Sleep apnea is associated with cardiovascular risk. Does CPAP treatment reduce that risk?

save results sleep apneaTreating sleep apnea reduces the risk of future cardiovascular events right? It seems not. An important trial published this week in the New England Journal of Medicine showed that in people with moderate to severe obstructive sleep apnea (OSA) who had established cardiovascular or cerebrovascular disease, treatment with continuous positive airway pressure (CPAP), did not reduce the risk of future cardiovascular events. Although sleep apnea is associated with increased risk of cardiovascular (heart) and cerebrovascular (stroke) problems, there have not been large studies looking at whether sleep apnea treatment reduces the risk of future cardiovascular events.  This was the purpose of the Sleep Apnea Cardiovascular Endpoints (SAVE) study. The largest intervention study in sleep apnea undertaken in sleep apnea to date.

The full publication of the SAVE study is available here.

Don’t we already have proof that treating sleep apnea prevents cardiovascular events?

Actually no.  Long-term observational studies (e.g. Marin et al. Lancet 2005) have suggested that those who use CPAP to treat sleep apnea have a reduced risk of future cardiovascular events compared to those who don’t use CPAP. However, the observational design of those studies means that other factors may have contributed to the reduced cardiovascular risk.  For example, people who chose to use CPAP may also look after other aspects of health, such as nutrition, physical fitness, weight, blood pressure and cholesterol levels, all of which have significant effects on cardiovascular risk.

There have also been small studies showing that sleep apnea treatment such as with CPAP or use of mandibular advancement splints reduces physiological measures associated with cardiovascular risk like blood pressure or sympathetic nervous system activity. These studies have led to a belief that treatment must be good for cardiovascular risk as it reduces these factors that can lead to cardiovascular events.

However, when studies have been designed specifically to look at the effect of treatment on cardiovascular events by randomising people to treatment with CPAP, they have not shown any reduction in future cardiovascular events. There have been three such studies before SAVE (Barbé et al JAMA 2012, Parra et al ERJ 2011, Peker et al AJRCCM 2016). All three of these studies have shown no benefit for use of CPAP.

What was the SAVE study?

The SAVE study was designed as a secondary prevention trial in adults with existing cardiovascular disease and moderate-to-severe sleep apnea. The aim of the study was to see whether treatment with CPAP reduced the future risk of serious cardiovascular events.  To answer this question, 2717 adults between the ages of 45 and 75 years with moderate-to-severe obstructive sleep apnea and existing coronary or cerebrovascular disease were randomised to treatment with CPAP plus usual care or to usual care alone.

The diagnosis of moderate-to-severe sleep apnea was based on a level 3 sleep study, recorded using a ResMed ApneaLink device showing at least 12 respiratory events per hour.  Events were defined as having an oxygen desaturation of 4% or greater.  Participants were excluded if they had very severe hypoxaemia (more than 10% of the night at an oxygen saturation of less than 80%) or severe excessive sleepiness (Epworth Sleepiness Score greater than 15).  Study participants were then followed for an average of 3.7 years

What did the SAVE study show?

The primary endpoint of the SAVE study was the rate of cardiovascular events. In those treated with CPAP, 17% had a cardiovascular event in the average of 3.5 years of follow-up, compared to 15.4% of those not treated with CPAP.

Although cardiovascular events were not reduced, there were significant improvements in:

  • Symptoms of sleepiness
  • Symptoms of anxiety and depression. The percentage of patients with clinically relevant depression scores was 25% to 30% lower in the CPAP group than in the usual care group at the end of followup
  • Quality of life
  • Days off work due to poor health

Why doesn’t CPAP reduce future cardiovascular events?

This is still an unanswered question and the subject of speculation and further research.

Critics of the SAVE study could suggest that the duration of CPAP use may not have been adequate. The average use was 3.3 hours of use per night and only 42% of people used CPAP for 4 hours or more per night. However, a post hoc analysis of the data did not show any relationship between the amount of CPAP use each night and the risk of future cardiovascular events.  The device used to treat CPAP was a Philips REMstar Auto device in auto-titrating (APAP) mode for 1 week, with pressure then set at the 90th centile for the remainder of the study.  Bench testing (Zhu et al JCSM 2015) suggests that the REM star Auto device recommends lower pressures than some other devices, and may under-treat sleep apnea, which may have also contributed to the negative results.

There is also the possibility that the people enrolled in SAVE, who were at least 45 years of age and already had cardiovascular or cerebrovascular events, were treated too late. Once people have established cardiovascular disease, it may be that treating sleep apnea, doesn’t prevent further cardiovascular events. It would take a much larger and longer study to look at people without established cardiovascular disease and follow them until a proportion did develop cardiovascular disease, but that is what would be needed to test this theory.

If obstructive sleep apnea was a risk factor, but didn’t independently cause cardiovascular events, that could account for the lack of effect of CPAP on cardiovascular events. It may be that sleep apnea is a sign that people are at increased cardiovascular risk, but just a marker of that risk not a cause of that risk. If this were the case, a better approach to reducing future cardiovascular risk would be to directly target other cardiovascular risk factors such as managing hypertension, cholesterol levels, diabetes, obesity and improving physical fitness.

How will the SAVE study results change practice?

The focus of sleep apnea treatment should be on managing symptoms. As such, treatments other than CPAP may have a role.  Treatments such as mandibular advancement splints (oral appliances) can improve symptoms of sleepiness and mood, and are an alternative to CPAP for those that have difficulties tolerating or do not wish to use CPAP.

The discussion I have with people who have moderate-to-severe obstructive sleep apnea but no significant symptoms will change. I will be able to reassure them that electing not to take up CPAP doesn’t place them at greater risk of future cardiovascular events. Previous research highlights that they are at greater cardiovascular risk, and therefore should be more proactive about managing other cardiovascular risk factors, but they don’t need to wear CPAP to reduce risk.

It is also important to ensure that if treatment is being recommended to you for obstructive sleep apnea, it is not just on the basis of an abnormal test.  The SAVE study shows that in people without significant symptoms, treatment with CPAP does not reduce future cardiovascular risk. So just going on to CPAP to treat an abnormal test result does not have any evidence to support it.

Will there be future studies on CPAP and cardiovascular events?

The ISAACC study (Esquinas et al Clin Cardiol 2013) is currently underway looking at the impact of sleep apnea on people with acute coronary syndrome and the effect of intervention with continuous positive airway pressure (CPAP).  This Spanish study aims to enrol around 1300 people with an acute coronary syndrome and look at the effects of CPAP on cardiovascular outcome such as death, heart attack and stroke.

What are the take-home messages from the SAVE study?

1.  For symptomatic people with obstructive sleep apnea, a trial of CPAP or other sleep apnea treatments should be offered.

2.  For people with severe obstructive sleep apnea and marked hypoxaemia (oxygen saturation less than 80% for greater than 10% of the night), it would be prudent to offer CPAP treatment. People with hyperaemia of this severity were excluded from the SAVE study, so may benefit from CPAP.

3.  For people without symptoms with obstructive sleep apnea, rather than focusing on sleep apnea treatment specifically with CPAP, the focus should be on reducing overall cardiovascular risk by managing other cardiovascular risk factors such as weight, fitness, blood pressure and cholesterol.

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