Treating Sleep Apnea Fails to Boost Outcomes in Patients With CVD: SAVE Trial

ROME, Italy—Continuous positive airway pressure (CPAP) has some benefits for patients with moderate-to-severe obstructive sleep apnea and either coronary or cerebrovascular disease in terms of sleep measures and quality of life, but it does not reduce cardiovascular outcomes, the large, randomized SAVE trial has shown.

Individual and composite cardiovascular outcomes were unaffected in patients using CPAP for an average of 3.3 hours per night during an average follow-up of 3.7 years, R. Doug McEvoy, MD (Flinders University, Adelaide, Australia), reported at the European Society of Cardiology Congress 2016. The results were published simultaneously online in the New England Journal of Medicine.

But McEvoy was not ready to declare that treatment of obstructive sleep apnea does not have a role in reducing cardiovascular risk, citing the strength of the association between the sleep disorder and cardiovascular outcomes in epidemiologic studies.

“It is still possible, I believe, that we have not hit the target in terms of the amount of treatment necessary to modify the [cardiovascular] risk associated with obstructive sleep apnea,” he said at a press conference.

Commenting on the study for TCTMD, Anthony DeMaria, MD (University of California, San Diego), agreed that SAVE does not provide a definitive answer, highlighting concerns both with the average use of CPAP in the study and with the potential for variation in the level of expertise in treating sleep apnea and following patients across the 89 centers in seven countries that participated.

“If there were a way to make CPAP more acceptable and easier to use, I think the results might be different, because there’d be longer period of use during the evening and perhaps more efficacy,” said DeMaria, a past president of the American College of Cardiology.

But even though this is an area worth pursuing further, DeMaria added, “at the moment one would have to say that we don’t have hard data to support that it’s a useful approach.”

Noncardiovascular Benefits Seen

Prior studies have shown that patients with obstructive sleep apnea have an elevated cardiovascular risk. Smaller trials have found that CPAP induces positive changes in systolic blood pressure, endothelial function, and insulin sensitivity, and some observational data suggest that the therapy reduces cardiovascular complications and death.

To more definitively assess the potential cardiovascular benefits of CPAP, investigators initiated the SAVE trial, which enrolled 2,717 adults ages 45 to 75 with moderate-to-severe obstructive sleep apnea and cardiovascular disease. All patients received sham CPAP for 1 week to establish adherence and were then randomized to CPAP plus usual cardiovascular care or to usual care alone.

In the CPAP group, patients used the device an average of 3.3 hours per night. Mean apnea-hypopnea index dropped from 29.0 events per hour at baseline to 3.7 during follow-up, an indication that sleep apnea was well controlled.

That translated into reductions in snoring, daytime sleepiness, anxiety, and depression and improvements in health-related quality of life and work attendance.

It did not, however, influence cardiovascular outcomes. During a mean follow-up of 3.7 years, the composite rate of cardiovascular death, MI, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack (primary endpoint) was 17.0% in the CPAP group and 15.4% in the controls (HR 1.10; 95% CI 0.91-1.32). There also were no effects on any other individual or composite cardiovascular endpoints.

In a separate propensity-matched analysis, patients who were deemed adherent to CPAP had a borderline lower risk for stroke (HR 0.56; 95% CI 0.32-1.00) and a nonprespecified composite endpoint of cerebral events (HR 0.52; 95% CI 0.30-0.90). The authors note, however, that neither outcome was adjusted for multiple testing.

Better Treatments Needed

In an editorial accompanying the NEJM paper, Babak Mokhlesi, MD (University of Chicago, IL), and Najib Ayas, MD (University of British Columbia, Vancouver, Canada), question whether the trial failed to show a cardiovascular benefit of CPAP because obstructive sleep apnea does not actually worsen cardiovascular risk in the first place—and thus no intervention would be successful—or because patients did not use CPAP enough each night.

“Given the substantial human and animal data that have consistently documented links between obstructive sleep apnea and cardiovascular health, we suspect that it may be the latter” they write, noting that using CPAP for a little over 3 hours each night might not be adequate to prevent cardiovascular events.

When CPAP was used during the night may also have contributed to the negative result, they write. Using it in the beginning of the night might be less effective than using it later during rapid-eye-movement sleep when apneic and hypopneic events are longer and oxygen desaturation is greater, they explain.

“We believe that for symptomatic patients with obstructive sleep apnea, a trial of CPAP should be offered. It would also 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,” the editorialists say. “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.”

They call for further research to evaluate whether better adherence to CPAP can improve cardiovascular outcomes, but add that new treatments conducive to better adherence are needed.

Sources: 

• McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med. 2016;Epub ahead of print.
• Mokhlesi B, Ayas NT. Cardiovascular events in obstructive sleep apnea—can CPAP therapy SAVE lives? N Engl J Med. 2016;Epub ahead of print.  

Disclosures:

• The study was supported by project grants from the National Health and Medical Research Council of Australia and by Respironics Sleep and Respiratory Research Foundation and Philips Respironics. Supplementary trial funding was provided by Fisher & Paykel Healthcare, the Australasian Sleep Trials Network, the Spanish Respiratory Society, and Fondo de Investigaciones Sanitarias. In-kind donations were provided by Respironics for CPAP equipment and by ResMed for sleep apnea diagnostic devices.
• McEvoy reports receiving research study equipment from Air Liquide and research funding from Philips Respironics, Air Liquide, ResMed, and the National Health and Medical Research Council of Australia. 
• DeMaria reports consulting for ResMed, which makes the ApneaLink device used to diagnose obstructive sleep apnea in the study.   

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