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Long term efficacy and safety comparison of the angiotensin receptor neprilysin inhibitor (ARNi), LCZ696, and valsartan, in patients with heart
failure and preserved ejection fraction: A randomized, double blind, morbidity and mortality trial
Prospective comparison of ARni with Arb Global Outcomes in heart failure with preserved ejectioN fraction (PARAGON-HF)
Solomon SD1, McMurray JJ2, Gong J3, Lefkowitz M3, Maggioni A4, Anand I5, Zannad F6, Bransford TL3, Redfield M7, Pfeffer M1, Packer M8, Zile M9, Martinez F10, Rouleau J11, Pieske B12, and van Veldhuisen D13
Brigham and Women’s Hospital, Boston, MA, 2University of Glasgow, Scotland, UK, 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, 4ANMCO Research Center, Florence, Italy, 5University of Minnesota Medical School, Minneapolis, MN, 6Institut Lorrain du Coeur et des Vaisseaux, France, 7Mayo Clinic, Rochester, MN,
8
University of Texas Southwestern, Dallas,TX, 9Medical University of South Carolina, Charleston, SC, 10Cordoba National University, Cordoba, Argentina, 11Institut de Cardiologie de Montréal, Université de Montréal, 12Medical University Graz, Graz, Austria, 13University Medical Center Groningen, Groningen,The Netherlands
1
BACKGROUND
Structural
Symptomatic
Cardiac stress – prognostic of outcome
LV pressures – prognostic of outcome
Improved physical functioning
1° Endpoint: NT-proBNP
(23% reduction by week 12)
2° Endpoint: Atrial size
(7% reduction by week 36)
2° Endpoint: NYHA
(9% improvement by week 36)
Several pathophysiologic mechanisms have been implicated in this
disorder, including abnormalities of diastolic function and impaired
natriuretic response to acute volume expansion.
Figure 1. Mechanism of action of LCZ696
2
1000
LCZ696
900
Valsartan
800
700
600
500
400
p = 0.005
p = 0.063
300
200
Damage
1
0
-1
-2
-3
-4
-5
12 Weeks
0 5 10 15 20 25 30 35 40
LCZ696
X
Inactive
fragments
Vasodilation
blood pressure
sympathetic tone
aldosterone levels
fibrosis
hypertrophy
Natriuresis/Diuresis
„„
„„
RAAS
Ang II
Dual
NEP/RAAS
inhibition
(LCZ696)
„„
Primary objective
„„
36 Weeks
Valsartan LCZ696
36 Weeks
Valsartan
NYHA: New York Heart
Association Classification
METHODS
HF
symptoms/
progression
X
AT1 receptor
PARAGON-HF will assess the effect of LCZ696 on outcomes
(cardiovascular [CV] death and total – first and recurrent – HF
hospitalizations) in patients with HFpEF.
Figure 3. Trial design
Randomization 1:1
Vasoconstriction
blood pressure
sympathetic tone
aldosterone
fibrosis
hypertrophy
Double-blind treatment period
Active run-in period
Screening
LCZ696 is a first in class, angiotensin receptor neprilysin inhibitor (ARNI),
providing systemic exposure to AHU377, a neprilysin (NEP) inhibitor and
valsartan, an ARB. The potential clinical benefits from NEP inhibition can
only be leveraged if the RAAS system is inhibited concomitantly.1, 2
The mechanisms of action of LCZ696 suggest that it may have an impact
on the pathophysiology of HFpEF, in which it is believed that excessive
fibrosis and myocyte hypertrophy lead to abnormal left ventricular
relaxation and filling, impaired diastolic distensibility and/or increased
vascular stiffness, with consequent elevated cardiac filling pressures.3
The PARAMOUNT trial tested the safety and efficacy of LCZ696 in
patients with HFpEF and showed a significant reduction in N-terminal
pro-B-type natriuretic peptide (NT-proBNP) at 12 weeks and significant
improvement in left atrial size and New York Heart Association
(NYHA) class in patients randomized to LCZ696 compared to valsartan
at 36 weeks.4 NT-proBNP is not a substrate for neprilysin.
Supporting a Phase 3 outcomes trial
„„
Primary and secondary objectives
„„
NT-proBNP: marker of left ventricular (LV) wall stress; left atrial
enlargement reflective of sustained elevations in LV filling pressures
Both reductions in NT-proBNP 5,6,7 and left atrial size8,9,10,11 have been
associated with improved cardiovascular outcomes
Sponsor & source of financial support: Novartis Pharmaceuticals Corporation.
LCZ696 200 mg BID
LCZ696
Valsartan
80 mg BID* 100 mg BID
Neurohormonal balance
„„
p = 0.051
RAAS blockade is used in the majority of patients with HFpEF to
treat comorbidities. Valsartan was chosen as the comparator as it is a
commonly used ARB and its use will standardize RAAS treatment for
the comparator arm of the trial.
A novel secondary endpoint, atrial fibrillation (AF), is being included
in PARAGON-HF. AF is the most common arrhythmia in patients
with HF. Its prevalence increases with the severity of HF, and its
occurrence is frequently associated with symptom deterioration and
increased morbidity.
The primary objective of this trial is to compare LCZ696 to valsartan in
reducing the rate of the composite endpoint of CV death and total (first
and recurrent) HF hospitalizations, in HF patients (NYHA Class II-IV)
with preserved EF (left ventricular ejection fraction [LVEF] ≥45%).
Valsartan 160 mg BID
On top of optimal background
medications for co-morbidities
(excluding ACEIs and ARBs)
up to 2 weeks
3–8 weeks
~240 weeks
Primary outcome: CV death and total (first and recurrent) HF
hospitalization (anticipated ~1,721 primary events)
To compare LCZ696 to valsartan in reducing the rate of the
composite endpoint of CV death, total HF hospitalizations, total nonfatal strokes, and total non-fatal myocardial infarctions (MIs). Total is
defined as the first and all recurrent events.
„„
To compare LCZ696 to valsartan in improving NYHA functional
classification at 8 months.
„„
To compare LCZ696 to valsartan in delaying the time to new onset AF
in patients with no history of AF and without AF on electrocardiogram
(ECG) at baseline.
„„
To compare LCZ696 to valsartan in delaying the time to all-cause
mortality.
Figure 4. Key inclusion criteria
„„
Screening: up to 2 weeks
„„
Active Run-In Period: 3-8 weeks (can be shorter for patients
previously exposed to standard doses of RAAS blockade; longer for
patients with no prior exposure or on low doses of ACEIs or ARBs.)
„„
Double Blind Period: Projected 2.75 years enrollment; with a minimum
of 2 years follow up
„„
„„
Systolic blood pressure (SBP) <110 mmHg OR SBP ≥180 mmHg
at time of screening. If SBP >150 mmHg and <180 mmHg, the patient
should be receiving at least 3 antihypertensive drugs.
Serum potassium >5.2 mmol/L at screening
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 at
baseline
Table 1. Key trial committees
AND at least one of the following:
A HF hospitalization within 9 months
Elevated NT-proBNP
prior to Visit 1
(>300 pg/ml for patients not in AF
OR >900 pg/ml for patients
Data Monitoring
Committee
Steering Committee
Scott D. Solomon, MD
(Co-Chair)
Brigham and Women’s
Hospital
Inder Anand, MD
University of Minnesota
Medical School
Felipe Martinez, MD
Cordoba National University
John J. McMurray, MD
(Co-Chair)
University of Glasgow
Burkert Pieske, MD
Medical University Graz
Margaret Redfield, MD
Mayo Clinic
Jean L. Rouleau, MD
Institut de Cardiologie de
Montréal, Université de
Montréal
Milton Packer, MD
Dirk van Veldhuisen, MD
University of Texas
University Medical Center
Southwestern Medical Center
Groningen
Marc Pfeffer, MD
Faiez Zannad, MD
Brigham and Women’s
Institut Lorrain du Coeur et
Hospital
des Vaisseaux
Carolyn SP Lam, MD
Michael R. Zile, MD
National University Health
Medical University of South
System Singapore
Carolina
Prof. Junbo Ge, MD
Zhongshan Hospital, Fudan
University, China
Henry J. Dargie, MD
(Chair)
Golden Jubilee National
Hospital, Glasgow
Michel Komajda, MD
Pitie-Salpetriere Hospital,
Institut de Cardiologie
Robert Foley, MD
Chronic Disease Research
Group, Minnesota
Gary Francis, MD
University of Minnesota,
Cardiovascular Division
Stuart Pocock, PhD
London School of Hygiene &
Tropical Medicine
Trial status
„„
1. ≥55 years of age and LVEF ≥45%
2. Symptom(s) of HF requiring treatment with diuretic(s) for HF for ≥30 days
prior to Visit 1
3. Current symptomatic HF (NYHA class II-IV)
4. Structural heart disease (LAE or LVH)
*Valsartan 40 mg BID (up to 2 weeks) followed by valsartan 80 mg BID as an optional starting run-in dose for
those patients being treated with less than the minimum dose of ACEI or ARB at Visit 1.
„„
Aldo Maggioni, MD
ANMCO Research Center
Secondary objective
„„
NEP
p = 0.003
110
100
90
80
70
60
50
40
30
20
10
0
„„
Worsened
Unchanged
Improved
Pathophysiological response
NP system
NPs
p = 0.18
-6
Weeks Post Randomization
Beneficial physiological response
Left Atrial Volume
Percent of Patients
To date both angiotensin converting enzyme inhibitors (ACEIs) and
angiotensin receptor blockers (ARBs) have been tested in clinical trials in
HFpEF and not been shown to improve the primary outcome.
Change in Left Atrial Volume (ml)
„„
NT-proBNP
p = 0.20
„„
Heart failure with preserved ejection fraction (HFpEF) accounts for up to
half of heart failure (HF) cases and is associated with substantial morbidity
and mortality.
NTproBNP (pg/ml)
„„
Figure 2. Summary of results of the PARAMOUNT trial
„„
Start of recruitment is planned for 4Q2013
REFERENCES
1.
2.
3.
4.
5.
6.
7.
Campbell DJ (2003) Hypertension; 41:383-89.
Mangiafico S, Costello-Boerrigter LC, Andersen IA, et al (2012) Eur Heart J; 34: 886-93.
Krum H, Abraham WT (2009) Lancet; 373:941-55
Solomon SD, Zile M, Pieske B, et al (2012) Lancet; 380: 1387-95.
Komajda M, Carson PE, Hetzel S, et al (2011); Circ Heart Fail; 4(1):27-35.
Anand IS (2003) Circulation;107:1278-83.
Massie BM, Carson PE, McMurray JJ, et al for the I-PRESERVE Investigators (2008); N Engl J Med;
359(23):2456-67.
8. Zile MR, Gottdiener JS, Hetzel SJ, et al for the I-Preserve Investigators (2011); Circulation;
124(23):2491-501.
9. Brenyo A, Link MS, Barsheshet A, et al (2011); J Am Coll Cardiol; 58:1682-9.
10. Meris A, Amigoni M, Uno H, et al (2009); Eur Heart J; 30:56-65.
11. Gerdts E, Wachtell K, Omvik P, et al (2007); Hypertension; 49:311-16.
in AF at baseline)
LAE = left atrial enlargement, LVH = left ventricular hypertrophy, AF = atrial fibrillation
Rationale for key trial design elements
„„
The trial uses a novel recurrent events trial design, with all primary
events (HF hospitalizations and CV death) included in the primary
endpoint analysis rather than a time-to-first event analysis. This
better reflects the true burden of a chronic illness characterized by
frequent and often repeat admissions. Recurrent hospitalizations are
a common occurrence in patients with HF and impose a substantial
clinical and economic burden on patients, caregivers, physicians, and
health systems.
Key exclusion criteria
„„
„„
„„
Contact information:
History of a prior echocardiographic (echo) measurement of LVEF <45%.
MI, coronary artery bypass graft (CABG) or any other event that could
have reduced EF unless an echo measurement performed after the
event confirms an LVEF ≥ 45%.
Required treatment with 2 or more of the following: an ACEI, an ARB
or a renin inhibitor.
Toni Bransford, MD
Novartis Pharmaceuticals Corporation
Phone: +1 862-778-2944
email: [email protected]
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Poster presented at: The Clinical Trials Forum, Heart Failure Congress, European Society of Cardiology, Lisbon, Portugal.