Concomitant Sleep Apnea and Diabetes Mellitus Are Independently Associated with Cardiovascular Events and Hospitalization for Heart Failure after Coronary Artery Bypass Grafting

Sleep apnea is a prevalent condition and an indicator of a poor outcome after coronary artery bypass grafting (CABG). Previous studies have not explored the relative and combined effects of sleep apnea with diabetes mellitus (DM) on cardiovascular outcomes in patients undergoing CABG. The was which encompasses mortality, non-fatal

Patients with other comorbid conditions, such as renal insu ciency and peripheral vascular disease, have particularly high cardiovascular risks [3,6]. Consequently, interest in the cardiovascular effects of concomitant comorbid conditions in patients with DM is increasing.
Sleep apnea has been identi ed as an important comorbid condition that is closely associated with DM [9,10]. The reported prevalence of sleep apnea in patients with DM ranged from 24-61% [9]. Sleep apnea is a chronic sleep disorder characterized by recurrent upper airway collapse during sleep, which leads to intermittent hypoxemia and hypercapnia. The sympathetic activation, blood pressure surges, and hypercoagulability caused by sleep apnea have been postulated as mediators of an increased cardiovascular risk [11]. Numerous studies have demonstrated the associations of sleep apnea with various short-and long-term complications after CABG, including new-onset atrial brillation, respiratory complications, hospital readmission, and major adverse cardiac and cerebrovascular events (MACCEs) [12][13][14][15]. These ndings were corroborated by the recently published results of the SABOT (Sleep Apnea and Bypass Operation) study, which revealed an association of sleep apnea with a 1.57-fold increase in the risk of developing MACCEs [16].
As both sleep apnea and DM are prevalent in patients undergoing CABG, it is essential to determine the prognostic effects of these concomitant disorders. In this secondary analysis of data from the SABOT study, we reported the relative and combined effects of sleep apnea and DM on the occurrence of MACCEs and hospitalization for heart failure in patients undergoing non-emergent CABG.

Study Design
The SABOT study was a prospective, observational study that aimed to evaluate the effect of sleep apnea on the cardiovascular outcomes of patients undergoing CABG. Details regarding the methodology, patient selection, and results of the SABOT study were recently published [16]. Brie y, patients aged 18-90 years who were scheduled to undergo non-emergent CABG were invited to participate in the study. The exclusion criteria included known sleep apnea on continuous positive airway pressure therapy, cardiogenic shock on mechanical ventilation and/or intra-aortic balloon pump, ongoing heart failure exacerbation requiring oxygen supplementation, perceived high risk of malignant arrhythmia, long-term use of α-blocker therapy, and severe chronic pulmonary disease. Diagnoses of DM were made by a physician based on the standard criteria [17]. The study protocol was approved by the local institutional review board (Domain Speci c Review Board-C, National Healthcare Group). All participants provided written informed consent. The SABOT study has been registered with ClinicalTrials.gov (NCT02701504).
All patients who consented to participate were asked to complete the Epworth Sleepiness Scale questionnaire and the Berlin questionnaire before the overnight sleep study [18,19]. All participants underwent an in-hospital overnight sleep study using a United States Food and Drug Administrationapproved wrist-worn portable device (Watch-PAT 200, Itamar Medical, Caesarea, Israel), which has been validated through in-laboratory polysomnography testing [20]. The Watch-PAT 200 measures the peripheral arterial tone (PAT), a marker of changes in arterial pulsatile volume in the nger that are regulated by α-adrenergic nerve activity in the vascular smooth muscle. This parameter re ects the sympathetic nervous system activity and was shown to be highly correlated with polysomnography data in a previous meta-analysis of 14 studies [apnea-hypopnea index (AHI), r = 0.893, 95% con dence interval: 0.857-0.920, p < 0.001] [20]. The Watch-PAT 200 also measures three additional channels: the heart rate (derived from the PAT signal), pulse oximetry, and actigraphy (via a built-in actigraph). Subsequently, the device uses proprietary algorithms to estimate the PAT signal amplitude, increases in heart rate and desaturation, AHI, oxygen desaturation index, and respiratory disturbance index. The participants were classi ed according to the presence or absence of sleep apnea, de ned respectively as a Watch-PAT AHI of ≥ 15 or < 15 events per hour.
In this pre-speci ed secondary analysis, 1007 patients from the SABOT study were reclassi ed into four groups according to their sleep apnea and DM statuses. All participants were followed using a combination of clinic visits, telephone contacts, and medical record reviews. All the reported outcome events were collected and adjudicated by an independent committee that was blinded to the patients' characteristics and sleep study results.

Outcomes
The pre-speci ed primary endpoint of this study was MACCEs, de ned as the four-component composite of cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, and unplanned revascularization. The secondary endpoints included hospitalization for heart failure, all-cause mortality, and sudden cardiac death or resuscitated cardiac arrest. All endpoint events were de ned according to the Standardized Data Collection for Cardiovascular Trials Initiative [21]. Clinical event data were collected by a team blinded to the sleep study results.

Statistical analysis
Categorical variables are presented as frequencies and percentages, and differences between the four groups were evaluated using the χ 2 test. Continuous variables with normally distributed data were summarized and compared using the independent samples t-test and are presented as means with standard deviations. Continuous variables with skewed data were compared using the Mann-Whitney U test and are presented as medians with interquartile ranges. Kaplan-Meier cumulative incidence curves for the incidence of MACCEs, all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, unplanned revascularization, and hospitalization for heart failure were constructed and compared between the four groups using the log-rank test. The time to occurrence of MACCEs was compared between the four groups using a Cox proportional hazards regression analysis after adjusting for potential confounders. The following covariates were included in the multivariable logistic models: age, sex, body mass index, hypertension, left ventricular ejection fraction, and excessive daytime sleepiness. Subsequently, the hazard ratios and 95% con dence intervals were calculated. A similar Cox proportional hazards model-based analysis was performed to compare the incidence of secondary endpoints between the four groups. The SPSS Statistics 25 software program (IBM Corp., Armonk, NY, USA) was used to calculate the descriptive statistics, obtain the Kaplan-Meier cumulative incidence curves, and perform the Cox regression analyses. All analyses were two-sided and p values of < 0.05 were considered to be statistically signi cant.  Table 1. Approximately half of the patients in each of the two DM (+) groups were receiving insulin therapy.

Baseline demographic and clinical characteristics
Patients in the sleep apnea (+) DM (+) and sleep apnea (−) DM (+) groups had similar glycosylated hemoglobin levels (7.7 ± 1.5% versus 7.7 ± 1.7%, p = 0.594). Patients in both DM (+) groups were more likely to be female, of non-Chinese ethnicity, and non-smokers relative to those in the DM (−) groups. Both DM (+) groups also had a higher prevalence of hyperlipidemia, hypertension, and chronic kidney disease, regardless of the sleep apnea status. Moreover, patients in both sleep apnea (+) groups had a higher body mass index than those in the sleep apnea (−) groups, regardless of the DM status.

Sleep Study Results
The results of the sleep apnea screenings and sleep studies are listed by group in Table 2. As expected, patients in the two sleep apnea (+) groups had a higher AHI, oxygen desaturation index, and respiratory disturbance index and experienced a longer oxygen saturation duration of < 90% than did patients in the two sleep apnea (−) groups, regardless of the DM status. The four groups had similar scores on the Epworth Sleepiness Scale, a measure of daytime sleepiness, and similar results in the Berlin Questionnaire.

Angiographic And Cabg Characteristics
Details of coronary angiography ndings and CABG are provided in Table 3. No signi cant differences were observed between the four groups with regard to the indications for angiography, number of diseased coronary vessels, and involvement of the left main and proximal left anterior descending arteries. Most patients had triple vessel disease, consistent with the current indications for CABG. More than 90% of the patients underwent conventional on-pump CABG with cardiopulmonary bypass and grafting of the left internal mammary artery to the left anterior descending artery. No signi cant differences were observed between the four groups in terms of the CABG characteristics, number of

Medications Upon Discharge
Details about the medications used at the time of discharge are provided in Table 4. Most of the patients were using aspirin, β blockers, and statins at discharge. Patients in both sleep apnea (+) groups were more likely to use frusemide, spironolactone, and warfarin than were those in both sleep apnea (−) groups, regardless of the DM status.   Fig. 1. The Kaplan-Meier cumulative incidence curves for cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure are presented in Fig. 2.

Discussion
In this secondary analysis of 1007 patients from the SABOT study who participated in an overnight sleep study before non-emergent CABG, we observed a high prevalence of concomitant sleep apnea and DM (29.3%). During a mean follow-up period of 2.1 years, we determined that a status of concomitant sleep apnea and DM was associated independently with a 3.2-fold increase in the risk of the four-component MACCE (cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, and unplanned revascularization) and a 12.6-fold increase in the risk of hospitalization for heart failure. This analysis should increase awareness of the global burden of sleep apnea and DM by providing data that can facilitate the development of strategies and health policies to address this important public health problem. Our research also highlights substantial gaps in pre-CABG risk strati cation, which should be very concerning because of the high prevalence and wide-ranging negative sequelae of both sleep apnea and DM.
In recent decades, the prevalence of DM has been increasing among adults worldwide. In 2017, approximately 5 million deaths among adults worldwide were attributable to DM [22]. In the same year, the total global healthcare expenditure related to DM was estimated to be USD 850 billion [22]. The prevalence of DM in Singapore is much higher than the global average (12.8% versus 8.3%) [23]. Recently, clinicians have tended to refer patients with DM to CABG for required revascularization. These trends may explain why the prevalence of DM in the present study (56.9%) was higher than those reported in earlier studies conducted in Western countries (13-31%) [3][4][5][6][7]. This discrepancy and the increasing recognition of sleep apnea as an important DM comorbidity and cardiovascular risk marker inspired our secondary analysis.
Although a recent report described a bidirectional association between sleep apnea and DM [24], the combined effects of these disorders on the cardiovascular outcomes of patients undergoing CABG have not been studied. No previous study on the association between DM and CABG outcomes has reported the additional prognostic effect of sleep apnea [3][4][5][6][7][8]. Recently, two relatively large-scale studies demonstrated an independent association of sleep apnea with adverse cardiovascular events in patients undergoing CABG and major non-cardiac surgery [16,25]. The predictive effects of sleep apnea and DM for adverse cardiovascular events were reported to be additive in patients undergoing percutaneous coronary intervention [26]. To the best of our knowledge, however, this is the rst study to report a similar association in patients undergoing CABG.
Notably, a sleep apnea (+) DM (+) status seems to exert differential effects on the outcome of hospitalization for heart failure between patients undergoing percutaneous coronary intervention and those undergoing CABG. We previously reported that a sleep apnea (+) DM (+) status was independently associated with the occurrence of MACCEs, but not with hospitalization for heart failure, in patients undergoing percutaneous coronary intervention [26]. Interestingly, in our analysis of patients undergoing CABG, we observed independent associations of a sleep apnea (+) DM (+) status with both MACCEs and hospitalization for heart failure. Particularly, our secondary analysis revealed a 12.6-fold increased risk of hospitalization for heart failure after CABG. This discrepancy between our studies is intriguing but might be explained by the higher prevalence of heart failure in the sleep apnea (+) DM (+) group, which was indicated by the lower left ventricular ejection fraction on echocardiography and more frequent use of diuretic, β-blocker, and angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapies in the sleep apnea (+) DM (+) group relative to the other three groups in this analysis. However, the relationship between a sleep apnea (+) DM (+) status and hospitalization for heart failure did not change after adjusting for covariates such as the left ventricular ejection fraction. As hospitalization after CABG remains a clinical challenge associated with reduced patient satisfaction and escalating healthcare costs, further studies are needed to evaluate the bene ts of sleep apnea screening and treatment in patients with DM undergoing CABG, as highlighted by the International Diabetes Federation's Task Force on Epidemiology and Prevention [27].
This study had several limitations that should be considered. This was a secondary analysis of a completed observational study without a proper sample size calculation, which might have affected the study power for the reported endpoints. When the SABOT study was conceptualized during 2011-2012, no existing large-scale study had subjected patients to an in-laboratory polysomnography prior to CABG. As these patients faced a high level of cardiac risk, we opted for a simple wrist-worn Watch-PAT 200 sleep monitoring device to diagnose sleep apnea safely, as this device could be worn in general cardiology wards with concurrent routine nursing care. Although the Watch-PAT 200 is not considered the goldstandard diagnostic device in the sleep community, it has been subjected to validation studies [20] and has been approved by the US Food and Drug Administration for patient use. Furthermore, information related to the diagnosis of DM was obtained from the patients' electronic medical records. All patients underwent a pre-CABG evaluation (including fasting blood glucose and glycosylated hemoglobin monitoring) at the same hospital, which used the latest American Diabetic Association criteria to diagnose DM. However, the records did not include some details related to DM, including the disease duration, microvascular complications, or medication doses and adherence. These unknown or uncaptured confounding variables might have affected the results of this study. Moreover, follow-up coronary angiography was not conducted, and therefore, we were unable to evaluate the patency of the native coronary arteries or bypass grafts. Regarding our study population, our ndings cannot be extrapolated to patients undergoing emergency CABG or major non-cardiac surgeries. Moreover, women were under-represented in our study population, which was predominantly Asian. It is uncertain whether our ndings could be generalized to a Western population.

Conclusion
In summary, we observed a high prevalence of concomitant sleep apnea and DM among patients undergoing non-emergent CABG. Patients with concomitant sleep apnea and DM had an increased risk of developing a MACCEs (cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, or unplanned revascularization). Moreover, a status of concomitant sleep apnea and DM was independently associated with hospitalization for heart failure. The screening and treatment of sleep apnea in patients with DM who are undergoing CABG might effectively reduce the healthcare costs and negative effects associated with this condition.