Positive airway pressure in patients with coronary artery disease and obstructive sleep apnea syndrome Davide Capodannoa,c, Giovanni Milazzoa, Miriam Cumboa, Anna Marchesea, Antonella Salemia, Laura Quartaronea, Emanuele Benvenutoa, Christine Galseranb, Sandro M. Distefanob and Corrado Tamburinoa,c Aims We designed a prospective nonrandomized study aiming at assessing the impact of continuous positive airway pressure (CPAP) after a new diagnosis of obstructive sleep apnea syndrome (OSAS) in patients with coronary artery disease (CAD). Methods Consecutive patients referred to coronary angiography underwent an overnight sleep study during their hospital stay. Among those with angiographically confirmed CAD and a new diagnosis of moderate or severe OSAS, we compared the 3-year major adverse cardiac or cerebrovascular event (MACCE)-free survival stratified by CPAP at discharge. Results Of 496 patients undergoing an overnight sleep study, 129 had angiographically confirmed CAD and presented with moderate or severe OSAS. The incidence of 3-year MACCE was significantly lower in the CPAP-treated group (n U 17) than in the untreated group (n U 112; 12 vs. 44%, P U 0.02). After adjusting for differences in baseline characteristics, CPAP was significantly associated with a decreased risk of MACCE [adjusted hazard ratio 0.18, 95% confidence interval (CI) 0.04–0.78, P U 0.02]. Among men,
Introduction Sleep-disordered breathing has been described in about 24% of men and 9% of women aged 30–60 years.1 The obstructive sleep apnea–hypopnea syndrome (OSAS) is the most common form of sleep disorder.1,2 OSAS has been linked with a significant 70% relative risk increase in cardiovascular morbidity and mortality,3 and the prevalence of OSAS has been demonstrated to be more than doubled in patients with coronary artery disease (CAD) compared with those without.4–7 OSAS patients undergoing revascularization for CAD might benefit from treatment with continuous positive airway pressure (CPAP).8,9 In a previous study, patients treated for OSAS experienced a statistically significant decreased number of cardiac deaths on follow-up compared with the untreated counterpart.8 However, in that study, OSAS diagnosis and treatment occurred before coronary revascularization and, therefore, a decrease in mortality as the mere effect of CPAP could not be ascertained beyond any doubt. Of note, a randomized prospective trial to test such a hypothesis might not 1558-2027 ß 2014 Italian Federation of Cardiology
CPAP was associated with a significant 3-year risk reduction in MACCE (adjusted hazard ratio 0.12, 95% CI 0.02–0.87, P U 0.04), whereas no significant benefit of CPAP was seen in women (adjusted hazard ratio 2.1, 95% CI 0.10– 41.6, P U 0.63). The statistical interaction between CPAP and sex trended to be significant (adjusted P for interaction U 0.10). Conclusion In patients with OSAS and CAD, the initiation of CPAP is associated with a significant reduction in MACCE compared with patients left untreated. J Cardiovasc Med 2014, 15:402–406 Keywords: continuous positive airway pressure, coronary artery disease, obstructive sleep apnea syndrome a Ferrarotto Hospital, University of Catania, bCannizzaro Hospital and cETNA Foundation, Catania, Italy
Correspondence to Davide Capodanno, MD, PhD, Department of Cardiology, Ferrarotto Hospital, University of Catania, Via Citelli 6, 95124 Catania, Italy Tel: +39 0957436202; fax: +39 095362429; e-mail: [email protected]
Received 7 September 2012 Revised 20 January 2014 Accepted 20 January 2014
be justifiable, as withholding CPAP therapy from patients with established OSAS might be not ethical. On this background, we designed a prospective nonrandomized study aiming at assessing the impact of CPAP after a new diagnosis of OSAS in patients with CAD.
Methods Study design, study population, and data collection
As part of a project in collaboration with a partner pneumology unit, consecutive patients referred to coronary angiography for various entry diagnoses underwent an overnight sleep study during their hospital stay in our cardiology unit, after signing an informed consent. None of these patients had previously undergone polysomnography or have received a diagnosis of OSAS. Patients with no vessel disease at coronary angiography were excluded. After discharge, the pneumology unit reviewed all the overnight sleep studies and contacted patients with a new diagnosis of OSAS in order to plan a treatment strategy with CPAP. The medical records of DOI:10.2459/JCM.0000000000000009
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Sleep apnea and coronary artery disease Capodanno et al. 403
patients who accepted the proposed therapy were regularly reviewed for compliance, which was satisfactory in all cases, and those patients were assigned to the treated group. Conversely, patients who declined the proposed treatment with CPAP were assigned to the untreated group. Key reasons from our patients for refusing CPAP included reluctance to undergo a treatment that would have changed radically their lifestyle and that of their ‘bed partners’; and socioeconomic reasons. Patients who refused CPAP treatment, however, were provided advice regarding behavioral strategies such as weight loss, correct posture to be taken during sleep, exercise, abstinence from alcohol and sedatives before going to sleep. Overnight sleep study and sleep disturbance assessment
Each patient underwent an 8-channel nocturnal cardiorespiratory monitoring with the portable SOMNOcheck2 system (2R&K, Weinmann, Germany). We ran the overnight sleep study before coronary angiography, but in the case of patients with acute coronary syndromes selected for early invasive management, the sleep study was performed after the interventional procedure. The apnea–hypopnea index (AHI) was defined as the number of apnea–hypopnea events per hour of sleep. OSAS was diagnosed in patients with AHI more than 15 events/h.8 The Epworth Sleepiness Scale was used as a validated measure to clinically detect daytime sleepiness associated with sleep disturbances.10 Outcome measures
The main outcome measure of interest was the 3-year cumulative incidence of major adverse cardiac or cerebrovascular events (MACCEs) defined as the composite of all-cause death, myocardial infarction, stroke, or repeat revascularization either percutaneous or surgical. Secondary outcome measures of interest were all-cause mortality, cardiac mortality, repeat revascularization, and the composite of all-cause mortality, myocardial infarction, or stroke. Statistical analysis
The main purpose of this study was to compare the MACCE-free survival in CAD patients with moderate or severe OSAS stratified by treatment with CPAP. Baseline demographic, clinical, angiographic, and sleep characteristics were reported as median and interquartile range (IQR) for continuous variables and number and percentage for categorical variables. Continuous variables were compared using the Mann–Whitney U-test. Categorical variables were compared using the x2 test or Fisher exact test, when appropriate. Unadjusted cumulative incidences of events were analyzed using Kaplan– Meier methods and compared using the log-rank test. All patients were censored at the time of an event or at a fixed interval of 3 years. When the cumulative incidence of composite outcomes was analyzed, the patient was
censored at the first event. Hazard ratios and 95% confidence intervals (CIs) were calculated with Cox proportional hazard models. Control of potential confounders was attempted by forcing in the models those variables with a P < 0.2 on univariate analysis or those that were deemed to be of clinical importance. The assumption of the proportional hazard was verified. All reported P values are two-sided, and P < 0.05 was considered statistically significant. SPSS software version 20 (SPSS Inc., Chicago, Illinois, USA) was used for all statistical analyses.
Results Patient characteristics
Of 496 patients undergoing an overnight sleep study from April 2008 to October 2008, 376 patients (75.8%) had angiographically confirmed CAD with at least one vessel involved. Of them, 129 (104 men and 25 women) presented with moderate or severe OSAS based on the overnight sleep study and were, therefore, included in the present analysis. The baseline characteristics for the treated (N ¼ 17) and untreated (N ¼ 112) groups of patients with OSAS are listed in Table 1. The baseline severity of OSAS was similar between the treated and untreated groups, as indicated by similar median AHI (25 vs. 22, P ¼ 0.37) and desaturations (163 vs. 164, P ¼ 0.92). Treated patients were less likely to be smokers. Otherwise the two groups were similar for multiple other relevant baseline characteristics, including age, sex, BMI, chronic kidney disease, and distribution of CAD. The percentage of patients presenting with an acute coronary syndrome or undergoing revascularization by percutaneous coronary intervention was similar in both groups. There was no statistical difference in the use of medications between the two groups. Three-year outcomes
The median duration of follow-up was 38 months (IQR 36–40 months) in the treated group and 34 months (IQR 8–36 months) in the untreated group (P ¼ 0.007). Kaplan–Meier estimates of key clinical outcomes are listed in Table 2. The incidence of 3-year MACCE was significantly lower in the treated group than in the untreated group (12 vs. 44%, P ¼ 0.02; Fig. 1), driven by a statistically significant reduction in repeat revascularization (0 vs. 30%, P ¼ 0.02) and a trend toward a reduction in the composite of death, myocardial infarction, or stroke (0 vs. 20%, P ¼ 0.06). CPAP was significantly associated with a reduced unadjusted risk of MACCE (hazard ratio 0.22, 95% CI 0.05–0.92, P ¼ 0.04). After adjusting for differences in BMI, smoking status, previous myocardial infarction, prior stroke, and left ventricular ejection fraction less than 40%, CPAP remained significantly associated with a decreased risk of MACCE (adjusted hazard ratio 0.18, 95% CI 0.04–0.78, P ¼ 0.02). Smoking habitus was not shown to represent a significant confounder (hazard ratio 0.99, 95% CI 0.56–1.77, P ¼ 0.96) and the hazard of CPAP treatment in the multivariable
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404 Journal of Cardiovascular Medicine 2014, Vol 15 No 5
Patient characteristics stratified by continuous positive airway pressure treatment
Variable Age, years (IQR) Male sex, n (%) BMI (kg/m2) median (IQR) Hypertension, n (%) Diabetes mellitus, n (%) Chronic kidney disease, n (%) Smoking status, n (%) Previous MI, n (%) Previous PCI, n (%) Previous CABG, n (%) Previous stroke, n (%) Previous congestive heart failure LVEF, % (IQR) LVEF