Pharmacological treatment for central sleep apnoea in adults

The term central sleep apnoea (CSA) encompasses diverse clinical situations where a dysfunctional drive to breathe leads to recurrent respiratory events, namely apnoea (complete absence of ventilation) and hypopnoea sleep (insufficient ventilation) during sleep. Studies have demonstrated that CSA responds to some extent to pharmacological agents with distinct mechanisms, such as sleep stabilisation and respiratory stimulation. Some therapies for CSA are associated with improved quality of life, although the evidence on this association is uncertain. Moreover, treatment of CSA with non-invasive positive pressure ventilation is not always effective or safe and may result in a residual apnoea-hypopnoea index.

To evaluate the benefits and harms of pharmacological treatment compared with active or inactive controls for central sleep apnoea in adults.

We used standard, extensive Cochrane search methods. The latest search date was 30 August 2022.

We included parallel and cross-over randomised controlled trials (RCTs) that evaluated any type of pharmacological agent compared with active controls (e.g. other medications) or passive controls (e.g. placebo, no treatment or usual care) in adults with CSA as defined by the International Classification of Sleep Disorders 3rd Edition. We did not exclude studies based on the duration of intervention or follow-up. We excluded studies focusing on CSA due to periodic breathing at high altitudes.

We used standard Cochrane methods. Our primary outcomes were central apnoea-hypopnoea index (cAHI), cardiovascular mortality and serious adverse events. Our secondary outcomes were quality of sleep, quality of life, daytime sleepiness, AHI, all-cause mortality, time to life-saving cardiovascular intervention, and non-serious adverse events. We used GRADE to assess certainty of evidence for each outcome.

We included four cross-over RCTs and one parallel RCT, involving a total of 68 participants. Mean age ranged from 66 to 71.3 years and most participants were men. Four trials recruited people with CSA associated with heart failure, and one study included people with primary CSA. Types of pharmacological agents were acetazolamide (carbonic anhydrase inhibitor), buspirone (anxiolytic), theophylline (methylxanthine derivative) and triazolam (hypnotic), which were given for between three days and one week. Only the study on buspirone reported a formal evaluation of adverse events. These events were rare and mild. No studies reported serious adverse events, quality of sleep, quality of life, all-cause mortality, or time to life-saving cardiovascular intervention. Carbonic anhydrase inhibitors versus inactive control Results were from two studies of acetazolamide versus placebo (n = 12) and acetazolamide versus no acetazolamide (n = 18) for CSA associated with heart failure. One study reported short-term outcomes and the other reported intermediate-term outcomes. We are uncertain whether carbonic anhydrase inhibitors compared to inactive control reduce cAHI in the short term (mean difference (MD) -26.00 events per hour, 95% CI -43.84 to -8.16; 1 study, 12 participants; very low certainty). Similarly, we are uncertain whether carbonic anhydrase inhibitors compared to inactive control reduce AHI in the short term (MD -23.00 events per hour, 95% CI -37.70 to 8.30; 1 study, 12 participants; very low certainty) or in the intermediate term (MD -6.98 events per hour, 95% CI -10.66 to -3.30; 1 study, 18 participants; very low certainty). The effect of carbonic anhydrase inhibitors on cardiovascular mortality in the intermediate term was also uncertain (odds ratio (OR) 0.21, 95% CI 0.02 to 2.48; 1 study, 18 participants; very low certainty). Anxiolytics versus inactive control Results were based on one study of buspirone versus placebo for CSA associated with heart failure (n = 16). The median difference between groups for cAHI was -5.00 events per hour (IQR -8.00 to -0.50), the median difference for AHI was -6.00 events per hour (IQR -8.80 to -1.80), and the median difference on the Epworth Sleepiness Scale for daytime sleepiness was 0 points (IQR -1.0 to 0.00). Methylxanthine derivatives versus inactive control Results were based on one study of theophylline versus placebo for CSA associated with heart failure (n = 15). We are uncertain whether methylxanthine derivatives compared to inactive control reduce cAHI (MD -20.00 events per hour, 95% CI -32.15 to -7.85; 15 participants; very low certainty) or AHI (MD -19.00 events per hour, 95% CI -30.27 to -7.73; 15 participants; very low certainty). Hypnotics versus inactive control Results were based on one trial of triazolam versus placebo for primary CSA (n = 5). Due to very serious methodological limitations and insufficient reporting of outcome measures, we were unable to draw any conclusions regarding the effects of this intervention.

There is insufficient evidence to support the use of pharmacological therapy in the treatment of CSA. Although small studies have reported positive effects of certain agents for CSA associated with heart failure in reducing the number of respiratory events during sleep, we were unable to assess whether this reduction may impact the quality of life of people with CSA, owing to scarce reporting of important clinical outcomes such as sleep quality or subjective impression of daytime sleepiness. Furthermore, the trials mostly had short-term follow-up. There is a need for high-quality trials that evaluate longer-term effects of pharmacological interventions.