Rationale and design of the CONSIDER AF study

The current prospective observational study, “Impact of sleep-disordered breathing on atrial fibrillation and perioperative complications in patients undergoing coronary artery bypass grafting surgery (CONSIDER AF),” is a single-center study designed to evaluate the impact of SDB on the rate of MACCE in patients undergoing elective CABG surgery at the University Medical Center Regensburg in Germany. Patients are screened for eligibility and informed consent is obtained from all eligible patients who are willing to participate in the study. Key inclusion and exclusion criteria are presented in Table 1.

At visit 1, variables that may influence perioperative risk, such as demographic characteristics, common comorbidities, medication use, laboratory data, and cardiac catheterization results, are assessed by means of an interview and the patients’ clinical records. Moreover, visit 1 also includes standardized echocardiography and assessment of SBD the night prior to CABG surgery. Visit 2 comprises the perioperative data obtained during CABG surgery. Postoperative complications during the first 7 days after CABG surgery, such as respiratory complications and major pulmonary complications, hemodynamic instability, enzymatic myocardial injury and coronary revascularization procedures, MACCE, presence and treatment of atrial fibrillation, acute kidney injury, and incidence of delirium, are assessed at visit 3. Assessment of long-term outcomes (use of positive airway pressure therapy, presence and treatment of atrial fibrillation, myocardial infarction, stroke, surgical and non-surgical coronary revascularization procedures, quality of life) is conducted at visits 4, 5, and 6, at 60 days, 1 year, and 2 years following CABG surgery, respectively (Fig. 1).

Recruitment was started in July 2016 and enrolment is expected to be completed in July 2021. As the duration of follow-up for each patient will be 2 years, data analysis will be finished by July 2023 and a final report will be available at the beginning of 2024. In advance, selected research questions may be analyzed in a purely exploratory manner, provided that data management is conducted according to the data handling plan described in the online supplement. In brief, the project proposal and statistical analysis plan need to be submitted to the steering committee for approval before any data analysis is performed.

Patients do not routinely receive any premedication prior to surgery . Induction and maintenance of anesthesia are at the discretion of the anesthesiologists. All patients receive postoperative treatment according to the fast-track recovery care protocol that aims at early extubation and prompt implementation of mobility and occupational therapy within the intensive (ICU) and intermediate care unit (IMC) settings [17, 18]. Patients are weaned from mechanical ventilation at the discretion of the ICU physicians. Recommended delirium-prevention strategies are implemented within the standard postoperative care of patients [19, 20].

The aim of the prospective observational study CONSIDER AF is to determine whether the rate of MACCE is higher and the occurrence of atrial fibrillation and perioperative complications more frequent in patients with SDB undergoing elective CABG surgery compared to those without SDB. Primary and secondary objectives as well as the objectives of the accompanying biomaterial study are presented in Table 2.

After enrolment into the study, SDB monitoring is performed during the night before CABG surgery. Nasal flow, pulse oximetry, and thoracic breathing effort are measured with the Alice NightOne device (Philips Respironics, Murrysville, PA, USA). As described previously [4], apnea is defined as a ≥ 80% decrease in airflow for ≥10 s, hypopnea as a decrease in airflow by ≥50–80% versus baseline for ≥10 s, and desaturation as a ≥ 4% decrease in oxygen saturation. The apnea–hypopnea index (AHI) is expressed as the frequency of apneas or hypopneas per hour of sleep, and an AHI of ≥15/h is considered the cut-off for the diagnosis of SDB. Patients with SDB and ≥50% central apneas are classified into the CSA group and patients with <50% central apneas into the OSA group.

By means of structured phone interviews at visits 4, 5, and 6, the use of mandibular advancement devices, long-term oxygen therapy, or positive airway pressure treatment is assessed. Details on recommendation and prescription of SDB therapies as well as treatment adherence are systematically examined.

Right atrial appendage biopsies are received from patients during elective CABG [36]. Biopsies are transported in ice-cold Custodiol® (Essential Pharmaceuticals, LLC, Durham, NC, USA) solution containing 2 mmol/L butanedione monoxime (BDM) for cardioplegia to our laboratories. Upon arrival, human biopsies are immediately frozen and stored in a tissue biobank at −80 °C. Tissue is used for measurement of protein or gene expression by western blotting or PCR, respectively. Besides tissue samples, blood samples are taken from the patients immediately before surgery and used for isolation of peripheral blood mononuclear cells (PBMCs). The PBMCs are rapidly frozen and stored in a liquid biobank at −80 °C. The remaining blood plasma is also collected and stored separately in the liquid biobank. It is planned to analyze PMBCs for gene expression by PCR or fluorescence-activated cell scanning (FACs). Plasma samples are analyzed for the presence of oxidized low-density lipoproteins. For some experiments, atrial biopsies are also used immediately for assessment of contractile function, arrhythmias, intracellular Ca and Na ion handling, and whole-cell patch clamp electrophysiology (ion currents and membrane potential). Briefly, human atrial trabeculae are microdissected and mounted onto a force transducer in an organ bath. Contraction is elicited by electrical field stimulation and the developed mechanical force is recorded. Besides contractility measurements, premature atrial contractions (PACs) are analyzed as a surrogate for atrial arrhythmias. In separate experiments, human atrial cardiomyocytes are isolated from tissue by chunk isolation [36]. Isolated atrial cardiomyocytes are plated onto laminin-coated measurement chambers, loaded with fluorescence dyes for assessment of intracellular Ca (Fluo-4, 10 µmol/L) or Na (SBFI, 10 µmol/L), and mounted on the stage of either epifluorescence microscopes (IonOptix Limited, Dublin, Ireland) or a confocal microscope (Zeiss LSM 700; Zeiss, Oberkochen, Germany). Some cardiomyocytes are used for measurement of sarcolemmal ion currents and membrane potential by whole-cell patch clamp (HEKA Elektronik Dr. Schulze GmbH, Lambrecht/Pfalz, Germany).

Sample size was calculated by means of the primary endpoint, i. e., MACCE within 60 days after CABG. The MACCE rate within 60 days is assumed to be 7% in the no SDB and 13% in the SDB group according to a recently published study by Uchoa et al. [3] These estimates result in an odds ratio (OR) of 1.99, which can be considered as highly clinically relevant. In a retrospective pilot data analysis, the prevalence of SDB (AHI ≥15/h) was 37%. Alpha (two-sided) was set to 0.05 and beta was set to 0.80 (power 80%).

To detect an odds ratio of 1.99 (patients with SDB vs. patients without SDB) with a prevalence of SDB of 37% with 80% power at a two-sided significance level of 0.05, a total of 815 patients are required. This calculation is based on a simple method of sample size calculation for logistic regression proposed by Hsieh et al. [37]. Since we expect confounding of the results by the covariates age, BMI, sex, heart failure, and diabetes mellitus, the primary analysis will be done using a multivariable logistic regression model. This may inflate the variance of the estimated parameter and thus reduce the power to detect the estimated effect. Therefore, the sample size will be adjusted by a conservative approach, dividing the sample size by the variance inflation factor (VIF) defined as 1‑R², where R² is the squared multiple correlation coefficient of the primary variable with the other covariates. The squared multiple correlation coefficient R² of AHI versus the other covariates was estimated to be 0.2 in our retrospective pilot data. Hence, the final sample size is n = 815/(1−0.2) = 1019 for fitting a multivariable logistic regression model. The sample size was calculated using R 3.2.1 (R Foundation for Statistical Computing, Vienna, Austria; http://​www.​R-project.​org/​).

According to a pilot analysis, we anticipate the failure rate to record a valid polygraphy to be 6% (n = 72) and the lost-to-follow-up rate to assess the primary endpoint MACCE at 60 days to be 8% (n = 96). Thus, 1200 participants have to be enrolled in the study in order to include 1019 participants in the analysis.

Approval for this prospective observational study was granted by the Ethics Committees of the University of Regensburg (no. 15-101-0238). The study is conducted within the principles of Good Clinical Practice and in accordance with the Declaration of Helsinki.

Previous studies on adverse outcome in patients with SDB undergoing cardiac surgery are limited by relatively small study populations comprising less than 250 patients (Table 3; [3, 4, 11, 13‐15, 38]. However, in order to analyze SDB as a potential modulator of new-onset atrial fibrillation and peri- and postoperative complications using multivariable regression models, a large patient cohort with a sufficient number of SDB cases is required. Since the present prospective observational study CONSIDER AF aims at enrolling 1200 patients, interpretation of the association between SDB and peri- and postoperative complications can be done in a meaningful way.

Recently, diagnosis of SDB with an AHI of ≥15/h was shown to be independently associated with length of hospital stay, prolonging hospitalization by 4 days in patients with OSA compared to patients without SDB [4]. This finding was consistent with a previous study by Bhama et al. [15], in which the diagnosis of OSA significantly increased length of hospital stay after CABG from 13 to 24 days. Moreover, patients with SDB had a higher incidence of postoperative hemodynamic instability [4], a higher incidence of MACCE, and were more prone to repeated revascularization procedures and typical angina [3]. Patients with SDB needed mechanical ventilation longer than patients without SDB [4, 14, 15] and were more likely to develop respiratory complications, e. g., pneumonia or acute respiratory distress syndrome [9]. Patients with SDB are more prone to developing cardiac complications, such as arrhythmia, myocardial infarction, the need for revascularization procedures, and cardiac arrest [3, 8]. Moreover, SDB is associated with a higher rate of respiratory complications such as pneumonia or ARDS as well as with prolonged intubation and mechanical ventilation [9‐12]. Furthermore, the occurrence of postoperative delirium is higher in patients with SDB than in patients without SDB [10, 13].

While previous studies only focused on certain postoperative complications (Table 3), CONSIDER AF covers a wide range of outcome parameters and aims at analyzing the impact of SDB on postoperative complications in a comprehensive manner. Moreover, not only short-term, but also long-term complications over a period of 2 years are investigated.

The present study will extend previous findings by evaluating the incidence of new-onset postoperative atrial fibrillation after elective CABG surgery in a sizable patient cohort with and without SDB. In a small-scale study by Uchôa et al. addressing the impact of OSA on new cardiovascular events in patients undergoing CABG surgery, newly diagnosed atrial fibrillation was more common in patients with than without OSA (22 vs. 0%, p < 0.01) in long-term follow-up [3]. This association between atrial fibrillation and OSA may be related to common risk factors and a mutually perpetuating pathophysiologic relationship between these conditions. Besides this, OSA promotes atrial fibrillation via electric and structural atrial remodeling [39].

In the present study, new-onset atrial fibrillation as detected within the postoperative clinical routine and its standard treatment are systematically assessed. Unlike in previous studies, continuous ECG monitoring is performed within a subset of the CONSIDER AF population to detect subclinical events of atrial fibrillation. Symptoms and severe complications arising from atrial fibrillation, e. g., stroke or TIA, are evaluated in the long-term follow-up. Moreover, a unique and distinguishing feature of our prospective observational study is the systematic sampling of human biomaterials (right atrial appendage biopsies and blood samples) that allow further assessment of potential pathogenetic mechanisms of postoperative atrial fibrillation at the cellular and multicellular level. The latter could also lead to identification of novel blood biomarkers which may improve SDB diagnostics and help identify patients at risk of atrial arrhythmias.

As a major limitation of previous studies addressing postoperative complications in patients with SDB undergoing cardiac surgery, there is little information available on the adverse impact of CSA on patients’ outcome. However, a significant proportion of CABG patients must be assumed to have CSA, as one third of these patients suffer from heart failure with a reduced ejection fraction [40] and prevalence estimates for CSA among patients with chronic heart failure vary between 30 and 50% [41]. Therefore, our study will complement previous research by differentiating between OSA and CSA and thus offer a more comprehensive assessment of SDB and its subtypes on postoperative outcome.

Though polysomnography is considered the gold standard for diagnosing SDB, portable SDB monitoring is used in this study. Consistent with routine clinical practice, the type of SDB is assessed by the frequency of obstructive and central apneas per hour of sleep. As measurements of nasal flow, pulse oximetry, and thoracic breathing effort are methodologically similar in portable SDB monitoring and polysomnography, there is no major difference in the discrimination between obstructive and central apneas.

For a more precise discrimination between OSA and CSA, hypopneas need to be classified into their obstructive and central nature [42‐44]. This is not feasible with portable SDB monitoring, since sleep stages are not assessed by electroencephalography and an abdominal effort band and a snore microphone are not available to detect paradoxical breathing and snoring. Moreover, total sleep time is not measured during portable SDB monitoring.

To ensure a consistently high quality of SDB monitoring and low failure rates, the portable SDB monitoring device and its sensors are attached to the patient by trained medical staff. The quality of the SDB monitoring is considered adequate with at least 4 h of acceptable scored recordings that include pulse oximetry, nasal flow, and thoracic breathing effort. Hence, for feasibility reasons within our sizable patient cohort undergoing cardiac surgery the following day, the Alice NightOne devices represented a valid alternative to polysomnography.