Novartis PARAGON-HF analyses suggest Entresto benefit beyond HFrEF .

Novartis announced new subgroup analyses from its global Phase III PARAGON-HF study of patients with heart failure with preserved ejection fraction (HFpEF) also known as diastolic heart failure . The data suggest that, in specific subgroups, treatment with Entresto may result in greater reductions in heart failure hospitalizations and cardiovascular death, as compared to valsartan. This greater benefit was seen in women with HFpEF and in HFpEF patients recently hospitalized for heart failure.

In addition, in a pooled analysis of PARAGON-HF (HFpEF) and PARADIGM-HF (heart failure with reduced ejection fraction (HFrEF)), greater treatment benefit was observed in patients with left ventricular ejection fraction (LVEF) below approximately 60%. HFpEF is a type of heart failure that has no currently approved treatment and disproportionately affects women. These new analyses were presented at the American Heart Association�s (AHA) Scientific Sessions 2019 with simultaneous publication of the gender analysis in Circulation and hospitalization analysis in the Journal of the American College of Cardiology.

Currently, Entresto (sacubitril/valsartan) is an approved and essential treatment for patients with HFrEF , which is typically defined as ejection fraction less than or equal to 40%. This is based on its superiority to the angiotensin-converting enzyme (ACE) inhibitor enalapril in reducing cardiovascular death and heart failure hospitalizations, as demonstrated in the PARADIGM-HF trial. The full results of the Phase III PARAGON-HF study were presented at ESC Congress 2019. The study showed a 13% relative reduction in the primary composite endpoint of cardiovascular death and total (first and recurrent) heart failure hospitalizations, but narrowly missed statistical significance.

�This new research suggests that sacubitril/valsartan may provide greater benefit in HFpEF patients who have recently been hospitalized for heart failure and suggests the potential benefit of initiating treatment during the vulnerable period following hospitalization in order to reduce further events,� said John McMurray, M.D., Professor of Medical Cardiology at University of Glasgow and PARAGON-HF Executive Committee Co-Chair. �Understanding the correlation between time since hospitalization and treatment benefit may help inform optimization of care for patients with heart failure.�

About the PARAGON-HF subgroup analyses presented at AHA�s Scientific Sessions : Data from the Phase III PARAGON-HF (n=4,796 patients with heart failure with preserved ejection fraction (HFpEF)) and the PARADIGM-HF (n=8,399 patients with heart failure with reduced ejection fraction (HFrEF)) studies were combined in a pooled analysis to assess cardiovascular death and total heart failure hospitalization, evaluating the effect of Entresto compared with renin-angiotensin-aldosterone system (RAAS) inhibition among different left ventricular ejection fraction (LVEF) categories. In the analysis of the combined groups, total heart failure hospitalizations and cardiovascular death were reduced in patients receiving Entresto compared with RAAS inhibition . Cardiovascular death reduction was driven by the results of the patients with LVEF of 40% or less from the PARADIGM-HF trial . These therapeutic effects of Entresto were stronger within subgroup populations of the study: � The greatest treatment benefits were observed in patients with LVEF below approximately 60%1. Magnitude of reduction in heart failure hospitalizations, cardiovascular death and all-cause mortality decreased with increasing LVEF1. The all-cause mortality reduction was driven by the reduction in HFrEF patients1. � Treatment benefits persisted up to a higher level of LVEF in women compared with men.

A pre-specified subgroup analysis of PARAGON-HF assessed gender differences in heart failure hospitalization and cardiovascular death , compared to valsartan, among patients with HFpEF (n=4,796; 2,479 women and 2,317 men) . In women, Entresto reduced the risk of total heart failure hospitalization, with a 33% relative rate reduction (95% CI: 15-47), and an absolute reduction of 4 events per 100 person-years. In men, there was a 7% relative rate increase in the Entresto group versus the valsartan group, with an absolute increase of 0.9 events per 100 person-years. Men saw improved treatment benefits with Entresto in exploratory secondary endpoints including change in the New York Heart Association (NYHA) class and less worsening in quality of life based on KCCQ Clinical Summary Score at 8 months.

In a separate post-hoc analysis in patients from PARAGON-HF (n=4,796), the effect of Entresto on total heart failure hospitalizations and cardiovascular death was compared with that of valsartan, evaluating patients by the time from their last hospitalization. The effect of Entresto on total heart failure hospitalizations and cardiovascular death was greatest among patients screened during or shortly after hospitalization3. Entresto was associated with a gradient of risk reduction ranging from patients hospitalized within 30 days of screening (rate ratio, 0.73; 95% CI: 0.53-0.99) to patients never hospitalized (rate ratio, 1.00; 95% CI: 0.80-1.24) 3. Shorter times from prior heart failure hospitalization were associated with higher risk of total heart failure hospitalizations or cardiovascular death.

About PARAGON-HF PARAGON-HF is the largest clinical trial in heart failure with preserved ejection fraction (HFpEF) conducted to date. The Phase III randomized, double-blind, parallel group, active-controlled, 2-arm, event-driven trial compared the long-term efficacy and safety of Entresto versus valsartan in 4,822 patients with HFpEF. The patients in the study represented ambulatory patients with established HFpEF being treated for symptoms and comorbidities, approximately half of whom had a history of heart failure hospitalizations. Results showed a 13% relative reduction in the primary composite endpoint compared to valsartan of total (first and recurrent) heart failure hospitalizations and cardiovascular death, narrowly missing statistical significance (RR=0.87; 95% CI: 0.75, 1.01; p=0.06) 4. Absolute rate reduction was 1.8 events per 100 person-years. More pronounced effects on the primary endpoint were observed for certain pre-defined subgroups: individuals with an ejection fraction less than or equal to the median of 57% (22% relative reduction; RR=0.78; 95% CI: 0.64, 0.95) (absolute rate reduction = 6.6 events per 100 person-years) and women (27% relative reduction; RR=0.73; 95% CI: 0.59, 0.9) (absolute rate reduction = 3.9 events per 100 person-years) as well as in investigator-reported (non-adjudicated) events (16.3% relative reduction; RR=0.84; 95% CI: 0.74, 0.97) (absolute rate reduction = 2.7 events per 100 person-years)

. Secondary endpoint analyses , exploratory in nature, showed that Entresto patients experienced less worsening in quality of life than valsartan patients based on KCCQ Clinical Summary Score (CSS) at 8 months. Change in the New York Heart Association (NYHA) class was also more favorable in the Entresto group than in the valsartan group. Additionally, treatment with Entresto resulted in a reduction in the risk of the composite renal endpoint. No difference in all-cause mortality was observed between groups

Safety and tolerability analyses found :� Entresto was safe and well tolerated in HFpEF patients, largely as observed in heart failure with reduced ejection fraction (HFrEF) patients in PARADIGM-HF.� Hypotension occurred more frequently with Entresto (n=2407; 15.8%) than with valsartan (n=2389;10.8%).� Overall incidence of confirmed angioedema events was low in the two treatment arms, with 14 events in the Entresto arm (0.6%) and 4 events in the valsartan arm (0.2%); no angioedema events resulted in airway compromise.� Entresto resulted in lower rates of worsening renal function (1.4% versus 2.7% compared to valsartan); and serious adverse events of hyperkalemia compared to valsartan (0.8% versus 1.8%). PARAGON-HF follows PARAMOUNT-HF, the Phase II trial in HFpEF. Additional studies investigating Entresto on other relevant endpoints in HFpEF are ongoing.

See- "Effects of Sacubitril-Valsartan, versus Valsartan, in Women Compared to Men with Heart Failure and Preserved Ejection Fraction: Insights from PARAGON-HF"- John J. V. McMurray, Alice M. Jackson, Carolyn S.P. Lam, Margaret M. Redfield, Inder S. Anand, Junbo Ge, Marty P. Lefkowitz, Aldo P. Maggioni, Felipe Martinez,et al.,10.1161/CIRCULATIONAHA.119.044491.