Background

There is conflicting evidence in the current literature regarding the association between obstructive sleep apnea (OSA) and risk of death, cardiovascular (CV) events, diabetes and depression. In addition, little is known about which specific clinical and physiological factors best predict the occurrence of these adverse outcomes in OSA.

Methods

A systematic review of the prognostic value of clinical and polysomnographic (PSG) characteristics of OSA for adverse long-term outcomes of untreated OSA in adult patients was performed. The review consisted of all English language studies, from Jan 1999 to Dec 2011, with longitudinal design in adults with OSA diagnosed by PSG recording. A comprehensive search strategy for prognosis studies, OSA, CV events, mortality, depression and diabetes was developed and employed through Medline, Embase and bibliographies of identified articles. The articles were selected for full text review by 2 independent reviewers. A third reviewer was consulted where consensus could not be reached. The study quality was assessed independently utilizing guidelines developed by Haden et al. for prognostic studies.

Results

2547 articles were initially identified and 49 were selected for full text review. Twenty six studies fulfilled the necessary criteria for inclusion. Among those, 10 evaluated the association of OSA with mortality, 9 with a composite CV outcome, 4 with stroke, 2 with diabetes and 1 with depression. Meta-analyses were not performed due to clinical heterogeneity among studies. However, significant relationships between the apnea-hypopnea index (AHI) and long term adverse outcomes were reported in 18 studies: seven for all-cause mortality, six for composite CV events, three for stroke, one for diabetes and one for depression. The effect of AHI was diminished by older age, female gender, higher body mass index and absence of daytime sleepiness.

Conclusion

The evidence supports a relationship between OSA, all-cause mortality and a composite CV outcome in men. Associations between OSA and other outcomes remain unclear. Apart from the traditional CV risk factors, AHI was the only OSA- specific markers to consistently predict events. Future studies should be geared towards evaluating the predictive ability of various AHI threshold values and hypopnea definitions. A validated set of OSA-specific predictors will allow better risk stratification to guide OSA treatment.

Commentary/Perspective

Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by repeated episodes of upper airway obstruction during sleep. It affects an estimated 9% of women and 24% of men and has been imputed in increasing the risk of sudden cardiac death, cardiovascular events, diabetes and depression. The gold standard for diagnosis is overnight polysomnography. During this test many clinical and physiological variables are usually obtained. However very little is known about the correlation of these variables to clinical outcomes and their ability to predict future adverse events. This review is an important initial step in addressing this issue and hopefully would direct researchers to explore these areas of uncertainty.

The methodology of the review was adequate and had the required scientific rigor. However, the results and conclusions must be interpreted within the context of the review and the inherent limitations accompanying retrospective analyses. There was significant heterogeneity in the primary studies not only regarding the populations studied but also the definition of OSA, AHI and the composite CV outcome. Women were significantly underrepresented. None of the studies distinguished patients with OSA from those with hypoventilation syndrome (OHS) or hypercarbia, both of which overlap significantly with OSA. Although 19 of 26 studies used full standard PSG recordings to diagnose OSA, there was considerable inter-study variation in PSG recording systems and the definition of PSG indexes used to diagnose OSA, particularly AHI; 5 events/hr (18 studies), ≥ 10 events/hr (5 studies), ≥ 15 events/hr (1 study) and ≥ 30 events/hr (2 studies).

Despite these limitations the findings are interesting. The 26 studies identified 15 factors that had statistically significant associations with one or more outcomes in patients with OSA. The most reproducible (reported in three or more studies) statistically significant predictors were: 1. OSA-related (AHI 18/26; SaO2 3/7; and OSA treatment, 7/10). 2. Demographic characteristics (age14/23 and sex 4/18). 3. History at baseline (CV comorbidities 8/18, diabetes 6/20, pulmonary disease 4/9 and smoking status 4/22). 4. Physical exam (blood pressure (BP) 5/21, and body mass index (BMI) 3/24).

Among the OSA specific markers, only AHI was a consistent predictor, with a higher AHI predicting increased risk of adverse CV events. However the predictive threshold varied from study to study. Several variables appeared to modify the effect of AHI on outcomes. These were: age, younger men showed excess all cause mortality; sex, men showed a significant positive association in adjusted models between AHI and ischemic stroke, mortality and incident CV events; BMI, elevated BMI attenuated the effect of AHI as well as absence of daytime sleepiness.

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Keywords: Airway Obstruction, Death, Sudden, Cardiac, Depression, Depressive Disorder, Diabetes Mellitus, Polysomnography, Sleep Apnea, Obstructive

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