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CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea: Synopsis and Comments

McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, Mediano O, Chen R, Drager LF, Liu Z, Chen G, Du B, McArdle N, Mukherjee S, Tripathi M, Billot L, Biostat QL, Lorenzi-Filho G, Barbe F, Redline S, Wang J, Arima H, Neal B, White D, Grunstein R, Zhong N, Anderson C.

N Engl J Med. 2016;375(10):919-31.

PMID: 27571048

       Observational studies clearly indicate that Obstructive Sleep Apnea (OSA) is associated with an increased risk of cardiovascular disease (CVD), most notably stroke, and to a lesser extent, myocardial infarction and heart failure incidence. Although there is strong experimental data and biological plausibility to support causal associations between OSA and CVD, the impact of treatment with continuous positive airway pressure (CPAP) on primary or secondary cardiovascular (CV) events prevention has been uncertain. In order to answer this question, the SAVE study was conducted. SAVE was an international, multicenter, randomized, parallel-group, and open-label trial. It enrolled 2,717 eligible adults between 45 and 75 years worldwide between (from December 2008 to January 2016). Participants had moderate-to-severe OSA and coronary or cerebrovascular disease or significant CVD risk factors and were randomized to receive CPAP treatment plus usual care or usual care alone. Most participants were men. The primary composite endpoint was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Mean follow-up was 3.7 years and the mean duration of adherence to CPAP therapy was 3.3h/night. Primary endpoints occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group, (15.4%) (hazard ratio with CPAP 1.10; 95% CI: 0.91, 1.32; p =0.34), resulting in a non-significant different in endpoint  In conclusion, CPAP therapy plus usual care, in comparison with usual care alone, did not prevent CV events in patients with moderate-to-severe OSA and established CVD. However, CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood.

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Comments:  CPAP has been shown to improve intermediate markers of CVD such as endothelial function and insulin sensitivity. Furthermore, multiple clinical trials have demonstrated that CPAP improves blood pressure, a key therapeutic target that directly associates with CVD risk and prevention strategies. As proposed by the SAVE authors, a major explanation for negative results is likely to relate to the modest levels of CPAP adherence, resulting in insufficient levels of treatment to substantially improve CVD. In support of this, a  propensity score-matched analysis of CPAP adherent versus usual care patients showed that the rate of cerebral vascular events was 2-fold higher in those who only received  usual care alone compared to those who used CPAP for more than 4 hours per night [HR=0.52, 95% CI (0.30, 0.90) p=0.02]. Another possible explanation relates to heterogeneity of the participant population. Individuals likely differ in their susceptibility to CV responses to sleep apnea (as well as response to CPAP).  SAVE was not powered to identify subgroup differences. In addition, we still know little about individual risk factors, such as genetics, duration of disease, and other comorbidities that may modify risk. However, it is possible that individuals with more severe OSA may have derived more benefit from CPAP and in fact, as SAVE excluded individuals with severe overnight hypoxemia, it is possible that the most vulnerable patients were not included in this study. Finally, it is possible that chronic intermittent hypoxia may lead to ischemic preconditioning of cardio protective responses, attenuating manifestations of coronary artery disease. While it is clear that there needs to be future research to better understand both subgroup susceptibility to CVD related to OSA as well as development of more effective therapies, this study indicates that patients do benefit from CPAP in terms of improved quality of life and mood.  Since OSA is prevalent among cardiovascular disease patients (from 40 to 60% of patients), and because the risk of recurrent CV events among these patients is high despite optimal medical therapy, CPAP could help reduce CV events in selected patients.

Comments by Glaucylara Reis Geovanini, MD, PhD
Postdoctoral research fellow at BWH and Harvard Medical School, Sleep Division
Boston, MA-USA