Entresto improved measures of heart structure and function in HFrEF patients in new Novartis study; additional data complement findings.

Novartis announced results from two new clinical trials evaluating improvement in heart structure and function and long-term safety of Entresto (sacubitril/valsartan) in patients with heart failure with reduced ejection fraction (HFrEF). Results suggest that Entresto, an essential treatment for HFrEF, not only positively impacts a biomarker shown to be associated with prognosis of clinical outcomes in HFrEF, but also that the effect is associated with significant improvement in the structural and functional changes, known as cardiac remodeling, that occur with this disease. Safety and tolerability were similar to that in previously reported studies.

Cardiac remodeling impairs the heart�s ability to pump blood to the body and leads to poor prognosis. Therefore, a positive impact on cardiac remodeling may be important in the treatment of HFrEF as it may result in reversed damage to the heart, which can lead to improved clinical outcomes. These data are the first to demonstrate that Entresto improved heart structure and function, indicative of reversal of cardiac remodeling, and that this improvement is correlated with positive changes in a biomarker. These results, which further support Entresto as a first-choice treatment for HFrEF, were presented as late-breakers at the ESC Congress 2019, the annual meeting of the European Society of Cardiology (ESC) and published in Journal of the American Medical Association.

The Phase IV, 52-week, single-arm, open-label PROVE-HF trial showed that treatment with Entresto significantly improved levels of an important biomarker shown to be associated with prognosis of clinical outcomes in HFrEF, N-terminal pro�B-type natriuretic peptide (NT-proBNP), which was linked for the first time to significant improvements in left ventricular remodeling and echocardiographic measures of cardiac structure and function. Importantly, the study demonstrated this association between improvement in this biomarker and these positive changes indicative of reversal of cardiac remodeling at six months and one year. The study found Entresto�s safety and tolerability to be largely consistent with that seen in the pivotal PARADIGM-HF trial with the exception of dizziness, which was reported more frequently in PROVE-HF.

Novartis also conducted the Phase IV, multicenter, randomized, double-blind, active-controlled EVALUATE-HF trial to examine Entresto�s effect on remodeling of the blood vessels of the heart and ventricular-vascular coupling � a measure of the mechanical efficiency of the heart � compared with enalapril. The study, also presented at ESC Congress 2019, showed that neither Entresto nor enalapril improved the primary endpoint of change in aortic impedance (a measure of vascular stiffness) It is possible that the short length of the study, as well as the specific patient population, which may already have experienced a degree of improved aortic impedance, may have contributed to this outcome. However, consistent with the findings in PROVE-HF, the study showed that Entresto improved the structure and function of the left ventricle � the chamber that pumps blood to the rest of the body � compared to enalapril, and safety was comparable to that seen in PARADIGM-HF.

About the PROVE-HF Trial : Seven hundred and ninety-four patients with HFrEF, NYHA Class II-IV, were treated in the Phase IV, single-arm, multicenter, open-label PROVE-HF trial in the United States, of which 654 (82.4%) completed the 52-week study. From baseline to 12 months, statistically significant correlations were observed between change in NT-proBNP and change in structural cardiac measurements � the primary endpoint of the trial. Results showed a clinically and statistically significant reduction in NT-proBNP of 30% from baseline by day 14 (median [interquartile range] NT-proBNP at baseline was 816 [332, 1822] pg/mL), which was maintained throughout 12 months (37% decrease from baseline at 12 months). Clinically and statistically significant improvements were observed in all echocardiographic parameters (LVEF, LAVi, LVEDVi, LVESVi and E/e�) at 12 months. LVEF increased from a median of 28.2% to 37.8% (difference, 9.4% [8.8, 9.9%]; P <.001), while lvedvi decreased from a median of 86.93 to 74.15 ml m2 difference -12.25 -12.92 -11.58 p><.001) and lvesvi decreased from a median of 61.68 to 45.46 ml m2 difference -15.29 -16.03 -14.55 p><.001). lavi and e e ratio also decreased significantly. significant correlation was found between change in concentration of nt-probnp and change in structural cardiac measurements from baseline to six months with strength of association less than that seen at one year. improvement in all echocardiographic measures was evident at six months but was more pronounced at one year. among three prespecified subgroups correlations between change in nt-probnp and cardiac volume and function were similar to the group as a whole as was quantitative improvement in cardiac structure and function.>

Safety and tolerability analyses : Frequency of adverse events was generally consistent with PARADIGM-HF, with the exception of dizziness (16.8% in PROVE-HF vs. 6% in PARADIGM-HF). 65% of patients achieved the target dose of Entresto, 97/103 mg BID, at some point during the 52-week study.Frequency of positively adjudicated angioedema was low, occurring in only two patients (0.3%), which were resolved with antihistamines or no therapy.

About the EVALUATE-HF Trial : Four hundred and sixty-four patients were randomized in the Phase IV, prospective, randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, forced-titration 12-week EVALUATE-HF trial. No statistically significant difference was shown between Entresto and enalapril in the primary endpoint of change from baseline in aortic characteristic impedance at 12 weeks (-2.9 vs -0.7 dyne-sec/cm5). Entresto improved several structural and functional echocardiographic measures versus enalapril at 12 weeks, including: Left atrial volume index (-2.8 mL/m2; 95% CI: -4.0, -1.6). Mitral E/e� ratio (-1.8; 95% CI: -2.8, -0.8). Left ventricular end systolic volume index (-1.6 mL/m2; 95% CI: -3.1, -0.03). Left ventricular end diastolic volume index (-2.0 mL/m2; 95% CI: -3.7, -0.3). No significant between-group differences were observed for global longitudinal strain, mitral e� velocity, left ventricular ejection fraction, and ventricular-vascular coupling (Ea/Ees) at 12 weeks. Safety and tolerability analyses : Frequency of adverse events was generally consistent with PARADIGM-HF and similar between treatment groups. 83% of patients achieved the target dose of sacubitril/valsartan 97/103 mg BID. One positively-adjudicated angioedema case occurred in the enalapril treatment group. One death occurred in each treatment group during the double-blind 12-week period of the study.

About NT-proBNP :NT-proBNP is a biomarker commonly used to assess the severity and prognosis of heart failure[10]. Levels of NT-proBNP increase when heart muscle cells are subjected to stress (such as stretching) that occurs in people with heart failure. Studies suggest that heart failure patients with elevated NT-proBNP are at an increased risk of cardiovascular death or heart failure hospitalization and that reducing levels of NT-proBNP in people with heart failure can be associated with a lower risk of these negative clinical outcomes, Entresto was also shown to reduce plasma NT-proBNP levels compared with enalapril in the PIONEER-HF and PARADIGM-HF trials.

About PARADIGM-HF : PARADIGM-HF was a randomized, double-blind, Phase III study evaluating the efficacy and safety profile of Entresto versus enalapril (a widely studied ACE inhibitor) in 8,442 patients with HFrEF. The baseline characteristics showed the patients enrolled were typical HFrEF patients with NYHA Class II-IV heart failure. PARADIGM-HF was specifically designed to see if Entresto could detect a relative reduction of 15% in the risk of cardiovascular mortality.Patients received Entresto or enalapril in addition to recommended therapy. The primary endpoint was a composite of time to first occurrence of either cardiovascular death or heart failure hospitalization. PARADIGM-HF was the largest heart failure study ever done.