The Angiotensin Receptor Neprilysin Inhibitor LCZ696 in Heart

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
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
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-angiotensinaldosterone 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
LCZ696
50 mg BID
LCZ696
100 mg BID
LCZ696 200 mg BID
Valsartan
40 mg BID
Valsartan
80 mg BID
Valsartan 160 mg BID
Placebo run-in
Discontinue ACEI or
ARB therapy one day
prior to randomization
Prior ACEi/ARB use discontinued
Week
Visit
-2
1
2 weeks
0
2
1
3
1 week
2
4
1 week
4
5
8
6
12
7
10 weeks
18
8
24
9
30
10
6 month extension
Population
M & F > 40, NYHA II-IV HF, LVEF ≥ 45%, NT-proBNP > 400 pg/ml
Primary
objective
NT pro-BNP reduction from baseline at 12 weeks (core study)
 Echocardiographic measures of diastolic function, left atrial size, LV size and function,
Secondary
objectives
PASP
 HF symptoms, Clinical composite assessment and Quality of life (KCCQ)
 Safety and tolerability
Baseline randomization visit and visit at end of 12 weeks of core study
Clinicaltrials.gov NCT00887588
36
11
Change in NT-proBNP at 12 and 36 weeks
1000
900
NTproBNP (pg/ml)
Valsartan
800
700
600
p = 0.063
500
p = 0.20
p = 0.005
400
LCZ696
300
N=301
N=261
N=241
200
0
5
10
15
20
25
30
Weeks Post Randomization
35
40
Key Secondary Endpoints
2
12 Weeks
NYHA Class
Worsened
Unchanged
Improved
36 Weeks
1
0
Percent of Patients
Change in Left Atrial Volume (ml)
Left Atrial Volume
-1
-2
-3
-4
-5
P = 0.18
P = 0.003
-6
110
100
90
80
70
60
50
40
30
20
10
0
P = 0.11
LCZ696
P = 0.05
Valsartan
Week 12
LCZ696
Valsartan
Week 36
LCZ696
Valsartan
No Significant Changes in LV volumes, Ejection Fraction, or LV mass at 12 or 36 weeks
Conclusions
• The angiotensin receptor neprilysin inhibitor LCZ696 reduced NTproBNP 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