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Sacubitril/Valsartan reduces CV mortality and hospitalizations - PARADIGM HF

Updated: Sep 10


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Heart failure (HF) is a clinical condition where the heart muscle is weakened and cannot pump enough blood to meet the needs of the body (1). Enalapril is an ACE inhibitor (ACEI) that primarily treats hypertension, heart failure, and left ventricular dysfunction (2).


Sacubitril/valsartan, a multifarious drug combination, is designed to reduce the risk of angioedema. The drug contains neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan (3). Neprilysin, an endopeptidase, breaks down the endogenous compensatory vasoactive peptides. The elevated levels of bradykinin, adrenomedullin, and natriuretic peptides lead to the activation of neurohormones. This results in maladaptive remodeling, sodium retention, and vasoconstriction (4, 5). Besides, valsartan plays a crucial role in blocking the renin-angiotensin system (6).


Clinical evidence – PARADIGM-HF TRIAL


The PARADIGM-HF trial was a double-blind, multicenter, randomized clinical study. The trial evaluated the efficacy of sacubitril/valsartan compared to enalapril in patients with chronic heart failure and reduced ejection fraction (HFrEF). A total of 8,399 patients were enrolled in this study. Study participants had New York Heart Association (NYHA) class II, III, or IV symptoms. They also had a left ventricular ejection fraction (LVEF) of 40% or less. Participants were randomly assigned to receive either sacubitril/valsartan or enalapril and were then assessed for CV death and hospitalization for HF (5,7).


The study compared three time points as follows: baseline (all participants were taking angiotensin-converting enzyme inhibitors [ACEI] or angiotensin-receptor blocker [ARB]), after 12 weeks, and after 24 weeks of randomization. Both sacubitril/valsartan and enalapril were started in a double-blind manner with progressive increase in titrated doses at 200 mg twice daily or at 20 mg twice daily, respectively (8).


The PARADIGM-HF study demonstrated that sacubitril/valsartan significantly outperforms enalapril in reducing both cardiovascular mortality and hospitalizations for heart failure in patients with HFrEF. These findings support the use of sacubitril/valsartan as a superior alternative to ACE inhibitors in eligible patients with symptomatic HFrEF and LVEF ≤40%. The study established the clinical superiority of sacubitril/valsartan than enalapril, as a preferred first-line therapy and use as part of guideline-directed medical therapy (8).


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About the Author


Dr Mamatha, holds a Ph.D. in Neurobiology and has experience as a Senior Research Scientist in a Contract Research Organization (CRO). During her tenure, she was actively involved in scientific writing, manuscript preparation, and report review, along with gaining hands-on expertise in in vitro research across diverse therapeutic areas. Driven by a passion for clear and impactful communication of science, Mamatha is actively pursuing opportunities in scientific and medical writing, where she aims to decode the complex scientific content into accessible and meaningful communication.


Abbreviations


ACEI: Angiotensin-Converting Enzyme Inhibitors; ARB: Angiotensin-Receptor Blocker; HF: Heart Failure; HFrEF: Heart Failure with reduced Ejection Fraction; LVEF: Left Ventricular Ejection Fraction; NYHA: New York Heart Association. 

References


  1. Jain A, et al. Effects of Angiotensin Receptor-Neprilysin Inhibitors Versus Enalapril or Valsartan on Patients With Heart Failure: A Systematic Review and Meta-Analysis. Cureus. 2023; 15(7):e41566.

  2. Gomez HJ, et al. Enalapril: a review of human pharmacology. Drugs. 1985; 30 Suppl 1:13-24.

  3. McMurray JJ, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. New Eng J Med. 2014; 371(11):993-1004.

  4. Evbayekha E, et al. Sacubitril/Valsartan vs ACE Inhibitors or ARBs: A Systematic Review and Meta-Analysis of Randomized Trials. JACC: Adv. 2025; 4(3):101598.

  5. Vardeny O, et al. Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM‐HF trial. Eur J Heart Fail. 2016; 18(10):1228-1234.

  6. Vardeny O, et al. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC: Heart Fail. 2014; 2(6):663-670.

  7. Desai AS, et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol. 2017; 2(1):79-85.

  8. Bhatt AS, et al. Effect of sacubitril/valsartan vs. enalapril on changes in heart failure therapies over time: the PARADIGM‐HF trial. Eur J Heart Fail. 2021; 23(9):1518-1524.

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