Highlight Session Heart failure and cardiomyopathies Michel KOMAJDA Paris France

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1 Highlight Session 2014 Heart failure and cardiomyopathies Michel KOMAJDA Paris France # esccongress

2 HEART FAILURE AND CARDIOMYOPATHIES TOPIC 1 Drug Therapy TOPIC 2 Device Therapy TOPIC 3 Transplantation

3 HEART FAILURE AND CARDIOMYOPATHIES Drug Therapy # esccongress

4 Angiotensin Receptor Neprilysin Inhibition LCZ696 Angiotensin receptor blocker Inhibition of neprilysin

5 Neprilysin inhibition potentiates actions of endogenous vasoactive peptides that counter maladaptive mechanisms in heart failure Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Inactive metabolites Neprilysin Neprilysin inhibition

6 Study Design Single-blind run-in period Double-blind period Enalapril LCZ696 LCZ mg BID 10 mg BID 100 mg BID 200 mg BID R 8399 patients randomized for ITT analysis Enalapril 10 mg BID 2 weeks 1-2 weeks 2-4 weeks M. Packer and JJV McMurray

7 PARADIGM-HF: Entry Criteria NYHA class II-IV heart failure LV ejection fraction d 40% 35% BNP e 100 (NT-proBNP e 400) if hospitalized for heart failure within 12 months or BNP e 150 (NT-proBNP e 600) if not hospitalized for heart failure within 12 months Stable ACE inhibitor or ARB at dose e enalapril 10 mg daily + beta-blocker (unless contraindicated or intolerant) + aldosterone antagonist (as indicated) Systolic BP e 95 mm Hg, egfr e 30 ml/min/1.73 m 2 and serum K d 5.4 meq/l at randomization

8 PARADIGM-HF Primary endpoint was cardiovascular death or hospitalization for heart failure, but the sample size of the trial was determined by effect on cardiovascular mortality The Data Monitoring Committee was allowed to stop the trial only for a compelling effect on cardiovascular mortality (in addition to the primary endpoint) M. Packer and JJV McMurray

9 PARADIGM-HF: Baseline Characteristics LCZ696 (n=4187) Enalapril (n=4212) Age (years) 63.8 ± ± 11.3 Women (%) 21.0% 22.6% Ischemic cardiomyopathy (%) 59.9% 60.1% LV ejection fraction (%) 29.6 ± ± 6.3 NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9% Systolic blood pressure (mm Hg) 122 ± ± 15 Heart rate (beats/min) 72 ± ± 12 N-terminal pro-bnp (pg/ml) 1631 ( ) 1594 ( ) B-type natriuretic peptide (pg/ml) 255 ( ) 251 ( ) History of diabetes 35% 35% Digitalis 29.3% 31.2% Beta-adrenergic blockers 93.1% 92.9% Mineralocorticoid antagonists 54.2% 57.0% ICD and/or CRT 26.9% 26.4%

10 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Patients at Risk LCZ696 Enalapril Enalapril (n=4212) LCZ696 (n=4187) HR = 0.80 ( ) P = Number needed to treat = Days After Randomization JJV McMurray et al NEJM 2014 online

11 PARADIGM-HF: Cardiovascular Death 32 Kaplan-Meier Estimate of Cumulative Rates (%) HR = 0.80 ( ) P = Number need to treat = 32 Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk LCZ696 Enalapril Days After Randomization JJV McMurray et al NEJM 2014 online

12 PARADIGM-HF: All-Cause Mortality 32 Kaplan-Meier Estimate of Cumulative Rates (%) HR = 0.84 ( ) P< Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk Days After Randomization LCZ696 Enalapril JJV McMurray et al NEJM 2014 online

13 PARADIGM-HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its Components LCZ696 (n=4187) Enalapril (n=4212) Hazard Ratio (95% CI) P Value Primary endpoint 914 (21.8%) 1117 (26.5%) 0.80 ( ) Cardiovascular death 558 (13.3%) 693 (16.5%) 0.80 ( ) Hospitalization for heart failure 537 (12.8%) 658 (15.6%) 0.79 ( )

14 PARADIGM-HF: Adverse Events LCZ696 (n=4187) Enalapril (n=4212) P Value Prospectively identified adverse events Symptomatic hypotension < Serum potassium > 6.0 mmol/l Serum creatinine e 2.5 mg/dl Cough < Discontinuation for adverse event Discontinuation for hypotension NS Discontinuation for hyperkalemia NS Discontinuation for renal impairment Angioedema (adjudicated) Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise

15 SAFETY Good renal and K+ safety More hypotension episodes (588 vs 388) p < but no more discontinuation (36 vs 29). More angioedema (19 vs 10).

16 QUESTIONS (1) Why was PARADIGM positive and OVERTURE (Omapatrilat) neutral? Run in period 12% patients discontinued for intolerance. Twice daily regimen fewer post dose BP / activity maintained at trough Drug = ARB + NEPi vs ACE-I + NEPi effect on Bradykinin fewer angioedema

17 Does PARADIGM HF set a new standard for first line therapy in HF with low EF? Cost effectiveness? Is benefit related to the action on natriuretic peptides? Role of ARNi in HFpEF? Role of ARNi in acute HF? QUESTIONS (2) How will ARNi compare to direct renin inhibitors? ( ATMOSPHERE) PARADIGM HF is the first modern trial proposing a substitution rather than an add on strategy in chronic HF.

18 Efficacy of beta-blockers in heart failure patients with atrial fibrillation: An individual patient data meta-analysis MDC 1993 ANZ 1997 COPERNICUS 2001 CIBIS 1994 CIBIS-II 1999 CAPRICORN 2001 US-HF 1996 MERIT-HF 1999 BEST 2001 Randomised controlled trials Reporting mortality as a major trial endpoint Planned >6m follow-up >300 patients (accounts for >95% of eligible RCT participants) CHRISTMAS * 2003 SENIORS 2005 Pooling of individual data from 18,254 heart failure patients randomised to beta-blockers or placebo, according to a published extraction and analysis plan. * Excluded from sinus rhythm versus AF analysis due to study exclusion criteria Kotecha D et al, Lancet 2014 on line

19 Efficacy of beta-blockers for preventing death All-cause mortality: Sinus rhythm All-cause mortality: Atrial fibrillation Unadjusted Kaplan-Meier survival (includes all reported deaths). Hazard ratios (HR) derived from the adjusted one-stage Cox model. Kotecha D et al, Lancet 2014 on line

20 Association between Use of Beta-Blockers and Mortality in Patients with Heart Failure and Preserved Ejection Fraction a Prospective Propensity Score-Matched Cohort Study 1-year survival 84% 5-year Survival β-blockers associated with reduced mortality in HFpEF 80% 79% 78% 51% 45% 42% 41% Un-adjusted HR: 0.73, p < Matched HR: 0.92, p = NNT=100 NNT=33 But β-blockers not associated with reduced combined mortality / HF hospitalization in HFpEF Lund LH on behalf of the Swedish Registry

21 Effect of ferric carboxymaltose on functional capacity in patients with heart failure and iron deficiency (CONFIRM-HF) Primary endpoint: change in 6-minutes walking test distance at Week 24 FCM vs placebo: 33 ± 11 m (least squares mean ± SE) LSM change in 6MWT distance from baseline (m) P=0.002 FCM (N=150) Placebo (N=151) -30 Week 24 Ponikowski P et al Eur Heart J 2014 online

22 Hospitalizations in CONFIRM-HF Secondary endpoint: First hospitalization due to worsening HF 30 Hospitalization rate (per 100 subjects) Log rank test P=0.009 Placebo FCM No. of subjects at risk Time (days) Placebo FCM FCM reduced the risk of recurrent hospitalisations due to worsening HF (post hoc): Hazard Ratio (95% CI) 0.30 ( ), p=0.0019

23 Study of dietary intervention under 100 MMOL in heart failure SODIUM-HF: A pilot study Meal plan Carbohydrates, 50-55%; protein, 15-20%; fat, 25-30%; and saturated fat, <7% Low-sodium diet 1500 mg/day Moderate-sodium diet 2300 mg/day Sample daily menus according to level of sodium restriction No fluid restriction (as per clinical practice) Adult Treatment Panel III. Circulation 2002;106: Lichtenstein AH et al. Circulation 2006;114(82-96.

24 SODIUM-HF Effect of 6 Month Sodium Diet in BNP and Quality of Life Low-sodium diet (n=18) Moderate-sodium diet (n=17) Baseline 6 months P value Baseline 6 months P value BNP, pg/ml 216 (25-670) 71 (39-222) ( ) 188 (69-410) 0.67 KCCQ overall summary score 59.6 ( ) 64.6 ( ) ( ) 72.4 ( ) 0.07 KCCQ: Kansas Cardiomyopathy Questionnaire Values are medians (25 th -75 th percentiles)

25 HEART FAILURE AND CARDIOMYOPATHIES Device Therapy # esccongress

26 Vagal Nerve Stimulation - Comparison of Ongoing Trials NECTAR-HF INOVATE-HF ANTHEM-HF Stimulator Precision, Boston Scientific Cardiofit, BioControl Medical Cyberonics IPG: Model 103 Number of patients 87 with paired data Trial design Double blind, randomised 2:1 (on/off) Open randomised 3:2 (device/no device) Not randomised, single arm study Primary Endpoint Stage 1:Change in LVESD from baseline Stage2: mortality Heart failure hospitalisations and all-cause mortality Procedure and device related complications Change in LVESV Duration of follow-up Stage 1: 6 months Stage 2: 18 months Up to 4.5 years per patient 6 months

27 Autonomic Regulation Therapy for the Improvement of Left Ventricular Function and Heart Failure Symptoms: The ANTHEM-HF Study Primary Efficacy Endpoints Echocardiographic Indices of LV Function Pooled LVESD LVESV LVEF (mm) (ml) (%) Left Right Pooled Left Right Pooled Left Right Pooled: n=57; Left: n=28; Right: n=29 Mean 95% Confidence Interval

28 NEuroCardiac TherApy for Heart Failure 6 month results Primary Endpoint LVESD ,9 4,9 5,2 5,1 LVESD (cm) Baseline 6 Months Baseline 6 Months Therapy Control Zannad F Eur Heart J 2014 online

29 HEART FAILURE AND CARDIOMYOPATHIES Transplantation # esccongress

30 MicroRNAs as non-invasive biomarkers of heart transplantation rejection 7 micrornas differentially expressed between rejecting and normal allografts 4 circulating mirnas identified allograft rejection MIR-155 Circulating micrornas identify ongoing heart allograft rejection and may spare 70-80% of endomyocardial biopsies JP Duong Van Huyen Eur Heart J online

31 How accurate is clinical assessment in the estimation of central venous pressure in acute heart failure? Insights from a prospective study 216 AHF patients presenting to the Emergency Department Examination of the neck veins by treating physician and then CVP measured Distribution of patients according to neck vein exam Central venous pressure values according to physical examination Percent Normal 32.4 Positive HJR 11.6 Distended neck veins 56 Total 100 ZL. Moreno Weidmann, (SW)

32 HIGHLIGHT 2014 HEART FAILURE AND CARDIOMYOPATHIES TAKE HOME MESSAGES In the PARADIGM-HF trial LCZ-696 improved cardiovascular mortality compared to enalapril in patients with chronic heart failure and reduced ejection fraction Comorbidities should be taken into consideration in the evaluation and treatment of patients with chronic heart failure Vagal Nerve stimulation should be evaluated in randomized clinical trials MicroRNAs are a promising biomarker for heart transplantation rejection

33 European Heart Journal (2014):doi: /eurheartj/ehu284

34 Flow chart for ICD implantation. European Heart Journal (2014):doi: /eurheartj/ehu284

35 Flow chart for ICD implantation. European Heart Journal (2014):doi: /eurheartj/ehu284

36 European Heart Journal (2014):doi: /eurheartj/ehu284