Are noradrenergics combined with antimuscarinics the future pharmacologic treatment for obstructive sleep apnea? A systematic review and meta-analysis of randomized controlled trials.

Purpose: Noradrenergics and antimuscarinics have been proposed as future pharmacotherapy for obstructive sleep apnea (OSA). However, the available randomized controlled trials (RCTs) showed heterogeneous results regarding the safety and efficacy of the combined regimen in OSA. Therefore, we performed this meta-analysis from the published RCTs to clarify this conflicting evidence.

Methods: A systematic search of four electronic databases was done till December 2023.

Results: Thirteen RCTs (n = 345) were systematically reviewed and meta-analyzed. The combined regimen significantly reduced apnea-hypopnea index (AHI): AHI 3% [events/h; Mean difference (MD): - 6.30; 95% Confidence interval (CI) (- 9.74, - 2.87); P = 0.0003], AHI 4% [events/h; MD: - 6.50; 95% CI (- 8.74, - 4.26 events/h); P < 0.00001]. All gasometric measures significantly improved in the combined regimen group except mean SpO2. No difference was found in total sleep time between the treatment and placebo. However, compared to placebo, the combined regimen altered sleep architecture and decreased sleep efficiency. Regarding OSA endotypes, the combined regimen significantly improved loop gain, pharyngeal muscle compensation, pharyngeal muscle recruitment, and respiratory arousal threshold.

Conclusion: The combined regimen effectively reduces AHI and OSA severity with improvement in almost all OSA endotypes. However, this regimen decreased sleep efficiency and altered sleep architecture. Short-term side effects can be confined to increased heart rate, dry mouth and urinary hesitancy. Therefore, noradrenergics and anti-muscarinics is a promising regimen for treating OSA, yet this optimism must be titrated by the lack of long-term effects of the regimen. Future RCTs with focus on the long-term efficacy of the regimen and cardiovascular outcomes is recommended.