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Treatment with ARNI improves mitral regurgitation in HF patients

ahajournals.org
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 an intention to treat analysis, change in EROA was significantly different between the sacubitril/valsartan group and the valsartan group (-0.058±0.095 vs -0.018±0.105 cm²; P=0.032).
  • In an analysis of completers (n=104), similar results were seen with greater change in EROA for sacubitril/valsartan compared to valsartan (-0.077 ± 0.080 vs. -0.030 ± 0.096; P=0.008).
  • Decrease in regurgitant volume was greater in the sacubitril/valsartan group vs valsartan (mean difference of change: -7.3 mL, 95% CI -12.6 to -1.9; P=0.009).
  • In an analysis of completers, similar results for regurgitant volume were observed with a greater decrease in the sacubitril/valsartan group vs the valsartan group (mean difference of change: -8.3 mL, 95% CI -13.6 to -2.9; P=0.003)
  • ESV and EDV of LV were significantly smaller in the sacubitril/valsartan group vs the valsartan group at follow-up (change in ESV and EDV were non-significantly greater for sacubitril/valsartan vs valsartan) and decrease in EDV index was significantly greater in the sacubitril/valsartan group vs the valsartan group.
  • There was a correlation between decrease in EROA and decrease in ESV (r = 0.70, p<0.001) or EDV (r=0.66, p<0.001) in the sacubitril/valsartan group as well as the valsartan group (ESV; r=0.67, p<0.001 and EDV; r=0.58, p<0.001).
  • No differences were observed between the 2 groups for incomplete mitral leaflet closure area.
  • In a secondary analysis on completers, decrease in EDV index was non-significantly greater in the sacubitril/valsartan group vs the valsartan group, and no differences were observed for changes in ESV, EDV and incomplete mitral leaflet closure area.
  • No difference in serious adverse events was observed between the 2 groups (12% in the sacubitril/valsartan group and 17% in the valsartan group).

Conclusion

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.

References

1. Lamas GA, Mitchell GF, Flaker GC et al. Clinical significance of mitral regurgitation after acute myocardial infarction. Circulation. 1997;96:827-833.

2. Bursi F, Enriquez-Sarano M, Nkomo T et al. Heart failure and death after myocardial infarction in the community: the emerging role of mitral regurgitation. Circulation. 2005;111:295-301.

3. Rossi A, Dini FL, Faggiano P et al. Independent prognostic value of functional mitral regurgitation in patients with heart failure: a quantitative analysis of 1256 patients with ischemic and non-ischemic dilated cardiomyopathy. Heart. 2011;97:1675-1680.

4. Nishimura RA, Otto CM, Bonow RO et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:e521–643.

5. Levine RA and Schwammenthal E. Ischemic mitral regurgitation on the threshold of a solution: from paradoxes to unifying concepts. Circulation. 2005;112:745-758.

6. Asgar AW, Mack MJ, Stone GW. Secondary mitral regurgitation in heart failure: pathophysiology, prognosis, and therapeutic considerations. J Am Coll Cardiol. 2015;65:1231-1248.

7. Agricola E, Ielasi A, Oppizzi M et al. Long-term prognosis of medically treated patients with functional mitral regurgitation and left ventricular dysfunction. Eur J Heart Fail. 2009;11:581-587.

8. Schiller NB, Shah PM, Crawford M et al.Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358-367.

9. Grayburn PA, Weissman NJ, Zamorano JL. Quantitation of mitral regurgitation. Circulation. 2012;126:2005-2017.

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