By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports he is a consultant for Alnylam Pharmaceuticals and Akcea Therapeutics.

SYNOPSIS: In patients with chronic heart failure and functional mitral regurgitation, sacubitril/valsartan was associated with greater reduction in mitral regurgitation compared to valsartan alone.

SOURCE: Kang DH, et al. Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation. Circulation 2019;139:1354-1365.

In patients with chronic heart failure (HF), left ventricular (LV) dysfunction and remodeling often lead to the development of functional (secondary) mitral regurgitation (MR). Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), was shown in a large clinical trial to be more effective than enalapril for reducing the combined outcome of cardiovascular mortality and HF hospitalization. However, the effect of sacubitril/valsartan on functional MR severity has not been studied.

The authors of the Pharmacological Reduction of Functional, Ischemic Mitral REgurgitation (PRIME) study randomized 118 patients with chronic HF and functional MR to sacubitril/valsartan or valsartan alone. All patients presented with stable functional class II-III symptoms, LV ejection fraction (EF) between 25% and 50%, and functional MR that had been present for at least six months despite medical therapy (including a beta-blocker and either an ACE inhibitor or ARB). All patients exhibited “significant” MR, defined as an effective regurgitant orifice area (EROA) > 0.1 cm2 measured by echocardiography. The primary outcome was change in EROA at 12 months of follow-up. The average subject age was 62.6 years, and mean EF was 34 ± 7%. The cause of functional MR was ischemic in 42 patients and nonischemic in 76 patients. For the primary outcome, patients randomized to sacubitril/valsartan showed significantly greater reduction in EROA (-0.058 cm2 vs. -0.018 cm2 in the valsartan group; P = 0.032). Also, the authors observed significant improvements in secondary outcomes, including regurgitant volume (a mean difference of -7.3 mL; P = 0.009) and LV end-diastolic volume index. Serious adverse events occurred in seven patients in the sacubitril/valsartan group and nine patients in the valsartan group.

The authors concluded that sacubitril/valsartan reduces functional MR to a greater extent than valsartan. Sacubitril/valsartan might be considered optimal medical therapy for patients with HF and functional MR.


Functional MR develops because of factors that include LV and mitral annular dilation, leaflet tethering, dyssynchrony, and reduced contractility. Optimal treatment of functional MR is a source of ongoing debate. Medical therapy for HF has been shown to improve LV remodeling and thereby functional MR, although the associated morbidity and mortality remain high. The authors of two recent trials evaluated the use of a percutaneous clip for the treatment of functional MR, with conflicting results.

The PRIME study arrives at an important time when the cardiology community is actively debating which treatments work best for which patients with functional MR. Sacubitril acts by increasing circulating levels of natriuretic peptides. This reduces both afterload and preload, important factors in the severity of MR. The sacubitril/valsartan group also experienced greater reduction in LV volume, which reduces contributing factors such as annular dilation and leaflet tethering.

Regardless of the mechanism, the authors demonstrated greater reduction in MR severity. Although the magnitude of change in the primary endpoint is difficult to put into clinical context, the degree of reduction in MR was substantial: EROA decreased by 30% in the sacubitril/valsartan group vs. 9% in the valsartan alone group. The authors made an interesting decision to include patients with EF up to 50%. They (correctly) noted that MR allows ejection into the low-pressure left atrium; therefore, EF overestimates the true systolic function of the left ventricle. While their point is valid, sacubitril/valsartan is only approved for HF with reduced EF. Treatment of patients with an EF > 40% would be off label, although ongoing clinical trials are evaluating the efficacy of sacubitril/valsartan in HF with preserved EF.

How do the results of PRIME fit into the evolving approach to treatment of functional MR? The authors of the landmark Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial recently demonstrated significant reductions in hospitalization and mortality associated with percutaneous mitral repair. Patients enrolled in PRIME were younger, less symptomatic, and presented with less severe MR at baseline. Direct comparison of the two groups is challenging.

Furthermore, the COAPT investigators evaluated clinical endpoints, whereas the PRIME investigators only studied echocardiographic measures of MR severity. Therefore, we cannot conclude that sacubitril/valsartan is comparable to percutaneous repair. However, it seems reasonable to initiate sacubitril/valsartan in patients with HF and functional MR while determining whether they also may benefit from invasive therapies that have been shown to improve functional MR, such as revascularization, cardiac resynchronization therapy, and percutaneous mitral repair. The PRIME authors concluded that sacubitril/valsartan should be considered part of optimal medical therapy for patients with chronic HF and functional MR. While certainly true, this is not a change from current guidelines. All patients in PRIME presented with class II-III symptoms despite treatment with an ACE inhibitor or ARB.

Current guidelines already give a class I indication for switching such patients to an ARNI (assuming they have reduced EF). Rather, the findings serve as a reminder of the importance of making sure patients with chronic HF and functional MR receive the best guideline-directed medical therapy possible as the foundation of their treatment regimen.