Effect of norepinephrine reuptake inhibitors combined with antimuscarinic agents vs monotherapy for OSA: a systematic review and meta-analysis

Abstract

Study objectives: Randomized controlled trials have shown that combining norepinephrine reuptake inhibitors and antimuscarinics can ameliorate the severity of obstructive sleep apnea. This article explores whether the effectiveness and safety of combining norepinephrine reuptake inhibitors with antimuscarinic agents surpass monotherapy for treating obstructive sleep apnea.

Methods: We searched randomized controlled trials including adult patients with obstructive sleep apnea who received combination therapy and monotherapy in 8 databases from inception until April 5, 2023 and evaluated the studies' quality and conducted a meta-analysis and systematic review. The primary outcome was the apnea-hypopnea index. Secondary outcome measures included loop gain, hypoxic burden, oxygen desaturation index, and ventilation at low ventilatory drive, among other indicators. We assessed the quality of the studies using Cochrane Methods criteria.

Results: We identified 4 randomized controlled trials for systematic review and 2 for meta-analysis. The results of the meta-analysis showed that norepinephrine reuptake inhibitors combined with antimuscarinic agents in patients with obstructive sleep apnea prolonged total sleep time by a mean of 28.20 minutes [95% confidence interval (5.78, 50.61), P = .01] and increased sleep efficiency by 4.73% [95% confidence interval (0.50, 8.97), P = .03] compared with norepinephrine reuptake inhibitors alone. Other indices and adverse events were of no statistical significance. The systematic reviews revealed that norepinephrine reuptake inhibitors combined with antimuscarinics may be superior to monotherapy in improving apnea-hypopnea index and endotypic traits.

Conclusions: This evaluation demonstrated the potential advantages of combining norepinephrine reuptake inhibitors plus antimuscarinics for treating OSA compared with norepinephrine reuptake inhibitors alone and revealed no statistically significant difference in drug safety.

Citation: Wang J, Ye Y, Shang Z, et al. Effect of norepinephrine reuptake inhibitors combined with antimuscarinic agents vs monotherapy for OSA: a systematic review and meta-analysis. J Clin Sleep Med. 2024;20(8):1363-1372.

Keywords: antimuscarinic agents; norepinephrine reuptake inhibitors; obstructive; pharmacotherapy; sleep apnea.

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of the literature search and selection.

Figure 2. Apnea-hypopnea indices.

(A) Apnea-hypopnea index using 3% desaturation for hypopneas (events/h). (B) Apnea-hypopnea index using 4% desaturation criterion for hypopneas (events/h). (C) Non-rapid eye movement sleep apnea-hypopnea index (events/h). CI = confidence interval, SD = standard deviation.

Figure 3. Endotypic traits.

(A) Vpassive (% eupnea). (B) Vmin (% eupnea). (C) Vactive (% eupnea). (D) Arousal threshold (% eupnea). (E) Vcomp (% eupnea). (F) LG1 (unitless). (G) LG subgroup analysis (unitless). % eupnea = percentage of the eupneic level of ventilation, CI = confidence interval, LG = loop gain (stability of ventilatory control), SD = standard deviation, Vactive = ventilation at the arousal threshold, Vmin = ventilation at the lowest decile of ventilatory drive, Vpassive = ventilation at low ventilatory drive.

Figure 4. Sleep architecture.

(A) Total sleep time (TST) in minutes. (B) Stage N1 sleep, %TST. (C) Stage N2 sleep, %TST. (D) Stage N3 sleep, %TST. (E) Non-rapid eye movement sleep, %TST. (F) Sleep efficiency (% time in bed). CI = confidence interval, SD = standard deviation.