CPAP still valuable for OSA patients despite absence of CV benefits in RCTs

The reasons why continuous positive airway pressure (CPAP) treatment has not been shown to reduce cardiovascular (CV) events in randomized trials on obstructive sleep apnoea (OSA) are multifaceted. However, research still suggests that such patients can benefit from CPAP, according to an evidence review presented at APSR 2024.

“I don't think we should get too depressed because of these negative trials,” said Professor Matthew Naughton, head of service for General Respiratory & Sleep Medicine, Alfred Health in Melbourne, Victoria, Australia. “We still have good evidence that our treatments for sleep-disordered breathing result in a better quality of life (QoL).”

Whether the findings from these randomized controlled trials (RCTs) are generalizable to a clinical population has been questioned. Upon scrutiny of the eligibility criteria of five recent major RCTs and a comparison with the characteristics of patients attending sleep clinics in the Western Australian Sleep Health Study (WASHS), it was revealed that ≤21.9 percent of OSA patients seen in sleep clinics would be eligible for any of the included RCTs. [APSR 2024, parallel session 1B; Sleep 2022;45:zsab264]

In contrast, the benefit of CPAP on QoL is more definitive. A meta-analysis of eight other RCTs showed that CPAP significantly improved health-related QoL by 4.63 points on the 36-item Short Form Health Survey vitality scale (p=0.0005; I² of 23 percent). [J Clin Sleep Med 2019;15:301-334]

Representativeness of RCTs?

Four of the five RCTs reviewed were secondary prevention trials in which all enrolled patients had established CV disease, which was present in only 11 percent of sleep clinic patients in the WASHS cohort. Secondly, all but the SAVE trial excluded sleepy participants, and sleepiness, measured by the Epworth Sleepiness Scale (ESS) scores, was significantly more severe among sleep clinic patients (mean ESS score 10) vs participants in the five trials (all p<0.00005).

The lower symptom burden among participants in RCTs is likely to contribute to inadequate adherence to CPAP therapy. Particularly, patients randomized to the CPAP plus usual care arm in SAVE (mean ESS score 7.3) adhered to CPAP for a mean of only 3.3 hrs per night, while it was 2.8 hrs per night in the more recent ISAACC trial (mean ESS score 5.4). [N Engl J Med 2016;375:919-931; Lancet Respir Med 2020;8:359-367]

Indeed, there were indications of a CV benefit from CPAP in the trials reviewed when the adherence level was considered. [Am J Respir Crit Care Med 2020;201:607-610] For example, a propensity score-matched analysis of SAVE suggested that adherence to CPAP for ≥4 hrs per night reduced cerebral events vs usual care alone (hazard ratio, 0.52, 95 percent confidence interval, 0.30–0.90; p=0.02).

Wisdom of physiology

Ischaemic preconditioning, our body’s protective response to intermittent hypoxia, may also help explain the neutral CV findings. As an illustration, patients with OSA have been found to have increased coronary collaterals, which may be the result of collateral recruitment during coronary occlusion influenced by intermittent hypoxia. [Lung 2021;199:409-416]

However, in addition to the adaptive responses from ischaemic preconditioning, intermittent hypoxia can also drive inflammatory responses, which CPAP has been found to help counteract. [Circulation 2005;112:2660-2667]

Naughton concluded the review by reiterating the benefits of CPAP that patients can experience first-hand: “At the end of the day, it’s your QoL that is probably the most important thing, particularly in the second half of your life, rather than the quantity of life.”