The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial.

Abstract

BACKGROUND:

Heart failure with preserved ejection fraction is associated with substantial morbidity and mortality, but effective treatments are lacking. We assessed the efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in patients with this disorder.

METHODS:

PARAMOUNT was a phase 2, randomised, parallel-group, double-blind multicentre trial in patients with New York Heart Association (NYHA) class II-III heart failure, left ventricular ejection fraction 45% or higher, and NT-proBNP greater than 400 pg/mL. Participants were randomly assigned (1:1) by central interactive voice response system to LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and treated for 36 weeks. Investigators and participants were masked to treatment assignment. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks; analysis included all patients randomly assigned to treatment groups who had a baseline and at least one postbaseline assessment. This trial is registered at Clinicaltrials.gov, number NCT00887588.

FINDINGS:

149 patients were randomly assigned to LCZ696 and 152 to valsartan; 134 in the LCZ696 group and 132 in the valsartan group were included in analysis of the primary endpoint. NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 pg/mL [95% CI 670-914], 12 weeks, 605 pg/mL [512-714]; valsartan: baseline, 862 pg/mL [733-1012], 12 weeks, 835 [710-981]; ratio LCZ696/valsartan, 0·77, 95% CI 0·64-0·92, p=0·005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event.

INTERPRETATION:

In patients with heart failure with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12 weeks and was well tolerated. Whether these effects would translate into improved outcomes needs to be tested prospectively.

FUNDING:

Novartis.

• Authors: Scott D Solomon, Michael Zile, Burkert Pieske, Adriaan Voors, Amil Shah, Elisabeth Kraigher-Krainer, Victor Shi, Toni Bransford, Madoka Takeuchi, Jianjian Gong, Martin Lefkowitz, Milton Packer, John J V McMurray, Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators
• Journal: Lancet (London, England) (Lancet) Vol. 380 Issue 9851 Pg. 1387-95 (Oct 20 2012) ISSN: 1474-547X [Electronic] England
• PMID: 22932717 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Aminobutyrates
• Angiotensin Receptor Antagonists
• Biphenyl Compounds
• Drug Combinations
• Peptide Fragments
• Tetrazoles
• pro-brain natriuretic peptide (1-76)
• Natriuretic Peptide, Brain
• Valsartan
• Neprilysin
• Valine
• sacubitril and valsartan sodium hydrate drug combination

Topics

• Aged
• Aminobutyrates (therapeutic use)
• Angiotensin Receptor Antagonists (therapeutic use)
• Biphenyl Compounds
• Double-Blind Method
• Drug Combinations
• Female
• Heart Failure (blood, drug therapy, physiopathology)
• Humans
• Male
• Middle Aged
• Natriuretic Peptide, Brain (blood)
• Neprilysin (antagonists & inhibitors)
• Peptide Fragments (blood)
• Stroke Volume
• Tetrazoles (therapeutic use)
• Valine (analogs & derivatives, therapeutic use)
• Valsartan