Oldenburg O, Wellmann B, Buchholz A, et al.
Eur Heart J 2016;37:1695-1703

Background

Sleep-disordered breathing (SDB) is often not recognised but highly prevalent in cardiovascular patients [1]. SDB can be categorised as obstructive (OSA) or central (CSA) in nature. Many patients experience both types. Consequences of both types are hypoxia and hypoxaemia, hypercapnia, increased sympathetic tone and chronic inflammation with endothelial dysfunction and apoptosis. This can contribute to or accelerate the atherosclerotic process, vascular and cardiac remodelling and cardiac arrhythmias [2].
OSA and CSA are often determined using the apnoea-hypopnoea index (AHI) which reflects the number of apnoeas and hypopnoeas per hour during sleep. Mild, moderate or severe is equivalent to an AHI of 5-14, 15-29, >30 per hour respectively [1,3]. The prevalence of moderate to severe SDB in HF patients with reduced left ventricular ejection fraction (HFrEF) is around 50%.
Although moderate-to-severe sleep apnoea has been identified as an independent predictor of mortality in stable HFrEF patients [4-6], the role of SDB (in particular CSA) as independent prognostic factor in these patients is still doubtful. As the AHI is used in these studies, the total number of events may be lower as the length of apnoeas and hypopnoeas are often increased with advanced HF [3,7,8]. Furthermore, the definitions of apnoeas and hypopnoeas were variable between studies, which may have resulted in a different graduation in SDB severity [9].

Using current guidelines for apnoea and hypopnoea [3], this study investigated the prognostic value of the AHI in HFrEF patients, in particular moderate-to-severe OSA and CSA. Furthermore, the total time a patient experienced nocturnal saturation <90% (T90) was evaluated as a predictor of all-cause mortality, to circumvent the lower event rate per hour for patients with increased lengths of apnoeas/hypopnoeas. Of the 963 patients included, 49.8% died within follow-up time (between December 2002 and July 2013).

Main results

Survival for no, mild, moderate or severe SDB (AHI):

• Mortality rates were 6.79, 9.43, 11.08 and 13.37 respectively
• 5-years survival probabilities were 71%, 63%, 58% and 54% respectively
• AHI as predictor for time to death from any cause HR 1.011 (p < 0.001), adjusted for age and gender HR 1.007 (p = 0.015), adjusted for age, gender, BMI, NYHA class, LVEF, CRT, ICM, diabetes, HF medication HR 1.005 (p = 0.085)

Predictive value of moderate-to-severe CSA and OSA:

• Mortality rates CSA 13.11, OSA 10.31, no or mild SDB 8.09
• Only moderate-to-severe CSA was associated with a significantly higher risk of death (HR 1.23, p = 0.038, in an adjusted model)

Predictive value of hypoxaemic burden (T90 quartiles 1, 2, 3 and 4):

• 5-years survival probabilities were 70%, 63%, 60% and 50%, respectively
• Mortality rates were 6.93, 9.40, 11.50 and 14.91, respectively
• T90 as predictor for time to death from any cause HR 1.161 (p < 0.001), adjusted for all predictors

Moderate-to-severe CSA versus OSA versus AHI versus T90:

• With both AHI and T90 in the model, T90 was the dominant predictor of all-cause mortality (T90 HR 1.15, p < 0.001, AHI HR 1.002, p = 0.444)
• There was a moderate correlation between AHI and T90 (Spearman r = 0.54, p < 0.001)
• Including SDB severity and CSA/OSA in the model, T90 was still the dominant predictor (T90 p < 0.001, CSA/OSA severity p = 0.153)

Potential T90 threshold: Using receiver operating characteristic analysis suggested that patients with <90% nocturnal oxygen saturation for over 22 minutes per night were at higher risk of dying than those with <90% for less than 22 minutes per night.

Conclusion

HF-REF patients with SDB, especially moderate-to-severe CSA, had reduced survival. Hypoxaemic burden (T90) was the most robust independent predictor of all-cause mortality. A total minutes of 22 minutes less than 90% nocturnal oxygen saturation was determined as cut off value for best predicting mortality in HFrEF patients.

Find this article online at Eur Heart J

Editorial comment [10]

Cowie remarks that a better description of ‘the many possible metrics’ to diagnose SDB and their association with cardiovascular events or mortality is crucial to reduce cardiovascular events. The diagnosis of SDB is complex and it is not generally appreciated that scoring systems to recognize SDB are consensus-based and very changeable, due to continuously new study data and technologies. The current definition of apnoea is a reduction of airflow by at least 90% of pre-event baseline for at least 10 seconds. The definition of hypoxaemia is much more controversial. Currently, the recommendation in adults is at least a 30% reduction in airflow for at least 10 seconds, combined with either a 3% or greater arterial oxygen saturation or an arousal. Also OSA and CSA classifications are important as they may influence the positive airway pressure (PAP) therapy applied. As this classification can be very difficult, some laboratory do not even attempt this. Based on the data of Oldenburg et al., SDB patients may be easily diagnosed by overnight oximetry and this requires further study. A bigger question remains according Cowie: “What treatment should be applied to SDB patients?” Some studies report benefit with PAP treatment, however the recently published large SERVE-HF trial reported an increase in cardiovascular mortality in PAP-treated SDB (predominantly CSA) patients. “We need further outcome studies that show that current treatments can improve cardiovascular morbidity and mortality.”

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