Angiotensin Receptor Neprilysin Inhibitor in Heart Failure With Preserved Ejection Fraction and Secondary Mitral Regurgitation: The PRAISE-MR Randomized Trial

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.