PracticeUpdate Cardiology March 2019

EDITOR’S PICKS 9

Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation Circulation Take-home message • Patients with chronic functional mitral regurgitation (MR) secondary to left ventricular (LV) dysfunction receiving standard heart failure therapy were randomized to receive sacubitril/valsartan or valsartan to compare outcomes. There was a significantly greater decrease in the effective regurgitant orifice area in the sacubitril/valsartan group compared with the valsartan group at 12 months. In addition, there was a significant decrease in the regurgitant volume in the sacubitril/valsartan group compared with the valsartan group. The rate of serious adverse events was similar in the two groups. • The use of sacubitril/valsartan among patients with secondary functional MR results in a greater reduction of MR than the use of valsartan. An angiotensin receptor neprilysin inhibitor should be considered when treating patients with functional MR secondary to heart failure.

COMMENT By Gervasio A. Lamas MD, FACC, FAHA, FESC T he PRIME study sheds an interesting light on the use of medical therapy in severe functional mitral regurgitation (MR). This mechanistic comparison of valsartan with sacu- bitril + valsartan in patients with functional MR suggests that that part of the effectiveness of angiotensin receptor–nepri- lysin inhibitors (ARNIs) may be related to reverse remodeling of the LV and subsequent reduction of mitral regurgitation. The study is designed simply and had excellent follow-up and methodology. There were 117 patients with an average EF of 34% and MR (principally nonischemic) with an effective regur- gitant orifice area (EROA) of 0.2 cm 2 . Regurgitant volume was also decreased by a mean difference of −7.3 mL (P = .009) favoring the sacubitril + valsartan group, which demonstrated a within-groups EROA reduction of 30%. Moreover, the difference in EDVI change favoring the sacubitril + valsartan group gives a hint as to the potential physiological underpinning of the MR reduction. That is, an ARNI may not be an MR drug, but rather an LV remodeling drug that secondarily reduces functional MR. An additional strength of this study lies in the concordance of results between the intention-to-treat group and the completers group (n=104). As pointed out, this study was heavily weighted toward nonischemic cardiomyo- pathies, and subgroup analysis of nonischemic vs ischemic myopathies may be considered in the future. Future outcome studies will be helpful in determining whether ARNIs should eventually take the place of ARBs or ACE inhib- itors in the treatment of functional MR. This is, however, an interesting and promising start.

Abstract BACKGROUND The morbidity and mortality of patients with functional mitral regurgitation (MR) remain high, but no pharmacological therapy has been proven effective. The hypothesis of this study was that sacubitril/valsartan would be superior to valsartan alone in improving functional MR via dual inhibition of the renin-angiotensin system and neprilysin. METHODS In this double-blind trial, we randomly assigned 118 heart fail- ure patients with chronic functional MR secondary to left ventricular (LV) dysfunction to receive either sacubitril/valsartan or valsartan, in addition to standard medical therapy for heart failure. The primary end point was the change in effective regurgitant orifice area (EROA) of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, LV end-systolic volume, LV end-diastolic volume and incomplete mitral leaflet closure area. RESULTS The decrease in EROA was significantly greater in the sacubitril/ valsartan group compared to the valsartan group (-0.058±0.095 versus -0.018±0.105 cm2; P=0.032) in an intention-to-treat analysis including 117 (99%) patients. Regurgitant volume was also significantly decreased in the sacubitril/valsartan group compared with the valsartan group (mean dif- ference -7.3 ml, 95% CI -12.6 to -1.9; P=0.009). There were no significant between-group differences regarding the changes in incomplete mitral leaflet closure area and LV volumes except LV end-diastolic volume index (P=0.044). We noted no significant difference in the change of blood pres- sure between the treatment groups and 7 patients (12%) in the sacubitril/ valsartan group and 9 (16%) in the valsartan group had one or more seri- ous adverse events (P=0.54). CONCLUSIONS Among patients with secondary functional MR, sacubitril/ valsartan reduced MR to a greater extent than did valsartan. Our find- ings suggest that an angiotensin receptor neprilysin inhibitor might be considered for optimal medical therapy of patients with heart failure and functional MR.

Dr. Lamas is Chairman of Medicine at Mount Sinai Medical Center in Miami Beach, Florida, and Professor of Medicine at Columbia University Medical Center in New York.

Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgi- tation: The PRIME Study. Circulation 2018 Dec 05;[EPub Ahead of Print], DH Kang, SJ Park, SH Shin, et al. www.practiceupdate.com/c/77281

VOL. 4 • NO. 1 • 2019