TABLE VIII.B. 4.d1.

Evidence for PAP and clinical outcomes in HFrEF

Study	Year	LOE	Study design	Study groups	Clinical endpoints	Conclusion
Tkacova et al.1230	1998	3b	Prospective CS	Pharmacologically treated HF patients with OSA were studied during PSG and recordings were done before, during, and after CPAP application. n = 8	BP and esophageal pressures before onset of sleep and during stage 2 NREM sleep before, during, and after application of CPAP	1. OSA was associated with increased systolic BP and systolic LVPtm from wakefulness to stage 2 NREM sleep. 2. CPAP alleviated OSA, improved SaO2, and reduced systolic BP in stage 2 NREM sleep, LVPtm, Pes amplitude, and RR.1230
Usui et al.1232	2005	1b	RCT	Pharmacologically treated HF patients with LVEF < 45% and OSA (AHI ≥ 20/h) randomized to PAP and usual therapy vs. only usual therapy. n = 17	Recording at baseline and at 1 month the morning after PSG: ECG BP peroneal MSNA With subjects awake, resting quietly supine, and breathing without apnea	1. In OSA patients treated with CPAP, there was significant reductions in daytime MSNA (from 58 ± 4 to 48 ± 5 bursts/min; 84 ± 4 bursts/100 heart beats to 72 ± 5 bursts/100 heart beats; p < 0.001 and p = 0.003, respectively), systolic BP (from 135 ± 5 to 120 ± 6 mmHg, p = 0.03), and HR (from 69 ± 2 min (−1) to 66 ± 2 min (−1); p = 0.013). 2. In control OSA patients, there were no changes in MSNA, systolic BP, or HR.1232
Kaneko et al.743	2003	1b	RCT	Pharmacologically treated HF patients with LVEF ≤ 45% and OSA (AHI ≥ 20/h) randomized to PAP and usual therapy vs. only usual therapy. n = 24	Recording at baseline and at 1 month: AHI Daytime BP and HR LV end-diastolic dimensions LVEF	1. In OSA patients treated with CPAP, there was significant reductions in AHI, daytime systolic BP, HR, LV end-diastolic dimension and improved LVEF (absolute improvement by 8.8%). 2. In control OSA patients, there were no changes in AHI, daytime systolic BP, HR, LV end-diastolic dimensions, and LVEF.743
Gilman et al.1233	2008	1b	RCT	Pharmacologically treated HF patients with LVEF ≤ 45% and OSA (AHI ≥ 20/h) randomized to PAP and usual therapy vs. only usual therapy. n = 19	Morning HF-HRV at baseline and at 1 month	1. In OSA patients treated with CPAP, there was HF-HRV increased significantly during wakefulness in the morning. 2. In control OSA patients, there were no changes in HF-HRV during wakefulness in the morning.1233
Mansfield et al.746	2004	1b	RCT	Pharmacologically treated HF with LVEF < 55% and NYHA II, AHI ≥ 5/h, CSA ≤ 20%) randomized to PAP and usual therapy vs. only usual therapy. n = 55	Recording at baseline and at 3 months: LVEF Overnight urinary norepinephrine BP quality of life	1. In OSA patients treated with CPAP, there was increased LVEF (absolute improvement by 5%), reduced urine norepinephrine excretion (42% decrease), ESS, and minimum oxygen saturation. 2. No changes in blood pressure or peak oxygen consumption were noted 3. In control OSA patients, there were no significant changes in LVEF, urine norepinephrine or ESS.746
Smith et al.1239	2007	1b	RCT with crossover design	Pharmacologically treated symptomatic HF with LVEF <45% and NYHA class II–VI with OSA (AHI ≥ 15/h) randomized to APAP vs. sham CPAP for 6 weeks each in crossover design. n = 23	Recordings at baseline, 6 and 13 weeks (1 week washout before cross over): Clinical assessment TTE CPET 6 min walk distance (MWD) neurohumoral markers (NT-pro-BNP and NT-pro-ANP) Oxford Sleep Resistance Test Quality of life	1. CPAP improved daytime sleepiness, but not LVEF, 6 MWD, Peak VO2, VE/VCO2, or quality of life. 2. Study limitations were poor adherence (∼3 h) and use of autoCPAP without report of treatment efficacy in AHI reduction.1239
Malone et al.1238	1991	3b	Prospective CS	Pharmacologically treated, obese patients with idiopathic cardiomyopathy, LVEF < 55%, and severe OSA. n = 8	Recording at baseline, 4 weeks after nasal CPAP, and 1 week after withdrawal of nasal CPAP TTE	1. CPAP results in mean LVEF increase of 37% to 49% from pre-treatment to 4 weeks after therapy. 2. Withdrawal of CPAP resulted in reduction of LVEF from 53% to 45%.1238
Egea et al.745	2008	1b	RCT	Pharmacologically treated HF with LVEF < 45% and OSA with AHI > 10/h and randomized to PAP vs. sham CpAP. n = 60	Recording and baseline and 3 months of treatment with optimal CPAP or sham-CPAP LVEF 6 min walking test ESS SF-36 NYHA Dyspnea	1. LVEF improved by an absolute 2.2% in the treatment group with even greater improvement in patients with LVEF > 30%. 2. ESS with significant improvement in both groups. 3. No change in NYHA, 6 min walk distance, SF-36, or dyspnea.745
Johnson et al.1237	2008	2b	Prospective CS	HF patients with NYHA class II or III and LVEF < 40% and AHI > 15/h. Patients with OSA were treated with CPAP and those without were Not. n = 12	TTE at baseline (awake, before, and after acute CPAP administration) and after CPAP therapy (7 weeks) in OSA patients Recording was done at baseline and follow-up for non-OSA patients	1. In OSA patients, acute CPAP resulted in decreased stroke volume and LVEF by ∼5% compared to baseline. 2. In OSA patients, chronic CPAP resulted in increased stroke volume and increased LVEF from 38.4% to 43.4%. 3. There was no change in LVEF, diastolic function, or filling pressures in patients without OSA.1237
Ferrier et al.1236	2008	2b	Prospective CS	Outpatient patients with HF (LVEF < 45%) and OSA (AHI > 15/h) treated with CPAP and control group with HF (LVEF < 45%) and AHI < 10/h. n = 26	Recording at baseline and at 6 months Minnesota HF score ESS Shuttle walk distance BNP Urine catecholamines TTE	1. In the study group, there was absolute improvement in LVEF by 4.7%. 2. In the study group, there was decrease in the LV end-diastolic volume, systolic blood pressure, and ESS. 3. Walk distance, catecholamines, BNP levels, and symptoms remained unchanged in both groups.1236
Yoshinaga et al.1234	2007	2b	Prospective CS	Outpatients with HF (LVEF < 40%, NYHA II or III, unchanged > 4 weeks) with and without OSA (AHI > 15/h). n = 12	Oxidative metabolism using mono-exponential fit of the of the myocardial [11C] acetate positron emission tomography time-activity curve (correlate for myocardial oxygen consumption) Myocardial efficiency from work metabolic index and at baseline, short-term CPAP and after 6 ± 3 weeks of CPAP	1. Short-term CPAP reduced oxidative metabolism and stroke volume index, but did not change work metabolic index. 2. Longer-term CPAP improved left ventricular ejection fraction by 5%, reduced oxidative metabolism and improved work metabolic index.1234
Kasai et al.754	2008	2b	Prospective CS	Medically optimized heart failure with LVEF ≤ 50%, without hospitalizations in the preceding month and AHI ≥ 15/h, NYHA class II or above, CAI < 50% of overall AHI. Participants grouped into CPAP untreated, “more compliant” and “less compliant” groups. n = 88	Baseline recordings: BMI heart rate ESS LVEF by echo plasma norepinephrine NYHA class etiology of HF (ischemic or nonischemic) presence of AFIB administered medications Primary end point: event-free survival at 25.3 months	1. Use of CPAP was associated with improved event-free survival compared to no CPAP use. 2. Greater adherence to CPAP therapy (∼6.0 h/night) was associated with greater improvement in event free-survival than less adherence (∼3.5 h/night).754
Wang et al.742	2007	2b	Prospective CS	Medically optimized heart failure patients with LVEF ≤ 45% and NYHA class II to IV with OSA (AHI ≥ 15) with a CPAP treated and untreated group. n = 164	Primary end point: Cumulative rate of death from the date of the diagnostic sleep study until January 1, 2005	There was trend for reduced mortality in the treated OSA group.742
Hall et al.1235	2014	1b	RCT	Medically optimized patients with HFrEF (EF < 45%, NYHA ≥ II and OSA (AHI > 10, OA > 80%) randomized to CPAP versus usual care. n = 45	Evaluated at baseline and 6–8 weeks after therapy initiation: ECG echocardiography c-acetate and c-hydroxyephedrine PET imaging	1. Short-term CPAP increased hydroxyephedrine retention, indicating improved sympathetic nerve function in patients with OSA and HFrEF. 2. No changes in hemodynamic, LV, or energetics parameters in the whole study population.1235
Aggarwal et al.1231	2014	1a	SR	Systemic review and meta-analysis with pooled data from 15 randomized controlled trials in which patients had sleep disordered breathing and heart failure and consisted of a group receiving PAP therapy and another group receiving no PAP therapy or sham PAP therapy.	End points analyzed are: Left ventricular ejection fraction Diastolic blood pressure Systolic blood pressure Heart rate Mortality	1. A significant improvement in LVEF was noted with CPAP (mean difference of 5.05%; 95% CI 3.72–6.38), diastolic blood pressure (mean difference of –1.67; 95% CI of –3.09–0.25) and heart rate (mean difference of –5.92; 95% CI of –10.12–1.72). 2. No significant changes in mortality (OR 0.63; 95% CI 0.40–1.00) and systolic blood pressure (mean difference –6.35; 95% CI –16.11–2.41) were noted.