An exploratory, open-label study in patients with heart failure and reduced ejection fraction (HFrEF) has shown that the reduction in NT-proBNP concentration achieved with sacubitril-valsartan was correlated – significantly but weakly – with signs of reverse cardiac remodeling at one year. The findings were presented Sept. 2 at ESC Congress 2019 and simultaneously published in the Journal of the American Medical Association.

While the clinical benefit of combined angiotensin receptor/neprilysin inhibitor (ARNI) therapy, vs. enalapril, was shown in the PARADIGM-HF study, the mechanism(s) for this benefit is unclear. PARADIGM-HF also demonstrated reductions in NT-proBNP. And reductions in NT-proBNP during guideline-directed medical therapy has been associated with reverse left ventricular (LV) remodeling.

Between Oct. 25, 2016 and Oct. 22, 2018, James L. Januzzi Jr., MD, FACC, et al., screened 1,031 patients at 78 outpatient sites in the U.S. Of these, 794 patients (mean age, 65.1 years; 23.7 percent ≥75 years;) were included in the open-label treatment phase; 28.5 percent were women and 22.7 percent were identified by investigators as black. A total of 654 patients (82.4 percent) completed the study.

In all participants, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were discontinued. The initial dose of sacubitril-valsartan was 24/26 mg twice daily in 81.7 percent of participants. By study end, 65.0 percent of participants achieved the goal dose of 97/103 mg twice daily, whereas the dose was 49/51mg twice daily in 21.2 percent and 24/26mg twice daily in 13.9 percent.

Echocardiography was performed at baseline and at six and 12 months and interpreted by a core laboratory.

The primary endpoint of a correlation between changes in the log2-NT-proBNP concentration and cardiac remodeling, as assessed by change from baseline to 12 months, was found for each parameter: LV ejection fraction (EF), LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e′) (p<0.001 for all).

The baseline median NT-proBNP concentration of 816 pg/mL was decreased to 455 pg/mL at 12 months (difference, p<0.001). For the same period, the mean LVEF increased from 28.2 percent to 37.8 percent; LVEDVI decreased from 86.93 to 74.15 mL/m2; LVESVI decreased from 61.68 to 45.46 mL/m2; and LVESVI decreased from 61.68 to 45.46 mL/m2; (p<0.001 for all). A significant decrease was also seen for LAVI and E/e′ ratio.

The authors note that most of the reduction in NT-proBNP with sacubitril-valsartan occurred early, during a period when most patients received the lowest dose of the drug. "Also, although improvement in cardiac structure and function was present at six months, at 12 months, further improvement in LVEF and volumes was present, with 25 percent of the study participants experiencing an absolute LVEF increase of more than 13 percent," they write.

"The observed reverse cardiac remodeling may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with HFrEF," they said.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: ESC 19, ESC Congress, Stroke Volume, Heart Failure

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