Future perspectives in Heart failure Sarajevo, May 2010

Have we been successful?

Cumulative benefit of poly-pharmacy in mild-moderate HF Diuretic/ digoxin ACE inhib. 13.2 8.8 8.7 6.1 5 10 15 20 1 year mortality (%) 15.7 12.4 Beta-blocker ARB CHARM-Added (Beta-blocker subgroup) 2003 CIBIS 2 1999 SOLVD-T 1991

Are there failures?

ACUTE HEART FAILURE

Negative trials TRIAL Drug Duration (Mo) N PEP ESSENTIAL Enoximone Low dose NEGATIVE 6 1.854 . AC death/CV hosp. . PGA . 6 MWT SURVIVE Levosimendan vs Dobutamine 1.327 AC death REVIVE Levosimendan vs pbo Composite better Increase death 600 Composite EVEREST Tolvaptan 3.600 . AC death 6

EVEREST: Primary Endpoint All-Cause Mortality CV Mortality or HF Hospitalization HR 0.98; 95% CI (.87–1.11) Meets criteria for non-inferiority 3 6 9 12 15 18 21 24 2072 1812 1446 1112 859 589 404 239 97 2061 1781 1440 1109 840 580 400 233 95 0.0 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.0 HR 1.04; 95%CI (.95–1.14) 0.9 0.8 0.7 Proportion alive Proportion without event 0.6 0.5 0.4 Peto-Peto Wilcoxon Test: P = .68 Peto-Peto Wilcoxon Test: P = .55 0.0 TLV 2072 1562 1146 834 607 396 271 149 58 TLV PLC 2061 1532 1137 819 597 385 255 143 55 PLC 3 6 9 12 15 18 21 24 Months In Study Months In Study Tolvaptan Placebo Konstam MA. JAMA. 2007. 7

Probability of Surviving Days Since Start of Study Drug Infusion SURVIVE 1.0 Levosimendan 0.9 Dobutamine 0.8 Probability of Surviving 0.7 Overall 180-d Mortality: 27% 0.6 0.5 During the 180 days after study drug infusion, there were 173 deaths (26%) in the levosimendan group and 185 deaths (28%) in the dobutamine group. Analysis of all-cause mortality at 31 days and cardiovascular mortality at 180 days also showed no statistically significant difference between the treatment groups. 0.4 30 60 90 120 150 180 Days Since Start of Study Drug Infusion A Mebazaa et al. JAMA 2007; 297:1883-1891 8 45

Adenosine Antagonists Afferent arteriolar constriction Proximal tubular sodium reabsorption Furosemide Increasd distal tubular sodium concentration Adenosine release

Randomisation Rolofylline to placebo, 2:1 PROTECT Placebo Rolofylline 30 mg Treatment phase Follow-up Randomisation Rolofylline to placebo, 2:1 All cause mortality CV/Renal hosp All cause mortality Kidney Function Days 1 2 3 4 5 6 7 14 60 180 Screening AHF & fluid overload, need of iv loop diuretic CrCl, 20-80 ml/min

Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09) Primary Endpoint Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09) Percent of Patients 36.0 44.2 19.8 40.6 37.5 21.8 20 40 60 80 100 Placebo Ro 30 mg Treatment Success Patient Unchanged Treatment Failure p=0.348 for comparison of distribution using the van Elteren extension of Wilcoxon test

Patient heterogeneity Substrate (ischaemic / non ischaemic, HT). Trigger ( ACS, arrhythmias, Hypertension crisis). Pathophysiology ( systolic vs diastolic HF / low vs high BP). Lack of standard comparator. Dose, Time points, Endpoints.

Heart failure with Preserved Ejection Fraction

RAAS blockade in HF-PEF: two key trials CHARM-Preserved Death or HF hospitalization PEP-CHF Death or HF hospitalization Cumulative incidence (%) HR 0.92; 95% CI (0.70-1.21); p=0.545 Placebo Perindopril 10 20 30 40 12 24 36 Cumulative incidence (%) Month 48 40 Placebo Candesartan 30 20 10 HR 0.92; 95% CI (0.80-1.05); p=0.221 12 24 36 48 Month Yusuf et al. Lancet 2003 Cleland et al. Eur Heart J 2006

Cumulative Incidence of Primary Events (%) I-PRESERVE: Primary Endpoint Death or protocol specified CV hospitalization Months from Randomization Cumulative Incidence of Primary Events (%) 40 - 0 - 10 - 20 - 30 - 6 12 18 24 36 42 30 48 60 54 2067 1929 1812 1730 1640 1513 1291 1569 1088 497 816 2061 1921 1808 1715 1618 1466 1246 1539 1051 446 776 No. at Risk Irbesartan Placebo HR (95% CI) = 0.95 (0.86-1.05) Log-rank p=0.35

Treatment Of Preserved Cardiac function heart failure with an Aldosterone anTagonist

New drugs

New drug trials Safe Inotropes (Istaroxime/Cardiac Myosin activator)? Renin inhibitors (ATMOSPHERE: aliskiren vs enalapril vs combination)? Safe Inotropes (Istaroxime/Cardiac Myosin activator)? New vasodilators /GMPc modulators. Chimeric Natriuretic peptides. Sinus node inhibition (SHIFT: ivabradine vs placebo. NEP inhibitors(+ ARB).

ATMOSPHERE: design overview Primary outcome: CV death or heart failure hospitalization (event driven: 2162 patients) Randomization Enalapril 10 mg twice daily (n=2,200) Open-label run-in Enalapril Enalapril +Aliskiren Aliskiren 300 mg once daily (n=2,200) Patients enrolled in the ALLAY study will be randomized to receive 2-weeks’ once-daily treatment with aliskiren 150 mg, losartan 50 mg, or aliskiren/losartan 150/50 mg combination therapy. After 2-weeks, the dosage of each treatment will be doubled for the remaining 34 weeks of the study. References 1. Clinicaltrials.gov. A Clinical Study Comparing the Efficacy and Safety of Aliskiren in Combination With Losartan Compared to Losartan on the Regression of Left Ventricular Hypertrophy in Overweight Patients With Essential Hypertension. ClinicalTrials.gov Identifier: NCT00219141. Accessed at: http://www.clinicaltrials.gov/ct/show/NCT00219141?order=1 2. Data on File, Novartis 2007. Study SPP100A2316. Aliskiren 300mg/enalapril 20 mg Daily (n=2,200) Double-blind 4-8 weeks ~48 weeks (event driven) 19

CK-1827452: Background Preclinical Selective activator of cardiac myosin Prolongs duration of systole by Increasing entry rate of myosin into force-producing state Therefore overall number of active cross-bridges increases Increases stroke volume No change in dP/dtmax No increase in MVO2

A New Calcium Cycling Modulator Istaroxime A New Calcium Cycling Modulator

HORIZON-HF PCWP During infusion, there was a rapid and sustained decrease in PCWP that was maintained at 6 hours with all 3 doses of istaroxime when compared to placebo. Note the trend towards increase in PCWP after discontinuation of istaroxime. PCWP Infusion period Post-infusion

HORIZON-HF Conclusions Istaroxime given over a short period in patients admitted with HF and LVEF ≤ 35% receiving standard therapy: decreased PCWP and LVEDV increased CI Improved some indices of diastolic function.* No changes in neurohormones, renal function, or troponin release. In contrast to other inotropic agents available, these changes were associated with: Increase in SBP. Reduction in HR. In conclusion, Mr. Chairman, A six-hour infusion of istaroxime in patients admitted with heart failure and reduced ejection fraction improved central hemodynamics, decreased left ventricular end-diastolic volume, improved indices of diastolic function. This hemodynamic improvement observed with istaroxime was not associated with changes in neurohormonal profile, renal function, or troponin release. In contrast to other available inotropes, these changes were associated with increases in systolic blood pressure and a reduction in heart rate. NEXT

Relaxin Mechanisms of Action Relaxin Receptor LGR7 Vasodilation NO, cGMP effectors Induction of NOS II/III Upregulation of endothelial endothelin type B receptor, which mediates vasodilation Preferential dilation of constricted vessels Relaxin-upregulated ETB receptors act as vasodilating ET-1 sink Anti-inflammatory Down-modulation of inflammatory cytokines linked to outcome in HF (TNF-, TGF-) Other: Anti-ischemic, Anti-apoptotic, Anti-fibrotic 24

CD-NP: A Rationally Designed Natriuretic Peptide CNP S G L K C F D R I M NPR-B agonist Vasodilation CD-NP P N A T - + DNP E V Y H NPR-A agonist Renal function = 25

HR predicts outcome (placebo group) Fox K, et al. Lancet. 2008;372:817-821.

SHIFT design paper

Study design 6500 pts randomised Results ESC 2010 NYHA II-IV . EF<35% .HF hosp in prior 12 months .HR >70 bpm 6500 pts randomised Results ESC 2010 Composite primary endpoint Cardiovascular death Hospitalisation for worsening heart failure www.controlled-trials.com 28

Angiotensin Receptor Neprilysin inhibitor A new approach? ARNi Angiotensin Receptor Neprilysin inhibitor

LCZ 696 Molecular complex of: An ARB - valsartan A NEP inhibitor – AHU 377

PARADIGM-HF A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure and reduced ejection fraction LCZ696 200 mg BID (n~4000) Enalapril 10 mg BID (n~4000) Outcomes driven (estimated mean f/u = 30-32 months) 1-2 weeks Enalapril 5-10 mg bid LCZ 100 mg bid LCZ 200 mg bid 2 weeks Prior ACEi/ARB use discontinued Single-blind period Double-blind period N = 7980 (1:1 randomization) Primary objectives Evaluate if LCZ696 is superior in delaying time to first occurrence of either CV mortality or HF hospitalization in CHF pts (NYHA Class II – IV) with reduced ejection fraction Secondary objectives All cause mortality Renal progression (eGFR change) Clinical summary score (assessed by KCCQ) Patient population 7980 patients with CHF NYHA class II – IV and reduced ejection fraction (LVEF < 40%) BNP>150 pg/ml (NTproBNP > 600 pg/ml) or BNP > 100 pg/ml (NTproBNP > 400 pg/ml) and hospitalization within the last 12 months. 31

New trials in acute HF

ASCEND-HF design completed in 2010 # 7000 pts enrolled

Design overview Acute HF Aliskiren Aliskiren 300 mg 150 mg Placebo Primary outcome: CV death or HF hospitalization at 6 months (381 events) Randomization Acute HF LVEF<40% BNP >400pg/mL SBP≥110mmHg ~1,800 patients Aliskiren 150 mg Aliskiren 300 mg Placebo Abbreviations ACEI = angiotensin-converting enzyme inhibitor ARB = angiotensin receptor blocker HF = heart failure Reference Data on File, Novartis Pharma AG, 2008: Study SPP100A2368 Protocol. Conventional therapy‡ In-hospital entry and initiation 2 weeks ~15 months (event-driven)* ‡ Except concomitant use of an ACEI and ARB * Follow-up at Week 2, Month 1, 2 and 3, with on-going assessments every 3 months thereafter Aliskiren HF programme slide kit Item code: TBC Release date: January 2009 34 34

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