1. 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 /expiry August 2015

2. SYMPTOMS & PROGRESSION RAAS inhibitors (ACEI, ARB, MRA)
Overactivation of the RAAS and SNS is detrimental in HFrEF and underpins the basis of therapy
β-blockers
SNS
Epinephrine
Norepinephrine
α1, β1, β2
receptors
Vasoconstriction
RAAS activity
Vasopressin
Heart rate
Contractility
Natriuretic peptide system
HFrEF
SYMPTOMS & PROGRESSION
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresis
Vasopressin
Aldosterone
Fibrosis
Hypertrophy
NPRs
NPs
RAAS inhibitors (ACEI, ARB, MRA)
RAAS
Vasoconstriction
Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
Ang II
AT1R
Abbreviations
ACEI=angiotensin-converting-enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker; AT1 = angiotensin II type 1; HF=heart failure; MRA=mineralocorticoid receptor antagonist; NEP=neprilysin; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system
References
1. McMurray et al. Eur J Heart Fail. 2013;15:1062–73;
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
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
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;

3. Natriuretic peptides have potential beneficial actions in HF
Release of ANP and BNP from heart and CNP in vasculature1
ANP/BNP2
Relaxation;  arterial stiffness4
CNP (endothelium)3
 Sympathetic outflow2
 Vasopressin2
 Salt appetite and water intake2
 Hypertrophy2,5–7
 Fibroblast proliferation4,8,9
 Na+/H2O loss2
 Aldosterone2
 Renin2
Abbreviations
ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-type natriuretic peptide; HF=heart failure
References
Forssmann et al. Arch Histol Cytol 1989;52 Suppl:293–315
Levin et al. N Engl J Med 1998;339;321–8
Lumsden et al. Curr Pharm Des 2010;16:4080–8
Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131–9
Gardner et al. Hypertension 2007;49:419–26
Tokudome et al. Circulation 2008;117;2329–39
Horio et al. Endocrinology 2003;144:2279–84
D'Souza et al. Pharmacol Ther 2004;101:113–29
Cao & Gardner. Hypertension 1995;25:227–34
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;

4. 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
in a 1:1 molar ratio
3D LCZ696 structure2
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

5. LCZ696 simultaneously inhibits NEP (via LBQ657) and blocks the AT1 receptor (via valsartan)
Natriuretic and other
vasoactive peptides*
RAAS
Angiotensinogen
(liver secretion) –
Neprilysin
Sacubitril
(AHU377; pro-drug)
Ang I
Inactive fragments
LBQ657
(NEP inhibitor) OH O HN HO
Valsartan N NH O OH –
Ang II
AT1 Receptor
Vasorelaxation
 Blood pressure
 Sympathetic tone
 Aldosterone levels
 Fibrosis
 Hypertrophy
 Natriuresis/diuresis
Enhancing
Vasoconstriction
 Blood pressure
 Sympathetic tone
 Aldosterone
 Fibrosis
 Hypertrophy
Inhibiting
Abbreviations
Ang=angiotensin; ANP=atrial natriuretic peptide; AT1=angiotensin II type 1; BNP=B-type natriuretic peptide; CNP=C-type natriuretic peptide; NEP=neprilysin; RAAS=renin angiotensin aldosterone system
Following oral administration LCZ696 dissociates into the prodrug sacubitril (AHU377), which is further metabolized to LBQ657, and valsartan
LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor. LCZ696 dissociates into the neprilysin inhibitor prodrug sacubitril (AHU377), which is subsequently converted to an active form (LBQ657) that inhibits neprilysin – the enzyme that degrades the biologically active natriuretic peptides – and the AT1 receptor blocker valsartan. Of note, the biologically inert NT-proBNP is not a substrate for LBQ657, and as such still represents a measure of cardiac wall stress even in the setting of neprilysin inhibition.
Neprilysin also contributes to the breakdown of angiotensin, which provides the rationale for simultaneous inhibition of neprilysin and blockade of the renin-angiotensin-aldosterone system (RAAS).
LCZ696 thus simultaneously inhibits the RAAS and augments the natriuretic peptide system, providing the potential for complementary benefits in heart failure.
References
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
*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

6. Study design

7. PARADIGM-HF: Study design
Randomization
n=8442
Double-blind
Treatment period
2 Weeks
1–2 Weeks
2–4 Weeks
Single-blind active run-in period
LCZ mg BID‡
Enalapril
10 mg BID*
LCZ696
100 mg BID†
LCZ696
200 mg BID‡
Enalapril 10 mg BID§
PARADIGM-HF: study design
The effect of LCZ696 on heart failure (HF) outcomes was assessed in the ‘Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure’ (PARADIGM-HF) study in patients with chronic HF (New York Heart Association [NYHA] II–IV) with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] ≤40%, lowered to ≤35% in a protocol amendment) and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide (BNP) levels. Patients entered a single-blind run-in period where they received enalapril 10 mg twice daily (BID) for 2 weeks or, for those patients currently treated with angiotensin receptor blockers (ARBs) or lower doses of angiotensin-converting enzyme inhibitor (ACEIs), received enalapril 5 mg BID for 1–2 weeks followed by enalapril 10 mg BID. After receiving enalapril 10 mg for 2 weeks, patients received LCZ mg BID, which was up-titrated after 1–2 weeks to LCZ mg BID for 2–4 weeks. Patients who tolerated both enalapril 10 mg BID and LCZ mg BID for at least 2 weeks were then randomized to double-blind treatment with either LCZ mg BID or enalapril 10 mg BID in addition to optimal therapy for chronic HF.
The primary outcome was CV death or HF hospitalization and was event driven (2,410 patients with primary events).
The study was event-driven and was initially planned to complete when 2,410 patients achieved the primary composite endpoint of cardiovascular (CV) death or hospitalization for HF (expected to be approximately 34 months).
Abbreviations
ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor neprilysin inhibitor; BID=twice daily; BNP=B-type natriuretic peptide; CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; NT-proBNP=N-terminal pro-B-type natriuretic peptide; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; TDD=total daily dose
References
McMurray et al. Eur J Heart Fail. 2013;15:106273. 
McMurray et al. Eur J Heart Fail. 2014;16:81725. 
Median of 27 months’ follow-up
On top of standard HFrEF therapy (excluding ACEIs and ARBs)
*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: /NEJMoa

8. PARADIGM-HF: LCZ696 dose selection rationale
AT1 receptor blockade
LCZ 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 LCZ mg provides ~90% of its maximal NEP inhibition4,5
Both LCZ 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
Abbreviations
NEP=neprilysin; MI=myocardial infarction; OVERTURE=Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events; QD=once daily; Val-HeFT=valsartan heart failure trial; VALIANT=valsartin in acute myocardial infarction;
References
McMurray et al. Eur J Heart Fail. 2013;15:1062–73
Valsartan Heart Failure Trial Investigators. N Engl J Med 2001;345:166775
Valsartan in Acute Myocardial Infarction Trial Investigators. N Engl J Med 2003;349:18931906
Gu et al. J Clin Pharmacol 2010;50:401–14
Ruilope et al. Lancet 2010;375:12551266.
Packer et al. Circulation 2002;106:920–6;
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.

9. 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)
PARADIGM-HF: key inclusion and exclusion criteria
For eligibility to be included in the study, patients were required to fulfil all of the following criteria: informed written consent prior to any assessment; male or female outpatient aged ≥18 years; a diagnosis of chronic HF (NYHA class II–IV and left ventricular ejection fraction [LVEF] ≤40% (lowered to ≤35% in a protocol amendment) plus either BNP ≥150 pg/mL (N-terminal proBNP [NT-proBNP] ≥600 pg/mL) or BNP ≥100 pg/mL (NT-proBNP ≥400 pg/ml) and a hospitalization for HF within the last 12 months; on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at a stable dosage (equivalent to enalapril ≥10 mg/day) for ≥4 weeks; treated with a β-blocker at a stable dosage for ≥4 weeks, unless contraindicated or not tolerated; optimized dosing of background HF medications and use of aldosterone antagonists, where indicated.
The PARADIGM-HF study excluded patients with any of the following: history of angioedema; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at screening or >35% decrease in eGFR between screening and end of enalapril run-in or 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 an ACEI and an ARB; symptomatic hypotension (systolic blood pressure [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. Additional exclusion criteria are described in the study design publication.1
Abbreviations
ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; BNP=B-type natriuretic peptide; eGFR=estimated glomerular filtration rate; HF=heart failure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; NT-proBNP=N-terminal proBNP; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; SBP=systolic blood pressure
References
McMurray et al. Eur J Heart Fail. 2013;15:106273. 
*The ejection fraction entry criteria was lowered to ≤35% in a protocol amendment #Dosage equivalent to enalapril ≥10 mg/day
McMurray et al. Eur J Heart Fail. 2013;15:1062–73

10. PARADIGM-HF: Key exclusion criteria
History of angioedema
eGFR <30 mL/min/1.73 m2 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
PARADIGM-HF: key inclusion and exclusion criteria
For eligibility to be included in the study, patients were required to fulfil all of the following criteria: informed written consent prior to any assessment; male or female outpatient aged ≥18 years; a diagnosis of chronic HF (NYHA class II–IV and left ventricular ejection fraction [LVEF] ≤40% (lowered to ≤35% in a protocol amendment) plus either BNP ≥150 pg/mL (N-terminal proBNP [NT-proBNP] ≥600 pg/mL) or BNP ≥100 pg/mL (NT-proBNP ≥400 pg/ml) and a hospitalization for HF within the last 12 months; on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at a stable dosage (equivalent to enalapril ≥10 mg/day) for ≥4 weeks; treated with a β-blocker at a stable dosage for ≥4 weeks, unless contraindicated or not tolerated; optimized dosing of background HF medications and use of aldosterone antagonists, where indicated.
The PARADIGM-HF study excluded patients with any of the following: history of angioedema; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at screening or >35% decrease in eGFR between screening and end of enalapril run-in or 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 an ACEI and an ARB; symptomatic hypotension (systolic blood pressure [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. Additional exclusion criteria are described in the study design publication.1
Abbreviations
ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; BNP=B-type natriuretic peptide; eGFR=estimated glomerular filtration rate; HF=heart failure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; NT-proBNP=N-terminal proBNP; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; PCI=percutaneous coronary intervention; SBP=systolic blood pressure
References
McMurray et al. Eur J Heart Fail. 2013;15:106273. 
McMurray et al. Eur J Heart Fail. 2013;15:1062–73

11. PARADIGM-HF: Primary objective
To evaluate the effect of LCZ 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
Abbreviations
CV=cardiovascular; HF=heart failure; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure
Reference
McMurray et al. Eur J Heart Fail. 2013;15:106273.
McMurray et al. Lancet 2003;362:767–77
Swedberg et al. Lancet 2010;376:875–88
Zannad et al. N Engl J Med 2011;364:11–2
Cowie et al. Improving care for patients with acute heart failure. Oxford Health policy Forum 2014
Hunt et al. J Am Coll Cardiol 2009;53:e1–90
Yancy et al. Circulation 2013;128:e240–327
Rodriguez-Artalejo et al. Rev Esp Cardiol 2004;57:163–70
Dunlay et al. Circ Cardiovasc Qual Outcomes 2011;4:68–75;
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

12. 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
Abbreviations
ACEI=angiotensin-converting enzyme inhibitor; ARNI=angiotensin receptor neprilysin inhibitor; BNP=B-type natriuretic peptide; CV=cardiovascular; eGFR=estimated glomerular filtration rate; EQ-5D=EuroQol; HF=heart failure; KCCQ=Kansas City Cardiomyopathy Questionnaire; NYHA=New York Heart Association; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure
Reference
McMurray et al. Eur J Heart Fail. 2013;15:106273.
McMurray et al. Eur J Heart Fail. 2013;15:1062–73

13. Patient population and baseline characteristics

14. 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
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: /NEJMoa

15. PARADIGM-HF: Summary of baseline characteristics
LCZ696 (n=4187)
Enalapril
(n=4212)
Age, years
63.8 ± 11.5
63.8 ± 11.3
Women, n (%)
879 (21.0)
953 (22.6)
Ischemic cardiomyopathy, n (%)
2506 (59.9)
2530 (60.1)
LV ejection fraction, %
29.6 ± 6.1
29.4 ± 6.3
NYHA functional class, n (%) II III
2998 (71.6) (23.1)
2921 (69.3) (24.9)
SBP, mmHg
122 ± 15
121 ± 15
Heart rate, beats/min
72 ± 12
73 ± 12
NT pro-BNP, pg/mL (IQR)
1631 (885–3154)
1594 (886–3305)
BNP, pg/mL (IQR)
255 (155–474)
251 (153–465)
History of diabetes, n (%)
1451 (34.7)
1456 (34.6)
Treatments at randomization, n (%)
Diuretics
3363 (80.3)
3375 (80.1)
Digitalis
1223 (29.2)
1316 (31.2)
β-blockers
3899 (93.1)
3912 (92.9
Mineralocorticoid antagonists
2271 (54.2)
2400 (57.0)
ICD
623 (14.9)
620 (14.7)
CRT
292 (7.0)
282 (6.7)
*mean ± standard deviation, unless stated
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: /NEJMoa

16. Results

17. Primary endpoint: Death from CV causes or first hospitalization for HF
1.0
0.6
0.4
0.2
180
360
540
720
900
1080
1260
Enalapril
LCZ696
Hazard ratio = 0.80 (95% CI: 0.73–0.87)
p<0.001
Cumulative probability
Days since randomization
No at risk
LCZ
Enalapril
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: /NEJMoa

18. Components of primary endpoint: Death from CV causes
1.0
0.6
0.4
0.2
180
360
540
720
900
1080
1260
Enalapril
LCZ696
Hazard ratio = 0.80 (95% CI: 0.71–0.89)
p<0.001
Cumulative probability
Days since randomization
No at risk
LCZ
Enalapril
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: /NEJMoa

19. Components of primary endpoint: First hospitalization for HF
1.0
0.6
0.4
0.2
180
360
540
720
900
1080
1260
Enalapril
LCZ696
Hazard ratio = 0.79 (95% CI: 0.71–0.89)
p<0.001
Cumulative probability
Days since randomization
No at risk
LCZ
Enalapril
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: /NEJMoa

20. Primary outcome Outcome, n % LCZ696 (n=4187) Enalapril (n=4212)
Hazard ratio*
(95% CI)
p-value‡
Primary composite outcome
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)
First hospitalization for worsening of HF
537 (12.8)
658 (15.6)
0.79 (0.71–0.89)
*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
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: /NEJMoa

21. Secondary outcomes Outcome LCZ696 (n=4187) Enalapril (n=4212)
Hazard ratio*
or difference (95% CI)
p-value‡
Death from any cause, n (%)
711 (17.0) )
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
*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 m2 decline in eGFR from randomization or to a value of <60 ml/min/1.73 m2, or (c) progression to end-stage renal disease
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: /NEJMoa

22. Death from any cause
1.0
0.6
0.4
0.2
180
360
540
720
900
1080
1260
Enalapril
LCZ696
Hazard ratio = 0.84 (95% CI: 0.76–0.93)
p<0.001
Cumulative probability
Days since randomization
No at risk
LCZ
Enalapril
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: /NEJMoa

23. Systolic blood pressure during run-in and after randomization
140
Compared with the randomization level, the mean SBP at 8 months was ± 0.4 mmHg lower in the LCZ696 group than in the enalapril group (p<0.001)
When modeled as a time-dependent covariate, the difference in BP was not a determinant of the incremental benefits of LCZ696
120
SBP (mmHg)
100
Enalapril
LCZ696 80
Randomization
Mean difference (LCZ696–enalapril):
–2.70 (–3.07, –2.34) (mmHg)
p-value: <0.001 60
–11w 4m 8m
1yr
2yrs
3yrs
Time
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: /NEJMoa (Supplementary appendix)

24. Prospectively defined safety events
Event, n (%)
LCZ696
(n=4187)
Enalapril
(n=4212)
p-value‡
Hypotension
Symptomatic
588 (14.0)
388 (9.2)
<0.001
Symptomatic with SBP <90 mmHg
112 (2.7)
59 (1.4)
Elevated serum creatinine
≥2.5 mg/dL
139 (3.3)
188 (4.5)
0.007
≥3.0 mg/dL
63 (1.5)
83 (2.0)
0.10
Elevated serum potassium
>5.5 mmol/L
674 (16.1)
727 (17.3)
0.15
>6.0 mmol/L
181 (4.3)
236 (5.6)
Cough
474 (11.3)
601 (14.3)
Angioedema (adjudicated by a blinded expert committee)
No treatment or use of antihistamines only
10 (0.2)
5 (0.1)
0.19
Catecholamines or glucocorticoids without hospitalization
6 (0.1)
4 (0.1)
0.52
Hospitalized without airway compromise
3 (0.1)
1 (<0.1)
0.31
Airway compromise
---
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: /NEJMoa

25. For further information please contact: Sander de Groot Medical Scientific Liaison Heart Failure

26. 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
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: /NEJMoa

27. 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
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: /NEJMoa