3 Cumulative benefit of poly-pharmacy in mild-moderate HF Diuretic/digoxinACE inhib.188.8.131.52.151015201 year mortality (%)15.712.4Beta-blockerARBCHARM-Added(Beta-blocker subgroup)2003CIBIS 21999SOLVD-T1991
6 Negative trials TRIAL Drug Duration (Mo) N PEP ESSENTIAL Enoximone Low doseNEGATIVE61.854. AC death/CV hosp.. PGA. 6 MWTSURVIVELevosimendan vs Dobutamine1.327AC deathREVIVELevosimendan vs pboComposite betterIncrease death600CompositeEVERESTTolvaptan3.600. AC death6
7 EVEREST: Primary Endpoint All-Cause MortalityCV Mortality or HF HospitalizationHR 0.98; 95% CI (.87–1.11)Meets criteria for non-inferiority36912151821242072181214461112859589404239972061178114401109840580400233950.00.40.50.184.108.40.206.01.0HR 1.04; 95%CI (.95–1.14)0.90.80.7Proportion aliveProportion without event0.60.50.4Peto-Peto Wilcoxon Test: P = .68Peto-Peto Wilcoxon Test: P = .550.0TLV20721562114683460739627114958TLVPLC20611532113781959738525514355PLC3691215182124Months In StudyMonths In StudyTolvaptanPlaceboKonstam MA. JAMA7
8 Probability of Surviving Days Since Start of Study Drug Infusion SURVIVE1.0Levosimendan0.9Dobutamine0.8Probability of Surviving0.7Overall 180-dMortality: 27%0.60.5During 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.0.4306090120150180Days Since Start of Study Drug InfusionA Mebazaa et al. JAMA 2007; 297:845
10 Randomisation Rolofylline to placebo, 2:1 PROTECTPlaceboRolofylline30 mgTreatment phase Follow-upRandomisation Rolofylline to placebo, 2:1All cause mortalityCV/Renal hospAll causemortalityKidney FunctionDaysScreeningAHF & fluid overload, need of iv loop diureticCrCl, ml/min
11 Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09) Primary EndpointOdds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09)Percent of Patients36.044.219.840.637.521.820406080100PlaceboRo 30 mgTreatment SuccessPatient UnchangedTreatment Failurep=0.348 for comparison of distribution using the van Elteren extension of Wilcoxon test
12 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.
14 RAAS blockade in HF-PEF: two key trials CHARM-PreservedDeath or HF hospitalizationPEP-CHFDeath or HF hospitalizationCumulative incidence (%)HR 0.92; 95% CI ( );p=0.545PlaceboPerindopril10203040122436Cumulative incidence (%)Month4840PlaceboCandesartan302010HR 0.92; 95% CI ( );p=0.22112243648MonthYusuf et al. Lancet 2003Cleland et al. Eur Heart J 2006
15 Cumulative Incidence of Primary Events (%) I-PRESERVE: Primary Endpoint Death or protocol specified CV hospitalizationMonths from RandomizationCumulative Incidence of Primary Events (%)40 -0 -10 -20 -30 -6121824364230486054206719291812173016401513129115691088497816206119211808171516181466124615391051446776No. at RiskIrbesartanPlaceboHR (95% CI) = 0.95 ( )Log-rank p=0.35
16 Treatment Of Preserved Cardiac function heart failure with an Aldosterone anTagonist
18 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).
19 ATMOSPHERE: design overview Primary outcome: CV death or heart failure hospitalization(event driven: 2162 patients)RandomizationEnalapril 10 mg twice daily (n=2,200)Open-label run-inEnalaprilEnalapril +AliskirenAliskiren 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.References1. 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: NCT Accessed at:2. Data on File, Novartis Study SPP100A2316.Aliskiren 300mg/enalapril20 mg Daily (n=2,200)Double-blind4-8 weeks~48 weeks (event driven)19
20 CK-1827452: Background Preclinical Selective activator of cardiac myosinProlongs duration of systole byIncreasing entry rate of myosin into force-producing stateTherefore overall number of active cross-bridges increasesIncreases stroke volumeNo change in dP/dtmaxNo increase in MVO2
21 A New Calcium Cycling Modulator IstaroximeA New Calcium Cycling Modulator
22 HORIZON-HF PCWPDuring 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.PCWPInfusion period Post-infusion
23 HORIZON-HF Conclusions Istaroxime given over a short period in patients admitted with HF and LVEF ≤ 35% receiving standard therapy:decreased PCWP and LVEDVincreased CIImproved 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
24 Relaxin Mechanisms of Action Relaxin Receptor LGR7VasodilationNO, cGMP effectorsInduction of NOS II/IIIUpregulation of endothelial endothelin type B receptor, which mediates vasodilationPreferential dilation of constricted vesselsRelaxin-upregulated ETB receptors act as vasodilating ET-1 sinkAnti-inflammatoryDown-modulation of inflammatory cytokines linked to outcome in HF (TNF-, TGF-)Other: Anti-ischemic, Anti-apoptotic, Anti-fibrotic24
25 CD-NP: A Rationally Designed Natriuretic Peptide CNPSGLKCFDRIMNPR-B agonistVasodilationCD-NPPNAT-+DNPEVYHNPR-A agonistRenal function=25
26 HR predicts outcome (placebo group) Fox K, et al. Lancet. 2008;372:
29 Angiotensin Receptor Neprilysin inhibitor A new approach?ARNiAngiotensin Receptor Neprilysin inhibitor
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 fractionLCZ mg BID (n~4000)Enalapril 10 mg BID (n~4000)Outcomes driven (estimated mean f/u = months)1-2 weeksEnalapril 5-10 mg bidLCZ 100 mg bidLCZ 200 mg bid2 weeksPrior ACEi/ARB use discontinuedSingle-blind periodDouble-blind periodN = 7980 (1:1 randomization)Primary objectivesEvaluate 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 fractionSecondary objectivesAll cause mortalityRenal progression (eGFR change)Clinical summary score (assessed by KCCQ)Patient population7980 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) andhospitalization within the last 12 months.31
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