Angiotensin Receptor Neprilysin Inhibitor in Heart Failure With Preserved Ejection Fraction and Secondary Mitral...

Atrial functional mitral regurgitation (AFMR) characterizes a high-risk phenotype in heart failure with preserved ejection fraction (HFpEF). Although sacubitril/valsartan reduces functional mitral regurgitation (MR) in HF with reduced EF (HFrEF), its impact on exercise hemodynamics and the dynamic burden of AFMR in HFpEF remains to be elucidated.

This multicenter, randomized, open-label trial with blinded primary endpoint assessment assigned 84 patients with symptomatic HFpEF and at least moderate AFMR within the previous year to sacubitril/valsartan (n=41) or standard-of-care (SOC; n=43). The primary outcome was the 6-month change in the exercise mean pulmonary arterial pressure to cardiac output (mPAP/CO) slope, assessed using cardiopulmonary exercise testing with simultaneous echocardiography (CPETecho). Secondary outcomes included changes in peak oxygen consumption (peak VO₂), Kansas City Cardiomyopathy Questionnaire (KCCQ), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, left atrial (LA) volume and function, and AFMR severity in rest and during stress.

At 6 months, sacubitril/valsartan significantly improved the mPAP/CO slope compared with SOC (adjusted between-group difference in change, -0.93 mm Hg/L/min; 95% CI, -1.80 to -0.07; P=0.035). This hemodynamic benefit was accompanied by improvements in peak VO₂ (mean change, +0.9 versus -0.6mL/kg/min; P=0.002) and KCCQ (median increase, 10 versus 2 points; P=0.002). Significant reductions in NT-proBNP and LA volume were observed (P<0.001 for both), alongside a significant blunting of the dynamic MR increase during exercise (P=0.020). Target dose was achieved in 60% of patients, with symptomatic hypotension as the primary titration-limiting factor.

In HFpEF and AFMR, sacubitril/valsartan was associated with improvements in exercise hemodynamics and peak VO₂, along with attenuation of the exercise-induced increase in AFMR. These findings suggest a phenotype-specific benefit, warranting confirmation in larger, placebo-controlled, clinical outcome trials.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT05991284. EudraCT: 2023-506634-70-00.