Treatment with sacubitril/valsartan (Entresto; Novartis) was found to provide greater benefits in certain patients with heart failure with preserved ejection fraction (HFpEF), according to subgroup analyses from the phase 3 PARAGON-HF trial.
The multicenter, double-blind, parallel group, active-controlled study compared sacubitril/valsartan to valsartan in reducing cardiovascular (CV) death and heart failure (HF) hospitalizations in HFpEF for up to 57 months. Patients (N=4822) were randomized to receive a target dose of sacubitril/valsartan 97mg/103mg or valsartan 160mg twice a day after meeting the safety criteria from a single blind run-in period of 3-8 weeks. The primary end point was the composite of CV death and total (first and recurrent) HF hospitalizations.
In July 2019, Novartis announced that the trial missed statistical significance with a 13% relative reduction in the primary composite end point, however new subgroup analyses suggest that a greater therapeutic benefit with the combination therapy was observed in women with HFpEF and patients with HFpEF who were recently hospitalized for HF.
In a study comparing the effects of sacubitril/valsartan in women vs men with HFpEF, the combination appeared to reduce the risk of heart failure hospitalization in women more than men. “For the primary outcome, the rate ratio for sacubitril/valsartan vs valsartan was 0.73 (95% CI 0.59-0.90) in women and 1.03 (0.84-1.25) in men; P interaction =.017. The benefit from sacubitril/valsartan was due to reduction in heart failure hospitalization,” the study authors reported.
In a separate post-hoc analysis, the treatment effect of sacubitril/valsartan on total heart failure hospitalizations and cardiovascular death was observed to be greatest among HFpEF patients screened during or within 30 days of hospitalization. Sacubitril/valsartan 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).
Additionally, pooled data from PARAGON-HF and PARADIGM-HF showed that the therapeutic effects of sacubitril/valsartan varied by left ventricular ejection fraction (LVEF), with an increased benefit seen in patients with LVEF <60%. Findings from the study demonstrated a decrease in the magnitude of effect with increasing LVEF, although therapeutic benefits persisted to a higher level of LVEF in women compared with men.
“These new data, suggesting potential benefit of Entresto beyond [heart failure with reduced ejection fraction], represent our ongoing work to develop treatments for patients, including for HFpEF, a complex condition with high unmet patient need,” said David Soergel, MD, Global Head of Cardiovascular, Renal and Metabolic Drug Development at Novartis.
Entresto is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker and is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is also approved to treat symptomatic heart failure with systemic left ventricular systolic dysfunction in children aged ≥1 year.
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