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)

John J V McMurray, Milton Packer, Akshay S. Desai, Jim Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg, Michael R. Zile

Research output: Contribution to journalArticle

184 Citations (Scopus)

Abstract

AimsAlthough 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.MethodsPatients 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.

Original languageEnglish (US)
Pages (from-to)1062-1073
Number of pages12
JournalEuropean Journal of Heart Failure
Volume15
Issue number9
DOIs
StatePublished - Sep 2013

Fingerprint

Systolic Heart Failure
Neprilysin
Angiotensin Receptors
Peptidyl-Dipeptidase A
Heart Failure
Morbidity
Mortality
Renin-Angiotensin System
Natriuretic Peptides
Enalapril
Drug Receptors
Natriuresis
Sympathetic Nervous System
Risk Reduction Behavior
Vasodilation
Hospitalization
Enzymes
Growth
LCZ 696

Keywords

  • ACE inhibitor
  • Angiotensin receptor blocker
  • Angiotensin receptor neprilysin inhibitor
  • Chronic heart failure
  • LCZ696
  • Natriuretic peptides
  • Neprilysin
  • Neutral endopeptidase
  • Renin-angiotensin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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). / McMurray, John J V; Packer, Milton; Desai, Akshay S.; Gong, Jim; Lefkowitz, Martin P.; Rizkala, Adel R.; Rouleau, Jean; Shi, Victor C.; Solomon, Scott D.; Swedberg, Karl; Zile, Michael R.

In: European Journal of Heart Failure, Vol. 15, No. 9, 09.2013, p. 1062-1073.

Research output: Contribution to journalArticle

McMurray, John J V ; Packer, Milton ; Desai, Akshay S. ; Gong, Jim ; Lefkowitz, Martin P. ; Rizkala, Adel R. ; Rouleau, Jean ; Shi, Victor C. ; Solomon, Scott D. ; Swedberg, Karl ; Zile, Michael R. / 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). In: European Journal of Heart Failure. 2013 ; Vol. 15, No. 9. pp. 1062-1073.
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abstract = "AimsAlthough 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.MethodsPatients 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.",
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T1 - Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure

T2 - 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)

AU - McMurray, John J V

AU - Packer, Milton

AU - Desai, Akshay S.

AU - Gong, Jim

AU - Lefkowitz, Martin P.

AU - Rizkala, Adel R.

AU - Rouleau, Jean

AU - Shi, Victor C.

AU - Solomon, Scott D.

AU - Swedberg, Karl

AU - Zile, Michael R.

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KW - Neutral endopeptidase

KW - Renin-angiotensin

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JO - European Journal of Heart Failure

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