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Alan Gass, M.D., F.A.C.C.
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Director, Cardiac Transplantation and Mechanical Circulatory Support
i
Westchester Medical Center
s
Controversies in Cardiac Failure
Controversies in Cardiac Failure
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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?
Controversies and Subtleties in HF
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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?
Valsartan in CHF: ValHeFT. Cohn et al. NEJM 2001
•
NYHA II-IV HF, 5010 pts, RCT, Valsartan 160 BID vs placebo
In 1610 pts on both
Ace and BB,
increased mortality
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
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)
Controversies and Subtleties in HF
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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?
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
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
0.5-0.8 ng/ml
>1.2 ng/ml
Conclusion: dig level 0.5-0.8
likely represents ideal target
for men and especially women
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
Controversies in Cardiac Failure
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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?
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
SUDDEN DEATH
BISOPROLOL FIRST
PUMP FAILURE
DEATH
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
Controversies in Cardiac Failure?
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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?
1987
1992
1991
1993
Controversies and Subtleties in HF
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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?
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?
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)
Decreased arrhythmic deaths from carvedilol in COMET
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
Controversies and Subtleties in HF
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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?
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
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
Study Design: DOSE
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
High Dose (2.5x
oral), Q12 IV bolus
Low Dose (1x 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 (1 x
oral), Q12 IV
bolus
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)
Controversies in Cardiac Failure
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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?
Metra et al. Should beta-blocker therapy be reduced or
withdrawn after an episode of ADHF? COMET
substudy.
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
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.
Controversies in Cardiac Failure
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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?
2009 guidelines
Class I:
 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.
Controversies in Cardiac Failure
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
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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?
“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)
Controversies in Cardiac Failure
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










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?
Acute Vasoconstrictor
Response to IV Lasix in CHF
Hemodynamic
Variable
Baseline
PAWP (mm Hg)
28 ± 7
33 ± 9
<0.01
SVI (mL/min-m2)
27 ± 8
24 ± 7
<0.01
HR (bpm)
87 ± 13
91 ± 16
<0.01
MAP (mm Hg)
90 ± 15
96 ± 15
<0.01
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
SVR (dyne-s-cm-5)
20 min After IV
Furosemide*
Francis GS., Ann Int Med., 1985;103:1–6.
P Value
Plasma Renin Activity (ng/mL/h)
Activation of the RAAS by Loop Diuretics
50
10
Mean
Confidence
Interval
2.5
0.5
Before Diuretic After Diuretic
(n = 11)
(n = 12)
Bayliss J et al. Br Heart J. 1987;57:17–22.
Controversies in Cardiac Failure
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








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?
Copyright © American Heart Association
Controversies in Cardiac Failure
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









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?
PA Catheter in ADHF
 Studies are controversial
 Guidelines
• Unexplained hypotension
 My reccomendations:
•
•
•
•
Shock
?Volume status
Poor response to therapy
Renal failure
• cardiorenal syndrome
Thanks for Your Attention
Questions?