Congestive Heart Failure and

Digitalis

New York Heart Association:

Classifications of Heart
Failure
Class I - no limitation of physical activity
Class II - slight limitation of activity

Class III - marked limitation of activity

dyspnea with moderate physical activity

dyspnea with minimal physical activity

Class IV - severe symptoms at rest

Classification Systems
NYHA based on
exercise capacity
(functional system)

Class I
Class II
Class III
Class IV

ACC/AHA staging of
heart failure
(progression)

Stage A
Stage B
Stage C
Stage D

New Approach to the

Classification of Heart Failure
Stage Patient Description

High risk for developing

heart failure (HF)

B
C

Asymptomatic HF

Refractory
end-stage HF

Symptomatic HF

Hypertension
CAD
Diabetes mellitus
Family history of cardiomyopathy

Previous MI
LV systolic dysfunction, LVH
Asymptomatic valvular disease
Known structural heart disease
Shortness of breath and fatigue
Reduced exercise tolerance
Marked symptoms at rest despite
maximal medical therapy (eg, those
who are recurrently hospitalized)

Modified from Hunt SA et al. J Am Coll Cardiol. 2001;38:21012113.

New Classification of Heart Failure

ACC/AHA Staging v/s NYHA Functional Class
ACC/AHA HF Stage1

NYHA Functional Class2

AAt high risk for heart failure but without

structural heart disease or symptoms
of heart failure (eg, patients with
HTN or coronary artery disease)

BStructural heart disease but without

symptoms of heart failure

CStructural heart disease with prior or

current symptoms of heart failure

DRefractory heart failure requiring

specialized interventions

None

Asymptomatic

II

Symptomatic with moderate exertion

III Symptomatic with minimal exertion

IV Symptomatic at rest

Hunt SA et al. J Am Coll Cardiol. 2001;38:21012113.

New York Heart Association/Little Brown and Company, 1964. Adapted from: Farrell MH et al.JAMA.2002;287:890897.

1
2

Cardiovascular responses to heart

failure
Inadequate cardiac output

Adrenergic
nervous
system
(norepinephrine)

Tachycardia

Renin
angiotensin
system
(aldosterone)

Systemic vasoconstriction

Pathophysiology of HF

Cardiac injury > depressed cardiac function

poor tissue perfusion
Cardiac output must increase

Activation of neurohormonal axis

Norepi, AVP, angiotensin II, endothelin

Chronic Neurohormonal release is

dysfunctional

Alterations in HR, contractility

Myocardial hypertrophy and ischemia

Conditions that may

precipitate CHF

Infections
Arrhythmias
Myocardial infarction
Pulmonary embolism
Undue physical
exertion
Excessive Na intake

Hemorrhage, anemia
Pregnancy
In- and trans-fusions
Anesthesia/surgery
High altitude
Hypertension
D/C digitalis

Pharmacotherapeutic approaches in heart failure

Reduction of volume overload (reduce
preload)

Diuretics

Ventricular unloading (reduce afterload)

Acute: nitroglycerin, sodium nitroprusside

Chronic: inhibit renin-angiotensinaldosterone system, diuretics, ACE
inhibitors, angiotensin antagonists
Beta-blockers (also reduce sympathetic
activation)

Inotropic interventions (improve Starling

function)

Acute: dobutamine

Chronic: phosphodiesterase inhibitors,

digitalis

Effects of
ouabain on
cardiac
function in
a patient
with CHF

Effects of ouabain on the CV system

of a patient in CHF

Effects of ouabain on the CV system

of a normal human volunteer

Digitalization can increase

myocardial efficiency in CHF

Determinants of myocardial
oxygen demand
Intramyocardial tension

blood pressure, ventricular volume

Myocardial contractility

Heart rate

Fiber shortening (Fenn effect)

Activation energy

Basal (resting) metabolism

Ventricular function (Starling) curves:

normal, CHF and with digitalis
Cardiac Output

normal

CHF + digitalis

adequate

inadequate,
fatigue

CHF
congestive symptoms,
edema, dyspne
a

ventricular end-diastolic volume

Mechanism of positive inotropic

effect of digitalis
VOC

ROC
PMCA

SR

Na/Ca
exchange

Ca2+
Na +

actin
myosin

mitochondria

VOC = voltage-operated channel

ROC = receptor-operated channel
PMCA = plasma membrane Ca2+ ATP-ase

Na/K
pump

digitalis

Effect of ouabain on cardiac cellular

functions
control

digitalis 25 min

digitalis 47 min

membrane
potential

intracellular
calcium
contractile
tension
100 msec

adapted from Weir & Hess, 1984

Digitalis: positive inotropic mechanism

Inhibition of Na, K ATPase

Altered balance of Na/Ca exchange
Enhanced Ca storage/release
Increased binding of Ca to troponin
Increased actin/myosin ATPase
Increased contractility

Pharmacotherapeutic approaches in heart failure

Reduction of volume overload (reduce preload)

diuretics

Ventricular unloading (reduce afterload)

Acute: nitroglycerin, sodium nitroprusside

Chronic: inhibit renin-angiotensin-aldosterone system,
diuretics, ACE inhibitors, angiotensin antagonists
Beta-blockers (also reduce sympathetic activation)

Inotropic interventions (improve Starling function)

Acute: dobutamine
Chronic: phosphodiesterase inhibitors, digitalis

dobutamine
Positive inotropic effect via beta-1 receptors
Reduces afterload via beta-2 receptors
Minor activation of alpha-1 receptors
May promote sinus tachycardia, PVCs,
angina, headache, hypertension
Half life about 2 minutes. IV infusion to titrate
dobutamine effects.

milrinone
Relatively selective inhibitor of type III cyclic
nucleotide phosphodiesterase (cGMP inhibited cAMP
hydrolysis) (exerts positive inotropic effect and
vasodilation and bronchodilation).
Indicated for IV treatment of heart failure. Chronic
oral dosage associated with increased mortality. Half
life is about 2 hours. Excreted mainly in urine, adjust
dosage in renal disease.
Adverse reactions included PVCs, SVT, VT and VF

Cardiovascular responses to heart

failure
Inadequate cardiac output

Beta blockers
Adrenergic
nervous
system
(norepinephrine)

Tachycardia

Renin
angiotensin
system
(aldosterone)

Systemic vasoconstriction

Beta adrenergic blockers:

decrease renin release and afterload (and
decrease sympathetic activation of heart)
Propranolol

Metoprolol

Carvedilol

decreases afterload in part by alpha adrenoceptor antagonism

Use of beta-blockers in carefully monitored patients

CHF may be beneficial. Until recently, beta blockers
were considered to be contraindicated in CHF.

Impact of atrial tachycardia on

circulation

Effect of digitalis on a supra-ventricular

tachycardia

Effects of
lanatoside C
on paroxysmal
atrial flutter

Circus movement atrial flutter model:

effect of digitalis

Vagal (ACh) actions on

supraventricular parts of the
heart
Decreases SA node automaticity (and slows heart rate)

Decreases duration of atrial muscle action potential (and

decreases refractory period)

Slows AV nodal conduction velocity and increases AV nodal

refractory period

All of the above effects are caused by a single mechanism

of action: increased potassium permeability

Effects of transient release of

acetylcholine on atrial action
potential and contractile force

Vagal (ACh) actions on

supraventricular parts of the
heart
Decreases SA node automaticity (and slows heart rate)
Decreases duration of atrial muscle action potential (and
decreases refractory period)
Slows AV nodal conduction velocity and increases AV
nodal refractory period

Effect of digoxin on AV nodal conduction in

normally innervated human heart

Lack of effect of digoxin on AV nodal

conduction in transplanted (denervated)
human heart

Pharmacokinetics of digoxin
Well, but variously absorbed from GI tract,
bioavailability = 70 13%
Vd = (3.12 CLcr + 3.83) 30% and
proportional to thyroid status
Most excreted in urine unchanged,
elimination depends on kidney function
Half life = 39 13 hours (1.6 days)

Accumulation of digoxin during chronic

dosing

Pharmacokinetics of digitoxin
Well absorbed from GI tract, bioavailability
> 90%
Vd = 0.54 0.14 liters/kg
Non-polar compound, elimination depends on
liver function
Half life = 6.7 1.7 days

Non-uniform bioavailability of several generic

and trade name digoxin preparations

Some adverse reactions to

digitalis
CNS
headache, malaise, confusion, dizziness, changes in color
vision
GI
anorexia, nausea, vomiting, diarrhea
CV
bradycardia, heart block (various degrees), arrhythmias,
ventricular tachycardia, fibrillation, hyperkalemia

digoxin in hospitalized patients

22.4% of patients (est. failure 8%)
CHF (78%), arrhythmias (21%), other (1%)

Route
PO (79%), IV (15%), IM (6%)

Adverse reactions

Arrhythmias 8.5%
GI disturbances 3.1%
CNS toxicity 0.1%
Gynecomastia 0.1%

Digitalis toxicity
In various studies

The minimal inotropic dose of = about 1/5 of the

lethal dose
The minimal toxic dose = about 2/3 of the lethal
dose

Thus, the therapeutic window is narrow

Diagnosis of digoxin toxicity

Are there predisposing factors?

large dose, decreased elimination

Are there extracardiac symptoms?

anorexia, nausea/vomiting, visual signs

Arrhythmias present?

Arrhythmias change when digoxin withheld?

What is serum digoxin concentration?

Serum digoxin levels in 179

patients

Serum
Serumconcentrations
concentrationsat
atwhich
whichthe
theprobability
probabilityof
ofdigoxin
digoxin
induced
inducedarrhythmias
arrhythmiasisis10%
10%==1.7,
1.7,50%
50%==2.5,
2.5,90%
90%==3.3
3.3

Treatment of acute digoxin intoxication by

digoxin immune Fab (Digibind)

Simplified diagram of apparent

digitalis-induced changes in ANS
activity
VF - death
CNS
output of
autonomic
tone

VT

sympathetic

PVCs
slowing

partial AV block

parasympathetic

Dose of digitalis

Digoxin overview

About 50% of patients with CHF have elevated

endogenous ouabain (EO)
EO level is inversely correlated with the cardiac index.
Digoxin reduces hospitalization for worsening heart
failure
Digoxin increases the risk of death from any cause in
women, but not in men.
Digoxin only benefits some patients - perhaps patients
with low levels of EO (untested at this time)
Improves the quality but not the length of life

2006 HF Treatment Algorithm by Stage

Stage A

Stage B

Stage C

Stage D

stage A, B
ACE-inhibitors
beta-blockers
diuretics

stages A, B, and C
IV inotropes ?
MCS (bridge to Tx)
heart transplantation

spironolactone
digitalis
bivent pacing +/- ICD
ARBs ?

IV inotropes
MCS (permanent)
hospice care

Angina
nitrate
amlodipine
PCI
CABG
AF
warfarin
rate control
cardioversion

treat HTN
smoking cessation
treat lipid disorders
exercise
treat diabetes

stage A
ACE-inhibitors
beta-blockers
ICD ?

Antiendothelin agents, anticytokines, oral inotropes, cardiac support devices, cell and gene Rx

ACE Inhibitors in Heart Failure:

From Asymptomatic LVD to Severe HF
SOLVD Prevention
(Asymptomatic LVD)

CONSENSUS
(Severe Heart Failure)

20%

death or HF hosp.

40%

mortality at 6 mos.

29%

death or new HF

31%

mortality at 1 year

27%

mortality at end of
study

SOLVD Treatment
(Chronic Heart Failure)
16%

mortality

No difference in incidence of
sudden cardiac death

SOLVD Investigators. N Engl J Med 1992;327:685-91.

SOLVD Investigators. N Engl J Med 1991;325:293-302.
CONSENSUS Study Trial Group. N Engl J Med 1987;316:1429-35.

Mortality Reductions with ACE - I

Relative Risk Reduction (%)

30
25
20
15
10
5
0

CONSENSUS
n = 253

SOLVD
n = 4228

SAVE
n = 2231

AIRE
n = 1986

HOPE
n = 3577

CONSENSUS: NEJM 1987;316:1429-435, SOLVD: NEJM 1991;325:293-302, SAVE: NEJM 1992;327:669-677

AIRE: Lancet 1993;342:821-828, HOPE: Lancet 2000;355:253-259

Effect of Beta Blockade on Outcome

in Patients With HF and Post-MI LVD
HF
Severity

Target
Dose (mg)

Outcome

Study

Drug

US Carvedilol1

carvedilol

mild/
moderate

6.2525 BID

48% disease progression

(p= .007)

CIBIS-II2

bisoprolol

moderate/
severe

10 QD

34% mortality (p <.0001)

MERIT-HF3

metoprolol
succinate

mild/
moderate

200 QD

34% mortality (p = .0062)

COPERNICUS4

carvedilol

severe

25 BID

35% mortality (p = .0014)

CAPRICORN5

carvedilol

post-MI
LVD

25 BID

23% mortality (p =.031)

4. Packer M et al. N Engl J Med 2001;3441651-8.

1. Colucci WS et al. Circulation 1196;94:2800-6.
5. The CAPRICORN Investigators. Lancet 2001;357:1385-90.
2. CIBIS II Investigators. Lancet 1999;353:9-13.
3. MERIT-HF Study Group. Lancet 1999;353:2001-7.

HFSA 2006 Practice Guideline (7.14-7.15)

Pharmacologic Therapy:
Aldosterone Antagonists
An aldosterone antagonist is recommended for
patients on standard therapy, including diuretics,
who have:

NYHA class IV HF (or class III, previously class IV)

due to LV systolic dysfunction (LVEF 35%)

One should be considered in patients post-MI

with clinical HF or diabetes and an LVEF < 40%
who are on standard therapy, including an ACE
inhibitor or an ARB.
Strength of Evidence = A
Adapted from: Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive
Heart Failure Guideline. J Card Fail 2006;12:e1-e122.

Aldosterone Antagonists in HF

Probability of Survival

RALES (Advanced HF)

EPHESUS (Post-MI)

1.00

1.00

0.90

0.90

0.80

Spironolactone

0.70

0.80

Placebo
0.70

0.60
0.50

Epleronone

Placebo

0.60
0.50

RR = 0.70
P < 0.001

0.40

RR = 0.85
P < 0.008

0.40
0 3 6 9 12 15 18 21 24 27 30 33 36

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

Months
Pitt B. N Engl J Med 1999;341:709-17.
Pitt B. N Engl J Med 2003;348:1309-21.

HFSA 2006 Practice Guideline (7.24)

Pharmacologic Therapy: Diuretics

Restoration of normal volume status may require multiple
adjustments.
Once a diuretic effect is achieved with short-acting loop
diuretics, increase frequency to 2-3 times a day if necessary,
rather than increasing a single dose.
Strength of Evidence = B
Oral torsemide may be considered in patients exhibiting poor
absorption of oral medication or erratic diuretic effect.
Strength of Evidence = C

IV administration of diuretics may be necessary .

Strength of Evidence = A

Diuretic refractoriness may represent patient noncompliance,

a direct effect of diuretic use on the kidney, or progression of
underlying dysfunction.
Adapted from: Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive
Heart Failure Guideline. J Card Fail 2006;12:e1-e122.

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