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Sacubitril/Valsartan reduces HF hospitalizations: PARAGON-HF Study

Updated: Sep 10


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Heart failure with preserved ejection fraction (HFpEF) occurs when the left ventricle maintains a normal ejection fraction (≥50%) but becomes stiff during diastole, impairing its ability to fill properly. This leads to an inadequate blood supply to meet the body's demands despite normal contraction (1). This condition often presents with symptoms such as exertional dyspnea, fatigue, orthopnea, and edema, with worsening of these symptoms during physical activity or at rest (2).


Heart failure (HF) affects an estimated 1.3 to 4.6 million people in India, with 491,600 to 1.8 million new cases diagnosed annually (3). In addition to increased mortality, HFpEF is associated with impaired health-related quality of life (HRQL), frequent hospitalizations, and comorbidities such as diabetes, chronic kidney disease and atrial fibrillation (1).


Conventional therapies for HFpEF focus on symptomatic relief and comorbidity management. However, these approaches often fall short in improving long-term outcomes. There is a need for therapies that go beyond symptom control and address the underlying pathophysiology of HFpEF (4).


Sacubitril/valsartan, a first-in-class angiotensin receptor–neprilysin inhibitor.


Sacubitril/valsartan is a first-in-class angiotensin receptor–neprilysin inhibitor (ARNI) used in the treatment of heart failure. Valsartan, an angiotensin receptor blocker (ARB), inhibits the renin–angiotensin–aldosterone system (RAAS) by blocking the angiotensin II type 1 receptor. This results in reduced vasoconstriction, sodium retention, and aldosterone secretion. Sacubitril inhibits neprilysin, the enzyme responsible for degrading natriuretic peptides, bradykinin, and other vasoactive substances. Neprilysin inhibition leads to increased levels of natriuretic peptides, which promote vasodilation, natriuresis, and diuresis (5).


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This dual action makes sacubitril/valsartan particularly suitable for HFpEF patients, where neurohormonal dysregulation, cardiac stiffness, and elevated filling pressures contribute to symptoms and progression. By targeting both RAAS and the natriuretic peptide system, the drug offers a broader mechanism of support than traditional monotherapies (5).


Clinical Evidence – PARAGON-HF study


PARAGON-HF was a randomized, double-blind, controlled trial comparing sacubitril/valsartan with valsartan in 4,796 adult patients with symptomatic HFpEF (LVEF ≥45%) and elevated natriuretic peptide levels. Patients also had structural heart disease and New York Heart Association (NYHA) class II–IV symptoms (6).


Sacubitril/valsartan reduced the composite endpoint of total HF hospitalizations and cardiovascular (CV) death by 14% compared to valsartan. Notably, the benefits were more pronounced in patients with LVEF below 57%, indicating potential efficacy in those closer to the HFrEF spectrum. In addition, sacubitril/valsartan significantly lowered N-terminal pro–B-type natriuretic peptide (NT-proBNP) by 24% at week 16 and 19% at week 48 versus just 6% and 3% reductions with valsartan. These biomarker improvements support the potential of sacubitril/valsartan to mitigate disease progression and reduce cardiac stress in HFpEF patients (6).


Based on emerging data, clinical guidelines have begun to incorporate sacubitril/valsartan into recommendations for HFpEF management. For patients with LVEF on the lower end of the preserved spectrum, ARNI therapy may be considered to reduce HF hospitalizations and improve overall clinical outcomes (5).


Study Summary


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Conclusion


Sacubitril/valsartan offers a novel and promising therapeutic option for patients with HFpEF. Its dual mechanism of action addresses the multifactorial pathophysiology of the disease, while clinical evidence from the PARAGON-HF study demonstrates reductions in heart failure hospitalizations and improvements in key biomarkers.  


About the Author


Ms. Hima Saxena is a medical writer and editor with a Master’s in Pharmaceutics and a strong background in medical communications. She creates clear, evidence-based content that supports healthcare professionals and empowers patients. Hima collaborates with pharmaceutical and healthcare clients to deliver accurate, impactful content across diverse therapeutic areas, bridging scientific integrity with accessible communication.


Abbreviations:


HFpEF: Heart Failure with Preserved Ejection Fraction; LVEF: Left Ventricular Ejection Fraction; BID: Bis in Die (Twice a Day); NYHA: New York Heart Association; HF: Heart Failure; CV: Cardiovascular;

References


  1. Pfeffer MA, Shah AM, Borlaug BA. Heart failure with preserved ejection fraction: In perspective. Circ Res. 2019 May 24;124(11):1598–1617.

  2. Yoon S, Eom GH. Heart failure with preserved ejection fraction: Present status and future directions. Exp Mol Med. 2019 Dec 19;51(12):161.

  3. Huffman MD, Prabhakaran D. Heart failure: Epidemiology and prevention in India. Natl Med J India. 2010 Sep-Oct;23(5):283–288.

  4. Campbell P, Rutten FH, Lee MMY, Hawkins NM, Petrie MC. Heart failure with preserved ejection fraction: Everything the clinician needs to know. Lancet. 2024 Mar 16;403(10431):1083–1092.

  5. Sauer AJ, Cole R, Jensen BC, Pal J, Sharma N, Yehya A, Vader J. Practical guidance on the use of sacubitril/valsartan for heart failure. Heart Fail Rev. 2018 Dec 18;24(2):167–176.

  6. Gronda E, Vanoli E, Iacoviello M. The PARAGON-HF trial: The sacubitril/valsartan in heart failure with preserved ejection fraction. Eur Heart J Suppl. 2020 Nov 18;22(Suppl L):L77–L81. 

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