Patients with severe obstructive sleep apnea (OSA) are five times more likely to experience cardiovascular mortality than those without sleep disordered breathing.1 OSA is strongly associated with hypertension, atrial fibrillation, stroke, coronary heart disease, myocardial ischemia and infarction.2 So why do clinical trials repeatedly show that treating OSA with continuous positive airway pressure (CPAP) makes little meaningful difference in cardiovascular outcomes? The answer, as Drs. Noah and Cook point out in a recent review article3, is in the details.
If RCT authors report it, it must be true, right?
We tend to take the results of randomized clinical trials (RCTs) as sacrosanct. And if we still have questions, a meta-analysis of RCTs quickly puts to rest any residual doubts to rest. In this regard, CPAP has been beaten up pretty badly. The largest RCT of its kind in published in the New England Journal of Medicine reported, “Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease.”4 If that was not enough, meta-analyses that included the results of nearly a half dozen similarly designed RCTs have come to the same conclusion: CPAP does not appreciably improve cardiovascular outcomes in patients with OSA.5-9
CPAP adherence in RCTs has been very low
Drs. Noah and Cook, specialists in sleep medicine and cardiovascular health, respectively, point out that despite several RCTs and corresponding meta-analyses reporting a lack of benefit, those same studies also report very low CPAP adherence rates. For instance, the authors of the NEJM paper came to their conclusions about the lack of effect while reporting “the mean duration of adherence to CPAP therapy was 3.3 hours per night” and only 42% of participants used CPAP for greater than 4 hours per night.4 In a way, that is like saying atorvastatin failed to change cardiovascular outcomes in patients with hyperlipidemia when the participants in the treatment arm took a dose of 1/3 of a pill per day, or, a full dose of the statin only 2-3 times per week. This poor adherence plagues all CPAP RCTs and their corresponding meta-analyses, which means we need to take a closer look at them.
Secondary analyses of three RCTs and a considerable number of observational studies (although they are not as highly regarded as RCTs, note they can be as informative in certain contexts) show a dose-dependent effect of CPAP usage on CVD in patients with OSA.2,3,7 Despite reporting results in patients with “severe” OSA (and therefore those who should benefit most from CPAP), RCTs often excluded certain at-risk groups due to the fact that investigators discouraged the practice. Their determination was that it would be a poor ethical choice to withhold CPAP in those patients with the most severe symptoms.3 Secondary analyses consistently show that patients who do manage to adhere to CPAP for more than 4 hours a night for months to years do reap a benefit in cardiovascular outcomes.3 This indicates that if patients with OSA can somehow be encouraged to adhere to CPAP, they would reap the long-promised CVD benefits of the treatment.
Current real world CPAP adherence is low, and that is a problem
There is a reason why CPAP adherence in RCTs was very low—it is low in real world settings. Perhaps as few as 1 in 3 patients with OSA actually adhere to treatment.3,10 The RCTs taken at face value may give the impression that there is of little to no benefit, if physicians do refer their patients for polysomnography, only small fraction will use CPAP enough to even hope to benefit. But this does not have to be the case.
CPAP adherence can be improved, substantially
Studies have shown that close, short term follow-up after CPAP deployment can improve adherence, e.g., working with a patient to choose the right type and size of mask, for example.6 Adherence can be further increased by targeted interventions such as motivational enhancement and cognitive behavioral therapy.11,12 Unfortunately, the incentives in the system do not currently reward healthcare providers for patient adherence, as Drs. Noah and Cook point out.3 The sleep specialist and the sleep center receive a large reimbursement for the sleep study itself, regardless of later patient adherence. Likewise, medical device providers make their biggest money on initial deployment and only need to hit almost absurdly low adherence rates—roughly 2.8 hours of use per night—to continue receiving reimbursements for supplying CPAP consumables. Drs. Noah and Cook suggest a change of incentive structure may be needed to combat this problem, one that focuses on more clinically relevant adherence targets.
What is at stake?
Secondary analyses of the CPAP RCTs found significant reductions in blood pressure, daytime sleepiness, and quality of life—despite poor adherence. However, we do not give up the struggle of trying to enhance medication adherence in patients with cardiovascular risk factors—that same risk factors that are exacerbated by OSA.
The book is not closed on CPAP for cardiovascular outcomes. It would be an extreme disservice to patients for physicians to fail to refer at-risk patients for sleep studies. Obtaining and maintaining CPAP is a problem, but it is a solvable problem with a little time and effort. Considering that untreated OSA carries the same mortality risk as a middle-aged patient with a total cholesterol of over 300 why would we only treat the latter and ignore the former?
1. Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep. 2008;31(8):1071-1078.
2. Drager LF, McEvoy RD, Barbe F, Lorenzi-Filho G, Redline S, Initiative I. Sleep Apnea and Cardiovascular Disease: Lessons From Recent Trials and Need for Team Science. Circulation. 2017;136(19):1840-1850. 10.1161/CIRCULATIONAHA.117.029400
3. Noah WH, Cook JL. “Using CPAP” Improves Cardiovascular Outcomes: Physicians Must Look Behind the RCT Veil and Focus on Long-Term Adherence. J Cardiol Clin Res. 2021;9(1).
4. McEvoy RD, Antic NA, Heeley E, et al. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med. 2016;375(10):919-931. 10.1056/NEJMoa1606599
5. Abuzaid AS, Al Ashry HS, Elbadawi A, et al. Meta-Analysis of Cardiovascular Outcomes With Continuous Positive Airway Pressure Therapy in Patients With Obstructive Sleep Apnea. Am J Cardiol. 2017;120(4):693-699. 10.1016/j.amjcard.2017.05.042
6. Patil SP, Ayappa IA, Caples SM, Kimoff RJ, Patel SR, Harrod CG. Treatment of Adult Obstructive Sleep Apnea With Positive Airway Pressure: An American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE Assessment. J Clin Sleep Med. 2019;15(2):301-334. 10.5664/jcsm.7638
7. Peker Y, Balcan B. Cardiovascular outcomes of continuous positive airway pressure therapy for obstructive sleep apnea. J Thorac Dis. 2018;10(Suppl 34):S4262-S4279. 10.21037/jtd.2018.11.48
8. Wang X, Zhang Y, Dong Z, Fan J, Nie S, Wei Y. Effect of continuous positive airway pressure on long-term cardiovascular outcomes in patients with coronary artery disease and obstructive sleep apnea: a systematic review and meta-analysis. Respir Res. 2018;19(1):61. 10.1186/s12931-018-0761-8
9. Yu J, Zhou Z, McEvoy RD, et al. Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis. JAMA. 2017;318(2):156-166. 10.1001/jama.2017.7967
10. Chervin RD, Rosen IM, Watson NF. CPAP in Obstructive Sleep Apnea. N Engl J Med. 2016;375(23):2301-2302. 10.1056/NEJMc1613219
11. Bakker JP, Wang R, Weng J, et al. Motivational Enhancement for Increasing Adherence to CPAP: A Randomized Controlled Trial. Chest. 2016;150(2):337-345. 10.1016/j.chest.2016.03.019
12. Andry JM, Jr., Toban G, Chafin C, Noah W. Positive airway pressure therapy supplied by an integrated sleep practice associated with greater adherence among pre-Medicare-aged patients with sleep-disordered breathing. J Clin Sleep Med. 2021;17(1):31-36. 10.5664/jcsm.8786
13. Ho PM, Bryson CL, Rumsfeld JS. Medication adherence: its importance in cardiovascular outcomes. Circulation. 2009;119(23):3028-3035. 10.1161/CIRCULATIONAHA.108.768986
14. Prospective Studies C, Lewington S, Whitlock G, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370(9602):1829-1839. 10.1016/S0140-6736(07)61778-4
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