Notfall-/Intensivmedizin: akute Herzinsuffizienz Therapie der akuten Herzinsuffizienz

Echokardiographie Update 2013 München 14.- 15. Dezember 2013 Notfall-/Intensivmedizin: akute Herzinsuffizienz Therapie der akuten Herzinsuffizienz S. Felix Klinik für Innere Medizin B Ernst-Moritz-Arndt-Universität Greifswald 1456 1856

Behandlung der akuten Herzinsuffizienz Definition Symptome Prognose Aktuelle Studienlage Neue Pharmaka

Acute Heart Failure Acute de novo heart failure (e. g. acute myocardial infarction, myocarditis) Acute acute decompensated (chronic) heart failure (ADHF) Transition from chronic compensated to acute decompensated heart failure Worsening HF De novo HF End-stage HF Decompensated HF Pulmonary oedema Cardiogenic shock Hypertensive HF Gheorghiade et al. J Am Coll Cardiol 2013;61:391 403 Right HF ESC Guidelines Eur Heart J 2008; 29: 2388 2442

Behandlung der akuten Herzinsuffizienz Definition Symptome Prognostische Faktoren Aktuelle Studienlage Neue Pharmaka

Abnormal LV function sytemic congestion Gheorghiade et al. Eur J Heart Failure 2010; 12: 423 433

AHF- Symptoms % 100 90 80 70 60 50 40 30 20 10 0 Dyspnea Adhere Rales Peripheral Edema DD ADHF vs pulmon. disease - ECG - Chest x-ray - NT-pro BNP 300 pg/ml BNP 100 pg/ml - ECHO ESC Guidelines 2012 From Adams et al. Am Heart J 2005;149:209-16

Mebazaa et al. Eur Heart J 2010; 31: 832 841 Abnormal LV function systemic congestion Gheorghiade et al. EurJ Heart Failure 2010; 12: 423 433 The impact of early standard therapy on dyspnoea in patients with AHF URGENT-dyspnoea study

EuroHeart Failure Survey II (2.981 AHF patients) Harjola et al. Eur J Heart Failure 2010;12: 239 248

Clinical Trials in worsening HF/ADHF Trial Agent Pts Effects on Effects on Outcome Symptoms OPTIME-CHF Milrinone 951 AEs No VERITAS Tezosentan 1.448 No No EVEREST Tolvaptan 4.133 No Yes LIDO Levosimendan 203 Yes No vs. Dobutamine Survive Levosimendan 1.327 No No vs. Dobutamine PROTECT Rolofylline 2.033 No No VMAC Nesiritide 489 - Yes ASCEND-HF Nesiritide 7.141 No No

Treatment of acute heart failure Well almost an evidence free zone JGF Cleland AHA 2010

ESC Guidelines 2012 McMurray et al. EHJ 2012; 33:1787 1847

Medikamentöse Therapie der dekomp. Herzinsuffizienz - Schleifendiuretika - Klinische Indikation - bei Hypervolämie und dekompensierter Herzinsuffizienz (IA) rasche symptomatische Besserung durch venöse Vasodilatation, Diurese durch Hemmung der Na + -K + 2Cl - Pumpe im aszendieren Schenkel der Henle-Schleife. Probleme - keine prospektiven kontrollierten Studien über den Einfluss einer akuten und chronischen Therapie mit Diuretika auf Prognose. - bei fortgeschrittener Herzinsuffizienz häufig Diuretikaresistenz. - intravaskuläre Volumendepletion, neurohumorale Aktivierung. - Nierenschädigung (struktur. Schädigung im distalen Tubulus). - Dosierung und Applikation ungeklärt Hochdosiert vs. niedrig dosiert Bolus vs. kontinuierliche Infusion

Dose Diuretic Strategies in Patients with Acute Decompensated Heart Failure 308 patients with ADHF: treatment with i.v. furosemide Bolus every 12 h Continuous infusion * * High dose Low dose High dose Low dose High dose: 2.5 times the previous oral dose Low dose: Equivalent to the previous oral dose Coprimary end points - patients global assessment of symptoms, quantified as the area under the curve of the score on a visual-analogue scale over the course of 72 h - change in the serum creatinine level from baseline to 72 hours

Dose Felker et al. N Engl J Med 2011;364:797-805

Dose Kaplan Meier Curves for the Clinical Composite End Point of Death, Rehospitalization, or Emergency Department Visit Felker et al. N Engl J Med 2011;364:797-805

Dose % patients 30 25 20 15 10 5 0 * dose increase at 48 h * switch to oral diuretics at 48 h high dose low dose From Felker et al. N Engl J Med 2011;364:797-805

Cotter et al. Lancet 1998; 351: 389 93 Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema Inclusion criteria Patients with pulmonary edema (chest X-ray), oxygen saturation < 90% Initial treatment Oxygen 10 L/min, furosemide 40 mg i.v., morphine 3 mg i.v. 110 patients randomized Group A * Group B * 56 patients 54 patients * * 3 mg ISDN i.v. every 5 min 80 mg bolus of furosemide i.v. every 15 min and ISDN 1 mg/h, increased by 1 mg/h every 10 min 52 patients completed trial 52 patients completed trial Treatment was continued in both groups until oxygen saturation increased to at least 96% or mean arterial blood pressure decreased by at least 30% or to lower than 90 mm Hg

Cotter et al. Lancet 1998; 351: 389 93 Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema High dose ISDN High dose Furosemide + low dose ISDN

Vitious Circle in Acute Decompensated Heart Failure Cardiac Lesion Depressed Ventricular Performance SVR Hypervolemia Cardiac Output Therapeutic target Decrease of SVR vitious circle Therapeutic target Decrease of preload Neurohumoral Activation Sympathetic Nervous System RAAS Endothelin

Loeb et al. Circulation 1977;55:375

Treatment of ADHF Limitations of Inotropic Agents - camp generating drugs: ventricular arrhythmias - Progression of LV dysfunction myocardial VO 2 induced by myocardial contractility and HR (catecholamies) cytoplasmic Ca ++ -overload Untoward mechanism associated with loop diuretics (furosemide) - Electrolyte abnormalities - Neurohormonal activation - Worsening of renal function - Loss of efficacy in advanced heart failure

Myosinaktivatoren Omecamtiv Mercabil scg-aktivatoren Cinaciguat Serelaxin Neue natriuretische Peptide Ularitide

Relaxin Relaxin ist ein Peptidhormon, dessen Blutspiegel bei schwangeren Frauen deutlich erhöht ist Produktionsorte: Corpus luteum, Endometrium, Placenta, Mamma, Prostata Teichmann et al. Curr Heart Fail Rep 2010; 7:75 82

Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure Inclusion criteria - AHF (within the previous 16 h) - dyspnoea at rest or with minimum exertion, - pulmonary congestion on chest radiograph, - BNP 350 ng/l or NT-proBNP 1400 ng/l - mild to-moderate renal dysfunction 2 (GFR MDRD 30-75 ml/min per 1.73 m ) - BPsyst. > 125 mm Hg - 40 mg intravenous furosemide or equivalent before screening Intervention 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h Primary endpoints Dyspnoea improvement - Change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 - Proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by ITT Teerlink et al. Lancet. 2013 5;381:29-39

RELAX-AHF Teerlink et al. Lancet. 2013 5;381:29-39

RELAX-AHF Cardiovascular death or readmission to hospital for heart failure or renal failure (%) Cardiovascular death All cause death The signs and symptoms of congestion present on study day 2 Teerlink et al. Lancet. 2013 5;381:29-39

Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) Development Program Risk for Death by Early Changes in Markers of Organ Function, Damage, and Congestion Metra et al. J Am Coll Cardiol 2013;61:196 206

Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) Development Program Early Changes From Baseline in Laboratory Values Metra et al. J Am Coll Cardiol 2013;61:196 206

RELAX-AHF-2 Primary objective To demonstrate that serelaxin is superior to placebo in reducing CV death in AHF patients during a follow-up period of 180 days

Akut dekompensierte (chronische) Herzinsuffizienz Zusammenfassung Dyspnoe das führende Symptom Schlechte Prognose: 1-Jahresmortalität > 25% Keine Evidenz-basierten Daten zur Prognosebesserung durch eine Pharmakotherapie Ziel: symptomatische Besserung ohne die Prognose zu verschlechtern Nitrate, Diuretika: Besserung der Symptome Neue Therapieansätze - Serelaxin -