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)

USA Center for Disease Control, National Center
for Health Statistics
4
Many elderly female patients with CHF
of all males or of all females
Source USA Center for Disease Control, National
Center for Health Statistics
Age (yrs)
5
Many etiologies of CHF

• Coronary artery disease
• Hypertension
• Valvular heart disease
• Congenital heart disease
• Toxins
• Peripartum cardiomyopathy
• Many others

McMurray, Pfeffer. JACC 2004442398-405 Pinski.
JAMA 2003289754-6 Schmitt. Science
20032991410-3
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

Aurigemma, Gassch. NEJM 20043511097-1105 Brucks.
Am J Cardiol 200595603-6
7
Heart failure with preservedsystolic function
8
Heart failure with preservedsystolic function

• Get new videos of systolic and diastolic
  dysfunction

Peak early diastolic mitral annular velocity lt8
cm/s
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!

Maurer, JACC 2004441543-9 McMurray, Pfeffer.
JACC 2004442398-405 Pinski. JAMA
2003289754-6 Schmitt. Science 20032991410-3
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

Aurigemma, Gassch. NEJM 20043511097-1105 Brucks.
Am J Cardiol 200595603-6
11
Chronic Systolic Dysfunction

• Get new videos of systolic and diastolic
  dysfunction

12
Pathophysiologic changes in CHF

• ?Renal blood flow activates renin-angiotensin-aldo
  sterone
• Compensatory changes
• ?blood volume
• ?total body water
• ?total body Na
• ?TNFa, ?ANP, ?BNP
• BNP lt15 pmol/L excludes HF etiology of dyspnea

(pg/mL)
Doust. Arch Int Med 20041641978-84 Rodeheffer.
JACC 200444740-9 Feldman JACC
200035537-44 Torre-Amione JACC 1996271201-6
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

?-AR G Adenylyl Protein
Cyclase
Cheng. Circ Res 200189599-606 Kilts. Circ Res
200087705-9 Movsesian. JACC 199934318-24
Ungerer. Circulation 199387454-63
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

NEJM 19933291-7 NEJM 20023471403-11 Ann Int
Med 2005142132-45
19
Effect of Digoxin on Mortality and Morbidity
Digoxin Investigation Group

• 6800 patients with LV EF lt.45 digoxin or placebo
• Mean 37 mo follow up
• Similar mortality (35)
• Digoxin fewer hospitalizations
• Use it when symptoms persist despite ß-blocker
  ACE inhibitor

Hospitalized for Worsening HF

NEJM 1997336525-33 Ann Int Med 2005142132-45
plt.001
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

Ann Int Med 2005142132-45
21
McMurray Circulation 20041103281-8
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

Ann Int Med 2005142132-45
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)

Sylvia Simpson and James Tait From Tan. Int J
Cardiol 2004 96321-333
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 plt.001

mortality
Pitt et al NEJM 1999341709-17
25
Epleronone reduces mortality in patients with LV
dysfunction after MI

• Patients assigned to epleronone 25-50 mg qd
  (n3313) or placebo (n3319)
• gt75 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

Number of Deaths
All All Sudden CV CV
NEJM 20033481309-21 Circulation 2005Feb 21 Epub
26
?-ARBs and chronic heart failure

• Long thought contraindicated for CHF
• Antiarrhythmic, antioxidant, antiischemic,
  sympatholytic effects
• Inhibit ß3 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

JACC 200545252-9 Ann Int Med 2005142132-45
27
Multicenter ?-ARB mortality trials
Gheorghiade. Circulation 20031071570-5
28
Carvedilol or Metoprolol European Trial (COMET)

• 1511 patients receive carvedilol (25 mg BID)
  1518 receive metoprolol (50 mg BID)
• NYHA II-IV EFlt.35 ACE-I diuretic (if
  tolerated)
• Mean 58 months in trial
• Carvedilol reduced all-cause (HR .83) and CV
  (.80) mortality relative to meto

Deaths Deaths
Poole-Wilson. Lancet 20033627-13
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

Iso Hydra
Overall survival ()
Placebo
Days since baseline visit
Taylor. NEJM 20043512049-2057
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 need3

• Intermittent outpatient therapy?
• Bridging until transplant?
• Destination end of life care?

1Stevenson. Circulation 2003108367-72 2Hayes.
NEJM 19943301717-22 3Cuffe. JAMA 20022871541-7
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
  µg/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)

Levo
Dob
Percent surviving
Time (days)
Follath. Lancet 2002360196-202
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)

Am Heart J 20021441102-8 JAMA
20022871531-40 J Cardiothorac Vasc Anesth
200418780-7
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

4 hr 8-16 hr
Breisblatt JACC 1990151261-9
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

Bolli. Circulation 1992861671-91
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

Bolli. Circulation 1992861671-91
38
Potential mechanisms of reversible heart failure
after heart surgery

• Stunning
• Hibernation
• Ischemia
• ?CBF
• Reversible with drugs or revascularization

Bolli. Circulation 1992861671-91
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

Royster. Anesth Analg 1991 72729-36
40
Factors associated with use of positive inotropes
in valve surgery

• Control group from neuroprotection RCT
• Logistic regression
• Multivariate associations age gt60, CHF, LVEF
  -5, anesthesiologist
• Unlike CABG, no association with female sex, CPB
  time

Odds ratios in multivariate logistic model
Butterworth. Anesth Analg 199886461-7
41
Positive inotropic drugs

• cAMP independent agents
• Cardiac glycosides
• Calcium salts
• Liothyronine (T3)
• ?-AR agonists
• Calcium sensitizers

• cAMP dependent agents
• ß-adrenergic agonists
• Epinephrine
• Dobutamine
• Dopaminergic agonists
• Dopamine
• Dopexamine
• Phosphodiesterase inhibitors
• Milrinone
• Inamrinone
• Olprinone

42
CaCl2 does not increase CIafter CABG

• N12 patients
• Studied on 1st postoperative day cross-over RCT
• CaCl2 10 mg/kg bolus 2 mg/kg/hr
• CaCl2 ?Cai ?MAP, but no ?CI

,
L/min/m2
plt.05 vs BL plt.05 vs Ca
Zaloga. Circulation 199081196-200
43
Ca sensitizing agents levosimendam
Cardiac output (L/min)

• 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 µg/kg loading doses 0.2-0.3 µg/kg/min
  infusion (?CO, ?SVR and ?PVR)
• Not available in USA

µg/kg
µg/kg
Elapsed time (min)
Kivikko. Circulation 200310781-86 Follath.
Lancet 2002360196-202 Nijhawan. J CV Pharmacol
199934219-28 Lilleberg. Eur Heart J
199819660-8
44
Positive inotropic drugs

• cAMP independent agents
• Cardiac glycosides
• Calcium salts
• Liothyronine (T3)
• ?-AR agonists
• Calcium sensitizers

• cAMP dependent agents
• ß-adrenergic agonists
• Epinephrine
• Dobutamine
• Dopaminergic agonists
• Dopamine
• Dopexamine
• Phosphodiesterase inhibitors
• Milrinone
• Inamrinone
• Olprinone

45
Stevenson. Circulation 2003108492-7
46
Dobutamine increases HR more than epinephrine
after CABG
change

• 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

Butterworth. J Cardiothorac Vasc Anes
19926535-41
47
Fullerton left vs right atrial administration of
epi
Greater ?cardiac output, less ?PA pressure with
left atrial than right atrial epinephrine
infusion (70 ng/kg/min)
48
Renal dose dopamine does not always produce
renal concentrations
DA in ?g/L

• 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

DA infusion rate (?g/kg/min)
MacGregor. Anesthesiology 200092338-46
49
Milrinone, an effective first-line inotrope to
wean sick patients from CPB

• 30 patients LVEF 35 or mean PAP 20 mmHg
• Recd milrinone 50 µg/kg 0.5 µg/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

N
Doolan. J Cardiothorac Vasc Anesth 19971137-41
50
Milrinone prevents low cardiac output syndrome
after correction of congenital heart disease

• 238 patients
• 3 groups
• Placebo
• 25 µg/kg 0.25 µg/kg/min
• 75 µg/kg 0.75 µg/kg/min
• 64 reduced incidence of LCOS by 75 µg/kg dose

Hoffman et al. Circulation 2003107996-1002
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
Calcium inhibits cardiac stimulation by
dobutamine (5 µg/kg/min) after CABG
Cardiac output
Stroke volume
Increase
Plt.05
After Ca Ca 1.61 mM
Before Ca Ca 1.13 mM
Butterworth. Chest 1992101174-80
53
Dobutamine antagonizes epinephrine CI and cAMP
production
cAMP production pmol/106 cells/10 min

• 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)

log DB (mol/L)
Prielipp. Anesthesiology 19988949-57
54
Amrinone epi Royster
Inamrinone (1.5 mg/kg) adds to epi (30 ng/kg/min)
after CPB Royster et al. Anesth Analg
199377662-72
Plac Plac
Plac Epi
Inam Plac
Inam Epi
Minutes
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
• ß-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