Physicians' Academy for Cardiovascular Education

Treatment with ARNI improves mitral regurgitation in HF patients

Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation: The PRIME Study

Literature - Kang D-H, Park S-J, Shin S-H et al. - Circulation 2018, doi: 10.1161/CIRCULATIONAHA

Introduction and methods

Mitral regurgitation (MR) is often observed in patients with myocardial infarction (MI) or heart failure (HF) [1-3]. Secondary functional MR is usually the result of left ventricular (LV) dysfunction and therapy consists of guideline-recommended therapy for HF [4]. Unfortunately, treatment with beta blockers, ARBs, ACEi has not resulted in a decrease in severity of MR and morbidity and mortality remain high in patients with functional MR [5-7]. Also, no trials have measured efficacy of medical therapy by quantitative assessment of MR. It was hypothesized that the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan might be beneficial in the treatment of functional MR. Therefore, The Pharmacological Reduction of Functional, Ischemic Mitral Regurgitation (PRIME) trial was conducted and the effect of sacubitril/valsartan on functional MR was tested against valsartan alone.

Eligibility criteria for this prospective, multicenter, double-blind, randomized, active-controlled trial were: ≥20 years old, stable HF with NYHA class II/III symptoms, EF 25%-<50%, functional MR lasting >6 months. Patients had to take beta blocker and ACEi or ARB at least 4 weeks before screening. After randomization to valsartan (max 160 mg twice daily) or sacubitril/valsartan (max 97/103 mg twice daily), patients were switched from the ACE inhibitor or ARB to the study drug.

Echocardiography was done at randomization and 12-month follow-up or early termination visits. End-systolic volume (ESV), end-diastolic volume (EDV) of the LV were calculated with the biplane Simpson method [8]. Effective regurgitant orifice area (EROA) was determined by dividing the regurgitant flow rate, calculated as 2πr² × aliasing velocity, where r is the proximal isovelocity surface area (PISA) radius, by peak MR velocity [9]. A significant change in the severity of MR was prespecified as the absolute value of change in EROA >0.1 cm² or the percentage change in EROA to baseline EROA >50%. A regurgitant volume was estimated as EROA multiplied by the velocity time integral of the MR jet.

The primary end point was change in EROA of functional MR from baseline to 12 months follow-up. Secondary end points included changes in regurgitant volume, ESV, EDV and incomplete mitral leaflet closure area. 118 Patients (60 assigned to sacubitril/valsartan and 58 to valsartan) were enrolled between March 2016 and Jan 2017.

Main results


In this randomized controlled trial, sacubitril/valsartan treatment resulted in a greater reduction of MR associated with HF compared to valsartan alone. This results suggests that sacubitril/valsartan may be considered as optimal medical therapy for patients with HF and functional MR.


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