. There are several other possible explanations for the disappointing findings of this study, including that controlling sleep-disordered breathing 90% of the time is not good enough, that 3.5 years is not long enough to see a difference in outcomes due to CPAP, and that excluding very sick (hypoxemic and sleepy) patients reduces the effect of therapy. There are randomized, controlled trials that demonstrate significant cardiac benefits of CPAP, including the ORBIT trial, which showed reduced likelihood of recurrent atrial fibrillation in sleep apnea patients who used CPAP.5

In the accompanying editorial, Mokhlesi and Ayas argued that the poor CPAP adherence in this trial likely contributed to the negative results.6 They noted that it would be “prudent to offer CPAP to patients with obstructive sleep apnea and severe hypoxemia during sleep regardless of symptoms — these patients were excluded from the SAVE trial. However, on the basis of the results from the SAVE trial, prescribing CPAP with the sole purpose of reducing future cardiovascular events in asymptomatic patients with obstructive sleep apnea and established cardiovascular disease cannot be recommended.”

Although this relatively short-term study of selected, poorly adherent patients did not show a benefit of CPAP in reducing cardiovascular disease, it most definitely demonstrated, as have many previous studies, a benefit of CPAP in improving symptoms that matter to patients, such as sleepiness, depression, anxiety, snoring, and time off work,7 without significant adverse events. Frankly, this is better than antidepressants and many other efforts we make to help improve such symptoms in patients. Sleepiness in particular is an important symptom since it predicts the likelihood of crash and death.8

Here’s what I tell my patients: “You have significant sleep apnea, which is a risk for heart attacks, heart failure, cardiac arrhythmias (especially atrial fibrillation), hypertension (especially medication-resistant hypertension), stroke, car crash, depression, cognitive depression, and death. The safest, cheapest, best-studied treatment for this is CPAP, a breathing mask you wear during sleep. CPAP has been shown to reduce or prevent some of these conditions, as well as improving sleepiness. So far, there essentially are no significant side effects reported for CPAP, but there are some follow-ups required. And it doesn’t work if you don’t use it. I would recommend that we give it a try.”

REFERENCES

  1. Redline S, Kapur VK, Sanders MH, et al. Effects of varying approaches for identifying respiratory disturbances on sleep apnea assessment. Am J Respir Crit Care Med 2000;161:369-374.
  2. Barbe F, Duran-Cantolla J, Sanchez-de-la-Torre M, et al. 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. JAMA 2012;307:2161-2168.
  3. Parra O, Sanchez-Armengol A, Bonnin M, et al. Early treatment of obstructive apnoea and stroke outcome: A randomized controlled trial. Eur Respir J 2011;37:1128-1136.
  4. Peker Y, Glantz H, Eulenburg C, et al. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with non-sleepy obstructive sleep apnea: The RICCADSA randomized controlled trial. Am J Respir Crit Care Med 2016;194:613-620.
  5. Holmqvist F, Guan N, Zhu Z, and the ORBIT-AF Investigators. Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation-results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Am Heart J 2015;169:647-654.
  6. Mokhlesi B, Ayas NT. Cardiovascular events in obstructive sleep apnea — Can CPAP therapy SAVE lives? N Engl J Med 2016;375:994-996.
  7. McMillan A, Bratton DJ, Faria R, et al. A multicentre randomised controlled trial and economic evaluation of continuous positive airway pressure for the treatment of obstructive sleep apnoea syndrome in older people: PREDICT. Health Technol Assess 2015;19:1-188.
  8. Empana JP, Dauvilliers Y, Dartigues JF, et al. Excessive daytime sleepiness is an independent risk indicator for cardiovascular mortality in community-dwelling elderly: The three city study. Stroke 2009;40:1219-1224.