Auto positive airway pressure therapy reduces pulmonary pressures in adults admitted for acute heart failure with pulmonary hypertension and obstructive sleep apnea. The ASAP-HF Pilot Trial

Auto positive airway pressure therapy reduces pulmonary pressures in adults admitted for acute... Abstract Objectives Pulmonary hypertension (PH) is extremely common in acute decompensated heart failure (ADHF) patients and predicts increased mortality. Obstructive sleep apnea (OSA), highly prevalent in congestive heart failure patients, may contribute to further elevated pulmonary pressures. This study evaluates the impact of positive airway pressure (PAP) therapy on PH in patients admitted for ADHF with OSA. Methods A two-center randomized control trial comparing standard of care (SOC) therapy for ADHF versus addition of PAP therapy in patients with concomitant OSA. Results Twenty-one consecutive patients were enrolled with 1:1 randomization to SOC versus SOC plus 48-hour PAP therapy protocol. In the intervention arm, the mean pulmonary artery systolic pressure (PASP) difference before therapy and after 48 hours of PAP therapy was −15.8 ± 3.2 (58.6 ± 2.5 mm Hg to 42.8 ± 2.7) versus the SOC arm where the mean PASP difference was −5.2 ± 2.6 (62.7 ± 3.3 mm Hg reduced to 57.5 ± 3.9) (p = 0.025). In addition, ejection fraction in the intervention arm improved (3.4 ± 1.5% versus −0.5 ± 0.5 %) (p = 0.01). Significant improvement was also noted in tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic area in the intervention arm but not in NT-pro-BNP or 6-minute walk distance. Conclusions In patients with ADHF and OSA, addition of 48 hours of PAP therapy to SOC treatment significantly reduced PH. In addition, PAP therapy was able to improve right and left ventricular function. ClinicalTrials.gov identifier: NCT02963597. acute decompensated heart failure, pulmonary hypertension, obstructive sleep apnea, positive airway pressure therapy Statement of Significance The relationship of pulmonary hypertension in patient with heart failure and sleep apnea is unclear. We randomized patients with acute heart failure who were found to have obstructive sleep apnea (OSA) and pulmonary hypertension to 48-hour therapy with auto- positive airway pressure (APAP) protocol versus standard therapy. Patient with APAP protocol had significant improvement in pulmonary pressures and cardiac function. Overall, the study improves our understanding on the impact of PAP therapy for OSA on pulmonary pressures in acute heart failure. If this effect is sustained, it may impact the natural history of congestive heart failure with pulmonary hypertension. Introduction Pulmonary hypertension (PH) in the setting of congestive heart failure (CHF) is widely common, a marker of poor prognosis, and associated with accelerated mortality [1, 2]. Currently available treatments targeting secondary PH in CHF have not yielded positive results [3], which still leaves these patients with no productive therapeutic option today. Obstructive sleep apnea (OSA) is highly prevalent [1, 2] and still largely under-diagnosed in CHF patients [4]. OSA is not only associated with increased mortality [4], but is also believed to have significant hemodynamic impact [2], which may play a role in development of PH in these patients. Our preliminary data from a retrospective review of heart failure service revealed significant reduction in positive airway pressures (PAP) in patients compliant with PAP therapy post-hospital discharge [5]. CHF is defined to be a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles, and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. The prevalence of heart failure depends on the definition applied but is approximately 1%–2% of the adult population in developed countries, rising to at least 10% among people older than 70 years. Among people older than 65 years presenting to primary care with breathlessness on exertion, one in six will have unrecognized heart failure (mainly CHFpEF) [6, 7]. Acute decompensated heart failure (ADHF) refers to rapid onset or worsening of symptoms and/or signs of heart failure. It is a life-threatening medical condition requiring urgent evaluation and treatment, typically leading to urgent hospital admission [6, 7]. In an acute setting of ADHF, the PH may be due to combination of fluid overload and obstructive apneas. Therefore, it is reasonable to hypothesize that therapy with automatic positive airway pressure (APAP) with fixed expiratory positive airway pressure (EPAP) minimum pressures of 8 cm and range of 8–20 cm (APAP protocol) may have a salutary effect on the PAP in the acute setting. We hypothesize that 48 hours of APAP protocol therapy in ADHF patients with OSA is superior in reducing pulmonary artery pressure compared to standard of care treatment. Secondary objectives were to evaluate the impact of APAP protocol therapy on right and left ventricular function, 6-minute walk distance (6MWD), and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) concentration. With this approach, APAP may offer a novel therapeutic option for patients with CHF who also have PH and OSA. Methodology Design The ASAP-HF study is a randomized, controlled, two-center, study with a parallel group design, with subjects randomized to either intervention arm (APAP protocol) or standard of care in a 1:1 ratio. This study was conducted at one center each in the United States and Germany. Enrollment Patients who had been admitted to the hospital with symptoms of ADHF were first evaluated for eligibility for the study based on chart review (Figure 1). Permission to review records was requested to conduct preliminary chart review and interview. Figure 1. View largeDownload slide Flow chart showing recruitment and randomization methodology. Figure 1. View largeDownload slide Flow chart showing recruitment and randomization methodology. If a subject was willing to participate in the ASAP-HF study, a written informed consent for the study was obtained prior to any study-related procedure. Before randomization, eligibility criteria were confirmed by reviewing the patient’s records. The randomization scheme was generated by using the following Web site: http://www.randomization.com. The randomization was stratified by site. Randomization was performed within 24 hours of admission of the patient to the hospital based on the admission echocardiography, overnight portable sleep testing, review of exclusion criteria, and obtaining consent. As per the protocol, patient’s baseline assessments were performed at the time patient was randomized (either intervention or control arm) and after 48 hours subsequently. The patients were admitted in specialized heart failure units at both sites under heart failure specialists. Since the European Society of Cardiology (ESC) guidelines are similar to ACC (American College of Cardiology), the medical therapy was expected to be equivalent across treatment arms. Informed consent The consent form was written in accordance with applicable data privacy acts and FDA Regulations. The study was approved by the responsible Institutional Review board (IRB)/Ethics Committee (EC) for both Institutions (institutional Review Board, Albert Einstein Healthcare Network , IRB # HN4889 and Ethikkommission der Medizinischen Fakultät der Ruhr-Universität Bochum, Sitz Bad Oeynhausen, Reg. -Nr.: 14/2016). The trial was performed in concordance with the Declaration of Helsinki and ex ante registered at ClinicalTrials.gov identifier: NCT02963597. Subject inclusion criteria Age 18 years or more ADHF with echocardiographically determined pulmonary artery systolic pressure (PASP) of at least 50 mm Hg Prior clinical diagnosis of heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). HFrEF defined as EF less than or equal to 40%. Moderate to severe OSA documented by polysomnography with Apnea–Hypopnea Index (AHI) of at least 20 e/hour and 5% of analyzed time spent less than 90% O2 saturation and a minimum recording time of 2 hours Patient is able to fully understand study information and sign informed consent Subject exclusion criteria Chronic renal insufficiency (on hemodialysis or serum creatinine > 2 mg/dL) Hemodynamically significant valvular disease Inability to complete 6-minute walk test (6MWT) for non-cardiac reasons Left ventricular assist device (LVAD)/heart transplant or hemodynamically unstable Patient taking any pulmonary vasodilators, including home oxygen Known diagnosis of OSA and on active therapy Fifty percentage or more of the respiratory events being central/Cheyne–Stokes breathing (CSR) Recent cardiac surgery (within 30 days of admission) Recent stroke (within 30 days of admission or with persistent neurological deficits) Severe chronic obstructive pulmonary disease (COPD) defined as forced expiratory volume in 1 second (FEV1) less than 50% Participation in a randomized controlled pharmaceutical or treatment-related cardiac or pulmonary clinical study within 1 month prior to randomization Patient weighing less than 66 pounds (30 kg) Study Devices ApneaLink Air The ApneaLink Air (ResMed, San Diego, CA) is a market-released portable device that has been FDA-cleared (K143272) and CE-marked in Germany for use by health care professionals, where it may aid in the diagnosis of sleep disordered breathing for adult patients (Table 1). Table 1. Baseline characteristics of the PAP versus control group (n = 21) for continuous parameters Mean ± SD, median/n (%) Characteristic PAP (N = 10) Control#8232;(N = 11) p value Age (years) 70.6 ± 11.5, 72.0 66.7 ± 11.2, 61.0 0.45 Body mass index (kg/m2) 28.8 ± 5.8, 27.6 31.2 ± 4.2, 31.4 0.27 Male 7 (70.0) 7 (63.6) 1.00 African American 5 (50.0) 4 (36.4) 0.67 Caucasian 5 (50.0) 7 (63.6) Beta-blockers 10 (100.0) 10 (90.9) 1.00 ACE inhibitor/ARB 8 (80.0) 9 (81.8) 1.00 Statin 6 (60.0) 9 (81.8) 0.36 Diuretics 10 (100.0) 11 (100.0) N/A Reduced EF 5 (50.0) 8 (72.7) 0.39 LVEF (%) 41.5 ± 20.1, 45.0 36.4 ± 19.2, 40.0 0.56 COPD 4 (40.0) 1 (9.1) 0.15 HTN 9 (90.0) 10 (90.9) 1.00 DM 5 (50.0) 9 (81.8) 0.18 CAD 7 (70.0) 6 (54.5) 0.66 Ischemic CM 6 (60.0) 6 (54.5) 1.00 NYHA = 3 8 (80.0) 5 (45.5) 0.18 NYHA = 4 2 (20.0) 6 (54.5) Na (meq/L) 141.9 ± 1.4, 142.0 138.7 ± 4.3, 139.0 0.04 Cr (mg/dL) 1.22 ± 0.33, 1.10 1.03 ± 0.22, 0.98 0.13 GFR (mL/min) 56.3 ± 13.5, 61.0 62.5 ± 7.2, 61.0 0.20 Troponin I (ng/mL) 0.04 ± 0.05, 0.02 0.05 ± 0.05, 0.02 0.82 Hemoglobin (g/dL) 12.4 ± 1.4, 12.4 13.5 ± 2.2, 13.4 0.20 Mean ± SD, median/n (%) Characteristic PAP (N = 10) Control#8232;(N = 11) p value Age (years) 70.6 ± 11.5, 72.0 66.7 ± 11.2, 61.0 0.45 Body mass index (kg/m2) 28.8 ± 5.8, 27.6 31.2 ± 4.2, 31.4 0.27 Male 7 (70.0) 7 (63.6) 1.00 African American 5 (50.0) 4 (36.4) 0.67 Caucasian 5 (50.0) 7 (63.6) Beta-blockers 10 (100.0) 10 (90.9) 1.00 ACE inhibitor/ARB 8 (80.0) 9 (81.8) 1.00 Statin 6 (60.0) 9 (81.8) 0.36 Diuretics 10 (100.0) 11 (100.0) N/A Reduced EF 5 (50.0) 8 (72.7) 0.39 LVEF (%) 41.5 ± 20.1, 45.0 36.4 ± 19.2, 40.0 0.56 COPD 4 (40.0) 1 (9.1) 0.15 HTN 9 (90.0) 10 (90.9) 1.00 DM 5 (50.0) 9 (81.8) 0.18 CAD 7 (70.0) 6 (54.5) 0.66 Ischemic CM 6 (60.0) 6 (54.5) 1.00 NYHA = 3 8 (80.0) 5 (45.5) 0.18 NYHA = 4 2 (20.0) 6 (54.5) Na (meq/L) 141.9 ± 1.4, 142.0 138.7 ± 4.3, 139.0 0.04 Cr (mg/dL) 1.22 ± 0.33, 1.10 1.03 ± 0.22, 0.98 0.13 GFR (mL/min) 56.3 ± 13.5, 61.0 62.5 ± 7.2, 61.0 0.20 Troponin I (ng/mL) 0.04 ± 0.05, 0.02 0.05 ± 0.05, 0.02 0.82 Hemoglobin (g/dL) 12.4 ± 1.4, 12.4 13.5 ± 2.2, 13.4 0.20 p value is from a two-sided t-test, comparing the means between the two treatment arms.#8232;For categorical parameters, p value is from a Fisher’s exact test, comparing the proportion between the two treatment arms. ACE = angiotensin converting enzyme; ARB = angiotensin II receptor blockers; CAD = coronary artery disease; CM = cardiomyopathy; Cr = creatinine; DM = diabetes mellitus; GFR = glomerular filtration rate; HTN = hypertension; NYHA = New York Heart Association. View Large Table 1. Baseline characteristics of the PAP versus control group (n = 21) for continuous parameters Mean ± SD, median/n (%) Characteristic PAP (N = 10) Control#8232;(N = 11) p value Age (years) 70.6 ± 11.5, 72.0 66.7 ± 11.2, 61.0 0.45 Body mass index (kg/m2) 28.8 ± 5.8, 27.6 31.2 ± 4.2, 31.4 0.27 Male 7 (70.0) 7 (63.6) 1.00 African American 5 (50.0) 4 (36.4) 0.67 Caucasian 5 (50.0) 7 (63.6) Beta-blockers 10 (100.0) 10 (90.9) 1.00 ACE inhibitor/ARB 8 (80.0) 9 (81.8) 1.00 Statin 6 (60.0) 9 (81.8) 0.36 Diuretics 10 (100.0) 11 (100.0) N/A Reduced EF 5 (50.0) 8 (72.7) 0.39 LVEF (%) 41.5 ± 20.1, 45.0 36.4 ± 19.2, 40.0 0.56 COPD 4 (40.0) 1 (9.1) 0.15 HTN 9 (90.0) 10 (90.9) 1.00 DM 5 (50.0) 9 (81.8) 0.18 CAD 7 (70.0) 6 (54.5) 0.66 Ischemic CM 6 (60.0) 6 (54.5) 1.00 NYHA = 3 8 (80.0) 5 (45.5) 0.18 NYHA = 4 2 (20.0) 6 (54.5) Na (meq/L) 141.9 ± 1.4, 142.0 138.7 ± 4.3, 139.0 0.04 Cr (mg/dL) 1.22 ± 0.33, 1.10 1.03 ± 0.22, 0.98 0.13 GFR (mL/min) 56.3 ± 13.5, 61.0 62.5 ± 7.2, 61.0 0.20 Troponin I (ng/mL) 0.04 ± 0.05, 0.02 0.05 ± 0.05, 0.02 0.82 Hemoglobin (g/dL) 12.4 ± 1.4, 12.4 13.5 ± 2.2, 13.4 0.20 Mean ± SD, median/n (%) Characteristic PAP (N = 10) Control#8232;(N = 11) p value Age (years) 70.6 ± 11.5, 72.0 66.7 ± 11.2, 61.0 0.45 Body mass index (kg/m2) 28.8 ± 5.8, 27.6 31.2 ± 4.2, 31.4 0.27 Male 7 (70.0) 7 (63.6) 1.00 African American 5 (50.0) 4 (36.4) 0.67 Caucasian 5 (50.0) 7 (63.6) Beta-blockers 10 (100.0) 10 (90.9) 1.00 ACE inhibitor/ARB 8 (80.0) 9 (81.8) 1.00 Statin 6 (60.0) 9 (81.8) 0.36 Diuretics 10 (100.0) 11 (100.0) N/A Reduced EF 5 (50.0) 8 (72.7) 0.39 LVEF (%) 41.5 ± 20.1, 45.0 36.4 ± 19.2, 40.0 0.56 COPD 4 (40.0) 1 (9.1) 0.15 HTN 9 (90.0) 10 (90.9) 1.00 DM 5 (50.0) 9 (81.8) 0.18 CAD 7 (70.0) 6 (54.5) 0.66 Ischemic CM 6 (60.0) 6 (54.5) 1.00 NYHA = 3 8 (80.0) 5 (45.5) 0.18 NYHA = 4 2 (20.0) 6 (54.5) Na (meq/L) 141.9 ± 1.4, 142.0 138.7 ± 4.3, 139.0 0.04 Cr (mg/dL) 1.22 ± 0.33, 1.10 1.03 ± 0.22, 0.98 0.13 GFR (mL/min) 56.3 ± 13.5, 61.0 62.5 ± 7.2, 61.0 0.20 Troponin I (ng/mL) 0.04 ± 0.05, 0.02 0.05 ± 0.05, 0.02 0.82 Hemoglobin (g/dL) 12.4 ± 1.4, 12.4 13.5 ± 2.2, 13.4 0.20 p value is from a two-sided t-test, comparing the means between the two treatment arms.#8232;For categorical parameters, p value is from a Fisher’s exact test, comparing the proportion between the two treatment arms. ACE = angiotensin converting enzyme; ARB = angiotensin II receptor blockers; CAD = coronary artery disease; CM = cardiomyopathy; Cr = creatinine; DM = diabetes mellitus; GFR = glomerular filtration rate; HTN = hypertension; NYHA = New York Heart Association. View Large The ApneaLink Air recorder is a three-channel battery-powered respiratory pressure sensor and oximetry system. The default settings for the ApneaLink Air includes a flow reduction of 30% combined with a desaturation of 4% to automatically score a hypopnea and a respiratory effort sensor to differentiate between central, obstructive, and mixed apneas. The data were reviewed by a board-certified sleep physician for study entry (Table 2). Table 2. Baseline portable monitor parameters in the intervention arm versus the usual care arm Mean ± SD, median/n (%) Parameter PAP#8232;(N = 10) Control#8232;(N = 11) p value [1] Recording time (minute) 547.2 ± 136.2, 480.0 557.4 ± 167.7, 559.0 0.88 Cannula time (minute) 336.9 ± 114.5, 320.0 352.4 ± 116.2, 382.0 0.76 AHI 31.8 ± 8.0, 29.2 34.3 ± 9.2, 36.3 0.51 ODI 33.6 ± 14.8, 30.4 36.1 ± 12.3, 37.9 0.68 Average O2 saturation 90.4 ± 4.9, 91.0 90.5 ± 1.9, 90.0 0.97 Lowest O2 saturation 67.8 ± 12.0, 66.0 65.1 ± 8.2, 65.0 0.55 Average O2 desaturation 39.1 ± 36.9, 27.5 31.9 ± 31.0, 6.0 0.63 T < 90 (minute) 231.2 ± 223.2, 193.0 233.3 ± 125.4, 211.0 0.98 T < 90 (%) 42.4 ± 41.0, 29.8 49.9 ± 44.3, 37.5 0.69 Mean ± SD, median/n (%) Parameter PAP#8232;(N = 10) Control#8232;(N = 11) p value [1] Recording time (minute) 547.2 ± 136.2, 480.0 557.4 ± 167.7, 559.0 0.88 Cannula time (minute) 336.9 ± 114.5, 320.0 352.4 ± 116.2, 382.0 0.76 AHI 31.8 ± 8.0, 29.2 34.3 ± 9.2, 36.3 0.51 ODI 33.6 ± 14.8, 30.4 36.1 ± 12.3, 37.9 0.68 Average O2 saturation 90.4 ± 4.9, 91.0 90.5 ± 1.9, 90.0 0.97 Lowest O2 saturation 67.8 ± 12.0, 66.0 65.1 ± 8.2, 65.0 0.55 Average O2 desaturation 39.1 ± 36.9, 27.5 31.9 ± 31.0, 6.0 0.63 T < 90 (minute) 231.2 ± 223.2, 193.0 233.3 ± 125.4, 211.0 0.98 T < 90 (%) 42.4 ± 41.0, 29.8 49.9 ± 44.3, 37.5 0.69 ODI = oxygen desaturation index. View Large Table 2. Baseline portable monitor parameters in the intervention arm versus the usual care arm Mean ± SD, median/n (%) Parameter PAP#8232;(N = 10) Control#8232;(N = 11) p value [1] Recording time (minute) 547.2 ± 136.2, 480.0 557.4 ± 167.7, 559.0 0.88 Cannula time (minute) 336.9 ± 114.5, 320.0 352.4 ± 116.2, 382.0 0.76 AHI 31.8 ± 8.0, 29.2 34.3 ± 9.2, 36.3 0.51 ODI 33.6 ± 14.8, 30.4 36.1 ± 12.3, 37.9 0.68 Average O2 saturation 90.4 ± 4.9, 91.0 90.5 ± 1.9, 90.0 0.97 Lowest O2 saturation 67.8 ± 12.0, 66.0 65.1 ± 8.2, 65.0 0.55 Average O2 desaturation 39.1 ± 36.9, 27.5 31.9 ± 31.0, 6.0 0.63 T < 90 (minute) 231.2 ± 223.2, 193.0 233.3 ± 125.4, 211.0 0.98 T < 90 (%) 42.4 ± 41.0, 29.8 49.9 ± 44.3, 37.5 0.69 Mean ± SD, median/n (%) Parameter PAP#8232;(N = 10) Control#8232;(N = 11) p value [1] Recording time (minute) 547.2 ± 136.2, 480.0 557.4 ± 167.7, 559.0 0.88 Cannula time (minute) 336.9 ± 114.5, 320.0 352.4 ± 116.2, 382.0 0.76 AHI 31.8 ± 8.0, 29.2 34.3 ± 9.2, 36.3 0.51 ODI 33.6 ± 14.8, 30.4 36.1 ± 12.3, 37.9 0.68 Average O2 saturation 90.4 ± 4.9, 91.0 90.5 ± 1.9, 90.0 0.97 Lowest O2 saturation 67.8 ± 12.0, 66.0 65.1 ± 8.2, 65.0 0.55 Average O2 desaturation 39.1 ± 36.9, 27.5 31.9 ± 31.0, 6.0 0.63 T < 90 (minute) 231.2 ± 223.2, 193.0 233.3 ± 125.4, 211.0 0.98 T < 90 (%) 42.4 ± 41.0, 29.8 49.9 ± 44.3, 37.5 0.69 ODI = oxygen desaturation index. View Large Echocardiography Echocardiography was performed at Einstein Medical Center by Philips iE33 (Koninklijke Philips N.V.) and in Germany by a GE (General Electric, Chicago, IL) Vivid E9 device. The interpretation of all echocardiograms was provided by a dedicated board-certified cardiologist at each site to reduce inter-observer variations, who was also blinded to the results of the apnea link or randomization protocol. The clinically meaningful difference between the pre- and post-intervention PASP was agreed upon to be 10 mm Hg. PH was defined as PASP of ≥50 mm Hg on admitting echocardiogram performed by a dedicated cardiologist as each site. The tricuspid regurgitation (TR) jet was used to determine right ventricular (RV) and PASP, done by calculating the RV to right atrial pressure (RAP) gradient using the modified Bernoulli equation and then adding the assumed RAP. IVC Collapsibility Index for RAP [8] was assumed in both sites according to: IVC with normal diameter and IVC collapses: 3 mm Hg IVC with normal diameter, but IVC does not collapse: 8 mm Hg IVC is dilated and IVC collapses: 8 mm Hg IVC is dilated, but IVC does not collapse: 15 mm Hg Additional echocardiographic parameters like left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), RAP, TR jet, right and left ventricular diameters and size were also evaluated. Functional capacity and biomarker testing The 6MWT served as an objective evaluation of the response to medical intervention. The 6MWD was measured. Exercise was performed on a level indoor surface following American Thoracic Society (ATS) guidelines in to assure minimal variability. If there were any signs of medical instability, the attending physician ended the test before 6 minutes [9]. Blood was collected and processed to obtain samples for NT pro-BNP. All samples were sent to the site’s local clinical laboratory for testing. Therapy AirSense 10 AutoSet The AirSense 10 AutoSet (ResMed, San Diego, CA) (“AutoSet”) is a market-released device that has been FDA-cleared (K140124) in the United States and CE-marked in Germany (EC149) to provide non-invasive ventilatory support to treat patients weighing more than 66 lbs (30 kg). The AirSense 10 AutoSet provides a minimum and maximum pressure within the range of 4–20 cm H2O. As per our study protocol, the minimum pressures were maintained at 8 cm and maximum pressure at 20 cm of H2O pressure. For initiation of therapy, the AutoSet device was set to a minimum continuous positive airway pressure (CPAP) of 8 cm H2O and a maximum CPAP of 20 cm H2O. The minimum CPAP may be lowered if patients were unable to tolerate higher CPAP. All subjects were provided humidifiers and climate line tubing to address any instance of upper airway dryness or other forms of discomfort with the airflow of the device during the initiation or during therapy with the device. For the initiation of therapy, a full-face mask was recommended, but if this mask was unsuitable for the subject, another type of mask such as a nasal mask was provided. Subjects who were unable to tolerate the minimum CPAP of 8 cm of H2O pressure, had the pressure reduced by 1 cm every 5 minutes until patient felt comfortable. If despite the acclimation trial the subject was unable to tolerate the pressure, the patients were to be discharged from the study. Standard medical therapy All subjects were treated standard of care therapy for heart failure in accordance to the applicable standard of care and most recent guidelines, particularly with reference to medication. Other guideline-recommended therapies were encouraged. All medications were documented. Statistical methods Baseline characteristics, medical history, and ApneaLink parameters were collected and compared between treatment groups. Descriptive statistics, including mean, SD, median, and quartiles were presented for each group. A two-sided test was used to compare means for continuous parameters, and a Fisher’s Exact test was used to compare proportions for categorical parameters. The primary study objective was to compare the APAP protocol intervention arm and the standard of care arm specifically to the change in pulmonary pressures from baseline to 48 hours post-treatment. Secondary objectives involved comparison of the change from baseline to 48 hours for the following parameters: 6MWD, NT-pro-BNP, and echocardiographic measures. Descriptive statistics were generated at baseline and 48 hours for each group and the paired mean/median change for each parameter was compared between treatment groups using an exact Wilcoxon test. All statistical comparisons of treatment groups were generated using a two-sided significance level of 0.05. Statistical software, SAS, version 9.4, was used for all analyses (Figure 2). Figure 2. View largeDownload slide Line plot of PASP at baseline and after 48 hours in the intervention arm (blue) and usual care arm (red). Figure 2. View largeDownload slide Line plot of PASP at baseline and after 48 hours in the intervention arm (blue) and usual care arm (red). Results Of the 21 patients enrolled (10 from United States and 11 from Germany), 14 were males, 9 were African-Americans. The mean age was 70.6 ± 11.5 years in the intervention arm and 66.7 ± 11.2 years in usual care arm. The BMI was 28.8 ± 5.8 kg/m2 in the intervention arm and 31.2 ± 4.2 kg/m2 in the usual care arm (Table 1). The mean AHI and T <90 were 31.8 ± 8.0 e/hour and 231.2 ± 223.2 minutes in the intervention arm versus 34.3 ± 9.2 and 233.3 ± 125.4 minutes in the standard of care arm, respectively (Table 2). In the intervention arm, the patients were on the APAP protocol therapy for a mean of 29.7 ± 3.1 hours. The mean minimum pressure setting was 7.4 cm of H2O (range: 4–9 cm) and mean pressure was 10.3 ± 0.7 cm of H2O, with a residual AHI of 7.2 ± 2.0. In the intervention arm, the mean PASP was 58.6 ± 2.5 mm Hg before therapy and 42.8 ± 2.7 mm Hg after 48 hours of APAP therapy. In the standard of care arm, the mean PASP was 62.7 ± 3.3 mm Hg and was reduced to 57.5 ± 3.9 after 48 hours of usual care. The mean paired difference in the reduction of PASP comparing the intervention arm (−15.8 ± 3.2) to the standard of care arm (−5.2 ± 2.6) was statistically significant (p = 0.025). Similarly, mean TR jet was significantly improved in the intervention arm compared to the standard of care arm (Supplement Table 3). Comparison of echocardiographic parameters revealed significant improvement in the mean change LVEF in the APAP intervention arm compared to the standard of care arm for both the combined group (3.4 ± 1.5% vs. −0.5 ± 0.5 %) (p = 0.01) and in the subset of patients with only systolic heart failure (n = 13) (6.8 ± 1.9% vs. −0.1 ± 0.1) (p = 0.01) (Supplement Figure 3). Significant improvement was also noted in RV function addressed by TAPSE. Mean TAPSE changed from 17.9 ± 1.0 mm to 18.6 ± 1.5 in the APAP intervention arm after 48 hours as compared to a mean reduction from 16.9 ± 1.7 to 14.3 ± 1.3 mm in the standard of care arm (p = 0.04) (Supplement Figure 4). Mean systolic RV area reduced significantly in the intervention arm (−17.4 ± 12.6 cm2) compared to the standard of care arm (−6.0 ± 8.1 cm2) (p = 0.04). Trends in improvements of left ventricular systolic volume index (LV SVI), RAP, left ventricular end diastolic diameter (LVEDD), and E/e ratio were noted in the intervention arm compared to standard of care arm but were not statistically significant. The improvement in mean 6MWT after 48 hours in the intervention arm was 20.0 ± 15.3 m (202.6 ± 26.0 prior to therapy to 222.6 ± 33.5 at 48 hours after therapy) in the APAP therapy group versus 8.2 ± 27.5 m (153.6 ± 29.2 to 161.8 ± 29.3) in the standard of care arm; however, the mean improvement was not statistically significant (p = 0.99) (Supplement Figure 1). The mean reduction in NT-pro-BNP after 48 hours in the intervention arm was −621.1 ± 222.5 pg/mL (1087.6 ± 285.4 to 466.6 ± 106.4 pg/mL) in the APAP group versus −32.5± 299.6 pg/mL (1532.7 ± 406.8 to 1500.2 ± 625.5 pg/mL) in the standard of care arm (p = 0.31) (Supplement Figure 2). The mean weight in both groups was recorded at time of intervention (PAP therapy or usual care) and after 48 hours of intervention. Both groups showed reduction in weight with PAP group showing change from 86.7 ± 7.7 to 85.3 ± 7.7 and usual care from 92.4 ± 5.0 to 90.3 ± 4.9. The change in weight in the PAP group was −1.4 ± 0.2 and usual care −2.0 ± 0.6 (p = 0.62). Discussion Our trial is the first to show a significant greater reduction in PASP with 48 hours of PAP (APAP) protocol treatment in ADHF patients with OSA as compared to guideline-driven standard of care treatment. Our study reveals a mean reduction of 15.8 mm Hg PASP in the intervention arm as compared to a mean reduction in standard of care arm of 5.2 mm Hg (p = 0.025). Furthermore, significant improvements are identified for mean LVEF and RV function (TAPSE) in the intervention arm compared to the standard of care arm. We also noted trends toward improvements in NT-pro-BNP and 6MWT in the intervention arm, although these did not reach statistical significance. Presence of PH in patients with CHF is a marker of increased mortality [1, 10]. In addition to left heart disease, the PH in CHF may also be influenced by OSA. PH has been noted in patients with OSA alone and treatment with CPAP has shown to reduce the pulmonary pressures [11]. The above suggests that there may be both a wake (left heart disease) and sleep (OSA) component to the pathogenesis of the PH in patients with heart failure. The relative contribution of the two components may vary based on the severity of each component. In order to treat both components, we utilized a unique protocol (APAP protocol) with fixed lower pressures of 8 cm of H2O pressure, which would target the pulmonary edema, and an “auto” pressure with maximum range of 20 cm of H2O pressure to target the apneic events which may occur during the sleep. This “dual” strategy during an acute decompensation we believed would result in improvements of pulmonary pressures and subsequent overall downstream benefits in patients with CHF and PH. CPAP in patients with moderate to severe OSA is not associated with a significant reduction in major cardiac events and all-cause cardiac mortality unless CPAP is applied for more than 4 hours per night [12]. Compliance with APAP therapy may be the most important factor in improving outcome and hence we encouraged our patients to be adherent to the therapy with minimum requirement of a total of 8 hours in 48 hours (average 4 hours/24 hours). The total hours our patients remained on therapy were 29.7 ± 3.1 hours. We believe excellent adherence in our patients consequentially resulted in a positive impact. CPAP therapy has been shown to have salutary effect on several cardiovascular disorders including CHF [13]. Negative intra-thoracic pressures created by repetitive glottis closure have been shown to increase transmural pressure, preload, afterload and reduce cardiac output [14, 15]. Reversal of negative pleural pressure and subsequent reduction in transmural pressures has been shown to reduced LV afterload [16, 17]. Additionally, resolution of apneas, hypoxemia, and sympathetic overdrive may improve myocardial energetics especially in severe OSA [18, 19]. Additionally, CPAP therapy by augmenting inspiratory and expiratory flow and pressures has been shown to reduce the work of breathing and improve muscle function [20–22]. CPAP therapy has shown other beneficial effects including improved alveolar ventilation, reduced intrinsic positive end expiratory pressure (PEEP), reduced dead space ventilation, reduced alveolar fluid, and prevented micro-atelectasis [23–25]. Use of CPAP in patients with acute pulmonary edema has also been shown to reduce pulmonary capillary wedge pressure (PCWP) as compared to oxygen and diuretics alone [26]. CPAP has also been shown to improve PH in patients with OSA [11]. Our protocol was designed to target differential benefits of varying pressures on pulmonary parenchyma/vasculature and upper airway dynamics. As noted above, during “wake periods” the fixed expiratory positive airway pressure (EPAP) improved pulmonary edema, alveolar ventilation and prevented micro-atelectasis. Additionally, during “sleep periods” the auto mode targeted the apneic events, subsequently reducing the transmural pressures and preload, thereby improving LV and RV function [27] as we showed for the first time. The above mechanisms potentially help improve LV function and reduce the PCWP which in turn reduces the pulmonary systolic pressures. This reduction in PCWP is “over and above” which would be affected by diuretics and afterload reduction alone, essentially by reversing the additional hemodynamic disadvantage induced by sleep apnea. Similarly, Tkacova et al. observed patients submitted to CPAP had a decrease in pulse pressure correlated to an increase in the EF originated by the reduction of the transmural pressure. In fact, our study is consistent with these findings of improvement in EF [28]. While trends toward improved exercise capacity as noted by 6MWT were documented, they did not reach statistical significance most likely due to the small number of patients and short duration of intervention investigated in this study. However, prior studies using CPAP in CHF have shown to improve 6MWT [29]. In addition, APAP therapy may improve cardiac and respiratory performances of HF patients, considering it enhances oxygenation and pulmonary mechanics, so it can also improve functional capacity of the lungs [30], which is exceptionally important as hypoxia drives mortality [31]. CPAP for 2 weeks in CHF patients has also been shown to improve lung function. CPAP progressively increased forced vital capacity (FVC) and FEV1 in HF patients when compared to the standard of care arm. This improvement may have occurred due to the increase in functional residual capacity and opening of collapsed alveoli [30]. We also noted trends toward reduced chamber diameters and area post-intervention. This is consistent with enlargement of the right-sided cardiac area due to increased preload generated by a volume overload in cardiac cavities during apneic episodes. CPAP therapy decreases this volume overload, momentarily, with an increase in cardiac contractility, which occurs with the advent of transmural pressure reduction. Additionally, CPAP therapy by virtue of increased PEEP helps recruit alveoli and promotes gas exchange [32–34]. Based on the fact that APAP/PEEP may have independent salutary effect on CHF with additional benefit from resolving hemodynamic consequences created by obstructive apneic events, we created a protocol which utilized and aligned both these principles to mitigate these deleterious pathological chain reactions. Utilizing a minimum of 8 cm of EPAP (or as tolerated), we aimed at reducing the transmural pressure while allowing the auto mode to mitigate the hemodynamic consequences of apneic events during sleep. The relative contribution of these two mechanisms is however, unclear in the pathogenesis of PH in patient with acute heart failure and OSA. Apart from the positive hemodynamic impact on patients with acute heart failure and PH, this protocol may have clinical implication by reducing length of stay in the hospital. Prior studies have noted reduction in 30-day and 6-month readmission in patients initiated early on CPAP therapy post-discharge from an acute heart failure episode [35, 36]. Some preliminary data also suggest that this reduction in pulmonary pressure is sustained on CPAP therapy post-discharge from the hospital [36]. Further studies to evaluate the impact of reduced PH on mortality in heart failure would be interesting as currently there is no treatment option for PH in CHF patients. This trial included patients with preserved ejection fraction (HFpEF) which traditionally has been resistant to any intervention. This positive signal may open the doors for further evaluation of the role of OSA and APAP therapy in this condition. In a recent study of 52 patients with severe OSA in a randomized, sham-controlled clinical trial with CPAP treatment for 3 months improved left ventricular diastolic function and showed improvements in arterial stiffness and ventricular-vascular coupling in the treatment group [37]. Limitations of the study include the small sample size investigated. Due to stringent inclusions criteria, only 10% of patients screened met the eligibility criteria, and thus these findings cannot be generalized to all patients with CHF with PH. We also did not include mild OSA (inclusion criteria was AHI ≥ 20) and central sleep apnea which may constitute a substantial portion of the sleep disordered breathing in heart failure population. Further studies on this cohort are required. As all patients were hospitalized with ADHF, polysomnography could not be performed in these patients, which is the gold standard for differentiating central from obstructive events. However, with respiratory effort channel and nasal canula flow signal, most of the central events and CSR can be reliably recognized [38]. PH was diagnosed by echocardiography and not right heart catheterization (RHC); however, almost all PH in left heart failure is pulmonary venous hypertension and data suggest that Doppler echocardiogram is a reliable method of measuring PASP [39, 40]. However, at lower pressure cutoff, overestimation of PASP by echocardiogram is common [41]. Studies using higher PASP cutoff (50 mm Hg) have been found to have minimal false positive results [42, 43]. Since RHC was not performed to confirm PH, it was imperative to have minimal/no false positive PH. Furthermore, the difference in change in pressures was pre-specified to be clinically meaningful only if 10 cm or more of H2O pressure drop was recorded. We also do not believe that there were significant variations in the clinical management of these patients at the two sites as the patients were admitted in specialized heart failure units at both sites under heart failure specialists. There are no major differences in treatment of acute heart failure between AHA/ACC and ESC guidelines. In conclusion, our study reveals significant improvement of PH in patients with acute heart failure with concomitant OSA treated with protocolized APAP therapy compared to the standard of care. These findings can help understanding PH in heart failure and translate it to improved outcome in this challenging population. Future studies confirming these findings with RHC and composite outcome are recommended. Funding The study was funded by unrestricted research grant provided by ReSMed Inc. Conflict of interest statement. S.S., PI has received unrestricted research grant from ResMed Inc. The remaining author declare no conflicts of interest. 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Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease . J Rheumatol. 2007 ; 34 ( 5 ): 1005 – 1011 . Google Scholar PubMed WorldCat © Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png SLEEP Oxford University Press

Auto positive airway pressure therapy reduces pulmonary pressures in adults admitted for acute heart failure with pulmonary hypertension and obstructive sleep apnea. The ASAP-HF Pilot Trial

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Oxford University Press
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© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.
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0161-8105
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1550-9109
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10.1093/sleep/zsz100
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Abstract

Abstract Objectives Pulmonary hypertension (PH) is extremely common in acute decompensated heart failure (ADHF) patients and predicts increased mortality. Obstructive sleep apnea (OSA), highly prevalent in congestive heart failure patients, may contribute to further elevated pulmonary pressures. This study evaluates the impact of positive airway pressure (PAP) therapy on PH in patients admitted for ADHF with OSA. Methods A two-center randomized control trial comparing standard of care (SOC) therapy for ADHF versus addition of PAP therapy in patients with concomitant OSA. Results Twenty-one consecutive patients were enrolled with 1:1 randomization to SOC versus SOC plus 48-hour PAP therapy protocol. In the intervention arm, the mean pulmonary artery systolic pressure (PASP) difference before therapy and after 48 hours of PAP therapy was −15.8 ± 3.2 (58.6 ± 2.5 mm Hg to 42.8 ± 2.7) versus the SOC arm where the mean PASP difference was −5.2 ± 2.6 (62.7 ± 3.3 mm Hg reduced to 57.5 ± 3.9) (p = 0.025). In addition, ejection fraction in the intervention arm improved (3.4 ± 1.5% versus −0.5 ± 0.5 %) (p = 0.01). Significant improvement was also noted in tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic area in the intervention arm but not in NT-pro-BNP or 6-minute walk distance. Conclusions In patients with ADHF and OSA, addition of 48 hours of PAP therapy to SOC treatment significantly reduced PH. In addition, PAP therapy was able to improve right and left ventricular function. ClinicalTrials.gov identifier: NCT02963597. acute decompensated heart failure, pulmonary hypertension, obstructive sleep apnea, positive airway pressure therapy Statement of Significance The relationship of pulmonary hypertension in patient with heart failure and sleep apnea is unclear. We randomized patients with acute heart failure who were found to have obstructive sleep apnea (OSA) and pulmonary hypertension to 48-hour therapy with auto- positive airway pressure (APAP) protocol versus standard therapy. Patient with APAP protocol had significant improvement in pulmonary pressures and cardiac function. Overall, the study improves our understanding on the impact of PAP therapy for OSA on pulmonary pressures in acute heart failure. If this effect is sustained, it may impact the natural history of congestive heart failure with pulmonary hypertension. Introduction Pulmonary hypertension (PH) in the setting of congestive heart failure (CHF) is widely common, a marker of poor prognosis, and associated with accelerated mortality [1, 2]. Currently available treatments targeting secondary PH in CHF have not yielded positive results [3], which still leaves these patients with no productive therapeutic option today. Obstructive sleep apnea (OSA) is highly prevalent [1, 2] and still largely under-diagnosed in CHF patients [4]. OSA is not only associated with increased mortality [4], but is also believed to have significant hemodynamic impact [2], which may play a role in development of PH in these patients. Our preliminary data from a retrospective review of heart failure service revealed significant reduction in positive airway pressures (PAP) in patients compliant with PAP therapy post-hospital discharge [5]. CHF is defined to be a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles, and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. The prevalence of heart failure depends on the definition applied but is approximately 1%–2% of the adult population in developed countries, rising to at least 10% among people older than 70 years. Among people older than 65 years presenting to primary care with breathlessness on exertion, one in six will have unrecognized heart failure (mainly CHFpEF) [6, 7]. Acute decompensated heart failure (ADHF) refers to rapid onset or worsening of symptoms and/or signs of heart failure. It is a life-threatening medical condition requiring urgent evaluation and treatment, typically leading to urgent hospital admission [6, 7]. In an acute setting of ADHF, the PH may be due to combination of fluid overload and obstructive apneas. Therefore, it is reasonable to hypothesize that therapy with automatic positive airway pressure (APAP) with fixed expiratory positive airway pressure (EPAP) minimum pressures of 8 cm and range of 8–20 cm (APAP protocol) may have a salutary effect on the PAP in the acute setting. We hypothesize that 48 hours of APAP protocol therapy in ADHF patients with OSA is superior in reducing pulmonary artery pressure compared to standard of care treatment. Secondary objectives were to evaluate the impact of APAP protocol therapy on right and left ventricular function, 6-minute walk distance (6MWD), and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) concentration. With this approach, APAP may offer a novel therapeutic option for patients with CHF who also have PH and OSA. Methodology Design The ASAP-HF study is a randomized, controlled, two-center, study with a parallel group design, with subjects randomized to either intervention arm (APAP protocol) or standard of care in a 1:1 ratio. This study was conducted at one center each in the United States and Germany. Enrollment Patients who had been admitted to the hospital with symptoms of ADHF were first evaluated for eligibility for the study based on chart review (Figure 1). Permission to review records was requested to conduct preliminary chart review and interview. Figure 1. View largeDownload slide Flow chart showing recruitment and randomization methodology. Figure 1. View largeDownload slide Flow chart showing recruitment and randomization methodology. If a subject was willing to participate in the ASAP-HF study, a written informed consent for the study was obtained prior to any study-related procedure. Before randomization, eligibility criteria were confirmed by reviewing the patient’s records. The randomization scheme was generated by using the following Web site: http://www.randomization.com. The randomization was stratified by site. Randomization was performed within 24 hours of admission of the patient to the hospital based on the admission echocardiography, overnight portable sleep testing, review of exclusion criteria, and obtaining consent. As per the protocol, patient’s baseline assessments were performed at the time patient was randomized (either intervention or control arm) and after 48 hours subsequently. The patients were admitted in specialized heart failure units at both sites under heart failure specialists. Since the European Society of Cardiology (ESC) guidelines are similar to ACC (American College of Cardiology), the medical therapy was expected to be equivalent across treatment arms. Informed consent The consent form was written in accordance with applicable data privacy acts and FDA Regulations. The study was approved by the responsible Institutional Review board (IRB)/Ethics Committee (EC) for both Institutions (institutional Review Board, Albert Einstein Healthcare Network , IRB # HN4889 and Ethikkommission der Medizinischen Fakultät der Ruhr-Universität Bochum, Sitz Bad Oeynhausen, Reg. -Nr.: 14/2016). The trial was performed in concordance with the Declaration of Helsinki and ex ante registered at ClinicalTrials.gov identifier: NCT02963597. Subject inclusion criteria Age 18 years or more ADHF with echocardiographically determined pulmonary artery systolic pressure (PASP) of at least 50 mm Hg Prior clinical diagnosis of heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). HFrEF defined as EF less than or equal to 40%. Moderate to severe OSA documented by polysomnography with Apnea–Hypopnea Index (AHI) of at least 20 e/hour and 5% of analyzed time spent less than 90% O2 saturation and a minimum recording time of 2 hours Patient is able to fully understand study information and sign informed consent Subject exclusion criteria Chronic renal insufficiency (on hemodialysis or serum creatinine > 2 mg/dL) Hemodynamically significant valvular disease Inability to complete 6-minute walk test (6MWT) for non-cardiac reasons Left ventricular assist device (LVAD)/heart transplant or hemodynamically unstable Patient taking any pulmonary vasodilators, including home oxygen Known diagnosis of OSA and on active therapy Fifty percentage or more of the respiratory events being central/Cheyne–Stokes breathing (CSR) Recent cardiac surgery (within 30 days of admission) Recent stroke (within 30 days of admission or with persistent neurological deficits) Severe chronic obstructive pulmonary disease (COPD) defined as forced expiratory volume in 1 second (FEV1) less than 50% Participation in a randomized controlled pharmaceutical or treatment-related cardiac or pulmonary clinical study within 1 month prior to randomization Patient weighing less than 66 pounds (30 kg) Study Devices ApneaLink Air The ApneaLink Air (ResMed, San Diego, CA) is a market-released portable device that has been FDA-cleared (K143272) and CE-marked in Germany for use by health care professionals, where it may aid in the diagnosis of sleep disordered breathing for adult patients (Table 1). Table 1. Baseline characteristics of the PAP versus control group (n = 21) for continuous parameters Mean ± SD, median/n (%) Characteristic PAP (N = 10) Control#8232;(N = 11) p value Age (years) 70.6 ± 11.5, 72.0 66.7 ± 11.2, 61.0 0.45 Body mass index (kg/m2) 28.8 ± 5.8, 27.6 31.2 ± 4.2, 31.4 0.27 Male 7 (70.0) 7 (63.6) 1.00 African American 5 (50.0) 4 (36.4) 0.67 Caucasian 5 (50.0) 7 (63.6) Beta-blockers 10 (100.0) 10 (90.9) 1.00 ACE inhibitor/ARB 8 (80.0) 9 (81.8) 1.00 Statin 6 (60.0) 9 (81.8) 0.36 Diuretics 10 (100.0) 11 (100.0) N/A Reduced EF 5 (50.0) 8 (72.7) 0.39 LVEF (%) 41.5 ± 20.1, 45.0 36.4 ± 19.2, 40.0 0.56 COPD 4 (40.0) 1 (9.1) 0.15 HTN 9 (90.0) 10 (90.9) 1.00 DM 5 (50.0) 9 (81.8) 0.18 CAD 7 (70.0) 6 (54.5) 0.66 Ischemic CM 6 (60.0) 6 (54.5) 1.00 NYHA = 3 8 (80.0) 5 (45.5) 0.18 NYHA = 4 2 (20.0) 6 (54.5) Na (meq/L) 141.9 ± 1.4, 142.0 138.7 ± 4.3, 139.0 0.04 Cr (mg/dL) 1.22 ± 0.33, 1.10 1.03 ± 0.22, 0.98 0.13 GFR (mL/min) 56.3 ± 13.5, 61.0 62.5 ± 7.2, 61.0 0.20 Troponin I (ng/mL) 0.04 ± 0.05, 0.02 0.05 ± 0.05, 0.02 0.82 Hemoglobin (g/dL) 12.4 ± 1.4, 12.4 13.5 ± 2.2, 13.4 0.20 Mean ± SD, median/n (%) Characteristic PAP (N = 10) Control#8232;(N = 11) p value Age (years) 70.6 ± 11.5, 72.0 66.7 ± 11.2, 61.0 0.45 Body mass index (kg/m2) 28.8 ± 5.8, 27.6 31.2 ± 4.2, 31.4 0.27 Male 7 (70.0) 7 (63.6) 1.00 African American 5 (50.0) 4 (36.4) 0.67 Caucasian 5 (50.0) 7 (63.6) Beta-blockers 10 (100.0) 10 (90.9) 1.00 ACE inhibitor/ARB 8 (80.0) 9 (81.8) 1.00 Statin 6 (60.0) 9 (81.8) 0.36 Diuretics 10 (100.0) 11 (100.0) N/A Reduced EF 5 (50.0) 8 (72.7) 0.39 LVEF (%) 41.5 ± 20.1, 45.0 36.4 ± 19.2, 40.0 0.56 COPD 4 (40.0) 1 (9.1) 0.15 HTN 9 (90.0) 10 (90.9) 1.00 DM 5 (50.0) 9 (81.8) 0.18 CAD 7 (70.0) 6 (54.5) 0.66 Ischemic CM 6 (60.0) 6 (54.5) 1.00 NYHA = 3 8 (80.0) 5 (45.5) 0.18 NYHA = 4 2 (20.0) 6 (54.5) Na (meq/L) 141.9 ± 1.4, 142.0 138.7 ± 4.3, 139.0 0.04 Cr (mg/dL) 1.22 ± 0.33, 1.10 1.03 ± 0.22, 0.98 0.13 GFR (mL/min) 56.3 ± 13.5, 61.0 62.5 ± 7.2, 61.0 0.20 Troponin I (ng/mL) 0.04 ± 0.05, 0.02 0.05 ± 0.05, 0.02 0.82 Hemoglobin (g/dL) 12.4 ± 1.4, 12.4 13.5 ± 2.2, 13.4 0.20 p value is from a two-sided t-test, comparing the means between the two treatment arms.#8232;For categorical parameters, p value is from a Fisher’s exact test, comparing the proportion between the two treatment arms. ACE = angiotensin converting enzyme; ARB = angiotensin II receptor blockers; CAD = coronary artery disease; CM = cardiomyopathy; Cr = creatinine; DM = diabetes mellitus; GFR = glomerular filtration rate; HTN = hypertension; NYHA = New York Heart Association. View Large Table 1. Baseline characteristics of the PAP versus control group (n = 21) for continuous parameters Mean ± SD, median/n (%) Characteristic PAP (N = 10) Control#8232;(N = 11) p value Age (years) 70.6 ± 11.5, 72.0 66.7 ± 11.2, 61.0 0.45 Body mass index (kg/m2) 28.8 ± 5.8, 27.6 31.2 ± 4.2, 31.4 0.27 Male 7 (70.0) 7 (63.6) 1.00 African American 5 (50.0) 4 (36.4) 0.67 Caucasian 5 (50.0) 7 (63.6) Beta-blockers 10 (100.0) 10 (90.9) 1.00 ACE inhibitor/ARB 8 (80.0) 9 (81.8) 1.00 Statin 6 (60.0) 9 (81.8) 0.36 Diuretics 10 (100.0) 11 (100.0) N/A Reduced EF 5 (50.0) 8 (72.7) 0.39 LVEF (%) 41.5 ± 20.1, 45.0 36.4 ± 19.2, 40.0 0.56 COPD 4 (40.0) 1 (9.1) 0.15 HTN 9 (90.0) 10 (90.9) 1.00 DM 5 (50.0) 9 (81.8) 0.18 CAD 7 (70.0) 6 (54.5) 0.66 Ischemic CM 6 (60.0) 6 (54.5) 1.00 NYHA = 3 8 (80.0) 5 (45.5) 0.18 NYHA = 4 2 (20.0) 6 (54.5) Na (meq/L) 141.9 ± 1.4, 142.0 138.7 ± 4.3, 139.0 0.04 Cr (mg/dL) 1.22 ± 0.33, 1.10 1.03 ± 0.22, 0.98 0.13 GFR (mL/min) 56.3 ± 13.5, 61.0 62.5 ± 7.2, 61.0 0.20 Troponin I (ng/mL) 0.04 ± 0.05, 0.02 0.05 ± 0.05, 0.02 0.82 Hemoglobin (g/dL) 12.4 ± 1.4, 12.4 13.5 ± 2.2, 13.4 0.20 Mean ± SD, median/n (%) Characteristic PAP (N = 10) Control#8232;(N = 11) p value Age (years) 70.6 ± 11.5, 72.0 66.7 ± 11.2, 61.0 0.45 Body mass index (kg/m2) 28.8 ± 5.8, 27.6 31.2 ± 4.2, 31.4 0.27 Male 7 (70.0) 7 (63.6) 1.00 African American 5 (50.0) 4 (36.4) 0.67 Caucasian 5 (50.0) 7 (63.6) Beta-blockers 10 (100.0) 10 (90.9) 1.00 ACE inhibitor/ARB 8 (80.0) 9 (81.8) 1.00 Statin 6 (60.0) 9 (81.8) 0.36 Diuretics 10 (100.0) 11 (100.0) N/A Reduced EF 5 (50.0) 8 (72.7) 0.39 LVEF (%) 41.5 ± 20.1, 45.0 36.4 ± 19.2, 40.0 0.56 COPD 4 (40.0) 1 (9.1) 0.15 HTN 9 (90.0) 10 (90.9) 1.00 DM 5 (50.0) 9 (81.8) 0.18 CAD 7 (70.0) 6 (54.5) 0.66 Ischemic CM 6 (60.0) 6 (54.5) 1.00 NYHA = 3 8 (80.0) 5 (45.5) 0.18 NYHA = 4 2 (20.0) 6 (54.5) Na (meq/L) 141.9 ± 1.4, 142.0 138.7 ± 4.3, 139.0 0.04 Cr (mg/dL) 1.22 ± 0.33, 1.10 1.03 ± 0.22, 0.98 0.13 GFR (mL/min) 56.3 ± 13.5, 61.0 62.5 ± 7.2, 61.0 0.20 Troponin I (ng/mL) 0.04 ± 0.05, 0.02 0.05 ± 0.05, 0.02 0.82 Hemoglobin (g/dL) 12.4 ± 1.4, 12.4 13.5 ± 2.2, 13.4 0.20 p value is from a two-sided t-test, comparing the means between the two treatment arms.#8232;For categorical parameters, p value is from a Fisher’s exact test, comparing the proportion between the two treatment arms. ACE = angiotensin converting enzyme; ARB = angiotensin II receptor blockers; CAD = coronary artery disease; CM = cardiomyopathy; Cr = creatinine; DM = diabetes mellitus; GFR = glomerular filtration rate; HTN = hypertension; NYHA = New York Heart Association. View Large The ApneaLink Air recorder is a three-channel battery-powered respiratory pressure sensor and oximetry system. The default settings for the ApneaLink Air includes a flow reduction of 30% combined with a desaturation of 4% to automatically score a hypopnea and a respiratory effort sensor to differentiate between central, obstructive, and mixed apneas. The data were reviewed by a board-certified sleep physician for study entry (Table 2). Table 2. Baseline portable monitor parameters in the intervention arm versus the usual care arm Mean ± SD, median/n (%) Parameter PAP#8232;(N = 10) Control#8232;(N = 11) p value [1] Recording time (minute) 547.2 ± 136.2, 480.0 557.4 ± 167.7, 559.0 0.88 Cannula time (minute) 336.9 ± 114.5, 320.0 352.4 ± 116.2, 382.0 0.76 AHI 31.8 ± 8.0, 29.2 34.3 ± 9.2, 36.3 0.51 ODI 33.6 ± 14.8, 30.4 36.1 ± 12.3, 37.9 0.68 Average O2 saturation 90.4 ± 4.9, 91.0 90.5 ± 1.9, 90.0 0.97 Lowest O2 saturation 67.8 ± 12.0, 66.0 65.1 ± 8.2, 65.0 0.55 Average O2 desaturation 39.1 ± 36.9, 27.5 31.9 ± 31.0, 6.0 0.63 T < 90 (minute) 231.2 ± 223.2, 193.0 233.3 ± 125.4, 211.0 0.98 T < 90 (%) 42.4 ± 41.0, 29.8 49.9 ± 44.3, 37.5 0.69 Mean ± SD, median/n (%) Parameter PAP#8232;(N = 10) Control#8232;(N = 11) p value [1] Recording time (minute) 547.2 ± 136.2, 480.0 557.4 ± 167.7, 559.0 0.88 Cannula time (minute) 336.9 ± 114.5, 320.0 352.4 ± 116.2, 382.0 0.76 AHI 31.8 ± 8.0, 29.2 34.3 ± 9.2, 36.3 0.51 ODI 33.6 ± 14.8, 30.4 36.1 ± 12.3, 37.9 0.68 Average O2 saturation 90.4 ± 4.9, 91.0 90.5 ± 1.9, 90.0 0.97 Lowest O2 saturation 67.8 ± 12.0, 66.0 65.1 ± 8.2, 65.0 0.55 Average O2 desaturation 39.1 ± 36.9, 27.5 31.9 ± 31.0, 6.0 0.63 T < 90 (minute) 231.2 ± 223.2, 193.0 233.3 ± 125.4, 211.0 0.98 T < 90 (%) 42.4 ± 41.0, 29.8 49.9 ± 44.3, 37.5 0.69 ODI = oxygen desaturation index. View Large Table 2. Baseline portable monitor parameters in the intervention arm versus the usual care arm Mean ± SD, median/n (%) Parameter PAP#8232;(N = 10) Control#8232;(N = 11) p value [1] Recording time (minute) 547.2 ± 136.2, 480.0 557.4 ± 167.7, 559.0 0.88 Cannula time (minute) 336.9 ± 114.5, 320.0 352.4 ± 116.2, 382.0 0.76 AHI 31.8 ± 8.0, 29.2 34.3 ± 9.2, 36.3 0.51 ODI 33.6 ± 14.8, 30.4 36.1 ± 12.3, 37.9 0.68 Average O2 saturation 90.4 ± 4.9, 91.0 90.5 ± 1.9, 90.0 0.97 Lowest O2 saturation 67.8 ± 12.0, 66.0 65.1 ± 8.2, 65.0 0.55 Average O2 desaturation 39.1 ± 36.9, 27.5 31.9 ± 31.0, 6.0 0.63 T < 90 (minute) 231.2 ± 223.2, 193.0 233.3 ± 125.4, 211.0 0.98 T < 90 (%) 42.4 ± 41.0, 29.8 49.9 ± 44.3, 37.5 0.69 Mean ± SD, median/n (%) Parameter PAP#8232;(N = 10) Control#8232;(N = 11) p value [1] Recording time (minute) 547.2 ± 136.2, 480.0 557.4 ± 167.7, 559.0 0.88 Cannula time (minute) 336.9 ± 114.5, 320.0 352.4 ± 116.2, 382.0 0.76 AHI 31.8 ± 8.0, 29.2 34.3 ± 9.2, 36.3 0.51 ODI 33.6 ± 14.8, 30.4 36.1 ± 12.3, 37.9 0.68 Average O2 saturation 90.4 ± 4.9, 91.0 90.5 ± 1.9, 90.0 0.97 Lowest O2 saturation 67.8 ± 12.0, 66.0 65.1 ± 8.2, 65.0 0.55 Average O2 desaturation 39.1 ± 36.9, 27.5 31.9 ± 31.0, 6.0 0.63 T < 90 (minute) 231.2 ± 223.2, 193.0 233.3 ± 125.4, 211.0 0.98 T < 90 (%) 42.4 ± 41.0, 29.8 49.9 ± 44.3, 37.5 0.69 ODI = oxygen desaturation index. View Large Echocardiography Echocardiography was performed at Einstein Medical Center by Philips iE33 (Koninklijke Philips N.V.) and in Germany by a GE (General Electric, Chicago, IL) Vivid E9 device. The interpretation of all echocardiograms was provided by a dedicated board-certified cardiologist at each site to reduce inter-observer variations, who was also blinded to the results of the apnea link or randomization protocol. The clinically meaningful difference between the pre- and post-intervention PASP was agreed upon to be 10 mm Hg. PH was defined as PASP of ≥50 mm Hg on admitting echocardiogram performed by a dedicated cardiologist as each site. The tricuspid regurgitation (TR) jet was used to determine right ventricular (RV) and PASP, done by calculating the RV to right atrial pressure (RAP) gradient using the modified Bernoulli equation and then adding the assumed RAP. IVC Collapsibility Index for RAP [8] was assumed in both sites according to: IVC with normal diameter and IVC collapses: 3 mm Hg IVC with normal diameter, but IVC does not collapse: 8 mm Hg IVC is dilated and IVC collapses: 8 mm Hg IVC is dilated, but IVC does not collapse: 15 mm Hg Additional echocardiographic parameters like left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), RAP, TR jet, right and left ventricular diameters and size were also evaluated. Functional capacity and biomarker testing The 6MWT served as an objective evaluation of the response to medical intervention. The 6MWD was measured. Exercise was performed on a level indoor surface following American Thoracic Society (ATS) guidelines in to assure minimal variability. If there were any signs of medical instability, the attending physician ended the test before 6 minutes [9]. Blood was collected and processed to obtain samples for NT pro-BNP. All samples were sent to the site’s local clinical laboratory for testing. Therapy AirSense 10 AutoSet The AirSense 10 AutoSet (ResMed, San Diego, CA) (“AutoSet”) is a market-released device that has been FDA-cleared (K140124) in the United States and CE-marked in Germany (EC149) to provide non-invasive ventilatory support to treat patients weighing more than 66 lbs (30 kg). The AirSense 10 AutoSet provides a minimum and maximum pressure within the range of 4–20 cm H2O. As per our study protocol, the minimum pressures were maintained at 8 cm and maximum pressure at 20 cm of H2O pressure. For initiation of therapy, the AutoSet device was set to a minimum continuous positive airway pressure (CPAP) of 8 cm H2O and a maximum CPAP of 20 cm H2O. The minimum CPAP may be lowered if patients were unable to tolerate higher CPAP. All subjects were provided humidifiers and climate line tubing to address any instance of upper airway dryness or other forms of discomfort with the airflow of the device during the initiation or during therapy with the device. For the initiation of therapy, a full-face mask was recommended, but if this mask was unsuitable for the subject, another type of mask such as a nasal mask was provided. Subjects who were unable to tolerate the minimum CPAP of 8 cm of H2O pressure, had the pressure reduced by 1 cm every 5 minutes until patient felt comfortable. If despite the acclimation trial the subject was unable to tolerate the pressure, the patients were to be discharged from the study. Standard medical therapy All subjects were treated standard of care therapy for heart failure in accordance to the applicable standard of care and most recent guidelines, particularly with reference to medication. Other guideline-recommended therapies were encouraged. All medications were documented. Statistical methods Baseline characteristics, medical history, and ApneaLink parameters were collected and compared between treatment groups. Descriptive statistics, including mean, SD, median, and quartiles were presented for each group. A two-sided test was used to compare means for continuous parameters, and a Fisher’s Exact test was used to compare proportions for categorical parameters. The primary study objective was to compare the APAP protocol intervention arm and the standard of care arm specifically to the change in pulmonary pressures from baseline to 48 hours post-treatment. Secondary objectives involved comparison of the change from baseline to 48 hours for the following parameters: 6MWD, NT-pro-BNP, and echocardiographic measures. Descriptive statistics were generated at baseline and 48 hours for each group and the paired mean/median change for each parameter was compared between treatment groups using an exact Wilcoxon test. All statistical comparisons of treatment groups were generated using a two-sided significance level of 0.05. Statistical software, SAS, version 9.4, was used for all analyses (Figure 2). Figure 2. View largeDownload slide Line plot of PASP at baseline and after 48 hours in the intervention arm (blue) and usual care arm (red). Figure 2. View largeDownload slide Line plot of PASP at baseline and after 48 hours in the intervention arm (blue) and usual care arm (red). Results Of the 21 patients enrolled (10 from United States and 11 from Germany), 14 were males, 9 were African-Americans. The mean age was 70.6 ± 11.5 years in the intervention arm and 66.7 ± 11.2 years in usual care arm. The BMI was 28.8 ± 5.8 kg/m2 in the intervention arm and 31.2 ± 4.2 kg/m2 in the usual care arm (Table 1). The mean AHI and T <90 were 31.8 ± 8.0 e/hour and 231.2 ± 223.2 minutes in the intervention arm versus 34.3 ± 9.2 and 233.3 ± 125.4 minutes in the standard of care arm, respectively (Table 2). In the intervention arm, the patients were on the APAP protocol therapy for a mean of 29.7 ± 3.1 hours. The mean minimum pressure setting was 7.4 cm of H2O (range: 4–9 cm) and mean pressure was 10.3 ± 0.7 cm of H2O, with a residual AHI of 7.2 ± 2.0. In the intervention arm, the mean PASP was 58.6 ± 2.5 mm Hg before therapy and 42.8 ± 2.7 mm Hg after 48 hours of APAP therapy. In the standard of care arm, the mean PASP was 62.7 ± 3.3 mm Hg and was reduced to 57.5 ± 3.9 after 48 hours of usual care. The mean paired difference in the reduction of PASP comparing the intervention arm (−15.8 ± 3.2) to the standard of care arm (−5.2 ± 2.6) was statistically significant (p = 0.025). Similarly, mean TR jet was significantly improved in the intervention arm compared to the standard of care arm (Supplement Table 3). Comparison of echocardiographic parameters revealed significant improvement in the mean change LVEF in the APAP intervention arm compared to the standard of care arm for both the combined group (3.4 ± 1.5% vs. −0.5 ± 0.5 %) (p = 0.01) and in the subset of patients with only systolic heart failure (n = 13) (6.8 ± 1.9% vs. −0.1 ± 0.1) (p = 0.01) (Supplement Figure 3). Significant improvement was also noted in RV function addressed by TAPSE. Mean TAPSE changed from 17.9 ± 1.0 mm to 18.6 ± 1.5 in the APAP intervention arm after 48 hours as compared to a mean reduction from 16.9 ± 1.7 to 14.3 ± 1.3 mm in the standard of care arm (p = 0.04) (Supplement Figure 4). Mean systolic RV area reduced significantly in the intervention arm (−17.4 ± 12.6 cm2) compared to the standard of care arm (−6.0 ± 8.1 cm2) (p = 0.04). Trends in improvements of left ventricular systolic volume index (LV SVI), RAP, left ventricular end diastolic diameter (LVEDD), and E/e ratio were noted in the intervention arm compared to standard of care arm but were not statistically significant. The improvement in mean 6MWT after 48 hours in the intervention arm was 20.0 ± 15.3 m (202.6 ± 26.0 prior to therapy to 222.6 ± 33.5 at 48 hours after therapy) in the APAP therapy group versus 8.2 ± 27.5 m (153.6 ± 29.2 to 161.8 ± 29.3) in the standard of care arm; however, the mean improvement was not statistically significant (p = 0.99) (Supplement Figure 1). The mean reduction in NT-pro-BNP after 48 hours in the intervention arm was −621.1 ± 222.5 pg/mL (1087.6 ± 285.4 to 466.6 ± 106.4 pg/mL) in the APAP group versus −32.5± 299.6 pg/mL (1532.7 ± 406.8 to 1500.2 ± 625.5 pg/mL) in the standard of care arm (p = 0.31) (Supplement Figure 2). The mean weight in both groups was recorded at time of intervention (PAP therapy or usual care) and after 48 hours of intervention. Both groups showed reduction in weight with PAP group showing change from 86.7 ± 7.7 to 85.3 ± 7.7 and usual care from 92.4 ± 5.0 to 90.3 ± 4.9. The change in weight in the PAP group was −1.4 ± 0.2 and usual care −2.0 ± 0.6 (p = 0.62). Discussion Our trial is the first to show a significant greater reduction in PASP with 48 hours of PAP (APAP) protocol treatment in ADHF patients with OSA as compared to guideline-driven standard of care treatment. Our study reveals a mean reduction of 15.8 mm Hg PASP in the intervention arm as compared to a mean reduction in standard of care arm of 5.2 mm Hg (p = 0.025). Furthermore, significant improvements are identified for mean LVEF and RV function (TAPSE) in the intervention arm compared to the standard of care arm. We also noted trends toward improvements in NT-pro-BNP and 6MWT in the intervention arm, although these did not reach statistical significance. Presence of PH in patients with CHF is a marker of increased mortality [1, 10]. In addition to left heart disease, the PH in CHF may also be influenced by OSA. PH has been noted in patients with OSA alone and treatment with CPAP has shown to reduce the pulmonary pressures [11]. The above suggests that there may be both a wake (left heart disease) and sleep (OSA) component to the pathogenesis of the PH in patients with heart failure. The relative contribution of the two components may vary based on the severity of each component. In order to treat both components, we utilized a unique protocol (APAP protocol) with fixed lower pressures of 8 cm of H2O pressure, which would target the pulmonary edema, and an “auto” pressure with maximum range of 20 cm of H2O pressure to target the apneic events which may occur during the sleep. This “dual” strategy during an acute decompensation we believed would result in improvements of pulmonary pressures and subsequent overall downstream benefits in patients with CHF and PH. CPAP in patients with moderate to severe OSA is not associated with a significant reduction in major cardiac events and all-cause cardiac mortality unless CPAP is applied for more than 4 hours per night [12]. Compliance with APAP therapy may be the most important factor in improving outcome and hence we encouraged our patients to be adherent to the therapy with minimum requirement of a total of 8 hours in 48 hours (average 4 hours/24 hours). The total hours our patients remained on therapy were 29.7 ± 3.1 hours. We believe excellent adherence in our patients consequentially resulted in a positive impact. CPAP therapy has been shown to have salutary effect on several cardiovascular disorders including CHF [13]. Negative intra-thoracic pressures created by repetitive glottis closure have been shown to increase transmural pressure, preload, afterload and reduce cardiac output [14, 15]. Reversal of negative pleural pressure and subsequent reduction in transmural pressures has been shown to reduced LV afterload [16, 17]. Additionally, resolution of apneas, hypoxemia, and sympathetic overdrive may improve myocardial energetics especially in severe OSA [18, 19]. Additionally, CPAP therapy by augmenting inspiratory and expiratory flow and pressures has been shown to reduce the work of breathing and improve muscle function [20–22]. CPAP therapy has shown other beneficial effects including improved alveolar ventilation, reduced intrinsic positive end expiratory pressure (PEEP), reduced dead space ventilation, reduced alveolar fluid, and prevented micro-atelectasis [23–25]. Use of CPAP in patients with acute pulmonary edema has also been shown to reduce pulmonary capillary wedge pressure (PCWP) as compared to oxygen and diuretics alone [26]. CPAP has also been shown to improve PH in patients with OSA [11]. Our protocol was designed to target differential benefits of varying pressures on pulmonary parenchyma/vasculature and upper airway dynamics. As noted above, during “wake periods” the fixed expiratory positive airway pressure (EPAP) improved pulmonary edema, alveolar ventilation and prevented micro-atelectasis. Additionally, during “sleep periods” the auto mode targeted the apneic events, subsequently reducing the transmural pressures and preload, thereby improving LV and RV function [27] as we showed for the first time. The above mechanisms potentially help improve LV function and reduce the PCWP which in turn reduces the pulmonary systolic pressures. This reduction in PCWP is “over and above” which would be affected by diuretics and afterload reduction alone, essentially by reversing the additional hemodynamic disadvantage induced by sleep apnea. Similarly, Tkacova et al. observed patients submitted to CPAP had a decrease in pulse pressure correlated to an increase in the EF originated by the reduction of the transmural pressure. In fact, our study is consistent with these findings of improvement in EF [28]. While trends toward improved exercise capacity as noted by 6MWT were documented, they did not reach statistical significance most likely due to the small number of patients and short duration of intervention investigated in this study. However, prior studies using CPAP in CHF have shown to improve 6MWT [29]. In addition, APAP therapy may improve cardiac and respiratory performances of HF patients, considering it enhances oxygenation and pulmonary mechanics, so it can also improve functional capacity of the lungs [30], which is exceptionally important as hypoxia drives mortality [31]. CPAP for 2 weeks in CHF patients has also been shown to improve lung function. CPAP progressively increased forced vital capacity (FVC) and FEV1 in HF patients when compared to the standard of care arm. This improvement may have occurred due to the increase in functional residual capacity and opening of collapsed alveoli [30]. We also noted trends toward reduced chamber diameters and area post-intervention. This is consistent with enlargement of the right-sided cardiac area due to increased preload generated by a volume overload in cardiac cavities during apneic episodes. CPAP therapy decreases this volume overload, momentarily, with an increase in cardiac contractility, which occurs with the advent of transmural pressure reduction. Additionally, CPAP therapy by virtue of increased PEEP helps recruit alveoli and promotes gas exchange [32–34]. Based on the fact that APAP/PEEP may have independent salutary effect on CHF with additional benefit from resolving hemodynamic consequences created by obstructive apneic events, we created a protocol which utilized and aligned both these principles to mitigate these deleterious pathological chain reactions. Utilizing a minimum of 8 cm of EPAP (or as tolerated), we aimed at reducing the transmural pressure while allowing the auto mode to mitigate the hemodynamic consequences of apneic events during sleep. The relative contribution of these two mechanisms is however, unclear in the pathogenesis of PH in patient with acute heart failure and OSA. Apart from the positive hemodynamic impact on patients with acute heart failure and PH, this protocol may have clinical implication by reducing length of stay in the hospital. Prior studies have noted reduction in 30-day and 6-month readmission in patients initiated early on CPAP therapy post-discharge from an acute heart failure episode [35, 36]. Some preliminary data also suggest that this reduction in pulmonary pressure is sustained on CPAP therapy post-discharge from the hospital [36]. Further studies to evaluate the impact of reduced PH on mortality in heart failure would be interesting as currently there is no treatment option for PH in CHF patients. This trial included patients with preserved ejection fraction (HFpEF) which traditionally has been resistant to any intervention. This positive signal may open the doors for further evaluation of the role of OSA and APAP therapy in this condition. In a recent study of 52 patients with severe OSA in a randomized, sham-controlled clinical trial with CPAP treatment for 3 months improved left ventricular diastolic function and showed improvements in arterial stiffness and ventricular-vascular coupling in the treatment group [37]. Limitations of the study include the small sample size investigated. Due to stringent inclusions criteria, only 10% of patients screened met the eligibility criteria, and thus these findings cannot be generalized to all patients with CHF with PH. We also did not include mild OSA (inclusion criteria was AHI ≥ 20) and central sleep apnea which may constitute a substantial portion of the sleep disordered breathing in heart failure population. Further studies on this cohort are required. As all patients were hospitalized with ADHF, polysomnography could not be performed in these patients, which is the gold standard for differentiating central from obstructive events. However, with respiratory effort channel and nasal canula flow signal, most of the central events and CSR can be reliably recognized [38]. PH was diagnosed by echocardiography and not right heart catheterization (RHC); however, almost all PH in left heart failure is pulmonary venous hypertension and data suggest that Doppler echocardiogram is a reliable method of measuring PASP [39, 40]. However, at lower pressure cutoff, overestimation of PASP by echocardiogram is common [41]. Studies using higher PASP cutoff (50 mm Hg) have been found to have minimal false positive results [42, 43]. Since RHC was not performed to confirm PH, it was imperative to have minimal/no false positive PH. Furthermore, the difference in change in pressures was pre-specified to be clinically meaningful only if 10 cm or more of H2O pressure drop was recorded. We also do not believe that there were significant variations in the clinical management of these patients at the two sites as the patients were admitted in specialized heart failure units at both sites under heart failure specialists. There are no major differences in treatment of acute heart failure between AHA/ACC and ESC guidelines. In conclusion, our study reveals significant improvement of PH in patients with acute heart failure with concomitant OSA treated with protocolized APAP therapy compared to the standard of care. These findings can help understanding PH in heart failure and translate it to improved outcome in this challenging population. Future studies confirming these findings with RHC and composite outcome are recommended. Funding The study was funded by unrestricted research grant provided by ReSMed Inc. Conflict of interest statement. S.S., PI has received unrestricted research grant from ResMed Inc. The remaining author declare no conflicts of interest. 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SLEEPOxford University Press

Published: Jul 8, 2019

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