Notfall-/Intensivmedizin: akute Herzinsuffizienz Therapie der akuten Herzinsuffizienz

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

2 Behandlung der akuten Herzinsuffizienz Definition Symptome Prognose Aktuelle Studienlage Neue Pharmaka

3 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: Right HF ESC Guidelines Eur Heart J 2008; 29:

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

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

6 AHF- Symptoms % 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

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

8 Behandlung der akuten Herzinsuffizienz Definition Symptome Prognose Aktuelle Studienlage Neue Pharmaka

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

10 Behandlung der akuten Herzinsuffizienz Definition Symptome Prognose Aktuelle Studienlage Neue Pharmaka

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

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

13 ESC Guidelines 2012 McMurray et al. EHJ 2012; 33:

14 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

15 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

16 Dose Felker et al. N Engl J Med 2011;364:

17 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:

18 Dose % patients * 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:

19 ESC Guidelines 2012 McMurray et al. EHJ 2012; 33:

20 Cotter et al. Lancet 1998; 351: 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

21 Cotter et al. Lancet 1998; 351: 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

22 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

23 ESC Guidelines 2012 McMurray et al. EHJ 2012; 33:

24 Loeb et al. Circulation 1977;55:375

25 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

26 Behandlung der akuten Herzinsuffizienz Definition Symptome Prognose Aktuelle Studienlage Neue Pharmaka

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

28 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

29 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 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 ;381:29-39

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

31 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 ;381:29-39

32 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:

33 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:

34 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

35 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 -