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PARAGON-HF trial in heart failure patients with preserved ejection fraction: Entresto misses statistical significance on the primary endpoint


The results from the global phase III PARAGON-HF study, investigating the safety and efficacy of Sacubitril / Valsartan ( Entresto ) versus the active comparator Valsartan in HFpEF ( heart failure with preserved ejection fraction ) patients, were presented.
The trial narrowly missed statistical significance for its composite primary endpoint of reducing cardiovascular death and total heart failure hospitalizations.
Safety and tolerability were consistent with previously reported Sacubitril / Valsartan data.

Around half of all heart failure patients, some 13 million people worldwide, are estimated to suffer from HFpEF, and there is currently no approved treatment.
The aim of PARAGON-HF trial was to determine whether Sacubitril / Valsartan could have a meaningful impact on the treatment of HFpEF, as it does in the treatment of heart failure with reduced ejection fraction.

There is currently no approved treatment for HFpEF.
Sacubitril / Valsartan is a first-choice treatment in heart failure with reduced ejection fraction ( HFrEF ), based on its superiority to the angiotensin-converting enzyme ( ACE ) inhibitor Enalapril and its ability to significantly reduce cardiovascular death and HFrEF hospitalizations.

PARAGON-HF is the largest clinical trial in heart failure with preserved ejection fraction 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 Sacubitril / Valsartan 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.
The primary endpoint of the trial is the composite of total ( first and recurrent ) heart failure hospitalizations and cardiovascular death.

PARAGON-HF follows the positive phase II trial in HFpEF, PARAMOUNT-HF, which has demonstrated that Sacubitril / Valsartan combination has reduced NT-proBNP ( a biomarker of cardiac strain ) to a greater extent than Valsartan at 12 weeks and was associated with improvement in NYHA class at 36 weeks.

HFpEF is a distinct type of heart failure where the heart muscle contracts normally but the ventricles do not relax as they should during ventricular filling.
HFpEF can be associated with high hospitalization rates, poor quality of life and increased mortality, and it is emerging as the predominant form of heart failure.

Entresto is a twice-a-day medicine that reduces the strain on the failing heart. It does this by enhancing the protective neurohormonal systems ( natriuretic peptide system ) while simultaneously inhibiting the harmful effects of the overactive renin-angiotensin-aldosterone system ( RAAS ).
Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers ( ARBs ), only block the harmful effects of the overactive RAAS.
Entresto contains the neprilysin inhibitor Sacubitril and the ARB Valsartan.

In Europe, Entresto is indicated in adult patients for the treatment of symptomatic chronic heart failure with reduced ejection fraction.
In the United States, Entresto is indicated for the treatment of heart failure ( NYHA class II-IV ) in patients with systolic dysfunction.
It has been shown to reduce the rate of cardiovascular death, heart failure hospitalization and 30-day hospital readmission compared to Enalapril, to reduce the rate of all-cause mortality compared to Enalapril, and to improve aspects of health-related quality of life ( including physical and social activities ) compared to Enalapril.
Entresto is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB. ( Xagena )

Source: Novartis, 2019

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