Heart Failure - part 5 potx

The discov-ery of “aldosterone escape” following treatment with RAS blockers raised the possibility that direct aldosterone blockade might provide incremental benefits and protection for

simultaneously, secretion of K+ These effects

con-tribute to fluid overload and also K+ depletion

The latter is of particular importance in the HF

population and/or post-MI population who are

already at increased risk of sudden cardiac death

and who are often being treated with loop or

thi-azide diuretics that potentiate K+loss Local

aldos-terone production, within the heart, is believed to

contribute to cardiac myocyte hypertrophy and

interstitial fibrosis An increase in the quantity of

fibrous tissue in the heart decreases ventricular

compliance and also, by disturbing the

homo-geneity of electrical conduction, creates a

sub-strate for arrhythmias In the vasculature,

aldosterone contributes to endothelial

dysfunc-tion by impairing acetylcholine and NO-mediated

vasodilatation It also increases vascular

inflam-mation by recruiting macrophages and promoting

monocyte infiltration of vessel walls The

discov-ery of “aldosterone escape” following treatment

with RAS blockers raised the possibility that direct

aldosterone blockade might provide incremental

benefits and protection for the HF population.48

Aldosterone Blockade in Chronic Heart

Failure Patients with LV Dysfunction

The RALES trial evaluated the effects of

spirono-lactone on all-cause mortality in patients with

advanced HF symptoms and evidence of systolic

dysfunction who were already receiving an ACE

inhibitor as background treatment.49 Patients

received spironolactone 25–50 mg qd, or placebo,

in addition to contemporary therapy with diuretics

(100%), digoxin (~75%), and an ACE inhibitor

(~95%) However, b-blockers were used in only

~10% of patients The trial was terminated early

after a 30% relative mortality reduction was

reported in patients randomized to

spironolac-tone There was a 29% relative reduction in

sud-den cardiac death and 36% reduction in death due

to progressive HF The risk of severe hyperkalemia

was low, at 2%, in this carefully monitored group

RALES proved that spironolactone, when added to

contemporary therapy in a carefully controlled

set-ting with well-defined follow-up monitoring of

renal function and electrolytes, is well-tolerated

and provides substantial clinical benefit

Aldosterone Blockade in Post-Acute Myocardial Infarction Patients with LV Dysfunction

The Eplerenone in Patients with Heart FailureDue to Systolic Dysfunction Complicating AcuteMyocardial Infarction (EPHESUS) trial assessedthe effects of aldosterone blockade following AMI

in patients with LV dysfunction and HF.50

Patientswith symptomatic HF were randomized 3–14days after the index event to eplerenone, a selec-tive mineralocorticoid receptor blocker, orplacebo Diabetics, a group at high risk for CVevents, were enrolled after the index MI with orwithout symptoms of HF Eplerenone was added

to standard therapy that included diuretics (60%),ACE inhibitor (86%), and b-blocker (75%) Many

of these patients were also receiving aspirin (88%)and a statin (47%) Despite the already compre-hensive therapy that was being administered tothese patients, treatment with eplerenone resulted

in significant 15% all-cause and 17% CV mortalityreductions These findings indicate that followingAMI, patients with impaired LV function and DM

or HF should receive eplerenone to reduce theirrisk of death and hospitalization for HF Moreover,the results of EPHESUS indicate that this approach

is of incremental benefit even in the setting ofbackground treatment with other neurohormonalblocking agents

How to Use Aldosterone Blockers

in Heart Failure and Post-Acute Myocardial Infarction Patients with LV Dysfunction

The use of aldosterone blockade in patients with

HF requires careful monitoring of serum K+andrenal function It should only be added oncepatients are on a stable dose of a diuretic, RASblocker, and b-receptor blocker Supplemental

K+ should be reduced or discontinued unlessserum K+levels fall below the lower limit of thenormal range followed up at 1 and 4 weeks fol-lowing initiation dose of 25 mg The doseshould be cut in half if K+>5 mEq/L and discon-tinued if >5.5 mEq/L At 4 weeks, if the eplerenone

25 mg/day is well-tolerated, increase the dose to

50 mg/day

Adverse Events and Patient

Monitoring

Monitoring for Hyperkalemia

In both the RALES and EPHESUS trials, there

was a significant increase in the incidence of

hyperkalemia in those patients treated with

spironolactone or eplerenone compared with

patients receiving placebo (2% vs 1% and 5.5

vs 3.9%, respectively) Notably, patients

receiv-ing placebo in the EPHESUS study were more

likely to develop hypokalemia, an equally

life-threatening electrolyte imbalance and this risk

was significantly ameliorated by treatment with

eplerenone Following the publication of

RALES, two groups documented a greater

inci-dence of hyperkalemia and inadequate patient

selection in both the community and an

acade-mic setting.51,52

Treating HF with aldosteroneblockade has a narrow therapeutic index,

requires strict monitoring, and is indicated only

in high-risk patients or those with HF, post-MI

with depressed LVEF, and/or diabetes In

patients with less severely symptomatic HF or

in those whom some time has passed since an

MI that resulted in reduced EF, the benefits of

aldosterone antagonists is uncertain In these

settings, the potential benefits of treatment

should be carefully weighed against the known

risks

Aldosterone antagonists should only be

initi-ated in patients with serum Cr ≤2.5 mg/dL or K+

≤5 mEq/L and on a stable regimen of an ACE

inhibitor, b-receptor blocker, and loop diuretic.

If the patient is currently receiving K+

supple-mentation, cut the dose by one-half The risk for

severe hyperkalemia can be mitigated by close

monitoring of serum creatinine and potassium

levels For this purpose we use the “rule of

ones” that is, measurement of renal function and

serum electrolytes is carried out 1 day prior to

and 1 week and 1 month after drug treatment is

begun In monitored patients who later develop

Cr>4 mg/dL or K+>5.5 mEq/L, stop the

medica-tion The medication should also be stopped

during periods of acute illness causing

dehydra-tion or renal dysfuncdehydra-tion In more mild cases of

hyperkalemia, K+5–5.5 mEq/L, decrease the dose

by half or if only tolerating 12.5 mg, change to qddosing

Gynecomastia

Spironolactone has activity at the androgen andestrogen receptor, which can result in gyneco-mastia In RALES, 9% of male patients wereaffected by this condition compared to a 1%incidence in the placebo group Patients whodevelop gynecomastia on spironolactone should

be switched to eplerenone, which has tially lower affinity for the androgen, proges-terone, and estrogen receptors and, which doesnot increase the likelihood of gynecomastiaabove that seen with placebo.50

substan-
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32 Dries DL, et al Efficacy of

angiotensin-convert-ing enzyme inhibition in reducangiotensin-convert-ing progression

from asymptomatic left ventricular dysfunction

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33 Packer M, et al The effect of carvedilol on

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heart failure N Engl J Med 1996;334(21):

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34 The Cardiac Insufficiency Bisoprolol Study II

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35 Effect of metoprolol CR/XL in chronic heart

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40 Poole-Wilson PA, et al Comparison of carvediloland metoprolol on clinical outcomes in patientswith chronic heart failure in the Carvedilol OrMetoprolol European Trial (COMET): randomised

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41 Sliwa K, et al Impact of initiating carvedilol beforeangiotensin-converting enzyme inhibitor therapy

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42 Antman EM, et al ACC/AHA guidelines for themanagement of patients with ST-elevation myocar-dial infarction: a report of the American College ofCardiology/American Heart Association Task Force

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45 Shekelle PG, et al Efficacy of ing enzyme inhibitors and beta-blockers in themanagement of left ventricular systolic dysfunc-tion according to race, gender, and diabeticstatus: a meta-analysis of major clinical trials

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47 Yancy CW, et al Race and the response toadrenergic blockade with carvedilol in patients

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mor-bidity and mortality in patients with severe heart

failure N Engl J Med 1999;341(10):709–717.

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543–551

Chapter 11

Is There Still a Role for Digitalis in Heart Failure?

JOSEPHS ROSSI, MD/MIHAIGHEORGHIADE, MD

Introduction 128

Background 128

Mechanisms of Action 128

Neuroendocrine Effects 129

Electrophysiological Effects 130

Hemodynamic Effects 130

Metabolism 130

Drug Interactions 130

Electrolytes 131

Digoxin Intoxication 132

Digoxin in Heart Failure with Reduced Systolic Function 132

Early Randomized Studies 132

Prospective Randomized Study of Ventricular Failure and the Efficacy of Digitalis (PROVED) and Randomized Assessment of Digitalis on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE) 135

The Digitalis Investigation Group Trial 137

Digitalis in Heart Failure and Preserved Systolic Function 137

Digitalis in Women 139

Chronic Heart Failure and Atrial Fibrillation 140

Digitalis and Coronary Artery Disease 140

Serum Digitalis Concentration 141

Digitalis in the Setting of Modern Therapy for Chronic Heart Failure 142

ACE Inhibitors 142

b-Blockers 143

Aldosterone Blocking Agents 143

Cardiac Resynchronization Therapy 143

Recommendations 143

127

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INTRODUCTION

Digitalis preparations have been a common

remedy in the treatment of heart disease for

cen-turies Oral digoxin first became available in the

twentieth century, and a large amount of data

from clinical trials has demonstrated it to be

both safe and effective in the treatment of

symp-tomatic heart failure (HF) with or without atrial

fibrillation Due to its wide availability and lack

of patent protection, it did not have extensive

support from the pharmaceutical industry, but

modern clinical trial data led to its approval by

the U.S Food and Drug Administration in 1999

for use in chronic HF, and recommendations for

its use by the American College of Cardiology

and American Heart Association (ACC/AHA) as

well as the Heart Failure Society of America

(HFSA) followed soon after.1,2However, the role

of digoxin therapy has recently been challenged

after its use was associated with increased

mor-tality in women.3In addition, its worth has not

been studied in the presence of modern

ther-apy with b-blockers and aldosterone

antago-nists Accordingly, the new ACC/AHA guidelines

no longer recommend digoxin as routine

ther-apy for patients with chronic HF and systolic

dys-function who are in sinus rhythm.4

BACKGROUND

The beneficial effects of digitalis preparations have

been recognized for centuries, however, they were

not formally introduced to the allopathic

commu-nity until 1785 when first described by Sir William

Withering, an English botanist and physician, in his

textbook describing the medical uses of foxglove.5

Withering described the ability of digitalis to cause

diuresis and slow the heart rate of patients with

irregular pulse Beginning in the twentieth century,

many studies in animals and humans demonstrated

positive inotropic properties of digitalis in normal

as well as failing myocardium

In the late 1970s, the use of digoxin was

chal-lenged when several nonrandomized studies in

patients with HF in normal sinus rhythm (many

of which did not assess left ventricular [LV] tion) failed to show clinical benefit In addition,there was a high incidence of digoxin intoxicationthat was associated with a mortality as high as40%.6 These findings led to a decreased empha-sis on its use, and newer therapies that includedpotent diuretics, vasodilators, and new inotropicagents were developed that provided clinicianswith important alternative therapies in a growingpopulation of HF patients

func-In the 1990s, interest was renewed when (1)newer inotropic agents were found to worsensurvival, (2) randomized studies demonstratedclinical benefits of digoxin in combination withdiuretics and ACE inhibitors, and (3) lower inci-dences of digoxin toxicity were demonstrateddue to increased recognition of drug interactions,lower dosing, and the monitoring of serumdigoxin concentration (SDC) The safety andclinical benefits of digoxin gained widespreadacceptance after the publication of the DigitalisInvestigation Group (DIG) trial in 1996, whendigoxin was shown to significantly decrease hos-pitalizations and improve symptoms in patientswith congestive heart failure (CHF) Theseresults led to strong recommendations for its use

by both the ACC/AHA in 2001 and the HFSA in

1999 (Table 11-1)

In the last decade, several landmark studiesdemonstrating significant mortality benefits of

b-blockers and aldosterone antagonists in patients

with chronic heart failure have been published.The interest in digoxin faded when these newtreatments became widely available However,background digoxin therapy ranged from 51% to90% in these clinical trials, leading to speculationabout the usefulness of these drugs in theabsence of digoxin therapy.7–10Digoxin was fur-ther challenged by a post-hoc analysis of the DIGtrial that reported an increased mortality inwomen, a finding that has been recently disputed.3

Mechanisms of Action For decades, physicians have debated the exactmechanism by which digitalis increases cardiac

performance Basic science studies have

demon-strated a clear affinity of the digitalis molecule for

the potassium (K+) receptor of the

sodium-potassium adenosine triphosphatase (ATPase) It is

through this action that digitalis inhibits the enzyme,

resulting in increased levels of intracellular Na This

results in increased transmembrane

sodium-calcium (Na-Ca) exchange, increasing intracellular

Ca levels, and improving myocardial contractility.11

This mechanism is also thought to account (at least

in part) for the neurohormonal effects of digitalis

by increasing baroreceptor sensitivity.12

Neuroendocrine Effects

HF causes neurohormonal activation, many phases

of which are countered by digitalis and may

explain its long-term beneficial effect in thispopulation These include the following: (1)Baroreceptor function: In patients with CHF, thefailure of the carotid sinus to respond properly maylead to stimulation of the sympathetic nervoussystem, which will increase the production of plasmarenin and vasopressin In low-output HF models,this decrease in baroreceptor function improveswith digoxin administration.12 (2) Vagomimeticeffect: At therapeutic doses, digitalis increasesvagal tone, resulting in decreased sinoatrial (SA)and atrioventricular (AV) conduction.13(3) Directsympathoinhibitory effect: It is mediated by directinhibition of sympathetic nerve discharge.14Thiseffect is, if independent of the increase in cardiacperformance, produced by digoxin, and is notseen in the administration of other medicationsthat increase cardiac output (e.g., dobutamine)

Table 11-1 Effects of digitalis in systolic heart failure at therapeutic concentrations

Hemodynamic effects:

Increases CO and decreases PCWP and systemic vascular resistance

At rest

During exercise

Alone or in combination with ACE inhibitors or systemic vasodilators

During chronic therapy

Increases left ventricular ejection fraction

Neurohormonal effects:

Vagomimetic action

Improves baroreceptor sensitivity

Decreases norepinephrine serum concentration

Decreases activation of renin-angiotensin system

May directly increase aldosterone release

Directs sympathoinhibitory effect

At high doses, increases sympathetic CNS outflow

Decreases cytokine concentrations

Increases release ANP and BNP

Electrophysiologic effects:

SA node: decreases automaticity, severe sinoatrial block in patients with sinus node disease

Atrium: no effect or decreases refractory period

AV node: decreases conduction velocity; increases effective refractory period; advanced heart block

in patients with AV node disease; increases antegrade conduction in accessory AV pathways

Ventricle: no effect; at higher doses or during ischemia

Cholinergic and antiadrenergic effects.

CO—cardiac output; PCWP—pulmonary capillary wedge pressure; ACE—angiotensin-converting enzyme; CNS—central nervous system; ANP—atrial natriuretic polypeptide; BNP—brain natriuretic peptide; SA—sinoatrial; AV—atrioventricular.

Source: Adapted from Eichhorn EJ, Gheorghiade M Digoxin Prog in Card Dis 2002; 44:251–256, with permission from

Elsevier.

(4) Effect on circulating neurohormones:

Therapeutic doses of digoxin decrease plasma

renin activity and circulating norepinephrine

lev-els.15In the Dutch Ibopamine Multicenter Trial

(DIMT), digoxin therapy was associated with a

decreased concentration of plasma norepinephrine

over a 6-month period (5) Antifibrotic effects:

Aldosterone stimulation of the sodium pump may

lead to perivascular fibrosis, which is inhibited

experimentally by digoxin.16

Electrophysiological Effects

Administration of nontoxic doses of digoxin

slows sinus rate by its parasympathomimetic

action This effect prolongs the refractory period

of the AV node Toxic doses predispose atrial

fibers to automatic impulse initiation that does

not depend on the autonomic nervous system,

high-grade AV block that is mediated by

cholin-ergic mechanisms, and an increase in the rate of

spontaneous diastolic depolarization leading to

the occurrence of rapid spontaneous rhythms of

Purkinje fibers Although it is clear that digitalis

intoxication may produce lethal ventricular

arrhythmias, therapeutic doses of digoxin do not

appear to increase arrhythmias in the absence of

ischemia.17

Hemodynamic Effects

Digitalis administration does not alter cardiac

output in normal subjects, although it does cause

significant increase in contractility This lack of

effect on cardiac output is likely due to an increase

in systemic vascular resistance produced by

dig-italis that prevents the increase in contractility

from translating into increased forward flow In

patients with reduced systolic function and

abnormal central hemodynamics who are in

sinus rhythm, digoxin improves LV performance

and reduces pulmonary capillary wedge

pres-sure while increasing cardiac output both at rest

and during exercise.18These beneficial

hemody-namic effects are potentiated in the presence of

ACE inhibitors and other afterload-reducingagents In HF, when hemodynamics are normal-ized first with diuretics and vasodilators, no fur-ther improvement in wedge pressure or cardiacoutput is achieved after acute administration ofdigoxin.19The improvement in hemodynamicspersists during chronic therapy due to lack ofdownregulation of the Na-K-ATPase sites (puta-tive digoxin receptor)

METABOLISMDigoxin has excellent oral bioavailability, withapproximately 80% of the dose being absorbedwithin 3 hours after ingestion from the distalsmall bowel and colon It can be partially inacti-vated by colonic bacteria, and therefore antibi-otic use that depletes enteric flora may increasethe amount of active drug that enters the circu-lation More than 80% of the active drug isexcreted unchanged in the urine The combina-tion of limited metabolism and relatively largevolume of distribution results in a relatively pro-longed half-life of 36–48 hours Steady stateserum concentrations therefore generally occurwithin 7 days after initiation of oral therapy.Digitalis is not removed by dialysis or exchangetransfusion

DRUG INTERACTIONS

Of commonly prescribed medications used totreat cardiovascular illness, it is likely that onlywarfarin surpasses digoxin in concern regardingdosing and drug interactions (Table 11-2) In par-ticular, many common medications used to treatcardiovascular disease complicate digoxin dosing.Propafenone and verapamil cause decreasedrenal reabsorption and therefore increase SDC.20,21Quinidine therapy decreases nonrenal clearance

of digoxin.22 Amiodarone, spironolactone, andflecainide all have been shown to increase SDC

by unknown mechanisms.23–25 sparing diuretics could be a major contributingfactor to digoxin toxicity by causing hypokalemia

Non-potassium-
ELECTROLYTES

Electrolyte disorders commonly accompany

and/or potentiate the toxic effects of digitalis

Serum potassium levels should be monitored

peri-odically, as most of the effects of digitalis are

through its interaction with the K+ site on the

Na-K-ATPase enzyme Decreased serum K+levels

result in the potentiation of the effects of digitalis,potentially leading to ventricular tachycardia orventricular fibrillation Similar effects have beenobserved with hypomagnesemia In the presence

of hyperkalemia, the autonomic effects of digitalispredominate, resulting in decreased AV nodal and

SA conduction, leading to heart block or cant bradycardia Digitalis toxicity itself can also

signifi-
Table 11-2 Drug interactions with digoxin

Non-potassium- Hypokalemia, hypomagnesemia, Increase in the risk of arrhythmiassparing diuretics promotes sodium pump

inhibitionIntravenous calcium Increases myocyte calcium Increase in the risk of arrhythmiasQuinidine, verapamil, Reduction in digoxin clearance Increase in serum digoxin amiodarone, propafenone, and decrease in volume concentration

itraconazole, alprazolam, of distribution

spironolactone

Erythromycin, Increase digoxin absorption by Increase in serum digoxin clarithromycin, inactivating intestinal bacterial concentration

Propantheline, Increase digoxin absorption Increase in serum digoxin

diphenoxylate by decreasing gut motility concentration

Antiacids, anticancer Decrease digoxin absorption Decrease serum digoxin

b-adrenergic blockers, Decrease sinoatrial or Increase the risk of sinoatrial and nondihydropyridines, atrioventricular node conduction atrioventricular block

calcium channel blockers,

worsen hyperkalemia and lead to ventricular

fib-rillation Hypercalcemia or administration of

intra-venous calcium may lead to life-threatening

arrhythmias or other manifestations of digoxin

tox-icity even in the setting of normal SDC

DIGOXIN INTOXICATION

Increased serum digitalis concentrations can lead

to intoxication, a clinical diagnosis, which can

cause a multitude of symptoms, the most

concern-ing of which are the electrophysiological effects,

which can lead to life-threatening arrhythmias by

mechanisms described previously The overall

incidence of digoxin toxicity is <1% per

patient-year, down from 35% in 1971.6 The commonly

described “digitalis effect” on 12-lead

electrocar-diogram (ECG) should be distinguished from true

intoxication It is commonly manifested by

sag-ging of the ST segments, can occur at normal SDC,

and requires no treatment Digitalis excess is

defined as the presence of significant ECG

changes such as heart block and/or mild clinical

symptoms such as nausea or fatigue Proper

treat-ment includes holding digoxin therapy with close

monitoring of electrolytes True “digitalis

intoxica-tion” is a relatively rare occurrence manifested by

life-threatening arrhythmias and severe

gastroin-testinal and neurological symptoms (Table 11-3) It

is best treated with antidigoxin antibodies.26 The

results of prospective trials with adults and

children have established the effectiveness and

safety of antidigoxin antigen binding fragments

(Fab) in treating cases of life-threatening digoxin

intoxication, including cases of massive ingestion

of the drug with suicidal intent (digoxin overdose).

Although hemodialysis does not remove digoxin

from the body, it can often be useful in cases

where hyperkalemia is also present

DIGOXIN IN HEART FAILURE WITH

REDUCED SYSTOLIC FUNCTION

In several studies, digoxin withdrawal in patients

with systolic dysfunction and sinus rhythm was

associated with a decrease in left ventricular (LV)ejection fraction (EF) and exercise tolerance and

an increase in resting heart rate, diastolic sure, body weight, and/or cardiac size on chestx-ray The majority of double-blind trials exam-ining the effect of digoxin in patients with HFand systolic dysfunction have noted an improve-ment in clinical status Although there has beenlittle evidence that digoxin therapy improvessurvival, the majority of published data consis-tently describe a variety of clinical benefits The body of clinical research establishing therole of digoxin therapy in HF took place in threedistinct phases Initially, observational studies ofdigoxin withdrawal were performed in patientswith chronic heart failure in normal sinus rhythm.Subsequently, placebo-controlled trials wereconducted examining withdrawal of digoxintherapy in patients receiving stable backgroundtherapy of diuretics with and without ACEinhibitors Some of these studies also comparedthe effects of digoxin withdrawal in patientsreceiving other oral inotropic agents Data fromthe Prospective Randomized Study of VentricularFailure and the Efficacy of Digitalis (PROVED)and the Randomized Assessment of Digitalis onInhibitors of the Angiotensin Converting Enzyme(RADIANCE) study provided solid evidencethat digoxin therapy improved symptoms anddecreased hospitalizations in patients withchronic heart failure.27,28None, however, addressedthe issue of mortality or survival, nor the effects of

pres-de novo digoxin therapy in HF This was the nale for conducting the DIG trial, a large random-ized clinical trial designed to assess the mortalitybenefit of digoxin therapy for HF patients in nor-mal sinus rhythm who were already receivingangiotensin-converting enzyme (ACE) inhibitorsand diuretics (Table 11-4).29

ratio-Early Randomized Studies

In a multicenter, double-blind, placebo-controlledstudy conducted by the Captopril-DigoxinMulticenter Research Group, digoxin was com-pared to captopril and placebo in a population

of 300 patients with mild to moderate HF.30

Patients were randomized to captopril (target

dose 50 mg tid), digoxin (target serum level

0.9–3.2 nmol/L), or placebo for 6 months In the

prerandomization phase of the study, only

patients who did not deteriorate when digoxin

was discontinued were randomized Despite

this initial bias against digoxin, the results forthe digoxin group show fewer hospitalizationsand emergency room visits for HF, a better EF,and a decrease in diuretic requirements compared

to patients randomized to placebo Except forthe changes in EF, similar benefits were alsonoted in the patients treated with captopril

Table 11-3 Manifestations of digoxin intoxication

• Cardiac disturbances

• Arrhythmias due to increased automaticity

• Premature ventricular depolarization

• Accelerated junctional (nodal) rhythm

• Unifocal or multifocal ventricular bigeminy

• Ventricular tachycardia

• Ventricular fibrillation

• Bidirectional ventricular tachycardia

• Arrhythmias due to decreased conduction velocity and ERP

• Asystole

• Sinoatrial block

• First or second (Wenckebach) AV block, advanced or complete heart block

• Acceleration or conduction via accessory pathway in WPW

• Multifocal or paroxysmal atrial tachycardia with block

• Idioventricular rhythm; AV dissociation

• Central nervous system

• Visual disturbances (blurred or yellow vision)

ERP—effective refractory period; WPW—Wolfe–Parkinson-White syndrome; AV—atrioventricular

Source: Adapted from Eichhorn EJ, Gheorghiade M Digoxin Prog in Card Dis 2002; 44:251–256, with permission from

Elsevier.

Dobbs et al., 1977 CO 6 46 NA NA 1.3 60 0 NA 0 34∗ 0 0Lee et al., 1982 CO 9 35 II–III 29 1.15 88 24 NA 24 56∗ 0 0Fleg et al., 1982 CO 12 40 II–III 23(FS) 1.4 77 17 NS 10 10 0 0Taggart et al., 1983 CO 12 22 I–II NA 0.8 96 36 NA 10 18 0 5Captopril- PA 24 196 II–III 25 0.7 86 0 No 15 29∗ 7 6Digoxin, 1988

Guyatt et al., 1988 CO 7 28 II–III 19(FS) 1.37 90 55 Yes† 0 35∗ 0 0German/Austrian PA 12 213 I–III NA 0.9 25 10 No 4 6 0 1Xamoterol, 1988

Haerer et al., 1988 PA 3 28 I–III 25(FS) 1.8 0 0 Yes∗ 14 36 0 0Milrinone Multicenter PA 12 111 II–III 25 1.2 100 48 Yes 15 47∗ 5 6Trial, 1989

Pugh et al., 1989 CO 8 44 NA 27(FS) 1.4 75 9 NA 7 25∗ 0 0Fleg et al., 1991 CO 4 10 II–III 33 1.4 100 50 NS 0 0 0 0Drexler et al., 1992 PA 104 133 II–III 50 NA 9 8 Yes† 9 9 2 2.5DIMT, 1993 PA 26 108 II–III 26 0.94 0 56 Yes∗ 0 4 4 6PROVED, 1993 PA 12 88 II–III 27 1.2 100 0 Yes∗ 19 39∗ 2 4RADIANCE, 1993 PA 12 178 II–III 26 1.2 100 100§ Yes∗ 7 25∗ 3.5 1DIG Trial, 1997 PA 148 6800 I–IV 29 0.9 82 95§ NA 25 34‡ 35 35

EF—ejection fraction; ExT—exercise tolerance; FC—functional class; FS—fractional shortening on echocardiogram; P—placebo; Dig—digoxin; HF—heart failure; NYHA—New York Heart Association; CO—crossover; V—vasodilator; PA—parallel; NA—not available; NS—not significant

Source: Adapted from Eichhorn EJ, Gheorghiade M Digoxin Prog in Card Dis 2002; 44:251–256, with permission from Elsevier.

However, digoxin had no effect on the New

York Heart Association (NYHA) class or exercise

capacity This study was not powered to assess

a mortality difference between groups but

demon-strated the effectiveness of digoxin therapy in

treating the signs and symptoms of HF in patients

receiving optimal doses of diuretic therapy

As intravenous and oral inotropic agents

began to emerge as possible therapies for HF,

investigators sought to compare these new

ther-apies to digoxin, the only established oral inotropic

therapy available at the time In a 12-week study

randomizing patients to milrinone, digoxin,

com-bination therapy, or placebo, a comcom-bination of

milrinone and digoxin was found to be

equiva-lent to digoxin alone for improvement in

exer-cise tolerance Digoxin was superior to placebo

and milrinone alone in improvement of exercise

tolerance.31 Patients randomized to digoxin

required fewer cointerventions, defined as

addi-tional therapy to control symptoms of HF, than

those taking placebo A trial of oral ibopamine,

another oral inotropic therapy, likewise failed to

demonstrate an advantage over oral digoxin

therapy.32 Both studies confirmed earlier data

that digoxin therapy significantly improved

exercise tolerance and decreased the frequency

of worsening HF compared to placebo

Prospective Randomized Study

of Ventricular Failure and the

Efficacy of Digitalis (PROVED)

and Randomized Assessment

of Digitalis on Inhibitors of the

Angiotensin Converting Enzyme

(RADIANCE)

The PROVED investigators conducted a

random-ized, placebo-controlled trial of digoxin

with-drawal after a 12-week stabilization period in

which all patients received digoxin Patients

received background therapy of diuretics only

A total of 88 patients were randomized Patients

withdrawn from digoxin therapy after 12 weeks

of stabilization showed worsened maximal

exercise capacity (median change in exercise

time -96 s) compared to those who continuedtherapy Patients who received digoxin had alower body weight and heart rate compared tothose who received placebo There was a two-foldincrease in the incidence of worsening HF inpatients taking placebo.27

Designed as a companion trial to PROVED,RADIANCE was a similarly designed digoxin with-drawal study on the background of ACE inhibitor(captopril or enalapril) and diuretic therapy Allpatients had clinical evidence NYHA Class II–III

HF, an EF <35%, and LV end-diastolic dimension

>60 mm by echocardiography Exercise testingwas performed at baseline and at follow-upintervals and was measured with simple treadmillwalk time, and 178 patients were randomized afterthe stabilization period Despite the fact that allpatients received background ACE inhibitor anddiuretics, the investigators found a six-foldincrease in worsening HF in the withdrawal group(after a stabilization period as in PROVED) andsignificant decrease in cardiac performance asmeasured by decrease in EF and increased heartrate In addition, body weight was significantlyreduced in the digoxin group Most striking werethe data indicating significantly improved quality

of life scores in patients who were maintained

on digoxin therapy

Several post-hoc analyses of the PROVEDand RADIANCE data have been published.Triple therapy with ACE inhibitors, diuretics, anddigoxin was associated with the best outcomesand patients with mild symptoms (NYHA Class II)also benefited from therapy (Fig 11-1, Table 11-5).The clinical deterioration rate was 5% in patientsreceiving triple therapy, compared to 30% inpatients receiving diuretics alone.33 In a cost-benefit analysis, one study concluded that digi-talis therapy has a 90% likelihood of saving thehealth-care system between $106 million to $822million annually.34These figures were based oncombined data of the two trials, and had thepatients in the PROVED study been taking ACEinhibitor therapy, the figures may have beeneven more robust

By the time PROVED and RADIANCE werepublished, ACE inhibitor therapy had become

the standard of care for patients with chronic

systolic HF, and it was time for a large randomized

study examining the use of digoxin with

back-ground ACE inhibitor therapy Because PROVED

and RADIANCE were designed to study digoxin

withdrawal, they did not address the impact of

de novo digoxin therapy in patients with HF,and they did not include patients with normalsystolic function In addition, these studies wereunderpowered to study any mortality differencebetween the groups The DIG trial was designed

to answer these important questions

Digoxin/Diuretic and ACE-I (N = 85)

Digoxin/Diuretic (N = 93)

Placebo/Diuretic and ACE-I (N = 93)

Figure 11-1 Probability of treatment failure in PROVED and RADIANCE: improved outcomes with “triple therapy.” ACE-I—angiotensin-converting enzyme inhibitor (Adapted from Young J, Gheorghiade M, Uretsky B, et al Superiority of “triple” drug therapy in heart failure: insights from

PROVED and RADIANCE trials J Am Coll Cardiol 1998;3:686–92.)

Table 11-5 PROVED and RADIANCE primary and secondary endpoints

Primary endpoints

Secondary endpoints

symptoms of CHF

Quality of life

Heart Failure Questionnaire)

CHF—congestive heart failure; LVEF—left ventricular ejection fraction; HR—heart rate; BP—blood pressure

Source: Adapted from Eichhorn EJ, Gheorghiade M Digoxin Prog in Card Dis 2002;44:251–256, with permission from

Elsevier.

The Digitalis Investigation Group Trial

In the largest placebo-controlled trial of digoxin

therapy ever conducted, 7788 patients with EF

<45% received 0.25 mg of digitalis or placebo

The trial was specifically designed to assess

mortality differences between the two groups and

the effect of de novo digoxin therapy Investigators

also sought to validate an existing formula for

the estimation of SDC Other important

ques-tions were the effect of LVEF, NHYA functional

class, and cardiothoracic ratio on clinical outcomes

of digoxin therapy All patients were maintained

on background CHF therapy of ACE inhibitors

and diuretics as needed Approximately

one-half of patients entering the trial were already

taking digitalis prior to randomization

At 37 months’ mean follow-up, there was no

difference in mortality between digitalis and

placebo The overall cardiovascular mortality was

approximately 30% However, there was a

signif-icant reduction in the primary endpoint of

com-bined death or hospitalization for worsening HF

in patients receiving digoxin therapy Therapy

was associated with a 28% reduction in the risk of

at least one hospitalization for recurrent HF and a

6.5% reduction in total hospitalizations compared

to placebo Analysis of the mortality data cates a reduction in death for worsening HF wasoffset by death from other causes, which manyhave presumed to be sudden death from arrhyth-mias related to digoxin toxicity In addition,investigators determined that SDC could be reli-ably estimated in patients with normal serum cre-atinine (Table 11-6, Fig 11-2)

indi-Importantly, this study using prespecifiedsubgroup analysis showed a reduction in totalmortality and total hospitalizations during thefirst 2 years after randomization in patients with

an EF of <25% or patients with moderate tosevere symptoms of CHF (NYHA Class III–IV),and patients with cardiomegaly on chest x-ray

DIGITALIS IN HEART FAILUREAND PRESERVED SYSTOLICFUNCTION

In the DIG trial, an additional 988 patients with EF

>45% were randomized to digoxin or placebo inthe same manner as the main trial.54For the com-bined endpoint of death or hospitalization for

Figure 11-2 Cumulative incidence of the combined endpoint in the DIG trial

(Adapted with permission from the Digitalis Investigation Group (DIG) Trial The effect of digitalis

on mortality and morbidity in patients with heart failure N Engl J Med 1997;336:525–533.)