1. Management in patients with Acute Decompensated Heart Failure Dr Elaine Chau HK Sanatorium & Hospital, Hong Kong 3 August 2014 1

2. Acute decompensated heart failure Acute heart failure defined as onset of symptoms or signs of heart failure in a patient with/without prior history of heart failure Heterogeneous group of disorders leading to worsening of left ventricular function About 50% of patients with HF have preserved systolic function (LVEF > 50%)  diastolic dysfunction (HF-PEF) 2

3. Causes of acute HF due to LV dysfunction Primary cardiac – cardiomyopathy, myocarditis, ischaemia, arrhythmia, valvular dysfunction, pericardial syndrome Pressure overload – hypertensive urgency or emergency Volume overload – sodium or volume load, renal or hepatic dysfunction High output – shunt, anaemia, septicaemia, thyroid disease Other – inflammation or infection, major surgery, lack of compliance with heart failure medications, substance abuse 3

4. Signs and symptoms Prior history of HF or myocardial injury Dyspnoea on exertion, orthopnoea, paroxysmal nocturnal dyspnoea Fatigue Increasing oedema, weight or abdominal girth Signs: Elevated JVP Peripheral oedema or ascites Rales, hypoxia or tachypnoea Tachycardia, arrhythmia 4

5. Evaluation of heart failure ECG, CXR echocardiogram blood tests - BNP, NT-proBNP or MR-proANP (to differentiate dyspnoea due to HF from dyspnoea of other causes) Evaluate possibility of coronary artery disease – coronary angiography Evaluate possibility of myocardial disease – endomyocardial biopsy (e.g. myocarditis, infiltrative heart disease, anthracycline toxicity in cancer patients) Functional capacity (6-min walk, exercise testing with measurement of peak oxygen uptake) 5

6. Assessment of patient with suspected acute HF 6

7. Precipitating factors Atrial fibrillation Other arrhythmias (eg, atrial flutter, other supraventricular tachycardia or ventricular tachycardia) Exacerbation of hypertension Myocardial ischemia/infarction Exacerbation of pulmonary congestion Anaemia Thyroid disease Significant drug interactions 7

8. Causes of acute heart failure 8

9. 9

10. Evidence of severely decompensated HF, including: Hypotension Worsening renal function Altered mentation Dyspnea at rest Typically reflected by resting tachypnea Less commonly reflected by oxygen saturation <90% Hemodynamically significant arrhythmia Including new onset of rapid atrial fibrillation Acute coronary syndromes Hospitalization recommended 10

11. Hospitalization should be considered Worsened congestion Even without dyspnea Typically reflected by a weight gain ≥5 kilograms Signs and symptoms of pulmonary or systemic congestion even in the absence of weight gain Major electrolyte disturbance Associated comorbid conditions Pneumonia Pulmonary embolus Diabetic ketoacidosis Symptoms suggestive of transient ischemic accident or stroke Repeated ICD firings Previously undiagnosed HF with signs and symptoms of systemic or pulmonary congestion 11

12. Treatment goals for patients admitted for ADHF Improve symptoms, especially congestion and low output symptoms Optimize volume status Identify etiology Identify precipitating factors Optimize chronic oral therapy Minimize side effects Identify patients who might benefit from revascularization Educate patients concerning medications and self-assessment of HF Consider and, where possible, initiate a disease management program 12

13. Current IV Treatments for Acute Heart Failure Diuretics Other agents (inotropes) ß-receptor agonists (dobutamine, dopamine) PDE inhibitors (milrinone) Nitrates and/or any other IV vasodilators Preload Contractility Afterload 13

14. Management of acute pulmonary oedema 14

15. Fluid overload i.v. loop diuretics Daily body weight, intake / output balance Daily RFT/electrolytes (K, Mg) Low sodium diet(2g daily) Fluid restriction (<2L/day)for patients with moderate hyponatraemia (congestion fails to improve) Increased doses of loop diuretics or continuous infusion of loop diuretic Add second type of oral diuretic (metolazone or spironolactone) or i.v. (chlorothiazide) 15

16. Diuretics For relief of congestion in patients with elevated filling pressures (PCWP > 25mmHg) due to volume overload Loop diuretics (e.g. frusemide) – when high doses are required, continuous infusion may have benefits over bolus dosing add metolazone to potentiate natriuresis spironolactone to stem potassium losses acetazolamide to correct hypochloremic metabolic acidosis 16

17. Ultrafiltration UNLOAD (Ultrafiltration versus Intravenous Diuretics for patients Hospitalized for Acute Decompensated Heart Failure) 200 patients with acute decompensated HF Peripheral venovenous ultrafiltration compared with diuretics alone Improved weight loss at 48 hours Decreased need for vasoactive drugs Reduced rate of readmission to hospital at 90 days Costanzo MR et al. J Am Coll Cardiol 2007; 49: 675-683 17

18. Respiratory therapies Supplementary oxygen Short-term positive pressure ventilation, e.g. CPAP (continuous positive airway pressure) or BiPAP (bilevel positive airway pressure) (in acute MI with respiratory distress) invasive mechanical ventilation 18

19. Management of acute pulmonary oedema 19

20. IV Vasodilators / Inotropes (absence of hypotension) i.v. nitroglycerin, nitroprusside or nesiritide iv vasodilators and diuretics recommended for rapid relief of acute pulmonary oedema and hypertension i.v. inotropes (milrinone or dobutamine) to improve symptoms and improve end-organ function in patients with advanced heart failure (LV dilatation,reduced LVEF, diminished peripheral perfusion or end- organ dysfunction, low-output syndrome, symptomatic hypotension despite adequate filling pressure or unresponsive to iv vasodilators) Continuous monitoring of cardiac rhythm Frequent blood pressure monitoring 20

21. Vasodilators For afterload reduction (by decreasing myocardial oxygen demand and improving forward flow) i.v. nitroglycerin (10-20mcg/min initially; increasing by 5- 20 mcg/min every 3-5 min as BP allows) i.v. morphine (bolus 2-4mg) i.v. nitroprusside (continuous infusion of 0.3mcg/kg/min; titrate rapidly to desired BP; max dose 10mcg/kg/) 21

22. i.v. vasodilators to treat acute heart failure 22

23. Positive inotropes or vasopressors for acute HF 23

24. Inotropes Vasodilating inotropes: for short-term use in patients with significantly impaired cardiac output Dobutamine 2-20mcg/kg/min Milrinone 0.125-0.75mcg/kg/min (renal adjustment necessary) Vasopressor inotropes: for patients with hypotension (avoid in pure HF with high systemic vascular resistance) Dopamine 1-50mcg/kg/min Norepinephrine 0.01-0.4mcg/kg/min 24

25. Inotropic drugs Gs Gi β-receptor ATP cAMP (active) rise in intracellular calcium Dobutamine AMP (inactive) PDE Na + /Ca 2+ exchanger Na + /K + exchanger [Ca 2+ ] [Na + ] [K + ] Digoxin Milrinone 25

26. Haemodynamic monitoring Routine invasive haemodynmaic monitoring not recommended Invasive haemodynamic monitoring to be considered in Patient refractory to initial therapy Patient whose volume status and cardiac filling pressures are unclear Patient with clinically significant hypotension (SBP <80mmHg) or worsening renal failure during therapy Patient in whom documentation of an adequate haemodynamic response to the inotropic agent is necessary when chronic outpatient infusion is being considered 26

27. Management of acute pulmonary oedema 27

28. Treatment of patients with acute heart failure 28

29. Treatment of patients with acute heart failure 29

30. Treatment of patients with acute heart failure 30

31. Treatment of patients with acute heart failure 31

32. Levosimendan Clinical EffectIdeal Agent Levosimendan PDE Inhibitors Dobutamine Cardiac Output Heart Rate Blood Pressure Oxygen Demand Arrhythmogenic Potential Cardiac Filling Pressure or Tachyphylaxis 32

33. Levosimendan for treatment of acute decompensated heart failure  Dual mechanism of action: 1) Calcium sensitization (improves cardiac contractility without concomitantly increasing myocyte oxygen consumption) 2) potassium-ATP channel opening (results in vasodilation, improving blood flow to vital organs) 33

34. Levosimendan Calcium sensitizer with inodilatory properties (PDE- III inhibitory activity) Pharmacokinetics: – Onset of action 10-20 min – Duration of action – haemodynamic effects maintained for at least 24 hours after discontinuation of a 24-hour infusion – Excretion : liver Adverse reaction: Dose-related hypotension No significant conduction disturbance or proarrhythmia 34

35. Levosimendan LIDO (Lancet 2002; 360:196-202) - Benefit & safety better than standard inotrope in ADHF RUSSLAN study (Eur Heart J 2002;23:1422-32) – Safe & effective for patients with LV failure complicating acute MI CASINO (Eur J Heart Fail 2004;6:673-6) – Clear mortality benefit in favour of levosimendan compared with dobutamine in class IV CHF patients REVIVE I trial (Crit Care 2004;8(suppl 1):P88) – Levosimendan reduces length of intensive and hospital day in patient with acute decompensated HF 35

36. Levosimendan for treatment of acute decompensated heart failure REVIVE II (Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy Study) (AHA Scientific Sessions 2005 Late Breaking Clinical Trials II)  600 patients, 103 sites  ADHF, dyspnoea at rest despite iv diuretics, LVEF <35%  Levo bolus (6-12 mcg/kg) + 24-hour infusion (0.1- 0.2mcg/kg/min) vs placebo  After 5 days, more Levo patients improved (19.4% vs 14.6%), fewer Levo patients worsened (19.4% vs 27.2%)  Significant BNP reduction in Levo arm at 24 hours & 5 days  No difference in mortality at 90 days 36

37. Levosimendan for treatment of acute decompensated heart failure SURVIVE (Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support Study) (JAMA 2007; 297:1883-1991)  1327 patients, 75 sites  ADHF, LVEF <35%, clinical requirement for iv inotropic therapy  Levosimendan bolus + infusion vs dobutamine  Reduction of mortality by 28% at 5 days and of 14% at 31 days in in Levo arm  Effect greatest (42% reduction at 5 days) in patients with previous heart failure  Statistically non-significant but consistently lower mortality at 6 months with Levo 37

38. Conclusions from REVIVE II and SURVIVE  Levosimendan represents an effective alternative to current therapies for ADHF  Short-term improvement in symptoms and clinical course, associated with marked reduction in BNP  Mortality was numerically greater vs placebo but lower vs dobutamine  AF was increased during 3- to 6-month FU period  VT was increased vs placebo but not increased vs dobutamine 38

39. Nesiritide B-type natriuretic peptide  counter-regulation of renin- angiotensin-aldosterone system  stimulating cGMP  smooth muscle cell relaxation Vasodilatory properties, natriuretic effects, neurohormonal antagonism VMAC (JAMA 2002; 287(12):1531-1540)  PAP, PCWP; no tachyphylaxis/tolerance (unlike nitroglycerin) PRECEDENT (Am Heart J 2002; 144(6):1102-1108) Nesiritide had no significant effect on HR or ventricular arrhythmias Dobutamine but not nesiritide was proarrhythmic 39

40. Nesiritide 2001 FDA approved for treatment of acute decompensated heart failure Pooled analysis of randomized controlled trials   risk of death at 1 month (Sackner-Bernstein et al, JAMA 2005;293:1900-1905) & worsening renal function (Sackner-Bernstein et al, Circulation 2005;111:1487-1491) 40

41. Nesiritide Expert panel (Braunwald et al 2005) Use of nesiritide should be limited to patients presenting to hospital with acutely decompensated CHF Should not be used to replace diuretics Not for Intermittent outpatient use Scheduled repetitive use Improvement of renal function Enhancement of diuresis 41

42. Serelaxin Recombinant human relaxin-2 (vasoactive peptide hormone) RELAX-AHF (randomised placebo-controlled trial – Serelaxin for treatment of acute heart failure) Patients with dypsnoea, congestion on CXR, increased BNP or NT- proBNP, mild-mod renal insuffuciency, SBP >125mmHg Standard care plus 48-hour infusion of placebo or serelaxin (30mcg/kg per day) within 16 hours from presentation Tx of acute HF with serelaxin was associated with – Dyspnoea relief (as measured by visual analogue scale area under the curve / VAS AUC to day 5) – Reduced 180-day mortality No effect on re-admission to hospital Teerlink JR et al - Lancet 2013; 381(9860):29-39 42

43. Goals of treatment in acute heart failure 43

44. Discharge criteria for HF patients Exacerbating factors addressed At least near optimal volume status achieved Transition from intravenous to oral diuretic successfully completed Patient and family education completed At least near optimal pharmacologic therapy achieved Follow-up clinic visit scheduled, usually for 7-10 days 44