Understanding the early mortality benefit observed in the PARADIGM-HF trial: considerations for the management of heart failure with sacubitril/valsartan

Abstract

This review aims to elucidate the optimal dosing of angiotensin receptor-neprilysin inhibitor (ARNI) therapy in the heart failure (HF) treatment paradigm through examination of the trial population characteristics and the mortality benefit observed in the Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF; NCT01035255) trial. Considerations regarding the initiation and titration of sacubitril/valsartan, a first-in-class ARNI, will also be addressed. The approval of sacubitril/valsartan heralded the first novel pharmacological class in over a decade for the treatment of heart failure with reduced ejection fraction (HFrEF). The PARADIGM-HF trial showed that treatment with valsartan/valsartan reduced the risk of first occurrence of either cardiovascular death or HF-related hospitalization (composite primary endpoint) by 20% compared with enalapril in patients with HFrEF. The incremental benefits of treatment with valsartan/valsartan over enalapril demonstrated in the PARADIGM-HF trial led to strong recommendations for its use over ACEIs or angiotensin receptor blockers to further reduce morbidity and mortality in the 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America updates to the guidelines for the management of HF. Although the optimal timing for the initiation of valsartan/valsartan has yet to be determined, its early use is likely to have a positive impact on patient outcomes.

Keywords:

• angiotensin receptor-neprilysin inhibitor
• cardiovascular death
• patient outcomes
• treatment recommendations

Human and animal rights and informed consent

This article does not contain any studies with human participants or animals performed by any of the authors.

Data availability

The data used to compile this review are available in the relevant source publications.

Acknowledgments

Medical writing assistance was provided by Marcel Kuttab, PharmD, of Oxford PharmaGenesis Inc., Newtown, Pennsylvania, USA, and was funded by Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.

Disclosure

Dr Sokos has served on the speakers’ bureaus of Bayer Pharmaceuticals, Actelion Pharmaceuticals, and Novartis Pharmaceuticals. He has served on the advisory boards of Gilead Sciences, Bayer Pharmaceuticals, and Novartis Pharmaceuticals. Dr Raina has received fees from Actelion, St. Jude, Bayer, and United Therapeutics, and has received nonfinancial support from Bellerophon and Oxford Pharmagenesis. The authors report no other conflicts of interest in this work.