Reviewed by Dr. Allexa Hammond
McEvoy R, et al. NEJM. 2016 Sep 375 (10): 919-931

Obstructive sleep apnea (OSA), when left untreated, has been associated with increased incidence of cardiovascular disease and stroke.1 The Sleep Apnea Cardiovascular Endpoints (SAVE) trial was an international, multicenter randomized study conducted to determine whether night-time continuous positive airway pressure (CPAP) use in addition to standard medical management for those with moderate-to-severe OSA and a history of coronary or cerebrovascular disease could lower risk for cardiovascular disease. A total of 2717 patients participated in the study, which took place over a period of five years. Participants were assigned to either ‘usual care without CPAP’ (n=1358; offered medical management and lifestyle interventions alone) or to ‘CPAP plus usual care’ (n=1359; required to use their CPAP for at least 3 hours per night). The primary end point of the study was a composite of death from any cardiovascular cause and incidence of major cardiovascular or cerebrovascular events. Secondary end points included all-cause mortality, individual components of the primary end point, new-onset atrial fibrillation, new-onset diabetes mellitus, cardiac revascularization, symptoms of OSA, health-related quality of life, and changes in mood.

The intention-to-treat population included a total of 2687 patients (1346 in CPAP group, 1341 in usual care group). A primary end point event was confirmed in 17.0% of those in the CPAP group, versus 15.4% in the usual care group (hazard ratio with CPAP, 1.10; 95% CI 0.91 to 1.32; p=0.34). CPAP was superior to usual care in the following secondary end points: reduction in anxiety, depression, and symptoms of OSA. No significant differences in all-cause mortality or individual cardiovascular and cerebrovascular outcomes were seen between the two groups.

The SAVE trial was one of the first randomized studies evaluating the effects of CPAP use on cardiovascular and cerebrovascular outcomes. Although the study resulted in a disappointing conclusion that CPAP did not provide a significant reduction in major adverse cardiovascular and cerebrovascular events in comparison to medical management alone, there are a few points to consider regarding the parameters and logistics of the study that could have ultimately created a statistical bias compromising the results of the trial.

Firstly, poor enrollment led to recruitment of only 2717 of the projected 5000 patients. Next, there was poor adherence to CPAP in the CPAP group (only 42% patients had ‘good’ adherence to treatment with at least 4 hours/night of CPAP use). Finally, the study population was 81% male, approximately 65% of Asian descent, and on average 61 years of age. Although there is well-established evidence that obstructive sleep apnea is more commonly seen in the male population and in those of older age, there are still many affected by OSA who do not fit in the study’s chosen demographic, particularly in the United States, where there is a high prevalence of OSA in populations largely underrepresented in the trial such as African Americans and Caucasians.2,3 Thus, some skepticism may be warranted when attempting to correlate the findings of this study into general practice, where it is likely that the provider managing OSA will care for both men and women of varying ages and of differing ethnic backgrounds.

In spite of its potential limitations, the SAVE trial has successfully ignited further interest in exploring the benefits of CPAP. With further research, CPAP may yet become an appropriate, evidence-based therapy to reduce the risk of cardiovascular and cerebrovascular events in those affected by OSA.

1. Mokhlesi B, et al. Cardiovascular Events in Obstructive Sleep Apnea- Can CPAP Therapy SAVE Lives? NEJM, 2016; 375 (10):994-6
2. Peppard P, et al. The Last 25 Years of Obstructive Sleep Apnea Epidemiology- and the Last 25? American Journal of Respiratory and Critical Care Medicine, 2017.
3. Punjabi, N. The Epidemiology of Adult Obstructive Sleep Apnea. Proceedings of the American Thoracic Society. 2008; 5 (2):136-143