Key messages
Studies in this area are small and we were unable to conclude whether any of the medicines studied helped people with central sleep apnoea (CSA) compared with dummy treatment.
What is central sleep apnoea and how is it treated?
CSA is a disorder in which breathing repeatedly stops and starts during sleep because the brain does not send proper signals to the muscles that control breathing. CSA mainly affects men and people with heart disease. The condition is different from and less common than obstructive sleep apnoea, where breathing is interrupted by blocked or narrowed airways. The treatment of CSA can involve using devices to help breathing, but people with CSA do not always like using them. Treatment with medicines, such as hypnotics (used to reduce tension and induce calm) and respiratory modulators (used to stimulate breathing), may be an alternative for adults with CSA.
What did we want to find out?
The aim of this review was to find out whether medicines can improve the following outcomes in people with CSA.
• Central apnoea-hypopnoea index (a key indicator of CSA that measures the number of times someone's breathing pauses per hour of sleep)
• Death related to heart disease
• Quality of sleep
• Quality of life
• Daytime sleepiness
• Apnoea-hypopnoea index (another score of apnoea events)
• Death from any cause
• Time to a life-saving heart-related intervention (such as a transplant)
We also wanted to know whether these medicines had any unwanted effects.
What did we do?
We searched for studies that investigated the use of medicines for CSA compared with a different treatment (such as the breathing devices commonly used to treat CSA), dummy treatment (placebo), no treatment or usual care. Participants had to be at least 18 years of age. We only included randomised controlled trials (RCTs), which allocate people to treatment groups at random.
What did we find?
We found five studies involving a total of 66 adults with CSA and an average age of 66 to 71 years. The included studies used four different medicines and mostly looked at men who had CSA together with heart disease. In one study, five men received either triazolam (a medicine to help sleep) or placebo. In another study, 16 men received either buspirone (a medicine to help reduce anxiety) or placebo. In a third study, 15 men received either theophylline (a medicine to help wheezing, shortness of breath and chest tightness) or placebo. Thirty adults in the two remaining studies received either acetazolamide (a medicine to help stimulate breathing) or placebo/no acetazolamide.
The studies that provided information on the length of treatment tested the medicines for between three days and one week.
We are uncertain about the effects of the medicines on the central apnoea-hypopnoea index, death related to heart disease, the apnoea-hypopnoea index and daytime sleepiness. The studies also could not tell us whether unwanted events were more common with medicines than with placebo. No studies reported our other outcomes of interest.
What are the limitations of the evidence?
Our confidence in the evidence is very low, mainly because it comes from small studies with very few participants.
How up to date is the evidence?
The evidence is up to date to 30 August 2022.
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.
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.