Presentation on theme: "Professor Michel KOMAJDA Université Pierre & Marie Curie – Hôpital Pitié Salpêtrière Département de Cardiologie Paris (France) Future perspectives in Heart."— Presentation transcript:
Professor Michel KOMAJDA Université Pierre & Marie Curie – Hôpital Pitié Salpêtrière Département de Cardiologie Paris (France) Future perspectives in Heart failure Sarajevo, May 2010
Have we been successful? Have we been successful?
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
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
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
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
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
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.
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
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
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
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 =
HR predicts outcome (placebo group) Fox K, et al. Lancet. 2008;372:817-821.
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
ARNi Angiotensin Receptor Neprilysin inhibitor A new approach?
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 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)