The Angiotensin Receptor Neprilysin Inhibitor LCZ696 in Heart - - PowerPoint PPT Presentation

Scott D. Solomon, MD, Professor of Medicine, Harvard Medical School Director, Noninvasive Cardiology Brigham and Women’s Hospital On behalf of the PARAMOUNT Investigators Disclosures: Dr. Solomon has received research support and has consulted for Novartis

The Angiotensin Receptor Neprilysin Inhibitor LCZ696 in Heart Failure with Preserved Ejection Fraction

The Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fraction (PARAMOUNT) Trial

Background

• Heart failure with preserved ejection fraction (HFpEF) accounts for up to half of

heart failure cases, and is associated with substantial morbidity and mortality, yet no therapies have been shown to improve clinical outcomes in this condition.

• LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that comprises

the molecular moieties of a neprilysin inhibitor and the angiotensin receptor blocker (ARB) valsartan as a single compound.

• As such, this compound simultaneously inhibits the renin-angiotensin-

aldosterone system and augments the endogenous natriuretic peptide system, both of which may offer benefits in patients with heart failure. This drug is currently being tested in an 8000 patient reduced ejection fraction heart failure trial.

• The PARAMOUNT trial was designed to test the safety and efficacy of LCZ696

in patients with HFpEF.

PARAMOUNT: Study Design

Population M & F > 40, NYHA II-IV HF, LVEF ≥ 45%, NT

• proBNP > 400 pg/ml

Primary

• bjective

NT pro-BNP reduction from baseline at 12 weeks (core study) Secondary

• bjectives
• Echocardiographic measures of diastolic function, left atrial size, LV size and function,

PASP

• HF symptoms, Clinical composite assessment and Quality of life (KCCQ)
• Safety and tolerability

LCZ696 100 mg BID LCZ696 50 mg BID Valsartan 40 mg BID

1 week 10 weeks 2 weeks

Placebo run-in

Discontinue ACEI or ARB therapy one day prior to randomization

LCZ696 200 mg BID Valsartan 80 mg BID Valsartan 160 mg BID

1 week

Prior ACEi/ARB use discontinued

6 month extension

Baseline randomization visit and visit at end of 12 weeks of core study

Week Visit

• 2

1 2 2 1 3 4 12 7 4 8 6 5 8 9 10 11 18 24 30 36

Clinicaltrials.gov NCT00887588

5 10 15 20 25 30 35 40 200 300 400 500 600 700 800 900 1000

NTproBNP (pg/ml) Weeks Post Randomization LCZ696 Valsartan

p = 0.005

p = 0.063 p = 0.20

Change in NT-proBNP at 12 and 36 weeks

N=301 N=261 N=241

Key Secondary Endpoints

Left Atrial Volume

12 Weeks 36 Weeks

• 6
• 5
• 4
• 3
• 2
• 1

1 2

Change in Left Atrial Volume (ml) Valsartan LCZ696

P = 0.18 P = 0.003

No Significant Changes in LV volumes, Ejection Fraction, or LV mass at 12 or 36 weeks

Worsened Unchanged Improved

LCZ696 Valsartan LCZ696 Valsartan

10 20 30 40 50 60 70 80 90 100 110

Percent of Patients

Week 12 Week 36

P = 0.11 P = 0.05

NYHA Class

Conclusions

• The angiotensin receptor neprilysin inhibitor LCZ696 reduced NT-

proBNP to a greater extent than valsartan after 12 weeks of therapy, in association with reduction in left atrial size and improvement in NYHA

• class. These are all measures that have been associated with worse

prognosis in patients with HFpEF.

• Overall LCZ696 was well tolerated with fewer serious and overall

adverse events than the comparator valsartan.

• We consider these findings hypothesis generating, but they suggest that

LCZ696 may have beneficial effects in patients with HFpEF and that further testing of this compound may be warranted in patients with this condition. Published simultaneously online in The Lancet