Long-term health effects of CPAP for obstructive sleep apnea: still an open question

In this issue of the Journal of Clinical Sleep Medicine, Balk et al¹ present a comprehensive and methodologically rigorous systematic review and meta-analysis that thoroughly evaluates the long-term effects of continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA) on a range of important health outcomes. Despite CPAP being the most widely used and recommended treatment for OSA, the authors highlight the lack of high-quality evidence from randomized controlled trials (RCTs) supporting its effectiveness in reducing long-term adverse health outcomes of substantial clinical importance, such as mortality, major cardiovascular events like stroke and myocardial infarction, and the development of conditions like anxiety. Ultimately, 38 eligible studies compared CPAP prescription, use, or adherence with no (or rarely, sham) CPAP prescription, use, or adherence. The 16 RCTs included a total of 7,664 participants.

The authors should be commended for the rigor of their methodology, which involved a comprehensive and systematic literature search across multiple databases to identify all relevant studies, an assessment of the risk of bias in each included study, and strict adherence to established best-practice guidelines for conducting systematic reviews and meta-analyses. A particular strength of their approach is the inclusion and synthesis of evidence not only from RCTs, which provide the highest level of evidence, but also from well-conducted propensity score–adjusted observational studies, which can provide valuable complementary evidence. The 22 nonrandomized comparative studies with multivariable adjustments for outcomes of interest included a total of 268,033 participants. This combined analysis of both RCT and high-quality observational data adds robustness and comprehensiveness to their findings.

One of the key findings of this review is the discrepancy between the results of RCTs and observational studies regarding the effect of CPAP on all-cause mortality. While RCTs did not demonstrate a significant effect of CPAP on mortality, with a summary effect size of 0.89 (95% confidence interval [CI], 0.66–1.21), observational studies suggested an association between CPAP use and reduced risk of death. This inconsistency underscores the need for further high-quality RCTs with longer follow-up periods and larger sample sizes to provide more definitive evidence. The authors also highlight the lack of evidence supporting the effectiveness of CPAP in reducing the risk of cardiovascular events, such as stroke, myocardial infarction, and atrial fibrillation (all statistically nonsignificant). For example, the summary effect size for CPAP vs no CPAP in terms of cardiovascular mortality was 0.99 (95% CI, 0.64–1.53), for stroke it was 0.99 (95% CI, 0.73–1.35), for myocardial infarction it was 1.05 (95% CI, 0.78–1.41), and for incident atrial fibrillation it was 0.89 (95% CI, 0.48–1.63), all indicating no significant impact on reducing cardiovascular deaths. Given the close relationship between OSA and cardiovascular disease, this finding is somewhat surprising and warrants further investigation.²

Another striking finding of this review is the lack of evidence for clinically meaningful benefits of CPAP on cognitive function, quality of life, and mental health outcomes like depression and anxiety. Regarding cognitive impacts, 5 randomized trials and 2 observational studies reported on various measures of cognitive function. Three trials evaluated the Mini-Mental State Examination, finding that scores improved modestly over time in both CPAP and control groups, but the difference between groups was small (average of 0.4 points) and nonsignificant at 6 or 12 months. These results may question the widely held assumption that CPAP therapy improves daytime functioning, neurocognitive performance, mood, and overall well-being in patients with OSA.^3–5 Given the significant burden of these impairments on patients’ daily lives, the lack of robust evidence supporting CPAP’s effectiveness in ameliorating these important domains is concerning and warrants further research.

However, a significant limitation to many of the studies highlighted by the authors is the substantial heterogeneity in inclusion of patients with OSA, as well as adherence to CPAP. Some studies excluded patients with mild or severe OSA, and the authors were unable to discern any obvious patterns across studies regarding low vs high lack of adherence, including duration of the studies.

While the systematic review did not find strong evidence from randomized trials that CPAP therapy improves long-term outcomes like mortality, cardiovascular events, or cognitive function in patients with OSA, this does not necessarily mean that CPAP is ineffective for long-term health. The authors caution that the available studies have been underpowered, had follow-up periods that were too short, and had methodological limitations, leaving the question about CPAP’s impacts on hard clinical endpoints largely unanswered still. They argue there remains clinical equipoise and uncertainty around whether CPAP confers long-term health benefits. The lack of robust positive data should not be interpreted as proof of no benefit, but rather is a call for larger, longer, and higher-quality RCTs in the future.

Overall, this important systematic review by Balk et al highlights crucial gaps in the evidence surrounding the long-term effects of CPAP for OSA. Despite CPAP being the standard treatment, the authors show a lack of high-quality data from randomized trials demonstrating benefits on critical health outcomes like mortality and cardiovascular events. These findings underscore the need for ongoing research, especially RCTs, to comprehensively understand the effects of CPAP therapy on health outcomes and to establish treatment strategies for the long-term benefit of patients with OSA.

DISCLOSURE STATEMENT

The author reports no conflicts of interest.