Management of Heart Failure: Acute vs. Chronic

1. Management of Heart Failure: Acute vs. Chronic John Butterworth, MD Professor & Head Section on Cardiothoracic Anesthesia Wake Forest University School of Medicine Winston-Salem, North Carolina

2. Management of Heart Failure: Acute vs. Chronic Chronic heart failure Perioperative acute heart failure Summary

3. CHF: Statistics Epidemic in western democracies USA data: 550,000 new cases annually (2004) 5 million (2.2% of population) total patients affected (2001) Hospital discharges 995,000 (2001) Mortality 19,805 (2001) $28.8 billion in annual health care costs (2004)

4. Many elderly female patients with CHF

5. Many etiologies of CHF Coronary artery disease Hypertension Valvular heart disease Congenital heart disease Toxins Peripartum cardiomyopathy Many others

6. CHF: Systole vs. Diastole Diastolic HF (HF-PSV) Dyspnea Congestion (edema) ?BNP Normal LVEF ?LV mass Normal LVEDV Abnormal mitral inflow Abnormal mitral annular velocity Systolic HF Dyspnea Congestion (edema) ?BNP ?LVEF ?LV mass ?LVEDV Usually also have diastolic abnormalities

7. Heart failure with preservedsystolic function

8. Heart failure with preservedsystolic function Get new videos of systolic and diastolic dysfunction

9. CHF: Systole vs. Diastole Diastolic filling dysfunction on echo is common NOT the same as myocardial diastolic dysfunction! NOT HF with preserved systolic function (HF-PSV)! Most 75+ year olds have at least mild diastolic filling abnormalities on echo (abnormal filling common without HF) HF-PSV more common in women Diastolic dysfunction more common in men!

10. CHF: Systole vs. Diastole Diastolic HF (HF-PSV) Dyspnea Congestion (edema) ?BNP Normal LVEF ?LV mass Normal LVEDV Abnormal mitral inflow Abnormal mitral annular velocity Systolic HF Dyspnea Congestion (edema) ?BNP ?LVEF ?LV mass ?LVEDV Usually also have diastolic abnormalities

11. Chronic Systolic Dysfunction Get new videos of systolic and diastolic dysfunction

12. Pathophysiologic changes in CHF ?Renal blood flow activates renin-angiotensin-aldosterone Compensatory changes ?blood volume ?total body water ?total body Na ?TNFa, ?ANP, & ?BNP BNP <15 pmol/L excludes HF etiology of dyspnea

13. CHF activates sympathetic nervous system Fewer ?1-receptors (?1-ARs) ?1-ARs uncouple from adenylyl cyclase ? ?-AR,nucleoside kinase ? G?i Preserved number of ?2-ARs (activate both Gs and Gi) Upregulation of ?3-ARs (neg. inotropy) End result: ?cAMP generation & ?inotropy

14. Chronic therapy and outcomes in HF Drugs that decrease mortality: ?-AR blockers ACE inhibitors Angio receptor blockers Aldosterone antagonists Isosorbide and hydralazine in blacks Drugs that may improve symptoms without worsening outcome: Cardiac glycosides Loop diuretics Drugs that increase mortality: Dobutamine Xamoterol Pimobendam Flosequinan Vesnarinone Ibopamine Inamrinone Milrinone Enoximone

15. Chronic therapy and outcomes in HF Drugs that decrease mortality: ?-AR blockers ACE inhibitors Aldosterone antagonists Angio receptor blockers Isosorbide and hydralazine in blacks Drugs that may improve symptoms without worsening outcome: Cardiac glycosides Loop diuretics Drugs that increase mortality: Dobutamine Xamoterol Pimobendam Flosequinan Vesnarinone Ibopamine Inamrinone Milrinone Enoximone

16. Chronic therapy and outcomes in HF Drugs that decrease mortality: ?-AR blockers ACE inhibitors Angio receptor blockers Aldosterone antagonists Isosorbide and hydralazine in blacks Drugs that may improve symptoms without worsening outcome: Cardiac glycosides Loop diuretics Drugs that increase mortality: Dobutamine Xamoterol Pimobendam Flosequinan Vesnarinone Ibopamine Inamrinone Milrinone Enoximone

17. Ineffective therapies in CHF Anti-adrenergic Moxonidine (MOXCON) Prazosin (V-HeFT 1) Anti-cytokine Anti-TNF (ATTACH) Etanercept (RENEWAL)

18. Cardiac glycosides William Withering used foxglove to treat edema in 1785: An Account of the Foxglove, and Some of Its Medical Uses Inhibits Na-K ATPase, ?intracellular Na, ?Ca through Na-Ca exchange Recent studies show digoxin Sensitizes cardiac baroreceptors Decreases sympathetic nervous outflow Decreases renin secretion Neurohormonal modulator

19. Effect of Digoxin on Mortality and Morbidity: Digoxin Investigation Group 6800 patients with LV EF <.45: digoxin or placebo Mean 37 mo follow up Similar mortality (35%) Digoxin: fewer hospitalizations Use it when symptoms persist despite �-blocker & ACE inhibitor

20. ACE-Is Should Generally be Used before ARBs in HF Incontrovertible evidence of ACE-I efficacy (SOLVD-T) ACE-Is inhibit bradykinin metabolism ACE-I intolerance ACE-I and/or ARB? Angio-II catalyzed by enzymes other than ACE VALIANT shows ARB as effective as ACE-I, combination leads to more AEs ELITE 2 shows ACE-I superior to ARB in HF CHARM-Added shows benefit to adding ARB to standard Rx

22. ACE-Is Should Generally be Used before ARBs in HF Incontrovertible evidence of ACE-I efficacy (SOLVD-T) Angio-II catalyzed by enzymes other than ACE ACE-Is inhibit bradykinin metabolism ACE-I intolerance ACE-I and/or ARB? VALIANT shows ARB as effective as ACE-I, but combination leads to more adverse events ELITE 2 shows ACE-I superior to ARB in HF CHARM-Added shows benefit to adding ARB to standard Rx

23. Key role of aldosterone in CHF Compound identified by Simpson and Tait (1951) Initial studies in renovascular hypertension Adverse LV remodelling with aldo (Brilla 1990) RALES and EPHESUS trials show benefit to aldo antagonists in CHF (Pitt 1999, 2003)

24. Spironolactone reduces mortality in patients with severe CHF 1663 NYHA III & IV patients with LVEF =35% treated with ACE, loop diuretic, � digoxin 25 mg spiro vs placebo; 24 mo follow up 30% reduced mortality; 35% reduction in hospitalization for worsening CHF, both p<.001

25. Epleronone reduces mortality in patients with LV dysfunction after MI Patients assigned to epleronone 25-50 mg qd (n=3313) or placebo (n=3319) >75% receiving ACE-I (or angio blocker), ?Bs, aspirin 90% have symptoms of CHF Epl reduced deaths (RR .85), CV deaths (RR .87), sudden CV deaths (RR .79) $10,400-$21,900 per life-year gained

26. ?-ARBs and chronic heart failure Long thought contraindicated for CHF Antiarrhythmic, antioxidant, antiischemic, sympatholytic effects Inhibit �3 actions? ?symptoms, ?functional capacity, ?LVF Use drugs shown to ?mortality in clinical trials (carvedilol, bisoprolol, and metoprolol) Outcome benefit to using target drug doses from clinical trials; outcome unrelated to HR reduction

28. Carvedilol or Metoprolol European Trial (COMET) 1511 patients receive carvedilol (25 mg BID); 1518 receive metoprolol (50 mg BID) NYHA II-IV; EF<.35; ACE-I + diuretic (if tolerated) Mean 58 months in trial Carvedilol reduced all-cause (HR .83) and CV (.80) mortality relative to meto

29. Combination of isosorbide and hydralazine in blacks with HF V-HeFT I suggests that black patients more likely to benefit 1050 blacks randomized to fixed dose iso/hydra or placebo + standard therapy NYHA III & IV Improved survival and QOL

30. Is there a role for positive inotropes for any patients with CHF?1 Cardiogenic shock Congestion, hypoperfusion no shock? Support until resolution of other conditions2 Hospitalization for HF, no �need�3 Intermittent outpatient therapy? Bridging until transplant? �Destination� end of life care?

31. Levosimendam vs dobutamine for severe low-output HF (LIDO study) 203 patients Levo 24 mg/kg 10 min + 0.1 mg/kg/min vs dob 5 �g/kg/min 1o outcome: CO to ? 30%; PCWP ?25% 28% Levo patients, 15% dob patients achieved primary outcome Fewer deaths with levo (HR 0.57)

32. Nesiritide (B-type natriuretic peptide) for acute exacerbations of HF Nesiritide better than nitroglycerine or placebo added to standard therapy for decompensated CHF (hemodynamics, symptoms) Nesiritide better than dobutamine for decompensated CHF (premature beats, tachycardia)

33. Management of Heart Failure: Acute vs. Chronic Chronic heart failure (CHF) Perioperative acute heart failure Summary

34. Reduced cardiac output syndrome in cardiac surgery GA + surgery + neuroendocrine response CPB Hemodilution Hypothermia ?Ca, ?Mg ?1-AR downregulation Systemic inflammatory response Ischemia + reperfusion = �stunning� with aortic clamping or OPCAB Preexisting congenital, coronary, or valvular heart disease; all ? CHF Occasional �vasoparesis� syndrome

35. Routine myocardial dysfunction and recovery after CABG

36. Potential mechanisms of reversible heart failure after heart surgery Stunning Follows ischemia and reperfusion Normal CBF and MVO2 Treatable with positive inotropes Reverses over time Hibernation Ischemia

37. Potential mechanisms of reversible heart failure after heart surgery Stunning Hibernation Associated with chronic ischemia ?CBF Recruitable by dobutamine stress echo Viable by PET study Potentially reversible with revascularization Ischemia

38. Potential mechanisms of reversible heart failure after heart surgery Stunning Hibernation Ischemia ?CBF Reversible with drugs or revascularization

39. Factors associated with inotropic drug support in elective coronary surgery Older age Female sex Cardiac enlargement on chest radiograph Reduced LVEF Greater LV end-diastolic pressure Prolonged CPB and Aortic X-clamp times

40. Factors associated with use of positive inotropes in valve surgery Control group from neuroprotection RCT Logistic regression Multivariate associations: age >60, CHF, LVEF -5%, anesthesiologist Unlike CABG, no association with female sex, CPB time

41. Positive inotropic drugs cAMP independent agents Cardiac glycosides Calcium salts Liothyronine (T3) ?-AR agonists Calcium sensitizers cAMP dependent agents �-adrenergic agonists Epinephrine Dobutamine Dopaminergic agonists Dopamine Dopexamine Phosphodiesterase inhibitors Milrinone Inamrinone Olprinone

42. CaCl2 does not increase CIafter CABG N=12 patients Studied on 1st postoperative day; cross-over RCT CaCl2 10 mg/kg bolus + 2 mg/kg/hr CaCl2 ?[Cai] & ?MAP, but no ?CI

43. Ca sensitizing agents: levosimendam Binds to troponin C [Cai] �dependently Does not impair diastolic relaxation Hemodynamic effects continue 24 hours after drug stopped in CHF patients; active metabolite? Small trials in cardiac surgery patients using 8-36 �g/kg loading doses � 0.2-0.3 �g/kg/min infusion (?CO, ?SVR and ?PVR) Not available in USA

44. Positive inotropic drugs cAMP independent agents Cardiac glycosides Calcium salts Liothyronine (T3) ?-AR agonists Calcium sensitizers cAMP dependent agents �-adrenergic agonists Epinephrine Dobutamine Dopaminergic agonists Dopamine Dopexamine Phosphodiesterase inhibitors Milrinone Inamrinone Olprinone

46. Dobutamine increases HR more than epinephrine after CABG 52 patients recovering from CABG awake and extubated in the ICU Dob 2.5 & 5 ?g/kg/min; Epi 10 & 30 ng/kg/min After high dose, stroke volume index similar; Dob ?HR more than Epi

47. Fullerton left vs right atrial administration of epi

48. �Renal� dose dopamine does not always produce �renal� concentrations 9 healthy male volunteers received DA 3 & 10 ?g/kg/min HPLC measurement of arterial [DA] Great variation in DA concentrations t1/2 ?, ?= 0.5, 12.3 min

49. Milrinone, an effective first-line inotrope to wean sick patients from CPB 30 patients: LVEF =35% or mean PAP =20 mmHg Rec�d milrinone 50 �g/kg + 0.5 �g/kg/min or saline prior to end of CPB Successful separation in 15/15 milrinone patients but only 5/15 saline Failures separated from CPB when given milrinone

50. Milrinone prevents low cardiac output syndrome after correction of congenital heart disease 238 patients 3 groups Placebo 25 �g/kg +0.25 �g/kg/min 75 �g/kg +0.75 �g/kg/min 64% reduced incidence of LCOS by 75 �g/kg dose

51. Drug Interactions Drugs can interact additively, synergistically, or antagonistically Interaction between ?-AR agonists and PDE inhibitors is at least additive, possibly synergistic Interaction between Ca salts and ?-AR agonists is antagonistic Interaction between dobutamine (partial agonist) and epinephrine (full agonist) can be antagonistic

52. Calcium inhibits dobutamine

53. Dobutamine antagonizes epinephrine: CI and cAMP production DB or Epi ?CI dose dependently in patients DB + Epi = less CI response than epi alone DB or Epi ?cAMP production in lymphs DB + Epi 10-6M = response no greater than DB (partial agonist)

54. Amrinone epi Royster

55. Management of Heart Failure: Acute vs. Chronic Chronic heart failure Perioperative acute heart failure Summary

56. Management of Heart Failure: Acute vs. Chronic: Summary Chronic Heart Failure: Neurohormones (R-A-A) Remodeling HF with preserved LVF BNP Treatment ACE-Is �-ARBs Aldo antagonists ARBs if ACE-I intolerant Digoxin, loop diuretics Levosimendan Nesiritide New perioperative LV dysfunction (NOT CHF) ischemia stunning hibernation; cAMP independent agents not useful (except levosimedan?) PDE inhibitors effective & likely synergize ?-AR agonists