Sessions Formació Continuada en Cardiologia i Especialitats Relacionades Cardioactualitat: Noves estratègies terapèutiques en el maneig de la IC

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1 Sessions Formació Continuada en Cardiologia i Especialitats Relacionades Cardioactualitat: Noves estratègies terapèutiques en el maneig de la IC J. Comin Colet Cap de Secció del Servei de Cardiologia i Coordinador del GREC

2 Novetats Terapèutiques Recents en IC Sistòlica (ESC Congress Barcelona 2014) Regulació Autonòmica Deficiència de Ferro Antagonisme Neurohormonal

3 Novetats Terapèutiques Recents en IC Sistòlica (ESC Congress Barcelona 2014) Regulació Autonòmica Deficiència de Ferro Antagonisme Neurohormonal

4 Effect of ferric carboxymaltose on functional capacity in patients with heart failure and iron deficiency (CONFIRM-HF) Piotr Ponikowski, Dirk J. van Veldhuisen, Josep Comin-Colet et al. for the CONFIRM-HF Investigators

5 CONFIRM-HF Study design Design: Multicentre, randomised (1:1), double-blind, placebo-controlled Main inclusion criteria: NYHA class II / III, LVEF 45% BNP > 100 pg/ml or NT-proBNP > 400 pg/ml Iron deficiency: serum ferritin <100 ng/ml or ng/ml if TSAT <20% Hb < 15 g/dl Blinding: Clinical staff: unblinded and blinded personnel Patients: usage of curtains and black syringes for injections Correction phase FCM up to 2000mg (2 x mg i.v.) Maintenance phase FCM treatment continues if ID is not corrected (500mg i.v.) Screening R FCM Placebo 1 EP: 6MWT D0 W6 W12 W24 W36 W52 Ponikowski P et al. ESC Heart Fail J 2014, in press

6 Primary endpoint: 6-minutes walking distance at week 24 LSM change in 6MWT distance from baseline (m) FCM improved 6MWT at week 24: FCM vs placebo: 33 ± 11 m (least squares mean ± standard error) P=0.002 FCM (n=150) Placebo (n=151) Week 24

7 Placebo better Odds ratio (95% CI) FCM better Placebo better Odds ratio (95% CI) FCM better Secondary endpoints: Changes in PGA & NYHA class over time Self-reported Patient Global Assessment (PGA) score No. of patients FCM Placebo P=0.29 P=0.035 P=0.047 P=0.001 P= Weeks since randomization Weeks since randomisation New York Heart Association Functional (NYHA) class P<0.001 P< P=0.004 No. of patients FCM Placebo P=0.093 P= Weeks since randomization Weeks since randomisation

8 Secondary end-point: Changes in 6MWT and Fatigue score over time Fatigue score change from baseline LSM 6MWT change from baseline LSM FCM vs placebo LSM (95% CI) P=0.16 BL ( 5, 33) P= ( 3, 35) 6MWT P= (13, 53) P< (21, 62) P< (16, 57) Weeks since randomisation FCM Placebo FCM vs placebo LSM (95% CI) Fatigue score P= P=0.40 P=0.002 P< P= Weeks since -1.4 randomisation BL ( 0.5, 0.2) 0.5 ( 0.9, 0.1) 0.6 ( 1.0, 0.2) 0.8 ( 1.2, 0.4) 0.7 ( 1.1, 0.2)

9 EQ-5D VAS change from baseline LSM Overall KCCQ score change from baseline LSM Secondary end-point: Changes in Quality of Life over time FCM vs placebo LSM (95% CI) P= ( 1.2, 4.8) P= (0.2, 6.4) KCCQ P=0.41 P=0.004 P=0.010 BL ( 1.9, 4.6) 5.0 (1.6, 8.3) 4.5 (1.1, 7.9) Weeks since randomisation FCM Placebo FCM vs placebo LSM (95% CI) P= ( 1.4, 4.4) P= ( 0.2, 5.8) EQ-5D VAS score P= ( 0.3, 5.9) P= (2.0, 8.5) P=0.120 BL ( 0.7, 5.9) Weeks since randomization

10 Secondary end-point: First hospitalization due to worsening HF Hospitalization rate (per 100 subjects) 30 Placebo FCM Log rank test P= Time (days) No. of subjects at risk Placebo FCM

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12 Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure John J.V. McMurray, Milton Packer, Akshay S. Desai et al for the PARADIGM-HF Investigators

13 Fisiopatologia de la IC Sistòlica Damage to cardiac myocytes and extracellular matrix leads to changes in the size, shape and function of the heart and cardiac wall stress Systemic neurohormonal overactivation Vasoconstriction, fibrosis, apoptosis, hypertrophy, cellular and molecular alterations, myotoxicity Maladaptive remodeling and progressive worsening of LV function Hemodynamic alterations, salt and water retention Morbidity and mortality: arrhythmias, pump failure HF symptoms: dyspnea, edema, fatigue 13 McMurray. N Engl J Med 2010;362:228 38; Francis et al. Ann Intern Med 1984;101:370 7; Krum, Abraham. Lancet 2009;373: HFrEF* - heart failure with reduced ejection function

14 Activació Neurohormonal a la IC Natriuretic peptide system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy HF SYMPTOMS & PROGRESSION Sympathetic nervous system Epinephrine Norepinephrine Renin angiotensin aldosterone system Ang II α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis Ang=angiotensin; AT 1 R=angiotensin II type 1 receptor; HF=heart failure; NPs=natriuretic peptides; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012; ; Schrier & Abraham. N Engl J Med 2009;341:577 85

15 Antagonisme Neurohormonal SNS β-blockers NP system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy INACTIVE FRAGMENTS HF SYMPTOMS & PROGRESSION Epinephrine Norepinephrine RAAS Ang II α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis RAAS inhibitors (ACEI, ARB, MRA) ACEI=angiotensin-converting-enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker; AT 1 = angiotensin II type 1; HF=heart failure; MRA=mineralocorticoid receptor antagonist; NEP=neprilysin; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=reninangiotensin-aldosterone system; SNS=sympathetic nervous system 1. McMurray et al. Eur J Heart Fail. 2013;15: ; 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; ; Schrier & Abraham N Engl J Med 2009;341:577 85

16 Reduction in relative risk of mortality vs placebo Beneficis Aplicació Hipòtesi Neurohumoral IC Survival rates in chronic HF have improved with the introduction of new therapies 1 ACEI* β-blocker* MRA* ARB* 16% (4.5% ARR; mean follow up of 41.4 months) SOLVD-T 1,2 34% (5.5% ARR; mean follow up of 1.3 years) CIBIS-II 3 30% (11.0% ARR; mean follow up of 24 months) RALES 4 17% (3.0% ARR; median follow-up of 33.7 months) CHARM- Alternative 5 However, significant mortality remains: ~50% of patients die within 5 years of diagnosis McMurray et al. Eur Heart J 2012;33: ; 2. SOLVD Investigators. N Engl J Med 1991;325: ; 3. CIBIS-II Investigators. Lancet 1999;353:9 13; 4. Pitt et al. N Engl J Med 1999;341:709-17; 50; 5. Granger et al. Lancet 2003;362:772 6; 6. Go et al. Circulation 2014;129:e28-e292; 7. Yancy et al. Circulation 2013;128:e ; 8. Levy et al. N Engl J Med 2002;347:

17 Està tot dit en el Bloqueig Neurohormonal? SNS β-blockers NP system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy Neprilysin inhibitors INACTIVE FRAGMENTS HF SYMPTOMS & PROGRESSION Epinephrine Norepinephrine RAAS Ang II α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis RAAS inhibitors (ACEI, ARB, MRA) ACEI=angiotensin-converting-enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker; AT 1 = angiotensin II type 1; HF=heart failure; MRA=mineralocorticoid receptor antagonist; NEP=neprilysin; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=reninangiotensin-aldosterone system; SNS=sympathetic nervous system 1. McMurray et al. Eur J Heart Fail. 2013;15: ; 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; ; Schrier & Abraham N Engl J Med 2009;341:577 85

18 Beneficis dels Pèptids Natriurètics Endògens Release of ANP and BNP from heart and CNP in vasculature 1 Sympathetic outflow 2 Vasopressin 2 Salt appetite and water intake 2 CNP (endothelium) 3 ANP/BNP 2 Relaxation; arterial stiffness 4 Hypertrophy 2,5 7 Fibroblast proliferation 4,8,9 Na + /H 2 O loss 2 Aldosterone 2 Renin 2 Vasodilation 2,3,4 Systemic vascular resistance 4 Pulmonary artery pressure 4 Pulmonary capillary wedge pressure 4 Right atrial pressure 4 1. Forssmann et al. Arch Histol Cytol 1989;52 Suppl: ; 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; ; 7. Horio et al. Endocrinology 2003;144: ; 8. D'Souza et al. Pharmacol Ther 2004 ;101:113 29; 9. Cao & Gardner. Hypertension 1995;25:227 34;

19 LCZ696: inhibidor del receptor de l angiotensina i de la neprilisina (ARNI en anglès) LCZ696: inhibició simultània de la NEPRILISINA + Receptor AT LCZ696 és una molècula complexe amb dues fraccions actives: 2,3 sacubitril (AHU377) un profàrmac metabolitzat a l inhibidor de la neprilisina LBQ657, + valsartan antagonista del receptor AT 1 LCZ696 en 3D 2 ARNI=angiotensin receptor neprilysin inhibitor; AT 1 =angiotensin II type 1 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

20 LCZ696 Mecanisme Acció LCZ696 Natriuretic and other vasoactive peptides* RAAS Sacubitril (AHU377; pro-drug) Angiotensinogen (liver secretion) Ang I Inactive fragments LBQ657 (NEP inhibitor) Valsartan Ang II Enhancing Vasorelaxation Blood pressure Sympathetic tone Aldosterone levels Fibrosis Hypertrophy Natriuresis/diuresis HN O HO O OH O O N O OH N N N NH AT 1 Receptor Inhibiting 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

21 Per què la inhibició de la NEP s ha d acompanyar de bloqueig dels AT1? Angiotensinogen Renin Ang I ACE Ang II NEP NEP Ang-(1 7) Inactive fragments AT 1 receptor Signaling cascade Biological actions Hypertrophy Fibrosis Vasoconstriction Hypertrophy Na + /H 2 O retention Aldosterone release Norepinephrine release Sympathetic tone ACE=angiotensin converting enzyme; AT 1 = angiotensin II type 1; Ang=angiotensin; NEP=neprilysin; RAAS=renin angiotensin aldosterone system 1. Von Lueder et al. Circ Heart Fail 2013;6: ; 2. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131 9

22 En que es difgerencia de l Omapatrilat Bradykinin breakdown Omapatrilat inhibits ACE, APP and NEP Active bradykinin Inactive bradykinin ACE APP NEP DPP-4 LCZ696 inhibits only NEP Active bradykinin Inactive bradykinin ACE=angiotensin-converting enzyme; APP=aminopeptidase P; AT 1 =angiotensin II type 1; DPP- 4=dipeptidyl peptidase-4; NEP=neprilysin The information presented in this slide is from publically available data and not head-to head clinical trials 1. McMurray et al. Eur J Heart Fail. 2014;16:817 25; 2. Fryer et al. Br J Pharmacol 2008;153:947 55; 3. Gu et al. J Clin Pharmacol 2010;50:401 14; 4. McMurray et al. Eur J Heart Fail. 2013;15:

23 The New Kid on The Block SNS β-blockers NP system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy Neprilysin inhibitors INACTIVE FRAGMENTS HF SYMPTOMS & PROGRESSION LCZ696 Epinephrine Norepinephrine RAAS Ang II α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis RAAS inhibitors (ACEI, ARB, MRA) ACEI=angiotensin-converting- enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker; AT 1 = 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 1. McMurray et al. Eur J Heart Fail. 2013;15: ; 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; ; Schrier & Abraham N Engl J Med 2009;341:577 85

24 PARADIGM-HF: disseny de l estudi Randomization (N=8,436 patients with chronic HF [NYHA Class II IV with LVEF 40%*] and elevated NTpro-BNP or BNP) Double-blind randomized treatment period Single-blind run-in period LCZ mg BID Enalapril 10 mg BID** LCZ mg BID LCZ mg BID Enalapril 10 mg BID Testing tolerability to target doses of enalapril and LCZ696 On top of standard HF therapy (excluding ACEIs and ARBs) 2 weeks 1 2 weeks 2 4 weeks ~34 months (event-driven) *The ejection fraction entry criteria was lowered to 35% in a protocol amendment; **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 [Epub ahead of print] Primary outcome: CV death or HF hospitalization (event driven: 2,410 patients with primary events)

25 PARADIGM-HF: pacients Characteristic* LCZ696 Enalapril (n=4187) (n=4212) Age, years 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 ± ± 6.3 NYHA functional class, n (%) II III 2998 (71.6) 969 (23.1) 2921 (69.3) 1049 (24.9) SBP, mmhg 122 ± ± 15 Heart rate, beats/min 72 ± ± 12 NT pro-bnp, pg/ml (IQR) 1631 ( ) 1594 ( ) BNP, pg/ml (IQR) 255 ( ) 251 ( ) 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

26 Cumulative probability Primary endpoint: Death from CV causes or first hospitalization for HF Enalapril LCZ Hazard ratio = 0.80 (95% CI: ) p< Days since randomization No at risk LCZ Enalapril McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

27 Cumulative probability Components of primary endpoint: Death from CV causes Enalapril LCZ696 Hazard ratio = 0.80 (95% CI: ) p< Days since randomization No at risk LCZ Enalapril McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

28 Components of primary endpoint: First hospitalization for HF Cumulative probability 1.0 Enalapril 0.6 LCZ Hazard ratio = 0.79 (95% CI: ) p< Days since randomization No at risk LCZ Enalapril McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

29 Cumulative probability Death from any cause Enalapril LCZ696 Hazard ratio = 0.84 (95% CI: ) p< Days since randomization No at risk LCZ Enalapril McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

30 Primary outcome Outcome, n % Primary composite outcome Death from CV causes or first hospitalization for worsening of HF LCZ696 (n=4187) Enalapril (n=4212) Hazard ratio* (95% CI) p-value 914 (21.8) 1117 (26.5) 0.80 ( ) <0.001 Death from CV causes 558 (13.3) 693 (16.5) 0.80 ( ) <0.001 First hospitalization for worsening of HF 537 (12.8) 658 (15.6) 0.79 ( ) <0.001 *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 30 McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

31 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 ( ) <0.001 Change in KCCQ clinical summary score at 8 months, mean ± SD ± ± ( ) New onset atrial fibrillation, n (%) 84 (3.1) 83 (3.1) 0.97 ( ) 0.83 Decline in renal function, n (%) 94 (2.2) 108 (2.6) 0.86 ( ) 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 m 2 decline in egfr from randomization or to a value of <60 ml/min/1.73 m 2, or (c) progression to end-stage renal disease 31 McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

32 SAEs 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) <0.001 Elevated serum creatinine 2.5 mg/dl 139 (3.3) 188 (4.5) 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) <0.001 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) 32 McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

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35 BACKUP

36 Enalapril 10 mg BID was chosen as the appropriate comparator dose Enalapril 10 mg BID is the regulatory gold-standard ACEI based upon CONSENSUS and SOLVD-T trial data 1 3 The target dose in PARADIGM-HF was 10 mg BID, a dose comparable with that achieved in major HF trials using enalapril 3 The mean daily dose achieved in CONSENSUS and SOLVD-T was 18.4 and 16.6 mg, respectively 1,2 Key HF trials with enalapril * Trial N Target dose (mg) Mean daily dose (mg) CONSENSUS BID 18.4 SOLVD-T BID 16.6 SOLVD-P BID 16.7 V-HeFT II BID 15.0 OVERTURE BID 17.7 CARMEN BID 16.8 * Adapted from McMurray et al. Eur J Heart Fail. 2013;15: CONSENSUS Study Group. N Engl J Med 1987;316: ; 2. SOLVD Investigators. N Engl J Med 1991;325: ; 3. McMurray et al. Eur J Heart Fail. 2013;15:

37 PARADIGM-HF: LCZ696 dose selection rationale AT 1 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 inhibition 4,5 Both LCZ and 200 mg QD (but not 100 mg LCZ696) provided meaningful pharmacodynamic effect (BP lowering) attributable to NEP inhibtion 5 BID dosing is considered essential to obtain 24-hour NEP inhibition 1,6 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, McMurray et al. Eur J Heart Fail. 2013;15: ; 2. Valsartan Heart Failure Trial Investigators. N Engl J Med 2001;345: ; 3. Valsartan in Acute Myocardial Infarction Trial Investigators. N Engl J Med 2003;349: ; 4. Gu et al. J Clin Pharmacol 2010;50:401 14; 5. Ruilope et al. Lancet 2010;375: ; 6. Packer et al. Circulation 2002;106:920 6.

38 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 38 McMurray et al. Eur J Heart Fail. 2013;15:

39 PARADIGM-HF: Key exclusion criteria History of angioedema egfr <30 ml/min/1.73 m 2 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 39 McMurray et al. Eur J Heart Fail. 2013;15:

40 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 hospitalization 1 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 HFrEF 1,9 ~80% of deaths in recent trials in patients with HFrEF are CV related 2 4 HF is associated with a high risk of hospitalization, 5 representing the leading cause of hospitalization in patients aged 65 years 5 8 The most commonly used primary endpoint in recent HF trials: CHARM-Added, SHIFT and EMPHASIS-HF McMurray et al. Eur J Heart Fail. 2013;15: ; 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:e ; 8.Rodriguez-Artalejo et al. Rev Esp Cardiol 2004;57:163 70; 9.Dunlay et al. Circ Cardiovasc Qual Outcomes 2011;4:68 75

41 PARADIGM-HF: Sample size and statistical considerations Annual event rate was estimated based on the CHARM-Added trial, adjusting for expected higher use of b-blockers and mineralocorticoid receptor antagonists (MRAs) Sample size was based on CV mortality 1,229 CV deaths were required for 80% power to detect a 15% relative risk reduction ~8,000 patients were required to ensure this number of events The study was event-driven: Planned to continue until 2,410 patients reached the primary composite endpoint >97% power to detect a 15% reduction in relative risk in the primary endpoint Three interim efficacy analyses were planned (after 1/3, 1/2 and 2/3 of primary events occurred) Data Monitoring Committee could recommend early trial termination based on efficacy, safety or futility reasons 41 McMurray et al. Eur J Heart Fail. 2013;15:

42 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 m 2 decline in egfr relative to baseline and to a value of <60 ml/min/1.73 m 2 (indicating the development of moderate renal dysfunction), or development of end-stage renal disease 42 McMurray et al. Eur J Heart Fail. 2013;15:

43 PARADIGM-HF: Exploratory objectives To compare the effects of LCZ696 and enalapril on: 43 Clinical outcomes Time to first occurrence of a composite of CV death, hospitalization for HF, non-fatal myocardial infarction, non-fatal stroke or resuscitated sudden death Hospitalization (all-cause and cause-specific) Days alive out of hospital at 12 months Time to treatment failure* Time to new onset diabetes Coronary revascularization procedure incidence Clinical composite score (NYHA class and patient global assessment) at 8 months Renal function Rate of decline in egfr Quality of life Other Quality of life assessed by total and individual scores of KCCQ and EQ-5D Biomarker changes from baseline Pharmacokinetics Health *Initiation resource of intravenous utilization treatment or a new (i.e. drug, number or an increase of in days/stays diuretic dose for >1 in month the for ICU; treatment number of worsening of HF ER visits) McMurray et al. Eur J Heart Fail. 2013;15:

44 PARADIGM-HF: Safety endpoints Monitoring for: Serious adverse events Hyperkalemia Symptomatic hypotension Increased serum creatinine Angioedema Other adverse events DMC performed a safety assessment after the first 100, 300 and 600 patients completed the single-blind run-in period Number of patients exposed to LCZ696 was limited to 600 until DMC completed a 4-week of double-blind therapy safety evaluation for the initial 200 randomized patients 44 McMurray et al. Eur J Heart Fail. 2013;15:

45 PARADIGM-HF: Patient disposition 10,513 patients entered enalapril run-in phase (median duration, 15 days; interquartile range [IQR], 14 21) 9419 entered LCZ696 run-in phase (median duration, 29 days; IQR, 26 35) 8442 underwent randomization 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 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 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 LCZ 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

46 Randomization SBP (mmhg) Systolic blood pressure during run-in and after randomization 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) Enalapril LCZ696 Mean difference (LCZ696 enalapril): 2.70 ( 3.07, 2.34) (mmhg) p-value: < w 4m 8m 1yr 2yrs 3yrs Time When modeled as a time-dependent covariate, the difference in BP was not a determinant of the incremental benefits of LCZ McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa (Supplementary appendix)