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ESC HF Guidelines 2012University Medical Center Groningen


ESC HF Guidelines 2012ESC-HF Guidelines 2012• What to do with diuretics in CHF?• ACE-inhibitor and beta-blocker as standardtherapy: what next?• Role of ivabradine• Treatment of Diastolic Heart Failure• Treatment of Acute Heart FailureUniversity Medical Center Groningen


ESC HF Guidelines 2012University Medical Center GroningenESC HF Guidelines 2012


ESC HF Guidelines 2012a) Diuretics may be used as needed to relieve the signs and symptoms ofcongestion (see Section 7.5) but they have not been shown to reducehospitalization or death.University Medical Center GroningenESC HF Guidelines 2012


ESC HF Guidelines 2012Diuretics• “The aim of using diuretics is to achieve andmaintain euvolaemia (the patient’s ‘dry weight’)with the lowest achievable dose. This meansthat the dose must be adjusted, particularly afterrestoration of dry body weight, to avoid the riskof dehydration leading to hypotension and renaldysfunction.”University Medical Center GroningenESC HF Guidelines 2012


ESC HF Guidelines 2012ESC-HF Guidelines 2012• What to do with diuretics in CHF?• ACE-inhibitor and beta-blocker as standardtherapy: what next?• Role of ivabradine• Treatment of Diastolic Heart Failure• Treatment of Acute Heart FailureUniversity Medical Center Groningen


ESC HF Guidelines 2012b) Should be titrated to evidence-based dose or maximum tolerated dosebelow the evidence-based dose.University Medical Center GroningenESC HF Guidelines 2012


ESC HF Guidelines 2012University Medical Center GroningenESC HF Guidelines 2008


ESC HF Guidelines 2012Introduction: EMPHASISRALES: CHF NYHA III-IV30% mortality reductionEPHESIS: LV-dysfunctionAfter AMI; 15 % mortalityreductionUniversity Medical Center Groningen


ESC HF Guidelines 2012Hypothesis and Methods• Eplerenone, added to evidence-based therapy,is associated with improved clinical outcomes inCHF patients with MILD symptoms.• 2737 patients with NYHA II HF and LVEF ≤ 35%to eplerenone (up to 50 mg daily) or placebo• primary outcome: composite of death from CVcauses or HF hospitalizationUniversity Medical Center Groningen


ESC HF Guidelines 2012University Medical Center GroningenNEJM 2010


ESC HF Guidelines 2012All EndpointsUniversity Medical Center GroningenNEJM 2010


ESC HF Guidelines 2012Recommendation MRA and ARBUniversity Medical Center Groningen


ESC HF Guidelines 2012ESC HF Guidelines 2012University Medical Center Groningen


ESC HF Guidelines 2012• 6558 Patients systolic HF patients and aLVEF ≤ 35%, in sinus rhythm with HR ≥ 70BPM, HF hosp


ESC HF Guidelines 2012SHIFT - resultsUniversity Medical Center GroningenLancet 2010


ESC HF Guidelines 2012Recommendations IvabradineUniversity Medical Center GroningenTeerlink, Lancet 2010


ESC HF Guidelines 2012University Medical Center Groningen


ESC HF Guidelines 2012Other RecommendationsUniversity Medical Center Groningen


ESC HF Guidelines 2012University Medical Center Groningen


ESC HF Guidelines 2012ESC-HF Guidelines 2012• What to do with a loop diuretic?• ACE-inhibitor and beta-blocker as standardtherapy: what next?• Role of ivabradine• Treatment of Diastolic Heart Failure• Treatment of Acute Heart FailureUniversity Medical Center Groningen


ESC HF Guidelines 2012Treatment of Diastolic Heart Failure“No treatment has yet been shown, convincingly, toreduce morbidity and mortality in patients with HF-PEF. Diuretics are used to control sodium and waterretention and relieve breathlessness and oedema asin HF-REF. Adequate treatment of hypertension andmyocardial ischaemia is also considered to beimportant, as is control of the ventricular rate inpatients with AF.”University Medical Center GroningenESC HF Guidelines 2012


ESC HF Guidelines 2012RCT’s in Diastolic Heart FailureDrug Candesartan 32mg vs. PlaceboCharm-Preserved PEP-CHF I-PRESERVEPerindopril 4 mgvs. PlaceboNumber 3023 850 4128Irbesartan 300mg vs. PlaceboAge 67 years 75 years 72 years% Female 40 55 60LVEF >40% (54) >40% (64) >45% (60)Primary OutcomeCV-death or HFhospDeath or HF-hospDeath or CV-hospFollow-up 37 months 25 months 50 monthsUniversity Medical Center Groningen


ESC HF Guidelines 2012A TRIAL FOR HEART FAILURE PATIENTS WITH PRESERVEDSYSTOLIC FUNCTIONTOPCAT is a multi-center, international, randomized, double blindplacebo-controlled trial of the aldosterone antagonist, spironolactone, in3,445 adult subjects with heart failure and left ventricular ejection fractionof at least 45%, recruited internationally from over 200 clinical centers inthe US, Canada, Russia, Republic of Georgia, Argentina, and Brazil.The trial is sponsored by the National Heart, Lung, and Blood Institute ofthe National Institutes of Health. New England Research Institutes, Inc.(NERI) and The Brigham & Women’s Hospital (BWH) serve as theClinical Trial Coordinating Center (CTCC) for this study.Enrollment started in August 2006 and recently ended on January 31,2012.University Medical Center Groningen


ESC HF Guidelines 2012LCZ696 has the potential to restore the appropriatebalance of the RAAS and natriuretic peptides in HFDamageBeneficial physiological responsePathophysiological responseNPsNP systemRAASAng IIVasodilation blood pressure sympathetic tonealdosterone levels fibrosis hypertrophyNatriuresis/DiuresisNEPXInactivefragmentsDualNEP/RAASinhibition(LCZ696)HFsymptoms/progressionXAT 1 receptorVasoconstriction blood pressure sympathetic tone aldosterone fibrosis hypertrophyUniversity Medical Center GroningenNeurohormonal balance


ESC HF Guidelines 2012PARAMOUNT: “Proof of concept”study in HF-PEFPlacebo run-inLCZ69650 mg BIDLCZ696100 mg BIDLCZ696 200 mg BIDWeekVisitDiscontinueACEI/ARB therapy1 day beforerandomization-21Design2 weeksPrimaryobjectiveSecondaryobjectivesPopulationSample sizeValsartan40 mg BID02Valsartan80 mg BID12 4 81218 24 30 363 4 5 678 9 10 111 week 1 week10 weeks6 month extension• 36 wks, randomized, double-blind, active controlled study evaluating LCZ 200 mg bidcompared to valsartan 160 mg bid (12 weeks core study followed by 6 monthextension)• LCZ 696 and valsartan will be progressively up-titrated to the target dosesNT pro-BNP reduction from baseline at 12 weeks (core study)• HF symptoms and QoL – KCCQ & Clinical Composite Assessment (NYHA + PGA• Echocardiographic parameters of diastolic function, cardiac filling pressures, and PASP• Evaluate the effects on BNP, ANP, and cGMP as well as collagen markers• Renal function and safety and tolerability• Arterial stiffness (PWV, AI, central BP) in sub-populationApproximately 300 pts >40 years, NYHA class II-IV, EF ≥45% & NT pro-BNP >400 pg/ml• 80% power to detect a 25% reduction in NT pro-BNP vs comparatorBaseline randomization visit and visit at end of 12 weeks of core studyUniversity Medical Center GroningenValsartan 160 mg BIDPrior ACEi/ARB use discontinuedwww.clinicaltrials.gov (NCT00887588)


ESC HF Guidelines 2012University Medical Center Groningen


ESC HF Guidelines 2012PARAMOUNT: main resultsUniversity Medical Center GroningenSolomon et al. Lancet 2012


ESC HF Guidelines 2012Change in E/E'Change in Left Atrial Volume (ml)Changes in Key Echocardiographic MeasuresChange in LA Width (cm)Change in Lateral Mitral AnnularRelaxation Velocity (E') (cm/s)Left Atrial VolumeLeft Atrial Width212 Weeks 36 Weeks0.0012 weeks 36 weeks1LCZ696Valsartan0-0.05-1-2-0.10-3-4-0.15-5-60.0-0.2P = 0.18 P = 0.003E/E’12 Weeks 36 Weeks-0.202.01.5P = 0.07 P = 0.03Lateral E’P = 0.40-0.4-0.61.0P = 0.56-0.8-1.0-1.20.5-1.4-1.6-1.8P = 0.71 P = 0.42-2.0University Medical Center Groningen0.012 weeks 36 weeksSolomon et al. Lancet 2012


ESC HF Guidelines 2012ESC-HF Guidelines 2012• What to do with a loop diuretic?• ACE-inhibitor and beta-blocker as standardtherapy: what next?• Role of ivabradine• Treatment of Diastolic Heart Failure• Treatment of Acute Heart FailureUniversity Medical Center Groningen


ESC HF Guidelines 2012University Medical Center GroningenESC HF Guidelines 2012


ESC HF Guidelines 2012University Medical Center GroningenESC HF Guidelines 2012


ESC HF Guidelines 2012RCTs in AHF not successful1. PDE-inhibitors: Milrinone: OPTIME-CHF2. Endothelin antagonists: Tezosentan: VERITAS3. Ca-sensitizers: Levosimendan; SURVIVE/REVIVE4. AVP Antagonists: Tolvaptan; EVEREST5. Adenosine A1-Receptor Antagonist: Rolofylline;PROTECT6. Natriuretic Peptides: Nesiritide: ASCEND-HFUniversity Medical Center Groningen


ESC HF Guidelines 2012Why were RCTs in AHFnot successful?1. Wrong drugs?2. Wrong endpoints? Dyspnea? Compositeendpoints? Clinical outcome?3. Wrong design (e.g. blood pressure, time ofinitiation of therapy, etc.)University Medical Center Groningen


ESC HF Guidelines 2012Relaxin• Naturally occurring hormone, discovered in1929• Elevated in circulation in first trimester ofpregnancy and throughout 9 months• Relaxin receptors, identified in 2002, localizedin blood vesselsRelaxin• Mechanism of action involves activation of theendothelial endothelin type B receptor• Contributes to maternal hemodynamicadjustments to pregnancyUniversity Medical Center GroningenHsu et al. Science 2002;295:671–674; Jeyabalan et al. Adv Exp Med Biol 2007;612:65–87;Dschietzig et al. Circ Res 2003;92:32–40


ESC HF Guidelines 2012Mechanisms of ActionUniversity Medical Center GroningenTeichman et al. Curr Heart Fail Rep 2010; 7:75-82


ESC HF Guidelines 2012Lancet 2009; published online March 29. DOI:10.1016/S0140-6736(09)60622-X.University Medical Center GroningenTeerlink et al. Lancet 2009;373:1429–1432


ESC HF Guidelines 2012Study DesignPhase IIb, Multicenter (54 sites), International (8 countries), Randomized,Double-Blind, Placebo-Controlled, Parallel-Group StudyAHF (dyspnea, BNP,CXR)SBP >125 mmHgCrCl 30-75 mL/minAfter ≥40 mg ivfurosemideWithin 16 hours ofpresentationRandomized 3:2:2:2:2Stratified by sitePlacebo (n=61)Serelaxin 10 µg/kg/d (n=40)Serelaxin 30 µg/kg/d (n=42)Serelaxin 100 µg/kg/d (n=37)Serelaxin 250 µg/kg/d (n=49)0 6 12 24 48h 5d 14d 60d 180d48 h Study Drug InfusionPost-discharge EvaluationsBNP = B-type natriuretic peptide; CXR = chest X-ray, SBP = systolic blood pressure; CrCl = creatinine clearanceTeerlink et al. Lancet 2009;373:1429–1432CONFIDENTIALUniversity Medical Center Groningen


ESC HF Guidelines 2012Serelaxin Caused Sustained Reliefof DyspneaMean Change from Baseline InPatient-Reported VAS Dyspnea Score (AUC)Serelaxin (μg/kg/d)Day 5Serelaxin (μg/kg/d)Day 14University Medical Center GroningenVAS = visual analogue scale; AUC = area under curveTeerlink et al. Lancet 2009;373:1429–1432


ESC HF Guidelines 2012%Outcome: Worsening Heart Failure25% Subjects with Worsening Heart Failure at Day 520151050Placebo Serelaxin Serelaxin Serelaxin Serelaxin10 μg/kg/d 30 μg/kg/d 100 μg/kg/d 250 μg/kg/dUniversity Medical Center GroningenTeerlink et al. Lancet 2009;373:1429–1432


ESC HF Guidelines 2012Fewer CV Deaths to Day 180Serelaxin 30 μg/kg/d*Serelaxin 10 μg/kg/dSerelaxin 100 μg/kg/d*Serelaxin 250 μg/kg/dPlacebo*p=0.04 vs placeboUniversity Medical Center GroningenTeerlink et al. Lancet 2009;373:1429–1432


ESC HF Guidelines 2012RELAX-AHF: 1160 patients12 Countries/Lead PIsNETHERLANDSVoorsUKClelandFRANCEJondeauGERMANYWerdanPOLANDPonikowskiUSATeerlinkHUNGARYApróARGENTINATheirer/GrinfeldROMANIADorobantuSPAINMasipITALYMetraISRAELMarmorUniversity Medical Center GroningenPhase 3 RELAX-AHF initiated in 2009Sponsored by Corthera, Inc. (a Novartis company)


ESC HF Guidelines 2012RELAX-AHF: Press release Sep 24,2012University Medical Center Groningen


ESC HF Guidelines 2012Conclusions• Diuretics: lowest dose to reach euvolemia• HFrEF: ACEi (or ARB) and beta-blocker• Still NYHA II or more: aldosterone blocker• In selected patients: ivabradine• Still no evidence based therapy for HFpEF• Maybe MRAs?• Maybe ARNI?• AHF: Serelaxin: first drug to lower mortality inAHFUniversity Medical Center Groningen

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