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PARADIGM-HF Study
Prospective comparison of ARNI with ACEI to Determine
Impact on Global Mortality and morbidity in Heart Failure
A multicenter, randomized, double-blind, parallel-group, active-controlled study to
evaluate the efficacy and safety of LCZ696 compared with enalapril on morbidity
and mortality in patients with chronic HF and reduced ejection fraction
August 2014/GMCC_NP4 request 275741/expiry August 2015
Overactivation of the RAAS and SNS is detrimental in HFrEF
and underpins the basis of therapy
β-blockers
SNS
Epinephrine
Norepinephrine
Natriuretic peptide
system
NPRs
NPs
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresis
Vasopressin
Aldosterone
Fibrosis
Hypertrophy
HFrEF
SYMPTOMS &
PROGRESSION
α1, β1, β2
receptors
Vasoconstriction
RAAS activity
Vasopressin
Heart rate
Contractility
RAAS inhibitors
(ACEI, ARB, MRA)
RAAS
Ang II
AT1R
Vasoconstriction
Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
 The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs1
 Benefits of β-blockers indicate that the SNS also plays a key role1
2
1. McMurray et al. Eur Heart J 2012;33:1787–847
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42;
Kemp & Conte. Cardiovascular Pathology 2012;365–371;
Schrier & Abraham. N Engl J Med 2009;341:577–85;
Natriuretic peptides have potential beneficial actions in HF
Release of ANP and BNP from heart and CNP in vasculature1
 Sympathetic outflow2
 Vasopressin2
 Salt appetite and water intake2
ANP/BNP2
CNP
(endothelium)3
Relaxation;  arterial stiffness4
 Hypertrophy2,5–7
 Fibroblast proliferation4,8,9
 Na+/H2O loss2
 Aldosterone2
 Renin2
3
Vasodilation2,3,4
 Systemic vascular resistance4
 Pulmonary artery pressure4
 Pulmonary capillary wedge pressure4
 Right atrial pressure4
1. Forssmann et al. Arch Histol Cytol 1989;52 Suppl:293–315; 2. Levin et al. N Engl J Med 1998;339;321–8;
3. Lumsden et al. Curr Pharm Des 2010;16:4080–8; 4. Langenickel & Dole. Drug Discovery Today: Ther Strateg
2012;9:e131–9; 5. Gardner et al. Hypertension 2007;49:419–26;
6. Tokudome et al. Circulation 2008;117;2329–39; 7. Horio et al. Endocrinology 2003;144:2279–84;
8. D'Souza et al. Pharmacol Ther 2004 ;101:113–29; 9. Cao & Gardner. Hypertension 1995;25:227–34;
LCZ696 is a first-in-class
angiotensin receptor neprilysin inhibitor (ARNI)
 LCZ696 is a novel drug which delivers
simultaneous neprilysin inhibition and
AT1 receptor blockade1–3
 LCZ696 is a salt complex that comprises
the two active moieties:2,3
– sacubitril (AHU377) – a pro-drug; further
metabolized to the neprilysin inhibitor
LBQ657, and
– valsartan – an AT1 receptor blocker
3D LCZ696 structure2
in a 1:1 molar ratio
4
1. Bloch, Basile. J Clin Hypertens 2010;12:809–12; 2. Gu et al. J Clin Pharmacol
2010;50:401–14; 3. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
LCZ696 simultaneously inhibits NEP (via LBQ657) and blocks the AT1
receptor (via valsartan)
LCZ696
Natriuretic and other
vasoactive peptides*
–
Inactive
fragments
RAAS
Angiotensinogen
(liver secretion)
Sacubitril
(AHU377; pro-drug)
LBQ657
(NEP inhibitor)
Ang I
Vasorelaxation
 Blood pressure
 Sympathetic tone
 Aldosterone levels
 Fibrosis
 Hypertrophy
 Natriuresis/diuresis
5
N
OH
Inhibiting
O
HN
OH
O
N
N
HO
O
– AT Receptor
1
O
O
Enhancing
Ang II
Valsartan
N NH
Vasoconstriction
 Blood pressure
 Sympathetic tone
 Aldosterone
 Fibrosis
 Hypertrophy
*Neprilysin substrates listed in order of relative affinity for NEP: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1, BNP
Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42;
Schrier & Abraham N Engl J Med 2009;341:577–85; Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9;
Feng et al. Tetrahedron Letters 2012;53:275–6
Study design
PARADIGM-HF: Study design
Randomization
n=8442
Double-blind
Treatment period
Single-blind active
run-in period
LCZ696 200 mg BID‡
Enalapril
10 mg BID*
LCZ696
100 mg BID†
LCZ696
200 mg BID‡
Enalapril 10 mg BID§
2 Weeks
1–2 Weeks
2–4 Weeks
Median of 27 months’ follow-up
On top of standard HFrEF therapy (excluding ACEIs and ARBs)
7
*Enalapril 5 mg BID (10 mg TDD) for 1–2 weeks followed by enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for
those patients who are treated with ARBs or with a low dose of ACEI; †200 mg TDD; ‡400 mg TDD; §20 mg TDD.
McMurray et al. Eur J Heart Fail. 2013;15:1062–73; McMurray et al. Eur J Heart Fail. 2014;16:817–25;
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
PARADIGM-HF: LCZ696 dose selection rationale
AT1 receptor blockade
 LCZ696 200 mg BID delivers similar exposures to valsartan as Diovan® 160 mg BID, the
dose recommended for treatment of HF and MI (based on Val-HeFT and VALIANT)13
Neprilysin (NEP) inhibition
 Biomarker analysis indicates that LCZ696 200 mg provides ~90% of its maximal
NEP inhibition4,5
 Both LCZ696 400 and 200 mg QD (but not 100 mg LCZ696) provided meaningful
pharmacodynamic effect (BP lowering) attributable to NEP inhibtion5
 BID dosing is considered essential to obtain 24-hour NEP inhibition1,6
 BID dosing mitigates risk of post-dose hypotension (two smaller doses, compared to one
larger once-daily dose, as used in the OVERTURE study with omapatrilat)1,6
8
1. McMurray et al. Eur J Heart Fail. 2013;15:1062–732; 2. Valsartan Heart Failure Trial Investigators. N Engl J Med 2001;345:166775;
3. Valsartan in Acute Myocardial Infarction Trial Investigators. N Engl J Med 2003;349:18931906; 4. Gu et al. J Clin Pharmacol 2010;50:401–14;
5. Ruilope et al. Lancet 2010;375:12551266; 6. Packer et al. Circulation 2002;106:920–6.
PARADIGM-HF: Key inclusion criteria
 Chronic HF NYHA FC II–IV with LVEF ≤40%*
 BNP (or NT-proBNP) levels as follows:
• ≥150 (or ≥600 pg/mL), or
• ≥100 (or ≥400 pg/mL) and a hospitalization for HFrEF
within the last 12 months
 ≥4 weeks’ stable treatment with an ACEI or an ARB#, and a β-blocker
 Aldosterone antagonist should be considered for all patients (with treatment
with a stable dose for ≥4 weeks, if given)
*The ejection fraction entry criteria was lowered to ≤35% in a protocol amendment
#Dosage equivalent to enalapril ≥10 mg/day
9
McMurray et al. Eur J Heart Fail. 2013;15:1062–73
PARADIGM-HF: Key exclusion criteria
 History of angioedema
2
 eGFR <30 mL/min/1.73 m at screening, end of enalapril run-in or randomization,
or a >35% decrease in eGFR between screening and end of enalapril run-in or between
screening and randomization
 Serum potassium >5.2 mmol/L at screening OR >5.4 mmol/L at the end of the enalapril
run-in or end of the LCZ696 run-in
 Requirement for treatment with both ACEI and ARBs
 Symptomatic hypotension, SBP <100 mmHg at screening, OR SBP <95 mmHg
at end of enalapril run-in or at randomization
 Current acute decompensated HF
 History of severe pulmonary disease
 Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid, or other
major CV surgery, PCI, or carotid angioplasty within the 3 months prior to screening
10
McMurray et al. Eur J Heart Fail. 2013;15:1062–73
PARADIGM-HF: Primary objective
 To evaluate the effect of LCZ696 200 mg BID compared with enalapril 10 mg
BID, in addition to conventional HFrEF treatment, in delaying time to first
occurrence of either CV death or HF hospitalization1
Rationale for endpoint selection
 Primary outcome of CV death or HF hospitalization was chosen as the one that
best reflects the major mortality and morbidity burden of HFrEF1,9
• ~80% of deaths in recent trials in patients with HFrEF are CV related24
• HF is associated with a high risk of hospitalization,5 representing the leading cause of
hospitalization in patients aged ≥65 years58
 The most commonly used primary endpoint in recent HF trials:
CHARM-Added, SHIFT and EMPHASIS-HF1
11
1. McMurray et al. Eur J Heart Fail. 2013;15:1062–73 ; 2.McMurray et al. Lancet 2003;362:767–77;
3. Swedberg et al. Lancet 2010;376:875–88; 4. Zannad et al. N Engl J Med 2011;364:11–2;
5. Cowie et al. Improving care for patients with acute heart failure. Oxford Health policy Forum 2014;
6.Hunt et al. J Am Coll Cardiol 2009;53:e1–90; 7.Yancy et al. Circulation 2013;128:e240–327;
8.Rodriguez-Artalejo et al. Rev Esp Cardiol 2004;57:163–70; 9.Dunlay et al. Circ Cardiovasc Qual Outcomes 2011;4:68–75
PARADIGM-HF: Secondary objectives
 To assess whether LCZ696 was superior to enalapril in:
• Improving quality of life (assessed by KCCQ score)
• Delaying time to all-cause mortality
• Delaying time to new-onset atrial fibrillation
• Delaying time to decline of renal function as defined by:
- 50% decline in eGFR from baseline, or
- >30 mL/min/1.73 m2 decline in eGFR relative to baseline and to a value of
<60 mL/min/1.73 m2 (indicating the development of moderate renal
dysfunction), or
- development of end-stage renal disease
12
McMurray et al. Eur J Heart Fail. 2013;15:1062–73
Patient population and baseline characteristics
PARADIGM-HF: Patient disposition
10,513 patients entered enalapril run-in phase
(median duration, 15 days; interquartile range [IQR], 14–21)
1102 discontinued study:
591 (5.6%) had adverse event
66 (0.6%) had abnormal laboratory or other test result
171 (1.6%) withdrew consent
138 (1.3%) had protocol deviation, administrative
problem or were lost to follow-up
49 (0.5%) died
87 (0.8%) had other reasons
9419 entered LCZ696 run-in phase
(median duration, 29 days; IQR, 26–35)
977 discontinued study:
547 (5.8%) had adverse event
58 (0.6%) had abnormal laboratory or other test result
100 (1.1%) withdrew consent
146 (1.6%) had protocol deviation, had administrative
problem, or were lost to follow-up
47 (0.5%) died
79 (0.8%) had other reasons
8442 underwent randomization
43 were excluded:
6 did not undergo valid randomization
37 were from four sites prematurely closed because
of major Good Clinical Practice violations
4187 were assigned to receive LCZ696
4176 had known final vital status
11 had unknown final vital status
14
4212 were assigned to receive enalapril
4203 had known final vital status
9 had unknown final vital status
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
PARADIGM-HF: Summary of baseline characteristics
Characteristic*
Age, years
Women, n (%)
Ischemic cardiomyopathy, n (%)
LV ejection fraction, %
NYHA functional class, n (%)
II
III
SBP, mmHg
Heart rate, beats/min
NT pro-BNP, pg/mL (IQR)
BNP, pg/mL (IQR)
History of diabetes, n (%)
Treatments at randomization, n (%)
Diuretics
Digitalis
β-blockers
Mineralocorticoid antagonists
ICD
CRT
15
LCZ696
(n=4187)
Enalapril
(n=4212)
63.8 ± 11.5
879 (21.0)
2506 (59.9)
29.6 ± 6.1
63.8 ± 11.3
953 (22.6)
2530 (60.1)
29.4 ± 6.3
2998 (71.6)
969 (23.1)
122 ± 15
72 ± 12
1631 (885–3154)
255 (155–474)
1451 (34.7)
2921 (69.3)
1049 (24.9)
121 ± 15
73 ± 12
1594 (886–3305)
251 (153–465)
1456 (34.6)
3363 (80.3)
1223 (29.2)
3899 (93.1)
2271 (54.2)
623 (14.9)
292 (7.0)
3375 (80.1)
1316 (31.2)
3912 (92.9
2400 (57.0)
620 (14.7)
282 (6.7)
*mean ± standard deviation, unless stated
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
Results
Primary endpoint:
Death from CV causes or first hospitalization for HF
1.0
Cumulative probability
Enalapril
0.6
LCZ696
Hazard ratio = 0.80 (95% CI: 0.73–0.87)
p<0.001
0.4
0.2
0
0
No at risk
LCZ696
Enalapril
17
180
360
540
720
900
1080
1260
896
853
249
236
Days since randomization
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
Components of primary endpoint:
Death from CV causes
1.0
Cumulative probability
Enalapril
0.6
LCZ696
Hazard ratio = 0.80 (95% CI: 0.71–0.89)
p<0.001
0.4
0.2
0
0
No at risk
LCZ696
Enalapril
18
180
360
540
720
900
1080
1260
1005
994
280
279
Days since randomization
4187
4212
4056
4051
3891
3860
3282
3231
2478
2410
1716
1726
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
Components of primary endpoint:
First hospitalization for HF
1.0
Cumulative probability
Enalapril
0.6
LCZ696
Hazard ratio = 0.79 (95% CI: 0.71–0.89)
p<0.001
0.4
0.2
0
No at risk
LCZ696
Enalapril
19
0
180
360
4187
4212
3922
3883
3663
3579
540
720
900
Days since randomization
3018
2922
2257
2123
1544
1488
1080
1260
896
853
249
236
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
Primary outcome
LCZ696
(n=4187)
Enalapril
(n=4212)
Hazard ratio*
(95% CI)
p-value‡
Death from CV causes or first
hospitalization for worsening of HF
914 (21.8)
1117 (26.5)
0.80 (0.73–0.87)
<0.001
Death from CV causes
558 (13.3)
693 (16.5)
0.80 (0.71–0.89)
<0.001
First hospitalization for worsening
of HF
537 (12.8)
658 (15.6)
0.79 (0.71–0.89)
<0.001
Outcome, n %
Primary composite outcome
*Calculated with the use of stratified cox proportional-hazard models
‡Two-sided p-values calculated by means of a stratified log-rank test without adjustment for multiple comparisons
 The difference in favor of LCZ696 was seen early in the trial and at each interim analysis
 Over the duration of the trial, the numbers of patients who would need to have been
treated (NNT) to prevent:
• one primary event was 21 patients, and
• one death from CV causes was 32 patients
20
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
Secondary outcomes
LCZ696
(n=4187)
Enalapril
(n=4212)
Hazard ratio*
or difference
(95% CI)
711 (17.0)
835 19.8)
0.84 (0.76–0.93)
<0.001
Change in KCCQ clinical summary
score† at 8 months, mean ± SD
-2.99 ± 0.36
-4.63 ± 0.36
1.64 (0.63–2.65)
0.001
New onset atrial fibrillation¶, n (%)
84 (3.1)
83 (3.1)
0.97 (0.72–1.31)
0.83
Decline in renal function§, n (%)
94 (2.2)
108 (2.6)
0.86 (0.65–1.13)
0.28
Outcome
Death from any cause, n (%)
*Calculated with the use of stratified cox proportional-hazard models
‡Two-sided p-values calculated by means of a stratified log-rank test without adjustment for multiple comparisons
†KCCQ scores range from 0 to 100 – higher scores indicate fewer symptoms and physical limitations associated with HF
¶2670 patients in the LCZ696 and 2638 in the enalapril group who did not have atrial fibrillation at randomization were evaluated
§Defined as: (a) ≥ 50% decline in eGFR from randomization; (b) > 30 mL/min/1.73 m 2 decline in eGFR from randomization or to a value of
<60 ml/min/1.73 m2, or (c) progression to end-stage renal disease
21
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
p-value‡
Death from any cause
1.0
Cumulative probability
Enalapril
0.6
LCZ696
Hazard ratio = 0.84 (95% CI: 0.76–0.93)
p<0.001
0.4
0.2
0
0
No at risk
LCZ696
Enalapril
22
180
360
540
720
900
1080
1260
1005
994
280
279
Days since randomization
4187
4212
4056
4051
3891
3860
3282
3231
2478
2410
1716
1726
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
Systolic blood pressure during run-in and after randomization
140
 Compared with the randomization
level, the mean SBP at 8 months was
3.2 ± 0.4 mmHg lower in the LCZ696
group than in the enalapril group
(p<0.001)
 When modeled as a time-dependent
100
80
Randomization
SBP (mmHg)
120
covariate, the difference in BP was not
a determinant of the incremental
benefits of LCZ696
Enalapril
LCZ696
Mean difference (LCZ696–enalapril):
–2.70 (–3.07, –2.34) (mmHg)
p-value: <0.001
60
–11w 4m 8m 1yr
2yrs
3yrs
Time
23
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
(Supplementary appendix)
Prospectively defined safety events
Event, n (%)
Hypotension
Symptomatic
Symptomatic with SBP <90 mmHg
Elevated serum creatinine
≥2.5 mg/dL
≥3.0 mg/dL
Elevated serum potassium
>5.5 mmol/L
>6.0 mmol/L
Cough
Angioedema (adjudicated by a blinded expert committee)
No treatment or use of antihistamines only
Catecholamines or glucocorticoids without hospitalization
Hospitalized without airway compromise
Airway compromise
•
24
LCZ696
(n=4187)
Enalapril
(n=4212)
p-value‡
588 (14.0)
112 (2.7)
388 (9.2)
59 (1.4)
<0.001
<0.001
139 (3.3)
63 (1.5)
188 (4.5)
83 (2.0)
0.007
0.10
674 (16.1)
181 (4.3)
474 (11.3)
727 (17.3)
236 (5.6)
601 (14.3)
0.15
0.007
<0.001
10 (0.2)
6 (0.1)
3 (0.1)
0
5 (0.1)
4 (0.1)
1 (<0.1)
0
0.19
0.52
0.31
---
Fewer patients in the LCZ696 group than in the enalapril group stopped their study medication
because of an AE (10.7 vs 12.3%, p=0.03)
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
For further information please contact:
Sander de Groot
Medical Scientific Liaison Heart Failure
+31 6 5024 8516
[email protected]
Summary of results – efficacy
 Primary outcome
• 20% reduction in CV death or HF hospitalization with LCZ696 compared
with enalapril
•
20% reduction in CV mortality
•
21% reduction in HF hospitalization
 Secondary outcomes
• 16% reduction in all-cause mortality with LCZ696 vs enalapril
• LCZ696 superior to enalapril in reducing symptoms and physical limitations
of HF (indicated by KCCQ score)
• No significant difference in incidence of new onset atrial fibrillation between
treatment groups
• No significant difference in protocol-defined decline in renal function
between treatment groups
26
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
Summary of results – safety
 The superiority of LCZ696 over enalapril was not accompanied by important
safety concerns
 Fewer patients stopped their study medication because of an adverse event in
the LCZ696 group than in the enalapril group
 There was no increase in the rate of discontinuation due to possible
hypotension-related adverse effects, despite a higher rate of symptomatic
hypotension in the LCZ696 group
 Fewer patients in the LCZ696 group developed renal impairment, hyperkalemia
or cough than in the enalapril group
 The LCZ696 group had a higher proportion of patients with non-serious
angioedema, but LCZ696 was not associated with an increase in serious
angioedema
27
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.