Comparison of Percutaneous Coronary Intervention Outcomes Among Patients With Obstructive Sleep Apnea, Chronic Obstructive Pulmonary Disease Overlap, and Pickwickian Syndrome (Obesity Hypoventilation Syndrome)

Background Obstructive sleep apnea (OSA) is often present in coronary artery disease patients and confers a high risk of complications following percutaneous coronary interventions (PCI). The impact of two commonly associated comorbid conditions, chronic obstructive pulmonary disease (COPD) and obesity hypoventilation syndrome (OHS, Pickwickian syndrome) in OSA patients undergoing PCI has never been studied. Methods The National Inpatient Sample (NIS; 2007-2014) was queried using the International Classification of Diseases, Clinical Modification 9 (ICD-9-CM) codes to compare baseline characteristics, comorbidities, and outcomes in adults undergoing PCI with OSA, COPD-overlap syndrome, and OSA+OHS. Results Of a total of 4,792,177 PCI-related inpatient encounters, OSA, OSA-COPD overlap syndrome, and OSA+OHS were found to be present in 153,706 (median age 62 years, 79.4% male), 65135 (median age 65 years, 66.0% male), and 2291 (median age 63 years, 58.2% males) patients, respectively. The OHS+OSA cohort, when compared to the COPD-OSA and OSA cohorts, was found to have the worst outcomes in terms of all-cause mortality (2.8% vs. 1.5% vs. 1.1%), hospital stay (median 6 vs. 3 vs. 2 days), hospital charges ($147, 209 vs. $101,416 vs. $87,983). Complications, including cardiogenic shock (7.3% vs. 3.4% vs. 2.6%), post-procedural myocardial infarction (11.2% vs. 7.1% vs. 6.0%), iatrogenic cardiac complications (6.1% vs. 3.5% vs. 3.7%), respiratory failure, acute kidney injury, infections, and pulmonary embolism, were also significantly higher in patients with OHS+OSA. Adjusted multivariable analysis revealed equivalent results with OHS+OSA having worse outcomes than OSA-COPD and OSA. Conclusion Concomitant OHS and COPD were linked to worse clinical outcomes in patients with OSA undergoing PCI. Future prospective studies are warranted to fully understand related pathophysiology, evaluate and validate long-term outcomes, and formulate effective preventive and management strategies.


Introduction
Obstructive sleep apnea (OSA) can worsen coronary atherosclerosis and is a predictor of symptomatic coronary artery disease (CAD) and subsequent adverse outcomes after percutaneous coronary interventions (PCI) [1][2]. OSA, at times, is accompanied by chronic obstructive pulmonary disease (COPD) and/or obesity hypoventilation syndrome (OHS). OSA and COPD coexist in an entity known as OSA-COPD overlap syndrome in the absence of any known confounders, other than smoking. The prevalence of OHS (Pickwickian syndrome) in OSA patients ranges from 4$ to 50%, obesity being a confounding factor [3]. Both disorders individually are known to alter oxygenation, predisposing to hypercapnia. Hence, it could be summarized and hypothesized in this national population-based analysis that the effect of OHS and COPD on OSA would lead to a further deterioration of clinical outcomes in CAD patients undergoing PCI.

Data source and study population
The National Inpatient Sample (NIS) database (2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014) provides hospital administrative data under the Healthcare Research and Quality Healthcare Cost and Utilization Project (HCUP) [4]. Using the International Classification of Diseases, Clinical Modification 9 (ICD-9-CM) codes, this database was sought to identify baseline characteristics, in-hospital outcomes in patients with OSA or OSA-COPD overlap syndrome, and OSA-OHS undergoing PCI.

Outcomes
We studied and compared the effect of OSA, OSA-COPD overlap syndrome, and OHA-OSA on PCI hospitalizations. Reported outcomes include all-cause in-hospital mortality, complications like cardiogenic shock, postoperative myocardial infarction (MI), pericardial complications, iatrogenic cardiovascular complications (cardiac arrest/insufficiency or cardiorespiratory failure during and after or resulting from a procedure), kidney failure requiring dialysis, postoperative respiratory failure, and pulmonary embolism, a requirement of mechanical ventilation, length of in-hospital stay, hospital charges incurred, and disposition of the patient (routine, transfer to short-term hospital, transfer to other facilities, and home health care).

Statistical analysis
The Statistical Package for the Social Sciences (SPSS) version 24 (IBM Corp, Armonk, NY) was employed, and appropriate weighting and clustering techniques were applied as per the recommendations by HCUP to account for the complex survey design of the NIS database. The χ2 test was used for categorical variables.

Results
Concurrent OHS and OSA were associated with the worst outcomes, followed by OSA-COPD overlap syndrome and OSA alone (   On adjusted multivariable analysis, the OSA+OHS cohort was more likely to suffer from post-procedural complications or death due to any cause than the OSA-COPD or OSA cohorts. The presence of OSA is found to be associated with a risk of recurrent major adverse cardiac events (MACE), all-cause and cardiac deaths, and repeat revascularization following PCI [5]. It is commonly seen in older adults and more so in patients who have CAD with a prevalence of 38%-65% [6].
OHS is an amalgamation of obesity, daytime hypercapnia (PaCO2 >45 mm hg), and sleep-disordered breathing in the absence of other causes of hypoventilation. Although OSA and OHS are similar in their clinical presentation (snoring, breathing sleep disorder, and daytime sleepiness), OSA does not commonly result in hypoventilation and hypercapnia, unlike OHS. The latter is a clinically more severe entity, resulting in a higher daytime PaCO2, chronic respiratory failure, pulmonary hypertension, enlarged right ventricle, systemic hypertension, and an overall complicated disease course [7][8][9]. Data suggest that 90% of OHS patients also suffer from co-existing OSA [10]. This coexistence can potentially worsen things, as revealed by a study that reported higher PaC02 levels and unfavorable respiratory indices compared to OSA patients [11].
The prevalence of COPD in OSA and vice versa is sometimes seen to be unexpectedly high, with the strongest data reported by the Sleep Heart Health Study [12]. Compared to patients with OSA alone, those suffering from the overlap syndrome tend to be older, have higher mean pulmonary arterial pressure, and are often hypercapnic and hypoxemia [13]. As seen in both OHS and OSA, sleep-disordered breathing could affect outcomes after PCI by causing a larger infarct area and impaired healing, as reported by Buchner and colleagues [14]. Adding to the postoperative risk is the concomitant presence of metabolic and cardiovascular co-morbidities in OHS patients, frequently diagnosed before the diagnosis of OHS. According to a study comparing OHS and OSA, OHS patients had a higher mortality rate, and the majority of deaths were attributable to fatal cardiovascular events [15]. The major contributing factor to adverse cardiovascular outcomes is the intermittent hypoxia triggered by repetitive episodes of apnea and hypopnea seen in OSA patients [16].
The combined presence of COPD and severe OSA defined by the Apnea-Hypopnea index (AHI) or degree of nocturnal hypoxemia is associated with adverse cardiovascular events and mortality [17]. The presence of obesity and airway obstruction in OHS and COPD respectively compound the limitation of inter-apneic ventilation in OSA, possibly exacerbating hypercapnia and worsening post-procedural respiratory failure.
OHS patients are at an increased risk of developing heart failure, ventricular dysfunction, cor pulmonale, pulmonary hypertension, and angina pectoris than obese eucapnic individuals [18]. A study found that the prevalence of left ventricular dysfunction was high in OHS patients even with mild to moderate OSA [19]. Prior studies reveal that OHS patients have a high prevalence of right ventricular dysfunction, left ventricular hypertrophy, arrhythmias, and pulmonary hypertension due to a reflex elevation of arterial blood pressure and increased heart workload following chronic hypoxia [20]. These changes in cardiac function could contribute to significantly higher odds of cardiovascular complications and the requirement of hemodynamic support post-PCI in patients with OHS and COPD overlap as compared to OSA alone.
The limitations of this analysis should be considered before drawing any firm conclusion. First, this retrospective study based on administrative ICD-9 CM coding runs the risk of under as well as overreporting outcomes and limits any causal association. Secondly, this analysis only reports in-patient outcomes as we did not have outpatient data, long-term follow-up data, or functional outcomes. Further, the results of arterial blood gas analysis, laboratory investigations, medication history, and echocardiographic or electrophysiological findings were not available. Moreover, the severity of OSA, OSA-COPD overlap, and OHS was not known before PCI. Although multivariable regression analysis was controlled for all potential confounding factors, residual confounding effects cannot be overlooked due to the retrospective nature of the study and variation in access, preference, and level of care provided among different hospitals.

Conclusions
Although OHS remains underdiagnosed globally, it can predict adverse in-hospital outcomes when presented with OSA as shown in our study. With the aggravation of OHS by conditions like COPD and OSA, complications tend to merge, resulting in worse outcomes after cardiac interventions. Such high-risk patients may require cardiorespiratory monitoring, leading to a prolonged hospital stay and higher healthcare costs. Future prospective studies are warranted to fully understand related pathophysiology, evaluate and validate long-term outcomes, and formulate effective preventive and management strategies.

Additional Information Disclosures
Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.