Sacubitril-valsartan initiation in chronic heart failure patients impacts sleep apnea: the ENTRESTO-SAS study

Abstract

Aims: Optimizing medical cardiac treatment for sleep apnoea (SA) in patients with chronic heart failure and reduced ejection fraction (HFrEF) is an expert Grade C recommendation based on six studies encompassing a total of 67 patients only. Whether sacubitril-valsartan (SV), a cornerstone of HFrEF medical treatment, impacts SA is unknown and requires evaluation.

Methods and results: The ENTRESTO-SAS trial is a six-centre, prospective, open-label real-life cohort study (NCT02916160). Ambulatory patients eligible for SV (i.e. HFrEF adults who remain symptomatic despite optimal treatment) were evaluated before and after 3 months of SV (including nocturnal ventilatory polygraphy); 118 patients were final analysed [median age was 66 (IQ_25-75 : 56-73) years, 81.4% male, 36.5% New York Heart Association III-IV, N-terminal pro-B-type natriuretic peptide level of 1564 (701-3376) ng/L, left ventricular ejection fraction of 30 (25-34)%, 60.7% ischaemic HFrEF, 97.5% initially treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, 83.9% with beta-blockers, 64.4% with mineralocorticoid receptor antagonists, and 74.6% with diuretics]. Three groups were defined according to initial central/obstructive apnoea-hypopnoea indices (AHIs): G1 (n = 49, AHI_central ≥ 5/h and AHI_obstructive < 15/h); G2 (n = 27, AHI_obstructive ≥ 15/h); and G3 (n = 42, AHI_central < 5/h and AHI_obstructive < 15/h). At 3 months, the AHI (main predefined outcome) decreased significantly by -7.10/h (IQ_25-75 : -16.10 to 0.40; P < 0.001) in G1 + G2 without positive airway pressure treatment (45 patients, median initial AHI of 24.20 (IQ_25-75 : 16.40-43.50)/h). Of these, 24.4% presented an AHI decrease ≥50% and 37.78% had a final AHI < 15/h (tendency for improvement from an initial value of 20%: P = 0.0574). For G1 patients (n = 37), AHI significantly decreased from a median of 22.90 (16.00-43.50)/h to 19.20 (12.70-31.10)/h (P = 0.002). For G2 patients (n = 8), AHI decreased from a median of 30.10 (26.40-47.60)/h to 22.75 (14.60-36.90)/h (statistically non-significant, P = 0.059).

Conclusions: In this real-life population, SV treatment for 3 months in SA patients is associated with a significant decrease in AHI. These results support the current guidelines that recommend first an optimization of the HFrEF treatment in patients with HFrEF and central SA. A potential positive airway pressure sparing effect merits further investigation.

Keywords: Continuous positive airway pressure; Heart failure; Sacubitril-valsartan; Sleep apnoea; Sleep-disordered breathing.

Figure 1

Study flow chart. Overview of screened, eligible, included, and excluded patients. Assessments included a physical examination, echocardiography, laboratory testing, the Minnesota Living with Heart Failure Questionnaire, the EQ‐5D‐3L questionnaire, the Epworth Sleepiness Scale, and the New York Heart Association score. Polygraphy was performed for Groups 1–3 at baseline and at 3 months for Groups 1 and 2. AHI, apnoea–hypopnoea index; CPAP, continuous positive airway pressure; HF, heart failure; PV, protocol violation; SV, sacubritil–valsartan.

Figure 2

Apnoea–hypopnoea index before vs. after 3 months of sacubritil–valsartan (SV). Change in apnoea–hypopnoea index before vs. after 3 months of SV in (A) Group 1 and (B) Group 2 patients without positive airway pressure treatment.