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Professor Michel KOMAJDA Université Pierre & Marie Curie – Hôpital Pitié Salpêtrière Département de Cardiologie Paris (France) Future perspectives in Heart.

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Presentation on theme: "Professor Michel KOMAJDA Université Pierre & Marie Curie – Hôpital Pitié Salpêtrière Département de Cardiologie Paris (France) Future perspectives in Heart."— Presentation transcript:

1 Professor Michel KOMAJDA Université Pierre & Marie Curie – Hôpital Pitié Salpêtrière Département de Cardiologie Paris (France) Future perspectives in Heart failure Sarajevo, May 2010

2 Have we been successful? Have we been successful?

3 Cumulative benefit of poly-pharmacy in mild-moderate HF Diuretic/ digoxin ACE inhib. Diuretic/ digoxin 13.2 8.88.8 8.78.7 6.16.1 0 5 10 15 20 1 year mortality (%) 15.7 12.4 Diuretic/ digoxin ACE inhib. Diuretic/ digoxin ACE inhib. Beta-blocker Diuretic/ digoxin ACE inhib. Beta-blocker Diuretic/ digoxin ACE inhib. Beta-blocker ARB CHARM-Added (Beta-blocker subgroup) 2003 CIBIS 2 1999 SOLVD-T 1991

4 Are there failures? Are there failures?

5 ACUTE HEART FAILURE

6 Negative trials TRIALDrug Duration (Mo) NPEP ESSENTIALEnoximone Low dose NEGATIVE61.854. AC death/CV hosp.. PGA. 6 MWT SURVIVE Levosimendan vs Dobutamine NEGATIVE61.327 AC death REVIVE Levosimendan vs pbo Composite better Increase death 6600Composite EVEREST Tolvaptan 3.600. AC death. AC death/CV hosp.. PGA

7 0.0 0.4 0.5 0.6 0.7 0.8 0.9 1.0 EVEREST: Primary Endpoint Peto-Peto Wilcoxon Test: P =.68 Proportion alive Months In Study HR 0.98; 95% CI (.87–1.11) Meets criteria for non-inferiority CV Mortality or HF Hospitalization Peto-Peto Wilcoxon Test: P =.55 Proportion without event 03691215182124 207215621146 834 607 396 271 149 58 206115321137 819 597 385 255 143 55 HR 1.04; 95%CI (.95–1.14) Months In Study Tolvaptan Placebo All-Cause Mortality Konstam MA. JAMA. 2007. 03691215182124 2072181214461112 859 589 404 239 97 2061178114401109 840 580 400 233 95 0.0 0.4 0.5 0.6 0.7 0.8 0.9 1.0 TLV PLC TLV PLC

8 A Mebazaa et al. JAMA 2007; 297:1883-1891 Overall 180-d Mortality: 27% 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0306090120150180 Days Since Start of Study Drug Infusion Probability of Surviving Levosimendan Dobutamine SURVIVE

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

10 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

11 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 0 20 40 60 80 100 PlaceboRo 30 mg Treatment Success Patient Unchanged Treatment Failure p=0.348 for comparison of distribution using the van Elteren extension of Wilcoxon test

12 1.Patient heterogeneity Substrate (ischaemic / non ischaemic, HT). Substrate (ischaemic / non ischaemic, HT). Trigger ( ACS, arrhythmias, Hypertension crisis). Trigger ( ACS, arrhythmias, Hypertension crisis). Pathophysiology ( systolic vs diastolic HF / low vs high BP). Pathophysiology ( systolic vs diastolic HF / low vs high BP). 2.Lack of standard comparator. 3.Dose, Time points, Endpoints.

13 Heart failure with Preserved Ejection Fraction

14 CHARM-Preserved Death or HF hospitalization PEP-CHF Death or HF hospitalization Yusuf et al. Lancet 2003 Cleland et al. Eur Heart J 2006 RAAS blockade in HF-PEF: two key trials HR 0.92; 95% CI (0.80-1.05); p=0.221 Placebo Candesartan 0 10 20 30 40 012243648 Cumulative incidence (%) Month HR 0.92; 95% CI (0.70-1.21); p=0.545 Placebo Perindopril 0 10 20 30 40 0122436 Cumulative incidence (%) Month 48

15 I-PRESERVE: Primary Endpoint Death or protocol specified CV hospitalization Months from Randomization Cumulative Incidence of Primary Events (%) 40 - 0 - 10 - 20 - 30 - 06121824364230486054 206719291812173016401513129115691088497816 206119211808171516181466124615391051446776 No. at Risk Irbesartan Placebo HR (95% CI) = 0.95 (0.86-1.05) Log-rank p=0.35 Placebo Irbesartan

16 Treatment Of Preserved Cardiac function heart failure with an Aldosterone anTagonist

17 New drugs

18 New drug trials Renin inhibitors (ATMOSPHERE: aliskiren vs 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).

19 ATMOSPHERE: design overview Aliskiren 300mg/enalapril 20 mg Daily (n=2,200) ~48 weeks (event driven) 4-8 weeks Enalapril Randomization Double-blind Primary outcome: CV death or heart failure hospitalization (event driven: 2162 patients) Enalapril +Aliskiren Open-label run-in Aliskiren 300 mg once daily (n=2,200) Enalapril 10 mg twice daily (n=2,200)

20 CK-1827452: Background Preclinical Preclinical Selective activator of cardiac myosin Selective activator of cardiac myosin Prolongs duration of systole by Prolongs duration of systole by Increasing entry rate of myosin into force- producing stateIncreasing entry rate of myosin into force- producing state Therefore overall number of active cross- bridges increasesTherefore overall number of active cross- bridges increases Increases stroke volume Increases stroke volume No change in dP/dt max No change in dP/dt max No increase in MVO 2 No increase in MVO 2

21 Istaroxime A New Calcium Cycling Modulator

22 Infusion period Post-infusion HORIZON-HF PCWP

23 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. HORIZON-HF Conclusions

24 Relaxin Mechanisms of Action 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 ET B 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 Relaxin Receptor LGR7

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

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

27 SHIFT design paper

28 Composite primary endpoint Cardiovascular death Hospitalisation for worsening heart failure Study design www.controlled-trials.com 6500 pts randomised Results ESC 2010 NYHA II-IV. EF 70 bpm

29 ARNi Angiotensin Receptor Neprilysin inhibitor A new approach?

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

31 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 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. 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 1-2 weeks 2 weeks Prior ACEi/ARB use discontinued Single-blind period Double-blind period N = 7980 (1:1 randomization)

32 New trials in acute HF

33 ASCEND-HF design completed in 2010 # 7000 pts enrolled

34 2 weeks Randomization Placebo Aliskiren 300 mg Conventional therapy Aliskiren 150 mg Acute HF LVEF<40% BNP >400pg/mL SBP110mmHg ~1,800 patients 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 ~15 months (event-driven)* In-hospital entry and initiation Design overview Primary outcome: CV death or HF hospitalization at 6 months (381 events)

35 THANK YOU !


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