Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF).
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AuthorsMcMurray, John J V
Desai, Akshay S
Lefkowitz, Martin P
Rizkala, Adel R
Shi, Victor C
Solomon, Scott D
Zile, Michael R
MetadataShow full item record
CitationEur. J. Heart Fail. 2013, 15(9):1062-73
AbstractAlthough the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin-angiotensin-aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides.
Patients with chronic HF, NYHA class II-IV symptoms, an elevated plasma BNP or NT-proBNP level, and an LVEF of ≤40% were enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM-HF). Patients entered a single-blind enalapril run-in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run-in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death.
PARADIGM-HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM-HF may change our approach to neurohormonal modulation in HF.
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- Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial.
- Authors: Solomon SD, Claggett B, Desai AS, Packer M, Zile M, Swedberg K, Rouleau JL, Shi VC, Starling RC, Kozan Ö, Dukat A, Lefkowitz MP, McMurray JJ
- Issue date: 2016 Mar
- Factors Associated With Noncompletion During the Run-In Period Before Randomization and Influence on the Estimated Benefit of LCZ696 in the PARADIGM-HF Trial.
- Authors: Desai AS, Solomon S, Claggett B, McMurray JJ, Rouleau J, Swedberg K, Zile M, Lefkowitz M, Shi V, Packer M
- Issue date: 2016 Jun
- Comparing LCZ696 with enalapril according to baseline risk using the MAGGIC and EMPHASIS-HF risk scores: an analysis of mortality and morbidity in PARADIGM-HF.
- Authors: Simpson J, Jhund PS, Silva Cardoso J, Martinez F, Mosterd A, Ramires F, Rizkala AR, Senni M, Squire I, Gong J, Lefkowitz MP, Shi VC, Desai AS, Rouleau JL, Swedberg K, Zile MR, McMurray JJV, Packer M, Solomon SD, PARADIGM-HF Investigators and Committees.
- Issue date: 2015 Nov 10
- Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances.
- Authors: McMurray JJ
- Issue date: 2015 Mar
- Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients.
- Authors: Desai AS, McMurray JJ, Packer M, Swedberg K, Rouleau JL, Chen F, Gong J, Rizkala AR, Brahimi A, Claggett B, Finn PV, Hartley LH, Liu J, Lefkowitz M, Shi V, Zile MR, Solomon SD
- Issue date: 2015 Aug 7