1. ControversisControversis Controversies in Cardiac Failure Alan Gass, M.D., F.A.C.C. Director, Cardiac Transplantation and Mechanical Circulatory Support Westchester Medical Center

2. Controversies in Cardiac Failure  Does adding an ARB to an ACE-inhibitor help?  Is there a role for aldactone / eplerenone in class I or II HF?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all Inotropes created equal?  PA catheter – yes or no?

3. Controversies and Subtleties in HF  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?

4. Valsartan in CHF: ValHeFT. Cohn et al. NEJM 2001 NYHA II-IV HF, 5010 pts, RCT, Valsartan 160 BID vs placebo

5. In 1610 pts on both Ace and BB, increased mortality

6. 2548 pts class II-IV HF, EF <40%, cadesartan 32 mg vs placebo; 55% on BB, 17% on aldactone and ACE-inh Primary outcome death and HF admission

9. Does adding an ARB to an ACE-inhibitor help? Guidelines Class IIb: Addition of ARB may be considered in persistently symptomatic pts with reduced EF already on conventional therapy (LOE B) Class III: Routine triple therapy with ACE-inh, ARB and aldosterone antagonist is not recommended (LOE C)

10. Controversies and Subtleties in HF  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

12. Rathore et al. Sex Based Differences in Dig Post-hoc subgroup analysis of the 6800 pts in the DIG trial NEJM 1997 Women on dig had death rate of 33.1% vs 28.9% on placebo; HR 1.23

13. Rathore et. Al. Association of Serum Dig Concentration and Outcomes JAMA 2003 Post-hoc analysis of DIG trial, anlaysis of only men 0.5-0.8: 29.9% mortality (6.3% lower mortality compared with placebo) 0.9-1.1: 38.8% mortality (no sig difference from placebo) >1.2: 48% (p=0.006 for trend); 11.8% higher mortality compared with placebo

14. >1.2 ng/ml 0.5-0.8 ng/ml Conclusion: dig level 0.5-0.8 likely represents ideal target for men and especially women

15. Class IIa In 2005 update – digoxin changed from class I to IIa recommendation because of narrow therapeutic window and no affect on mortality “Digitalis can be beneficial in pts with current or prior HF symptoms and reduced EF to decrease hospitalizations” LOE B

16. Controversies in Cardiac Failure  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

17. ACE-I vs beta blocker first? Most common practice is to start with ACE-I, then add BB (since historically, the BB trials were done with ACE-inh as background therapy) CIBIS III – 1010 pts (mean EF 28%, age 72, mild to mod HF, stable, randomized to bisoprolol or enalapril for 6 months then combination for 6-24 months Willenheimer et al. Effect on Survival and Hosp. of Initiating Treatment for CHF with Bisoprolol followed by Enalapril as comparted with opposite sequence. CIBIS III Circ 2005

19. SUDDEN DEATH PUMP FAILURE DEATH BISOPROLOL FIRST

20. Guidelines Class I recommendation for both ACE-inh and BB for any LV dysfunction No comment on the order, but discussion does state that ACE-inh were historically already on-board when BB started; and that ACE-inh dose can be low, so as to allow starting BB to decrease arrhythmic death rate

21. Controversies in Cardiac Failure?  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

22. 1987 1992 1991 1993

23. Controversies and Subtleties in HF  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

24. Which beta blocker is better? No direct comparison of the three approved drugs: carvedilol (alpha/beta nonselective), metoprolol succinate (b1 selective), bisoprolol (b1 selective) By having more adrenergic blockade, does coreg have more/less side effects? Alpha blockade with Coreg?

25. Comparison of carvedilol and metoprolol on clinical outcomes in patients with CHF: COMET Lancet 2003 Primary outcome: all-cause mortality or all-cause mortality or all-cause admission Results: 58 months, all cause mortality 34 vs 40% (coreg vs metop, p=0.0017, HR 0.83)

26. Decreased arrhythmic deaths from carvedilol in COMET

27. Guidelines Class 1: Use of 1 of the 3 beta blockers proven to reduce mortality (i.e., bisoprolol, carvedilol, and sustained release metoprolol succinate) is recommended for all stable patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated No comment about which beta blocker is best

28. Controversies and Subtleties in HF  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

29. Salvatore et al. Cochrane Database: meta-analysis of Continuous Infusion vs bolus injection of loop diuretics in CHF, 2005 8 trials (254 pts) included More urine output with continuous infusion Hypokalemia/hypomag not significantly different Based on 2 studies, no difference in mortality (RR 0.47) Less tinnitus and hearing loss with continuous infusion (RR 0.06) Insufficient data to recommend one strategy over the other Felker, GM et al. Circulation: Heart Failure, 2009 Observational data suggest that higher diuretic doses may be associated with risk of worsening renal function, heart failure progression, or death

30. Thomson et al. Continuous vs Intermittent Infusion of Furosemide in ADHF. J Card Fail 2010 Prospective, randomized, parallel-group study, 56 pts ADHF; Primary outcome: net urine output Results: more urine output with gtt Length of stay shortened 6.9 +/- 3.7 vs 10.9 +/- 8.3 d Lasix drip

31. Acute Heart Failure (1 symptom AND 1 sign) Home diuretics dose ≥ 80 mg and ≤240 mg furosemide <24 hours after admission 2x2 factorial randomization High Dose (2.5x oral), Continuous infusion Co-Primary endpoints: Change in creatinine from baseline to 72 hours Patient Global Assessement area under curve over 72 hours Low Dose (1x oral), Continuous infusion High Dose (2.5x oral), Q12 IV bolus Low Dose (1 x oral), Q12 IV bolus Study Design: DOSE

33. 2009 guideline Class I: Diuretics and salt restriction are indicated in patients with current or prior symptoms of HF and reduced LVEF who have evidence of fluid retention Class I: When diuresis is inadequate to relieve congestion, as evidenced by clinical evaluation, the diuretic regimen should be intensified using either: higher doses of loop diuretics; addition of a second diuretic (such as metolazone, spironolactone, or intravenous chlorothiazide) continuous infusion of a loop diuretic. (Level of Evidence: C)

34. Controversies in Cardiac Failure  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Shouls Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

35. Metra et al. Should beta-blocker therapy be reduced or withdrawn after an episode of ADHF? COMET substudy.

36. Influence of Beta-Blocker Continuation or Withdrawal on Outcomes in Pts Hospitalized with HF: Substudy of OPTIMIZE-HF. JACC 2008 OPTIMIZE-HF – registry of pts admitted to US hospitals with HF, 5791, followed at 60 and 90 days Sub-analysis of beta blocker use, continuation, initiation 2373 (of 5791) were eligible for BB at time of d/c

38. Guidelines Class I recommendation Comment in paragraph that if hemodynamic instability, compromise, or marked volume overload, the dose of the beta blocker should be decreased or stopped.

39. Controversies in Cardiac Failure  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

40. 2009 guidelines Comment: Clinical experience in patients who are hemodynamically or clinically unstable suggests that the hypotensive effects of ACE inhibition may attenuate the natriuretic response to diuretics and antagonize the pressor response to intravenous vasoconstrictors As a result, in such patients (particularly those who are responding poorly to diuretic drugs), it may be prudent to interrupt treatment with the ACEI temporarily until the clinical status of the patient stabilizes. Class I:

41. Controversies in Cardiac Failure  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

42. “Renal dose” dopamine 1-3 mcg/kg/min – DA-1 receptor will induce intrarenal vasodilation; 3-10 mcg/kg/min – augment renal perfusion by increased B1 adrenoreceptor effect (increased CO) 5-20 mcg/kg/min – peripheral vasoconstriction by alpha-1 adrenoreceptors (increase BP, but possible renal vasoconstriction) Downside – extravasation can cause necrosis/ischemia Trigger tachyarrhythmias and MI Multiple small studies have shown increased renal blood flow and increased GFR, but clinically, no decreased ARF in high risk pts or improvement in renal function in pts with ARF (mostly ICU or surgical studies, 50 pts or so)

43. Controversies in Cardiac Failure  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

44. Acute Vasoconstrictor Response to IV Lasix in CHF Hemodynamic 20 min After IV VariableBaselineFurosemide* P Value PAWP (mm Hg) 28 ± 7 33 ± 9 <0.01 SVI (mL/min-m 2 ) 27 ± 8 24 ± 7<0.01 HR (bpm) 87 ± 13 91 ± 16<0.01 MAP (mm Hg) 90 ± 15 96 ± 15<0.01 SVR (dyne-s-cm -5 )1454 ± 394 1676 ± 415<0.01 PRA (ng/mL) 9.9 ± 8.5 17.8 ± 16<0.05 PNE (pg/mL) 667 ± 390 839 ± 368<0.01 Francis GS., Ann Int Med., 1985;103:1–6.

45. Bayliss J et al. Br Heart J. 1987;57:17–22 Bayliss J et al. Br Heart J. 1987;57:17–22. Activation of the RAAS by Loop Diuretics Plasma Renin Activity (ng/mL/h) Before Diuretic (n = 12) After Diuretic (n = 11) 50 10 2.5 0.5 Mean Confidence Interval

46. Controversies in Cardiac Failure  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

47. Copyright © American Heart Association

48. Controversies in Cardiac Failure  Does adding an ARB to an ACE-inhibitor help?  Do I need to check a dig level?  Which should you start first, an ACE-inhibitor or BB?  Which ACE-inhibitor is the best?  Which BB is better, coreg or toprol xl?  Lasix intermittent bolus or drip?  When a patient is admitted for acute decompensated HF, should you hold, continue, or decrease the BB? For cardiogenic shock?  When a patient is admitted for acute decompensated HF (with volume overload; assuming no acute renal failure), should you hold, continue, or decrease the ACE-inhibitor (or ARB)?  Does renal dose dopamine work?  Should Lasix be given with hypotension?  Are all inotropes created equal?  PA catheter – yes or no?

49. PA Catheter in ADHF  Studies are controversial  Guidelines Unexplained hypotension  My reccomendations: Shock ?Volume status Poor response to therapy Renal failure cardiorenal syndrome

51. Thanks for Your Attention Questions?