The use of digitalis in heart failure

Current Problems in

Cardiology Volume 21

Number 12

December 1996

The Use of Digitalis in Heart Failure* Shahbudin H. Rahimtoola, MB, FRCP,MRCP Division of Cardiology, Department of Medicine University of Southern California Los Angeles, California

Tahir Tak, MD, PhD Division of Cardiology, Department of Medicine University of Southern California Los Angeles, California *Reproduced with changes from Rahimtoola SH, Tak T. Digitalis in heart failure. In: McCall D, Rahimtoola SH, editors. Heart failure. New York: Chapman & Hall, 1995, with permission of the publisher.

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Current Problems in

Cardiology

+

The Use of Digitalis in Heart Failure

Foreword

785

Introduction

787

Actions of Cardiac Glycosides

787

Inotropic Electrophysiologic Diuretic Neurohormonal

Digitalis in Heart Failure Introduction Clinical Studies Left Ventricular Ejection Fraction Summary Digitalis in Acute Myocardial Infarction

Pharmacokinetics, Bioavailability, and Dosage of Digitalis Digoxin Digitoxin Ouabain

787 791 799 801

803 8O3 8O4 821 823 829

832 832 834 835

Interactions with Digitalis Glycosides

836

Digitalis Glycosides and Pregnancy

836

Digitalis Toxicity

837

Clinical Manifestations Treatment

Value of Digoxin Blood Levels Curr Probl Cardiol, December 1996

838 84O 841 783

Overview

842

Addendum

844

References

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Curr Probl Cardiol, December 1996

Foreword There has been considerable controversy concerning the usefulness of digitalis in patients with congestive heart failure, and digitalis has never been shown in appropriate studies to prolong survival when used in the treatment of congestive heart failure. There is general agreement that digitalis is not indicated in patients with cardiac decompensation due entirely to left ventricular diastolic dysfunction. Its usefulness in patients with documented supraventricular arrhythmias resulting in left ventricular failure has been well demonstrated. In the December 1996 issue of Current Problems in Cardiology, Dr. Shahbudin Rahimtoola, a noted authority on the topic, and his colleague, Dr. Tahir Tak, present old and recent data supporting the use of digitalis in patients with systolic heart failure and defining the benefits of its use together with diuretics and angiotensin-converting enzyme (ACE) inhibitors in most patients with symptomatic left ventricular systolic dysfunction. The Editorial Board of CPC is grateful to Drs. Rahimtoola and Tak for their authoritative, up-to-date analysis of this important clinical topic. Robert A. O'Rourke, MD Editor-in-Chief

Curr Probl Cardiol, December 1996

785

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Dr. ShahbudinH. Rahimtoola received his MRCP from the Royal College of Physicians --of Edinburgh in 1963 and was awarded the fellowship in 1972. Since 1980 he has been a Professor of Medicine, University of Southern California. He was Chief, Division of Cardiology, University of Southern California and LAC-USC Medical Center from 1980 to 1992. In 1984 he was appointed the first George C. Griffith Professor of Cardiology, which is funded in part by the American Heart Association-Greater Los Angeles Affiliate. In 1993 Dr. Rahimtoola was awarded the title of Distinguished Professor, University of Southern California. In 1996 he was awarded MASTER of the American College of Physicians. He is Past Chairman, Council on Clinical Cardiology, American Heart Association, and is a Past Trustee of the American College of Cardiology. Dr. Rahimtoola serves on the editorial boards of Circulation and numerous other journals. He has received numerous awards and citations, including the Gifted Teacher Award from the American College of Cardiology in 1986 and the James B. Herrick Award from the American Heart Association/Council on Clinical Cardiology in 1989. Dr. Rahimtoola's research interests are broad and extensive. He is best known for his work in valvular heart disease, coronary artery disease, results of cardiac surgery, arrhythmias, and also for his work in heart failure, cardiomyopathy, and congenital heart disease. (~

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Tahir Tak, MD, PhD, is Assistant Professor of Medicine at the University of Southern California and Los Angeles County + University of Southern California Medical Center, Los Angeles. He received his medical degree from the University of Nijmegen, The Netherlands, in 1980 and completed his clinical cardiology fellowship at the Academic Medical Center of the University of Amsterdam in 1985. From 1985 to 1988, he held a cardiology research fellowship at the Los Angeles County + University of Southern California Medical Center under the direction of Drs. P.A.N. Chandraratna and S. H. Rahimtoola. In 1989 Dr. Tak received his PhD degree from the University of Maastricht, The Netherlands, under the direction of Dr. H.J.J. Wellens. The title of his thesis was "Ultrasonic tissue characterization of the heart." His current research interests include echocardiography and Doppler ultrasonography, in particular, the digital image processing of ultrasound information.

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Curr Probl Cardiol, December1996

The Use of Digitalis in Heart Failure 1~ illiamWithering (Fig. 1) began to use digitalis for dropsical cases during 1775.1 The first recorded use of digitalis was on December 8 of that year when he administered a "decoction of fol digital" to a man ~50 years of age who complained "of an asthma"; as a result of the therapy, the patient "made a large quantity of water." 1This is also the first description of the diuretic effect of the drug. His classic work "AnAccount of the Foxglove" was published in 1785 (Fig. 2); he cautioned that optimal use of this drug requires considerable skill and knowledge on the part of the physician. 2 This work also contains probably the earliest description of alcoholic cardiomyopathy. In this chapter, "digitalis" is used to refer to any of the steroid or steroid glycoside compounds that exert a positive inotropic, electrophysiologic, or other effects on the heart. The majority of digitalis drugs in clinical use today are either steroid glycosides derived from the leaves of the common flowering plant called "foxglove" (Fig. 3) or digitalispurpurea (digitoxin, gitalin, digitalis leaf) or from leaves of D. lanata (digoxin, lanatoside C, deslanoside). Ouabain is an exception, obtained from the seeds of Strophanthus gratus.

Actions of Cardiac Glycosides The large number of beneficial effects of digitalis are summarized in Table 1.

Inotropic Digoxin exerts its positive inotropic effect by inhibiting membrane-bound Na+-K+ adenosine triphosphatase (ATPase). This enzyme hydrolyzes ATE which powers the pump that exchanges intracellular sodium for extracellular potassium against an electrochemical gradient. Inhibition of Na÷-K+ ATPase results in an increase in intracellular sodium, which in turn is exchanged for extracellular calcium. Increased intracellular calcium facilitates myocardial contractility by enhancing the mechanical force achieved by myocyte contractile proteins.3'4 The individual parts involved in cellular Ca 2+homeostasis include the contractile proteins, intracellular Ca 2+levels, sarcolemmal processes, and intracellular organelles involved in calcium turnover. Cardiac glycosides increase the availability of Ca 2+ to the contractile element at the time of excitation/contraction coupling (Fig. 4). Curr Probl Cardiol, December 1996

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FIG. 1. William Withering. The portrait is bythe Swedish artist E von Breda, 1792. The original • is in the national museum in Stockholm. (From Rahimtoola SH. Digitalis and William Withering: the clinical investigator [editorial]. Circulation 1975;52:969-71. Reproduced by permission.)

Wiggers and Stimson 5 showed that digitalis increased the rate of increase of left ventricular pressure (LVdp/at). Cattell and Gold 6 showed that ouabain increased the force of contraction in isolated, electrically driven cat papillary muscles. Both the velocity of shortening and maximum tension devel, opment were increased in the normal cat papillary muscle. 7 The inotropic action of digitalis has been demonstrated in the normal heart of animals 8 and human beings 9 (Figs. 5 and 6). The inotropic action occurs in both ventricles, and there is a reduction of ventricular dimension; the inotropic action also is present in both atria. 788

Curr Probl Cardiol, December 1996

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FIG. 2. Frontispiece of Withering's classic book. (From Withering W. An account of the foxglove, and some of its medical uses_ London: GGJ and J Robinson, 1785. (Special Edition Copyright 1979, Classics of Medicine Library, Division of Gryphon Editions, Ltd., Birmingham, AL). Reproduced by permission.)

In normal human beings, the left ventricular function curve is moved upward and to the left (Fig. 7). There is a reduction of left ventricular volume in addition to an increase of stroke volume at any given end-diastolic volume so that cardiac output is unchanged. In patients with coronary Curr Probl Cardiol, December 1996

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FIG. 3. The purple foxglove from Withering's book. (From Withering W. An account of the foxglove, and some of its medical uses. London: GGJ and J Robinson, 1785. (Special Edition Copyright 1979, Classicsof Medicine Library, Division of Gryphon Editions,Ltd., Birmingham, AL). Reproduced by permission.) 790

Curr Probl Cardiol, December 1996

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FIG. 4. Mechanism of inotropic action of digitalis. (From Smith TW, Braunwald E, Kelly RA. The management of heart failure. In: Braunwald E, editor. Heart disease: a textbook of cardiovascular medicine. 4th ed. Philadelphia: Saunders, 1992:464-519. Reproduced by permission.)

TABLE 1. Multiple actions of digitalis in heart failure Positive inotropic Vasodilation Diuresis Slowing of rapid ventricular rate Reducing plasma neurohormones Increasing baroreceptor sensitivity Increasing vagal tone

artery disease but with normal left ventricular systolic pump function, intravenous ouabain produced reductions of left ventricular end-diastolic pressure and of left ventricular end-diastolic and end-systolic volumes; there was a nonsignificant increase of left ventficular ejection fraction ~° (Fig. 8). The effect of digitalis on the left ventricular function curve (Frank-Starling mechanism) is illustrated in Fig. 9. In normal subjects, the left ventricular function curve is quite steep. In moderate to severe heart failure, the curve is moved to the right and downward and is quite flat. Diuretic therapy produces a reduction of left ventricular filling pressure, but the patient remains on the same depressed function curve. Digitalis moves the function curves upward and to the left, as do arterial dilators and angiotensin-converting enzyme (ACE) inhibitors, particularly when combined with careful use of diuretics. Combined digitalis andACE-inhibitor therapy are additive in heart failure (see subsequent sections) and move the function curve more toward normal than does either therapy alone.

Electrophysiologic The major electrophysiologic effects of digitalis on the heart are summarized in Table 2. The integrity of the active Na+-K ÷ pump mechanism helps to maintain Na + and K ÷ gradients, which produce the 80 to 90 mV transmembrane Curr Probl Cardiol, December 1996

791

TABLE 2. Some major effects of digitalis on the electrophysiologic properties of the heart Property Pacemaker automaticity S-A node Purkinje fibers Excitability Atrium Ventricle Purkinje fibers Membrane responsiveness Atrium Ventricle Purkinje fibers Conduction velocity Atrium, ventricle A-V node Purkinje fibers Effective refractory period Atrium Ventricle A-V node Purkinje fibers

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Arrows, direction, not magnitude of changes indicated;l',increased;$,decreased;--~,no significant change. *Decreased with high or toxic doses of digitalis. From Moe GK, Farah AE. Digitalis and allied cardiac glycoside. In: Goodman LS, Gilman A. The pharmacological basis of therapeutics. 5th ed. New York: Macmillan, 1975:75. Reproduced by permission.

resting potential of cardiac cells. Digitalis inhibits the pump mechanism and may have a significant effect on the electrophySiology of the intact heart, as well as on isolated muscle preparations. The actions of digitalis on electrical activity of the myocardium contribute to its antiarrhythmic effects and to cardiac toxicity. Digitalis reduces action potential duration, increases the slope of phase 4 depolarization, reduces resting membrane potential, and decreases the maximum rate of increase of phase 0 (Vmax).Depending on the dose of digitalis, these changes may cause increased automaticity and variable degrees of heart block, n,~2 These effects are similar in atrial and ventricular tissue. The major clinical electrophysiologic effect of digitalis is to slow the ventricular rate in atrial fibrillation by increasing parasympathetic stimulation, which results in an increase of the refractory period and conduction velocity in the A-V node. In sinus rhythm, heart rate is slowed because of an improvement in heart failure and a withdrawal of sympathetic stimulation. 792

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Details of electrophysiologic effects of cardiac glycosides may be found elsewhere. 12-14 Vasodilatation. Digitalis constricts isolated arterial and venous segments; animal studies have documented both arterial and venous constriction. 1516 The seminal observations of Mason and Braunwald 17were the first to document in human beings the effects of digitalis on the peripheral a r t e r i a l and venous beds. T h e y d e m o n s t r a t e d that i n t r a v e n o u s Curr Probl Cardiol, December 1996

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FIG. 6. Effect of ouabain on the right ventricle (left) and left ventricle (right). Radiopaque markers placed on the right ventricle at time of surgery for atrial septal defect and on the left ventricle at time of surgery for mitral stenosis. In spite of an increase of ventricular systolic pressure, there is a marked increase of the velocity of shortening. (From Sonnenblick EH, Williams JF Jr, Glick G, Mason DT, Braunwald E. Studies on digitalis. XV. Effects of cardiac glycosides on myocardial force-velocity relations in the nonfailing human heart. Circulation 1966,'34:532-9~ Reproduced by permission.)

administration of ouabain in normal subjects produced forearm arterial and v e n o u s v a s o c o n s t r i c t i o n (Fig. 10). H o w e v e r , the a r t e r i a l vasoconstriction (systemic and coronary) is related to the speed of administration of the drug and is obviated by administering it slowly over a 15- to 20-minute period (Fig. 11); moreover, the effect is transient and lasts up to 30 minutes. 18The vasoconstriction is mediated by (1)A direct action on vascular smooth muscle, and (2) neurogenically mediated increase in sympathetic tone~ 19-23 The landmark study of Mason and Braunwald 17 also demonstrated that intravenous administration of the drug in patients with heart failure produced an increase of blood flow and a decrease of vascular resistance, as well as venodilatation and a decrease of central venous pressure and heart rate (Fig. 12). The reduction of systemic vascular resistance in patients in heart failure has been repeatedly confirmed (vide infra). The vasodilation is the result of an increase in cardiac output and direct baroreflex-mediated withdrawal of sympathetic vasoconstriction (see Baroreflexes). Coronary Circulation. A large digitizing dose of digitalis given intravenously produces a short-term increase o f coronary vascular resistance in animals, 24'25 in normal subjects, and in those with coronary artery disease. 26,27The increase is short lived (<30 minutes) and can be prevented if the intravenous dose is injected slowly over a period of 15 to 20 minutes rather than rapidly over a 10-second or 2-minute period (Fig. 13). TM In patients with coronary artery disease and in animals with global ischemia after a rapid infusion or a bolus injection of digitalis, coronary blood flow 794

Curr Probl Cardiol, December 1996

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is reduced, myocardial ischemia may result, and in animals, ventricular fibrillation has been produced. 18,28 Digitalis is a positive inotropic agent that would increase myocardial oxygen consumption (MVO2). However, it also results in a decrease of left ventricular end-diastolic and end-systolic volumes 1° (Fig. 8), which would lead to a reduction in myocardial tension and M V O 2. Thus there is a tradeoff between the increased M V O 2 caused by the inotropic action of digitalis and the reduced M V O 2 caused by a reduction of ventricular volumes, and there is a net small increase in MVO2.10,29Moreover, there is also asmall increase of coronary blood flow, which helps to meet the increased M V O 2.10 In patients with coronary artery disease not in heart failure and with normal Curr Probl Cardiol, December 1996

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FIG. 8. Left ventricular end-diastolic pressure (LVEDP), end-diastolic and end-systolic volumes, and ejection fraction (LVEF) in patients with coronary artery disease and normal left ventricular ejection fraction at rest. Patients were selected for study because they had normal left ventricular size and function. In the same study, a group of patients was given intravenous saline, and they showed no significant change (not shown). All patients underwent diagnostic cardiac catheterization for anginal chest pain. One hour after a full digitalizing dose of intravenous ouabain, there was a reduction of left ventricular end-diastolic pressure and volumes and an increase of ejection fraction. (Drawn from the data of DeMots H, Rahimtoola SH, Kremkau EL, Bennett W, Mahler D. Effects of ouabain on myocardial oxygen supply and demand in patients with chronic coronary artery disease: a hemodynamic volumetric, and metabolic study in patients without heart failure. J Clin Invest 1976;58:312-9. Reproduced by permission.)

left ventricular size and function, the slow infusion of digitalis produces a very small increase of MVO 2, an average increase of 1.6 ml OJminute or 12.5 %, 1~which is met by an increase of coronary blood flow, and myocardial ischemia does not occur (Fig. 14). In the presence of heart failure, the reduction of MVO 2by a slowing of heart rate and reduction of the increased ventricular volumes combined with the likely increase of coronary blood flow caused by an increased cardiac output and reduced ventricular filling pressure would be expected to more than offset the increased MVO 2resulting from an increase of myocardial contractility. Therefore in all probability, it is likely that in heart failure, MVO 2 would be reduced by digitalis therapy. Baroreflexes. Baroreflex mechanisms are blunted in heart failure3° and 796

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LV E N D - D I A S T O L I C V O L U M E ( O R LV E D P ) FIG. 9. Left ventricular function curve depicting the relation of left ventricular stroke volume to end-diastolic volume. In the normal head, small increases of end-diastolic volume in the physiologic range produce large increases of stroke volume. In severe heart failure (HF), the function curve is moved downward and to the right; large increases of end-diastolic volume produce small increases, if any, of stroke volume. Diuretics decrease end-diastolic volume with no change or a decrease of stroke volume. Digitalis and ACE inhibilors result in an increase of stroke volume, and the decrease of end-diastolic volume is increased with both drugs, particularly if they are combined with diuretics. Combined triple therapy with digitalis, diuretics, and ACE inhibitors produces a major decrease of end-diastolic and increase of stroke volume and allows the heart to be well compensated at least in the early stages of heart failure.

thus contribute to the increased sympathetic nervous system activity 3°,31 and to the downregulation of cardiac ~3-receptors. Digitalis has been shown to alter baroreflex mechanisms and cardiopulmonary reflexes in animals 3234 and in human beings. 35-37The mechanism(s) by which digitalis alters the baroreflexes is(are) likely multiple: 1. In heart failure, the abnormalities in baroreflex mechanisms may be related to excessive activation of the sodium/potassiumATPase pump. 38 Digitalis decreases this excessive activation and thus results in an increased sensitivity of the baroreceptors. 39 2. Direct stimulation of the receptors. 32,38,4° Curr Probl Cardiol, December 1996

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3. Reduced ventricular filling pressures, increasing cardiac outpuP 1 and increasing blood pressure if it is low. Animal studies have demonstrated sympathoinhibition with digitalisY 34,4°,41 Digitalis glycosides were shown by Ferguson et al. 31'4z to normalize forearm vascular response to lower body negative pressure by normalizing impaired baroreflex mechanisms in patients with moderate to severe heart failure and to produce a rapid and profound attenuation of sympathetic nerve activity (Fig. 15) before the hemodynamic effects are observed. The latter effect suggests that the decrease in sympathoexcitatory action is a result of a sensitizing effect on afferent baroreflex mechanisms and that there may be a dissociation between the neuroendocrine T98

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FIG. 11. Percentage change in systemic vascular resistance after a full digitalizing dose of ouabain was administered intravenously in patients with coronary artery disease and normal left ventricular function. Bolus injection (10 seconds) produced an almost 24% increase, and a 2-rninute infusion produced an almost 18% increase of systemic vascular resistance. A 15minute infusion produced no change initially, and subsequently, a decrease of 10% in systemic vascular resistance. (From DeMots H, Rahimtoola SH, McAnulty JH, PorterGA. Effectsof ouabain on coronary and systemic vascular resistance and myocardial oxygen consumption in patients without heart failure. Am J Cardiol 1978;41:88-93. Reproduced by permission.)

and hemodynamic effects. Thus digitalis can be expected to be o f benefit in patients with left ventricular dysfunction even in the absence of the potential of hemodynamic benefit. In human beings, the autonomic actions of digitalis have been studied only in the short term; however, animal studies have documented sustained potentiation of vagally mediated cardiopulmonary baroreflex with chronic administration of digitalis.43 The subject was reviewed by Gheorghiade and Ferguson. 44

Diuretic An important effect of digitalis is the induction of diuresis in patients with heart failure who have fluid retention. It inhibits tubular reabsorption of sodium, 45 inhibits renal Na+-K÷-ATPase and impairment of both concentrating and diluting ability. 46 It also results in an increased secreCurr Probl Cardiol, December 1996

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tion of atrial natriuretic peptide from atrial cardiocyte cell culture, 47which may partly explain the diuresis seen with digitalis in heart failure. 4SFurther, by increasing cardiac output and by producing vasodilation, renal hemodynamics are improved, which induces diuresis. Clinically, reduced 800

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FIG. 13. Percentage change in coronary vascular resistance after a full digitalizing dose of ouabain was administered intravenously in patients with coronary artery disease and normal left ventricular function. A bolus injection produced a - 1 4 % increase of coronary vascular resistance, whereas a 15-minute infusion produced no significant change. (From DeMots H, Rahimtoola SH, McAnulty JH, Porter GA. Effects of ouabain on coronary and systemic vascular resistance and myocardial oxygen consumption in patients without heart failure. Am J Cardiol 1978;41:88-93. Reproduced by permission.)

creatinine clearance is improved, and decreases have been demonstrated in blood urea nitrogen, serum creatinine, and body weight (vide infra).

Neurohormonal Plasma norepinephrine levels reflect sympathetic outflow. Elevated levels are a reflection of increased sympathetic levels and are an important prognostic indicator in patients with heart failure. 49 As a result of therapy for heart failure, a decrease of plasma norepinephrine occurs with clinical improvement of heart failure, whereas an increase of plasma norepinephrine levels is associated with a poor prognosis.S° The elevated levels of plasma norepinephrine contribute to the elevated peripheral vascular resistance, provide some positive inotropic stimulus, but p r o b a b l y cause a downregulation of 13-adrenergic receptors. Digitalis therapy in heart failure has been shown to reduce plasma Curr Probl Cardiol, December 1996

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FIG. 14. Data from the same study as in Fig. 13. Afull digitalizing dose of intravenous digitalis resulted in a very small increase of MV@2. (From DeMots H, Rahimtoola SH, McAnul~ JH, Porter GA. Effects of ouabain on coronary and systemic vascular resistance and myocardial oxygen consumption in patients without heart failure_Am J Cardiol 1978;41:88-93. Reproduced by permission.)

norepinephrine levels, 51-54serum aldosterone, s2,54,55and plasma renal activity s2,55 (Fig. 16). These beneficial effects are sustained during prolonged treatment with the drug. 54a

D, McCall: It is well recognized that neurohormonal activation is one of the hallmarks of congestive heart failure. Further, it has been shown that this activation, especially sympathetic activation, correlates with the severity of the disease and is a powerful predictor of prognosis. In light of this, it is likely that at least some of the beneficial effects of digitalis in heart failure can be attributed to the drug's ability to favorably decrease sympathetic drive to the heart. As pointed out by the authors, digitalis corrects the abnormal baroreflex mechanisms found in heart failure and, in so doing, enhances parasympathetic activity and reduces central sympathetic outflow. This is most commonly manifest by a reduction in resting heart rate in heart failure patients following the administration of digoxin. Not only is heart rate reduced, there is also seen an improvement in heart rate variability, which shows progressive deterioration with worsening heart failure (J Am Coil Cardiol 802

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FIG. 15. Digitalis in patients with congestive heart failure produced an increase of cardiac index and forearm blood flow and a decrease in heart rate and pulmonary artery diastolic pressure. There was a rapid and profound attenuation of sympathetic nerve activity (MSNA)before the hemodynamic effects were observed. (From Ferguson DW, Berg W J, Sanders JS, Roach PJ, Kempf JS, Kienzle MG. Sympathoinhibitory responses to digitalis glycosides in heart failure patients. Circulation 1989;80:65-77. Reproduced by permission.)

1995;26:983). The impaired heart rate variability seen in heart failure appears to correlate with neurohormonal activation, and the improvement seen with digoxin administration correlates with the improvement seen in the various markers of neurohormonal activation.

Digitalis in Heart Failure

Introduction For many decades, the mainstays of therapy for patients with heart failure were digitalis and diuretics. Oral diuretics were introduced into clinical medicine in the middle 1950s; before that, only parenteral diuretics were available and had to be used only a few times each week. Digitalis and diuretics were effective for control of symptoms and probably prolonged Curr Probl CardJol, December 1996

803

Plasma R e n i n A c t i v i t y

(ng/ml/hr)

Serum A l d o s t e r o n e (pg/ml)

Plasma Norepinephrine (pglml)

P<0.02

P<0.05

P<0.001

500 -

4

1000 -

[] Off Digoxin [ ] On Digoxin

3F

2-

I

1

0 "

500

250 -

D

O-

J

0

FIG. 16. Patients in heart failure had a rapid and important reduction of plasma renin activity, aldosterone, and norepinephrine. (Drawn from the data of Ribner HS, Plucinski DH, Hsieh A-M, Bresnahan D, Molteni A, Askenazi J, et al. Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: a hemodynamic-hormonal study. Am J Cardiol 1985;56:896-904. Reproduced by permission.)

life in many patients, 56,57particularly those who had severe heart failure (Figs. 17 and 18).

Clinical Studies Numerous clinical studies 51-55'58-79"examined the role of digitalis in the treatment of patients with heart failure of varying degrees of severity. The overwhelming majority of these studies have found digitalis to be of clinical benefit (Table 3). Nonrandomized Studies. Arnold et al. 59 studied nine patients in sinus rhythm who had symptomatic heart failure and were 27 to 67 years old (mean age, 5 1 years). The patients were receiving long-term therapy with digitalis and diuretics, and withdrawal of digitalis resulted in the decrease of the cardiac index, stroke-work index, and stroke volume index, and in 804

Curr Probl Cardiol, December 1996

FIG. 17. Patientswith acute myocardial infarction and acute pulmonary edema. Note the classic bat-wing appearance in the lungs of pulmonary edema (upper). Patientwas treated with digitalis and diuretics in the late 1960s and recovered "completely."Chest radiograph at time of hospital discharge a week later(lower) showed complete clearing of the pulmonary edema. The patient had no clinical or other evidence for heart failure. (From Rahimtoola SH. Oral vasodilators should not be used routinely in the treatment of congestive heart failure. In: Rapaport E, editor. Current controversies in cardiovascular disease. Philadelphia: Saunders, 1980:613-30. Reproduced by permission.)

increases of mean pulmonary artery wedge pressure and heart rate. On exercise at the same work load, mean pulmonary artery wedge pressure increased further, and there were further reductions in cardiac index, strokework index, and stroke volume. Six hours after readministration of 1.0 mg IV digoxin, there was a decrease in mean pulmonary artery wedge pressure and in heart rate and an increase in cardiac index, stroke-work index, and stroke volume index. Four of the nine patients were in New York Heart Curr Probl Cardiol, December 1996

805

TABLE 3. Clinical studies of digitalis in heart failure Author Dobbs et al. Arnold et al. Fleg et al. Lee et al. Murray ef al. Taggar~ et al. Gheorghiade et al. Boman Cantelli et al. Ribner et al. Gheorghiade et al. Alicandri et el. CaptopriI-Digoxin Guyatt et al. G-A Xamoterol Pugh et al. Sullivan et al. Beaune DiBianco et al. Gheorghiade et al. Kromer et al. Davies et al. Fleg et al. Uretsky et al. Packer et al. vanVeldhuisenetal. Gorg and Gorlin

Year

Cited Ref. No.

1977 1980 1982 1982 1982 1983 1983 1983 1984 1985 1987 1987 1988 1988 1988 1989 1989 1989 1989 1989 1990 1991 1991 1993 1993 1993 1996

58 59 60 61 62 63 64 65 66 52 67 54 68 69 70 71 72 73 74 51 75 76 77 78 79 53 79a

No, of patients 46 9 30 25 10 22 24 41 8 11 11 16 300 20 433 44 11 142 230 16 19 145 10 113 178 161 7788

NYHAFC

Randomized study

-II, III II, III II, III III, IV I, III II, III -II-IV II, III IV II, III II, III II, III II, III -II, III I-IV II-IV Ill-IV II II, III II, III II, III II, III II, III II, III (I, IV)

Yes No Yes Yes No Yes No Yes No No No Yes Yes Yes Yes Yes No Yes Yes No Yes Yes Yes Yes Yes Yes Yes

Benefit with digitalis* Yes Yes (No)t Yes Yes No No (No) Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes (No) Yes Yes Yes Yes

*Compared with baseline or placebo or both. #(No), There was some small benefit of digitalis therapy. tOnly selected benefits are listed. For all benefits, please see text.

Association Functional Class (NYHAFC) II, and one of the four had clinical deterioration; five patients were in N Y H A F C III, and four of the five deteriorated during the time that digoxin was discontinued. Left ventricular ejection fraction while taking digoxin was 41% + 14% and while not taking digoxin decreased to 30% _+ 14% (p < 0.05). Creatinine clearance was 78 _+ 15 ml/min and declined to 55 _+ 9 ml/min, p < 0.001, on withdrawal of digoxin. Murray et al.62 studied 1Opatients in sinus rhythm with symptomatic cardiac failure who were receiving diuretics. Their ages ranged from 42 to 65 years (mean, 51 years). The patients were given 0.5 mg of ouabain, and there were no significant changes in cardiac hemodynamics at rest. However, on exercise, there were significant increases in cardiac index, stroke volume index, strokework index, and left ventricular ejection fraction. Patients were then maintained 806

Curr Probl Cardiol, December 1 9 9 6

TABLE 3 (CONTINUED)

Type of benefit~ Clinical improvement; worsening of heart failure if taking placebo Clinical improvement; improvement of hemodynamics at rest and on exercise; improved LVEF Reduced LV dimension; increased mean Vcf Improved heart failure score; clinical improvement; heart size reduced; weight loss Improved hemodynamics and LVEF on exercise.

Worsening heart failure on placebo during digoxin discontinuation problem because of atrial fibrillation Reduction of heart rate, ventricular filling pressures, increase of stroke volume Improved hemodynamics on rest and exercise; reduced neurohormones Improved hemodynamics; improved LVEF Increased exercise capacity; reduced body weight and neurohormones Improved LVEF and clinical status; increased exercise capacity. Improved heart failure score, exercise capacity, LV dimension, and heart size Improved heart failure and symptoms, weight loss Clinical deterioration on discontinuation of digoxin Increased exercise capacity and VO 2. Clinical improvement; improved exercise capacity Clinical improvement; increased LVEF;worsening heart failure taking placebo; increased exercise time Improved hemodynamics at rest and on exercise; reduced neurohormones Increased exercise capacity and percentage fractional shortening; reduced LV dimension Improved LVEF on exercise Reduced worsening heart failure, hospitalization, BUN, creatinine, LVEF, exercise capacity Reduced worsening heart failure, exercise capacity, LVEF, quality of life Clinical improvement; improved heart failure score, exercise capacity; reduced neurohormones Reduced worsening heart failure, heart failure deaths, hospitalization for heart failure LV, Left ventricular; LVEF, left ventricular ejection fraction; Vcf, velocity of circumferential fiber shortening.

on 6 weeks of oral digoxin therapy and, at the end of 6 weeks, the improvement noted in the exercise hemodynamics and left ventricular ejection fraction with short-term studies were maintained at the end of 6 weeks. Gheorghiade and Beller 64 studied the effects of digoxin withdrawal in 24 patients in sinus rhythm who were in NYHAFC II and III who had been taking diuretic, vasodilator, or both, as well as digoxin. There were no deleterious effects of digoxin withdrawal. In this study, 8 (33%) of 24 patients had left ventricular ejection fraction >0.50, and 33% of the patients had no cardiomegaly on chest radiograph. Cantelli et al. 66 studied the effects of captopril, digoxin, and their combination in eight patients who were in NYHAFC II to IV. Their ages ranged from 18 to 75 years (average age, 55 years). Digoxin resulted in significant reduction of heart rate, mean pulmonary artery and mean Curr Probl Cardiol, December 1996

807

FIG. 18. Patientwith idiopathic dilated cardiomyopathy and in NYHAFC III. Patientwas clinically stable. Digitalis therapy was stopped, and within 6 weeks, patient had clinically deteriorated markedly. In spite of the addition of nitroglycerin and aminophylline to diuretic therapy when patient was readmitted to hospital, the left ventricular ejection fraction (EF) had decreased from 0.36 to 0.11 ; pulmonary artery wedge pressure (LVFP) had increased from 28 to 36 mm Hg, and left ventricular stroke-work index (LVSWI) had decreased from 41 to 22 gm/min/mL Intravenous digoxin resulted in a major improvement in the patient's clinical condition.

pulmonary artery wedge pressures, and an increase of stroke volume and stroke-work index. Combination therapy resulted in a reduction of heart rate, right atrial and mean pulmonary artery wedge pressures, and of systemic vascular resistance, and an increase of cardiac index, stroke-volume index, and stroke-work index (Fig. 19). Ribner et al. 52studied 11 patients in sinus rhythm with heart failure caused by dilated cardiomyopathy; 10 patients were in NYHAFC III, and 1 was in class II. Their ages ranged from 45 to 64 years (mean, 55 years). Patients were monitored at rest and during submaximal exercise before and 6 hours after intravenous infusion of 1.0 mg of digoxin. At rest, digoxin produced significant reductions in heart rate, cardiac output, mean pulmonary artery wedge and mean right atrial pressures, and an increase in cardiac output. These improvements in cardiac hemodynamics also were present on exercise. In addition, digoxin produced significant reductions in plasma renal activity and aldosterone and norepinephrine levels (Fig. 16). Gheorghiade et al. 67 studied 11 patients who were in NYHAFC IV. Their ages ranged from 48 to 72 years (mean, 52 years). They had been treated with intravenous furosemide and various vasodilators for a mean period of 4.3 __. 2.1 days. This therapy had resulted in subjective and objective 808

Curr Probl Cardiol, December $996

SVI =- 35 33 t~ 31 29 27

[IIG+CPI

|

I

I

10

12

14

I

16

18 2'0 22 L V F P (mmFIg)

FIG. 19. A patient in heart failure had reductions of left ventricular filling pressure (LVFP)and an increase of stroke volume index (SVI) with digoxin (DIG) and with captopril (CPT). Combined digoxin and captopril therapy produced further reductions of LVFPand increases of SVI. (From Contelli I, Vitolo A, Lombardi G, gomba E, Bracchetti D. Combined haemodynamic effects of digoxin and captopril in patients with congestive heart failure. Curr Ther Res 1984;36:323-31. Reproduced by permission.)

improvement in all patients, as reflected by a significant decrease in heart failure score from 9.5 _ 2.2 to 2.7 _+2.3 (p < 0.001). When compensation for the heart failure was achieved by clinical criteria, the patients had hemodynamic monitoring. Data were obtained before and serially thereafter for 6 hours after the intravenous administration of digoxin, given in two 0.5 mg doses 2 hours apart. In response to digoxin, cardiac index and left ventricular stroke-work index increased, and mean heart rate and mean pulmonary artery wedge and mean fight atrial pressures decreased. There was also an increase in left ventricular ejection fraction from 21% + 13% to 29% + 11% (p < 0.04). Six of the 11 patients had major improvements in hemodynamics and were called responders. Sullivan et al. 7z studied 11 patients with chronic congestive heart failure; 5 patients were in N Y H A F C III, and 6 were in class II. Their ages ranged from 41 to 75 years (mean, 57 + 9 years). Ten of the 11 had a third heart sound, and the resting mean ejection fraction of the group was 24% + 10%. After digoxin therapy, there were significant increases in ventilatory oxygen uptake at the gas-exchange anaerobic threshold and at maximum exercise (mean increase o f V O 2 of 2.6 ml/kg per minute; p < 0.02; Fig. 20). Gheorghiade et al. 51 studied the effects of intravenous captopril and intravenous digoxin given separately and in combination, both at rest and during exercise, in 16 patients who were in N Y H A F C III and IV and in sinus rhythm. Their ages ranged from 33 to 81 years (mean, 58 years). Curr Probl Cardiol, December 1996

809

30

28

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16

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FIG. 20. On exercise there was increase of total body 02 consumption (maximal go2) when patients with heart failure received digitalis therapy. (From Sullivan M, Atwood JE, Myers J, Feuer J, Hall P, Kellerman B, et al. Increased exercise capacity after digoxin administration in patients with heart failure. J Am Coil Cardiol 1989;13.1138-43. Reproduced by permission.)

With digoxin there were reductions of mean pulmonary artery wedge pressure, mean fight atrial pressure, and systemic vascular resistance, and there were increases in cardiac index and stroke-work index. With digitalis on exercise, there were reductions in mean pulmonary artery wedge and mean right atrial pressures, and there were increases in cardiac index, strokework index, and exercise duration. Intravenous digoxin was added for patients who had initially received intravenous captopril: at rest, there were further reductions in mean pulmonary artery wedge pressure and systemic vascular resistance, and there were increases in cardiac index and strokework index (Fig. 21). On exercise, the addition of digoxin to captopril 810

Curr Probl Cardiol, December 1996

EFFECTS OF DIGOXIN AND CAPTOPRIL ON PA WEDGE PRESSURE AND CARDIAC INDEX IN PATIENTS WITH HEART FAILURE, NYHA F.C. III AND IV I o B = Baseline

•

D = IV D i g o x i n

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Baseline + Captopril + Digoxin n=9 --5

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40

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PA WEDGE PRESSURE (ram Hg)

50

PA WEDGE PRESSURE (mm Hg)

FIG. 21. Patientswith heart failure had high pulmonary artery(PA) wedge pressures and reduced cardiac indices at baseline (B). With intravenous digoxin (D) as initial therapy (left), there were redudions of PA wedge pressure and increase of cardiac index both at rest and on exercise. Subsequently captopril produced additional beneficial effects. With captopril as initial therapy (right), there were reductions of PA wedge pressure and increase of cardiac index both at rest and on exercise. Subsequently digoxin produced additional benefits. (Drawn from data of Gheorghiade M, Hall V, Lakier JB, Goldstein S. Comparative hemodynamic and neurohormonal effects of intravenous captopril and digoxin and their combinations in patients with severe heart failure. J Am Coil Cardiol 1989;13:134-42. Reproduced by permission.)

resulted in further decrease of mean pulmonary artery wedge and mean right atrial pressures and further increases in cardiac index and stroke-work index and a decrease in systemic vascular resistance. Digoxin resulted in a significant reduction of the elevated norepinephrine levels from 730 _ 233 pg/ml to 604 _ 107 pg/ml; p = 0.03. Randomized Studies. The study of Dobbs et al? 8 was a double-blind, variable-dose, crossover comparison of digoxin treatment with placebo in 46 patients, of whom 13 were in atrial fibrillation and the remainder were in sinus rhythm. Serum digoxin levels were 0.97 nmol/L or 1.33 nmol/L. Sixteen patients deteriorated on placebo, and 8 of the 16 completely recovered on institution of digoxin therapy. With digoxin therapy, there was an improvement in systolic intervals and in spirometric measurements (FEV 1 and FVC). Fleg et al. 6° studied 30 patients in a double-blind, placebo-controlled, crossover trial. Their ages ranged from 37 to 89 years (mean, 69 + 2 years). Curr Probl Cardiol, December 1996

811

Sixteen subjects were in NYHAFC II for heart failure, 13 were in class III, and 1 was in class IV; nevertheless, an S 3 gallop was present in only 1 subject. Digitalis had no demonstrable clinical effect in any of the 30 patients. However, there was a significant reduction in left ventricular end-diastolic dimension (57.6 _ 2.2 m m vs 55.8 _ 2.3 mm; p < 0.001). Lee et al. 61 studied 25 outpatients with heart failure in sinus rhythm in a randomized, double-blind, placebo-controlled, crossover trial. Four of the 25 patients had a diagnosis of hypertrophic cardiomyopathy and 5 of the patients had an ejection fraction of >0.5 (range, 0.5 to 0.64). Their ages ranged from 40 to 83 years. Fourteen of the 25 patients improved with digoxin; these were best separated by the presence of a third heart sound detected by auscultation. Excluding from analysis those patients whose ejection fraction was normal (>0.50) at the beginning of the study and those patients who had subtherapeutic digoxin levels continuously during the duration of the protocol (that is, always <0.5 ng/ml), then 14 of the remaining 16 patients were digoxin responders.S° Taggart et i]i.63studied 22 patients in sinus rhythm in a double-blind, placebocontrolled, crossover trial in patients who had a history of frank heart failure. Their ages ranged from 47 to 78 years (mean, 65 years). Four of the 22 patients deteriorated while receiving placebo and 3 while taking digoxin. Compared with those taking placebo, patients taking digoxin had a lower resting heart rate. Boman 65studied 41 "geriatric inpatients" in a randomized, double-blind, crossover trial of patients. Their ages ranged from 55 to 90 years; for 23 women, the mean age was 80 years, and for 18 men, the mean age was 77 years. Eleven of the 41 patients were in atrial fibrillation. Five (14%) of the 37 patients deteriorated during the placebo phase; in 4 of these, rapid atrial fibrillation developed, and in 1 patient, sinus tachycardia and symptoms of heart failure. Most of the patients who were stable when digitalis was discontinued, initially, had no clear indications for the use of digoxin therapy. Alicandri et al., 54 in a randomized, double-blind, crossover trial of 16 patients, compared digoxin with captopril. Their ages ranged from 39 to 73 years (mean, 61 years). With digoxin therapy, the patients had a reduction in plasma aldosterone and norepinephrine levels. Exercise duration and total work performed were higher in patients taking digoxin than in the placebo phase. Captopril and digoxin had similar results. The Captopril-Digoxin MRG Trial 68 was a multicenter, double-blind, placebo-controlled study that compared captopril plus diuretic (n = 104; mean age, 55 years), digitalis plus diuretics (n = 96; mean age, 58 years), and a placebo group who received a diuretic (n = 100; mean age, 57 years). Patients who could not tolerate digoxin discontinuation were not entered 812

Curr Probl Cardiol, December 1996

into the trial, thus biasing the study against digoxin. Those who had a reaction to captopril on a test dose were not entered into the study. Furthermore, the number of patients who crossed over is not given, and only a small part of the data was analyzed on the basis of an intention-totreat principle. Digoxin significantly improved left ventricular ejection fraction. The improved exercise time on digoxin was greater than that on placebo but was not significantly different from either captopril or placebo. Both digoxin and captopril were similarly effective in reducing morbidity by ~50% compared with placebo in terms of diuretic requirement, hospitalization, and emergency department visits. 8° Guyatt et al. 69 studied 20 patients with heart failure and sinus rhythm in a randomized, placebo-controlled, double-blind, crossover trial. Their age was 63 _+ 11 years (mean _+SD). They also titrated the serum digoxin level to between 1.2 and 2.1 ng/ml. Seven of the 20 patients required treatment during the placebo period for worsening heart failure, but no patient worsened while receiving digoxin therapy. The German andAustrian Xamoterol Study Group 7° studied 433 patients in a double-blind placebo-controlled comparison of digoxin and xamoterol in chronic heart failure. Their median age was 62 years. Patients were assessed at baseline and after 3 months. Patients in both the digoxin and xamoterol groups demonstrated significant improvement in symptoms compared with those taking placebo. Patients in the digoxin group lost weight; xamoterol subsequently has been reported to cause excess mortality in patients with heart failure. 8° Pugh et al.71 included 14 patients with stable heart failure in sinus rhythm in a randomized, double-blind, placebo-controlled, crossover study. Digoxin blood levels were >0.8 ng/ml. Their ages ranged from 36 to 76 years (median, 62 years). Twenty-five percent of the patients deteriorated clinically on discontinuation of digoxin therapy. Beaune 73 reported on the Enalapril Versus Digoxin French Multicenter Study, a multicenter, randomized, double-blind, parallel-group trial. Seventytwo patients received enalapril plus diuretics and 70 received digoxin plus diuretics. Their ages were 71 _+ 12 years and 71 _+ 14 years, respectively. After 8 weeks of treatment, 17 (28%) of 61 patients in the digoxin group had a significant improvement in the NYHA functional classification. These patients also had an increase in exercise time. Adverse events were reported in 13 patients in the enalapril group and in 7 patients in the digoxin group. Otherwise, enalapril was shown to have results similar to those of digoxin. DiBianco et al. TM reported on the Milrinone Multicenter Trial, a randomized, placebo-controlled, double-blind study. Two-hundred thirty patients in sinus rhythm with moderately severe heart failure were Curr Probl Cardiol, December 1996

813

RADIANCETRIAL

PROVED TRIAL 3O

501 25

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FIG. 22. In the PROVED trial (left), discontinuation of digoxin (placebo [i.e., monotherapy with diuretics]) in patients who were stable with digoxin and diuretic therapy resulted in a progressive reduction of maximal exercise duration• Patients who continued taking digoxin plus diuretic therapy (digoxin) maintained the maximal exercise duration. In lhe RADIANCE trial (right), discontinuation of digoxin (placebo [i.e., diuretic + ACE inhibitor therapy]) in patients who were stable with digoxin, diuretic, and ACE inhibitor therapy resulted in a progressive reduction of maximal exercise duration. Patients who continued with digexin, diuretic, and ACE inhibitor therapy (digoxin) maintained the maximal exercise duration. (From Uretsky BF,Young JB, Shahidi FE, Yellen LG, Harrison MC, King Jolly M. Randomized study assessing the effect of digexin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED Trial. J Am Coil Cardiol 1993;22:955-62, and Packer M, Gheorghiade M, Young JB, Constantini PJ, Adams KF, Cody RJ, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors_ N Engl J Med 1993;329:1-7. Reproduced by permission•)

randomized to digoxin, milrinone, both drugs, or placebo in addition to baseline diuretic therapy. The mean age of the digoxin and placebo groups was 60 + 1 years and 60 + 2 years, respectively. After 3 months of therapy, digoxin improved the left ventricular ejection fraction when compared with placebo (p < 0.01) and exercise tolerance improved by 14% (p < 0.05) compared with placebo. Forty-seven percent of the patients had a worsening of heart failure in the placebo group compared with 15% in the digoxin group (p < 0.01). Kromer et al. 75studied 22 patients in a randomized, single-blind, crossover trial and compared the efficacy of digoxin, ACE inhibition by quinapril, and their combination. Patients had mild heart failure, were in functional class II, and were in sinus rhythm. Their age was 48 + 3 years. Digoxin added to quinapril increased left ventricular fractional shortening significantly. Davies et al. 76reported for the Canadian Enalapril versus Digoxin Study Group. They performed a multicenter randomized, double-blind trial comparing enalapril (n = 72) with digoxin (n = 73). Patients were in functional classes II or III and were stabilized with furosemide therapy. 814

Curr Probl Cardiol, December 1996

PROYED TRIAL

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FIG. 23. In the PROVEDtrial, discontinuation of digoxin (placebo [i.e., monotherapy with diuretics]) in patients receiving digoxin plus diuretic resulted in a much higher rate of probabilily of worsening of heart failure than that in those who continued to receive digoxin (digoxin [i.e., those taking digoxin and diuretics]). In the RADIANCE trial, discontinuation of digoxin (placebo [i.e., diuretic + ACE-inhibitor therapy]) in patients who were stable with digoxin, diuretic, and ACE-inhibitor therapy resulted in a higher rate of probability of worsening of heart failure than were those who continued to receive digoxin (digoxin, [those receiving digaxin, diuretic, and ACE inhibitor)_ (From PackerM, Ghearghiade M, Young JB, Constantini PJ, Adams KF,Cody RJ, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. N Engl J Med 1993;329:1-7, and Uretsky BF,Young JB, Shahidi FE, Yellen LG, Harrison MC, King Jolly M. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVEDTrial. J Am Coil Cardiol 1993;22:955-62. Reproduced by permission.)

Their ages were 59 + 8 years and 59 _ 9 years, respectively. The digoxin group had an improvement in exercise time, left ventricular end-systolic dimension, and percentage of fractional shortening. More patients in the digoxin group were excluded because of an adverse clinical event (p < 0.05) than those in the enalapril; 30% of patients worsened while taking digoxin compared with 13% who worsened while taking enalapril. Fleg et al. 77 studied 10 ambulatory patients in sinus rhythm with mild to moderate stable congestive heart failure. Their ages ranged from 46 to 70 years (mean, 58 years). All underwent maximal treadmill exercise with respiratory gas analysis and upright bicycle ergometry with gated radionuclide angiography after 4 weeks of digoxin or placebo therapy, administered in a randomized, double-blind, crossover protocol. The digoxin-treated group had an improvement in left ventricular performance and left ventricular ejection fraction during exercise, but there was no increase in aerobic capacity. Uretsky et al. 7~ reported on the PROVED Trial, a randomized, doubleblind, placebo-controlled multicenter trial. One hundred thirteen patients who were in functional classes II or III with regard to heart failure Curr Probl Cardiol, December 1996

815

TABLE 4. DIG trial

Age (yr) Gender, female (%) Race, minority (%) Duration of HF (mo) LVEF (%) NYHA FC I(%) II (%) III (%) IV (%) Origin Ischemia (%) Hypertension (%)

Placebo

Digoxin

64.0 24.7 14.6 17 31.9

63.8 24.7 14.3 16 32.0

14.0 54.8 29.3 1.9

14.4 54.1 29.5 2.0

68.7 10

69.1 10

LVEF,Left ventficular ejection fraction; NYHAFC,New York Heart Association Functional Class. From Garg G, Gorlin R, DIG Trial. Presented at Annual Scientific Sessions of the American College of Cardiology, Orlando, Florida, March 26, 1996. From notes made at the meeting by one of the authors (S.H.R.).

participated in a digoxin-discontinuation trial. The ages of both groups were 64 + 2 years. Before the start of this trial, the patients were taking digoxin and diuretic; digoxin was discontinued in one group and replaced with a placebo; in the other group, digoxin was continued. Thus this was a comparison (albeit a discontinuation trial) of digoxin plus diuretics versus diuretics alone. Patients in the placebo group (diuretics alone) showed a significant reduction in exercise duration (p = 0.003) and significantly increased treatment failures (39% in placebo group vs 19% in the digoxin group; p = 0.039; Figs. 22 and 23). There was also a decreased time to treatment failure (p = 0.037) in the placebo group (Fig. 22). Patients for whom the digoxin had been discontinued had a decrease in left ventricular ejection fraction and an increase in heart rate, body weight, and serum creatinine. All of these differences were statistically highly significant. Packer et al. 79reported on the RADIANCE Study, a randomized, doubleblind, placebo-controlled multicenter trial. One hundred seventy-eight patients who were in functional classes II and ffl with regard to heart failure participated in a digoxin-discontinuation trial. The ages of the placebo and digoxin groups were 59 _+ 1 and 61 + 1 years, respectively. Initially the patients had been taking digoxin, diuretics, and an ACE inhibitor. In one group, digoxin was discontinued (n = 93; placebo group), and in the other, digoxin was continued (n = 85). Thus this was a comparison (albeit a withdrawal trial) between digitalis, diuretics, and anACE inhibitor versus diuretics and anACE inhibitor. Patients in the placebo group (diuretics plus an ACE inhibitor) showed a significant reduction in exercise duration (p = 0.033) and significantly 816

Curr Probl Cardiol, December 1996

TABLE 5. DIG trial summary

Digoxin Had no overall effect on survival Reduced incidence of Worsening heart failure Heart failure deaths Hospitalization for heart failure Was efficacious in all subgroups Was safe Had benefits incremental to use of diuretics and ACE I

increased treatment failures (p < 0.001; Figs. 22 and 23). Twenty-three patients in the placebo group (diuretics plus an ACE inhibitor) deteriorated with worsening heart failure, whereas only 4 of the digoxin group did so (p < 0.001). The relative risk of worsening heart failure in the placebo group compared with the digoxin group was 5.9 (95% confidence interval, 2.1 to 17.2). Patients who received placebo compared with digoxin had a significant deterioration in functional capacity (maximal exercise parameters, submaximal exercise tolerance, and NYHA functional class). In addition, patients who were taking placebo had lower quality-of-life scores (p = 0.04), decreased left ventricular ejection fraction (p = 0.001), and increases in heart rate (p = 0.001) and body weight (p < 0.001).

D. McCall: It must be remembered that, in both the RADIANCE and PROVED trials, there was very careful regulation of the digoxin dosage and serum digoxin levels. During the run-in period, digoxin dosage was adjusted to maintain a serum digoxin level of around 1.2 ng/ml. This required an average daily digoxin dosage of 0.38 mg/day, which is considerably above the 0.25 mg/day commonly used. This, in turn, raises the interesting point, as addressed by the authors later, as to whether we should be more assiduous in defining the optimal dose of digoxin for our patients. The rather dramatic results of these trials would suggest that optimal benefit can only be seen with these higher doses, a fact strengthened by the observations of Gheorghiade et al. (Circulation 1 9 9 5 ; 9 2 : 1 8 0 1 ) that higher doses resulted in improved left ventricular function.

By using data from the PROVED and RADIANCE trials, Ward et al. s°a calculated that use of digoxin therapy in patients with stable congestive heart failure would result in the United States in net annual savings of $406 million, with a 90% range of probability of $106 to $822 million. van Veldhuisen et al? 3 reported on behalf of the DIMT Study group. They performed a double-blind, placebo controlled, study of ibopamine versus Curt Probl Cardiol, December 1996

817

TABLE 6. Predictor of mortality in V-HeFT I and V-HeFT II V-HeFt i Variable

V-HeFT ii p

Variable

p

Univariate analysis LVEF ~o2 CTR CAD VAr

<0.00001 <0.00001 <0.00001 <0.03 <0.02

LVEF ~o2 CTR PNE PRA VAr (CAD)

<0.0001 <0.0001 <0.0001 <0.0001 <0.005 <0.0001 0.26

Multivariate analysis (stratified by treatment) LVEF ~o2 CTR VAr (CAD)

<0.0001 <0.005 <0.003 <0.23 <0.41

LVEF ~7o2 CTR VAr PNE* PNEt (PRA)

<0.0006 <0.0001 <0.0012 <0.01 <0.061 <0.02 <0.35

V-HeFT, Department of Veterans Affairs Cooperative Vasodilator-Heart Failure Trials; LVEF, left ventricular ejection fraction; (/o2, peak oxygen consumption during exercise test; CTR, cardiothoracic ratio; CAD, coronary artery disease; VAt, couplets or runs of ventricular tachycardia; PNE, plasma norepinephrine; PRA, plasma renin activity; O, variable not in model, p value for variable if it was added to the model. *PNE included as a continuous variable. t l f PNE was included in two groups, more than or less than 700 or 900 pg/ml. From Cohn JN, Johnson GR, Shabetai R, Loeb H, Tristani F, Rector T, et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracie ratio, ventricular arrhythrnias, and plasma norepinephrine as determinants of prognosis in heart failure. Circulation 1993;87 suppl Vh5-16. Reproduced by permission.

digoxin in patients with mild to moderate heart failure. One hundred sixtyone patients were randomized; they were in NYHAFC II and IlL The digoxin group consisted of 55 patients (61 +_9 years); the placebo group (furosemide) consisted of 53 patients (61 _+8 years); the ibopamine group had 53 patients (60 _ 8 years); they were treated for 6 months.All patients received furosemide therapy. Compared with placebo, digoxin significantly increased exercise time after 6 months (p = 0.008 by intention-to-treat analysis). No patient receiving digoxin withdrew from the study because of progressive heart failure; 2 patients in the placebo group and 6 in the ibopamine group withdrew from the study because of advancing heart failure. Data from the DIG Trial were recently presented at the Annual Scientific Meeting of theAmerican College of Cardiology.79a~ The DIG Trial is a randomized, double-blind, placebo-controlled study of digoxin "~All of the DIG trial information is from notes made at the American College of Cardiology meeting by one of the authors (S.H.R.). 818

Curr Probl Cardiol, December 1 9 9 6

35

=1

V-He 5

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. . . .

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EJECTIONFRAGTION FIG. 24. In both V-HeFT I and II, patients with left ventricular ejection fraction of <0.35 had a higher annual mortality; fhose wifh an ejection fraction of < - 0 . 3 6 ~-HeFT I) and of < 0.'27 had a much higher annual mortality. (From Cohn JN, Johnson GR, Shabetai R, Loeb H, Tristani F, Rector T, et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. Circulation 1993;87 suppl V1:5-16. Reproduced by permission.)

versus placebo in 6800 patients with heart failure in sinus rhythm who had symptoms of heart failure and a left ventricular ejection fraction <0.45. An ancillary group of 988 patients had heart failure and left ventricular ejection fraction >0.45. The follow-up time averaged 37 months (range, 28 to 58 months). Some of the patient characteristics are shown in Table 4. The main findings of the DIG Trial 79a were l. There was no significant difference between the two groups with regard to all-cause mortality. This was true for patients with left ventricular ejection fraction <0.45 and >0.45. 2. There were statistically significant reductions of deaths attributable to heart failure, worsening of heart failure, and hospitalization for heart failure. 3. In the group of patients with left ventricular ejection fraction >0.45, there was a statistically significant reduction of worsening heart failCurr Probl Cardiol, December 1996

819

V-HeFT I

V-HeFT II 1.O

1.C

i~ - 6 & S 6

. . . . . . .

-5&~s

p<0.0WI ------

Q.1

p
> 5 & ~; 10 > 10

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t2

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~1

a0

m

4~

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4

84

W

86

72

8

12

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24

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4,?.

4

B4

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68

"~

Mobm-IS

FIG. 25. Data showing the relation of subsequent survival to the change in ejection fraction in those who survived 6 months (V-HeFTI) and 12 months (V-HeFT II) after randomization and had the change in ejection fraction determined. As ejection fraction decreased (<5 units) to those in whom it increased (> 10 units), the subsequent survival progressively improved. (From Cintron G, Johnson G, Francis G, Cobb F, Cohn JN. Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. Circulation 1993;87 suppl VI: 17-23_ Reproduced by permission.)

ure, all-cause death plus hospitalization for heart failure, and heart failure death plus hospitalization for heart failure. In summary, the DIG Trial showed that digoxin added to diuretic plus an ACE inhibitor (1) had no overall effect on survival, (2) resulted in reduction of worsening heart failure and of heart failure deaths irrespective of left ventricular ejection fraction, (3) was efficacious in all subgroups, (4) was safe, and (5) had benefits that were incremental to use of diuretics and ACE-inhibitor therapy (Table 5).

D. McCall: In contrast to the RADIANCE and PROVED trials, there was no titration of digoxin dosage, or attempts to maintain a specific serum digoxin level in the DIG trial. As a result, it is uncertain as to how many of the subjects in this trial had truly "therapeutic" digoxin levels or how many had "subtherapeutic" levels throughout the duration of the study. How much this influenced the survival component of the study will never be known and must remain a matter of conjecture. On the other hand, as pointed out by the authors, the principal finding of the study was the observation that digoxin had no adverse effect on survival in patients with heart failure.

It is of interest that a recent analysis of data from V-HeFT I and [ I 79b showed that in patients with left ventricular ejection fraction >0.35 (1) 820

Curr Probl Cardiol, December 1996

hydralazine-isosorbide dinitrate plus digitalis and diuretic was not associated with a better survival compared with digitalis and diuretic (p = 0,93), and (2) those taking enalapril combined with digitalis and diuretic had a better survival than those taking hydralazine-isosorbide dinitrate combined with digitalis and diuretic (p = 0.035). In the DIG Trial, there was an increase of "presumed" arrhythrnic deaths; these were out-of-hospital, unwitnessed "sudden" deaths. It is important to be very cautious of this finding because a large percentage of deaths in patients in heart failure are sudden. Analyzing data from patients with automatic implantable cardioverter-defibrillators whose death was classified as sudden, Pratt et al. 79cfound that deaths classified as sudden cardiac were not associated with ventricular tachycardia or ventricular fibrillation and they were often noncardiac. It was possible to create a wide range of sudden cardiac death rates (more than fourfold) by using the identical clinical database in spite of objective, prespecified criteria. Autopsy results frequently revealed noncardiac causes of clinical events simulating sudden cardiac death, and automatic implantable cardioverterdefibrillator discharges were often related to terminal arrhythmias incidental to the primary pathophysiologic process leading to death. Even in patients with advanced heart failure, unexpected cardiac arrest results from diverse mechanisms including severe bradycardia, electromechanical dissociation, and ventricular tachycardia/ventricular fibrillation, and in many patients the precipitating factors cannot be identified. 79d Philosophically, the important issues are total mortality and not just sudden death but premature, unexpected sudden d e a t h . 79~

Left Ventricular Ejection Fraction Left ventficular ejection fraction is one of the most important predictors of mortality in patients in heart failure 81 (Table 6). In one study, the 5-year survival of those with left ventricular ejection fraction >0.35 was 94% versus 71% (p = 0.01) in those with left ventricular ejection fraction <0.35. 82In the study of DiBianco et al., 74left ventricular ejection fraction in those who died was 15.6% _+ 1.4% versus 24.8% __0.8% (p < 0.01) in those who survived. There is a cut-off point in left ventricular ejection fraction below which the mortality is high (Fig. 24) and the benefits of vasodilators is greater and above which the mortality is lower and the improvement in survival is difficult to demonstrate. In the randomized trials, the cut-off point in left ventricular ejection fraction ranged from 0.28 to 0.32. 83-86 The question is whether increasing the left ventricular ejection fraction with pharmacologic therapy is a predictor of an improved survival. Data from V-HeFT I show that improvement in left ventricular ejection fraction Curr Probl Cardiol, December 1996

821

'"] Off Digoxin • P Value

0.05

<0.04

<0.01

0.004

<0.01

On Digoxin 0.016

0,001

<0.02

<0.05

0"50f ZO 0 , 4 0

+o+i 11111 1

~, 0.10I

0.0 ~

Arnold 1980

Oheorghiade Captopril 1987

-Digoxin 1988

Guyatt

DiBianco

Uretsky

Packer

M u r r a y Fleg et al

1988

1989

1993

1993

1982 1991 * * • On Exercise

FIG. 26. Left ventricular (LV) ejection fraction in patients who were receiving (solid bars) and not receiving digoxin (open bars). In two studies (*), the improvement in LVejection fraction was present on the exercise studies. In two nonrandomized studies and five randomized studies, LV ejection fraction was significantly higher in those receiving digoxin therapy than in those receiving no digoxin.

after 6 months of treatment improves the subsequent survival; the greater the increase of left ventricular ejection fraction, the better the subsequent survival (Fig. 25). 87 Similar data are available in V-HeFT II for left ventricular ejection fraction after 1 year of treatment (Fig. 25). 87 In both studies, the effect of an earlier improvement in left ventricular ejection fraction, for example, at 2 to 4 weeks, was not evaluated, and thus the deleterious effect of lack of increase of ejection fraction during the first 6 to 12 months was not evaluated in these studies. In the Captopril-Digoxin trial and V-HeFT II, 68"87 with ACE inhibitors (captopril and enalapril), the change in left ventricular ejection fraction was not statistically significant. In V-HeFT I and II, the combination of hydralazine and isosorbide dinitrate increased left ventricular ejection fraction significantly for 2 and 1 years, respectively. 87 Left ventricular ejection fraction did not increase with digoxin in one randomized trial. 61 However, in this study, 4 (16%) of 25 patients had hypertrophic cardiomyopathy, and in 6 (24%) of 25 patients, the baseline ejection fraction ranged from 0.52 to 0.67. 61 In another study, 64 left ventricular ejection fraction also did not increase significantly with digoxin. However, in this study, 8 (33%) of 24 patients had left ventricular ejection fraction >0.50, and 33% of the patients had no cardiomegaly on chest radiograph. 64 In two studies, left ventricular ejection fraction increased with digoxin only on exercise. 62,77The remaining seven studies of d i g o x i n , 59,67-69'74,78,79 which included randomized trials, showed that 822

Curr Probl Cardiol, December 1996

WORSENING

OF H E A R T F A I L U R E

DATA FROM 12 RANDOMIZED TRIALS 50-

40

Z m

30

20

10

0

m NO YES DIGOXIN

FIG. 27. Data from 12 randomized trials indicate that worsening of heart failure occurred in an average of 24% of patients when they were not taking digoxin compared with an average of 5% of patients taking digoxin. This does not include the data from the DIG Trial.

digoxin therapy increases left ventricular ejection fraction significantly (Fig. 26). The modest increase of left ventricular ejection fraction with digitalis is of clinical benefit. Summary Many studies have addressed many issues relative to various aspects of heart failure and have demonstrated beneficial effects of digitalis. Each Curr Probl Cardiol,, December 1996

823

TABLE 7. Beneficial clinical effects of digitalis therapy in heart failure* Improves clinical symptoms Reduces symptoms Improves functional class Improves heart failure score Increases exercise capacity Increases exercise time Increases total body 02 consumption on exercise Decreases frequency of clinical decompensation Decreases frequency of hospitalization Reduces costs of treatment of heart failure Improves left ventricular systolic function Increases ejection fraction at rest and on exercise Reduces left ventdcular size Left ventricular end-diastolic and end-systolic volumes reduced Left ventricular dimensions reduced Improves hemodynamics Reduces ventricular filling pressures and increases cardiac output and stroke-work index at rest and on exercise Decreases ventricular rate In sinus rhythm In atrial fibrillation Reduces neurohormones Plasma renin activity Plasma aldosterone Plasma norepinephdne Reduces heart size on chest radiograph Reduces BUN, serum creatinine and body weight Increases creatinine clearance *All studies evaluated only selected parameters. All beneficial effects may not occur in all patients.

study evaluated only a selected few parameters, and in many instances, demonstrated only selected benefits. Thus all the beneficial effects may not occur in all patients. The benefits that have been demonstrated include: Type of benefit with digitalis Cited reference numbers Heart failure score improved and/or improvement in clinical status and/ or worsening of heart failure on discontinuation 53, 54, 58, 59, 61, 68, 69, 71, 73, 74, 78, 79, 79a Reduction of hospitalization 68, 78, 79, 79a Reduction of cardiothoracic (C-T) ratio on CXR 61, 69 Reduction of heart rate 52, 54, 58, 59, 61-63, 66, 67, 71, 78, 79 Increase of exercise time 79 824

23, 24, 51, 53, 54, 67, 68, 72-74, 76, 78,

Curr Probl Cardiol, December 1996

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End 15' 30" 4.5" 60' of Ouaboin Infusion

FIG. 28. During the acute phase of acute myocardial infarction (MI), a full digitalizing dose of ouabain resulted in a significant decrease of left ventricular end-diastolic pressure (directly measured from inside the left ventricle) and a significant increase of left ventricular stroke-work index. These patients were not in clinical heart failure. (From Rahimtoola SH, Sinno MZ, Chuquimia R, Loeb HS, Rosen KM, Gunnar RM. Effects of ouabain on impaired left ventricular function in acute myocardial infarction. N Engl J Med 1972;287:527-31. Reproduced by permission.)

Increase of maximum VO 2 on exercise Increase of LV ejection fraction Reduction Of LV dimensions Curr Probl Cardiol, December 1996

72 59, 62, 67-69, 74, 77-79

60-62, 69, 76 825

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I~f*jseon FIG. 29. During the convalescent phase of acute myocardial infarction (MI), a full digitalizing dose of ouabain r#sulted in a significant decrease of left ventricular end-diastolic pressure (directly measured from inside the left ventricle) and a significant increase of left ventricular stroke-work index. These patients were not in cliniCal heart failure. (From Rahimtoola SH, DiGilio MM, Sinno MZ, Loeb HS, Rosen KM, Gunnar RM_ Effects of ouabain on impaired left ventricular function during convalescence after acute myocardial infarction. Circulation 1971 ;44:866-76. Reproduced by permission.)

Hemodynamics at rest Reduction of PA wedge pressure 51, 52, 59, 66, 67 Reduction of right atrial pressure 51, 52, 66, 67 Increase of cardiac output 51, 52, 59, 67 826

Curr Probl Cardiol, December 1996

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m

FIG. 30. Effects of furosemide (left) and ouabain (center) on left ventricular (LV) function during the acute phase of myocardial infarction. Furosemide results in a decrease of pulmonary artery wedge pressure and of LV stroke-work index; data from Kiely et al. 97 It should be remembered that in such patients, mean pulmonary artery wedge pressure is frequently not the same as LV end-diastolic pressure. After ouabain administration, the decrease of LV enddiastolic pressure is accompanied by an increase of LV stroke work; data from Rahimtoola et al, cited reference number 95. The relation (right) of LV end-diastolic pressure to LV stroke Work at rest and on exercise in the control state (open circles) and after ouabain administration (closed circles) during the convalescent phase of acute myocardial infarction (mean of four patients); data from Rahimtoola et al, cited reference number 96. After ouabain, the LV "function curve" has moved upward and to the left. (From Rahimtoola SH, Gunnar RM. Digitalis in acute myocardial infarction: help or hazard.g Ann Intern Med 1975;82:234-40. Reproduced by permission.)

Reduction of systemic vascular resistance 31, 51, 52, 67 Increase of LV stroke-work index 51, 52, 59, 66, 67 Hemodynamics on exercise Reduction of PA wedge pressure 51, 52, 59, 62 Reduction of right atrial pressure 51, 52 Increase of cardiac output 51, 52, 59, 62 Increase of LV stroke-work index 51, 59, 62 Reduction of elevated neurohormones 51-55 Reduction of BUN 78 Reduction of creatinine 78 Increased creatinine clearance Reduction of body weight

59

54, 61, 70, 78, 79

Reduced costs of treatment of heart failure 80a CXR, Chest radiograph; LV, left ventficular; PA, pulmonary artery; BUN, blood urea nitrogen. Curr Probl Cardiol, December 1996

827

THERAPEUTIC EFFECT

0

0.5

1.0 1.5 2.0 SERUM DIGOXlN LEVEL ngmlml

2.5

FIG. 31. The beneficial effect and incidence of toxicity at various levels of serum digoxin are depicted. Perhaps the best level may be at 1.5 ng/ml (range, 1.0 to 1.8 ng/ml), for routine clinical practice, the level may be in the range of 1.0 to 1.5 ng/ml. (From Lewis RP.Digitalis. In: Leier CV, editor. Cardiotonic drugs: a clinical survey_New York: Marcel Dekker, 1991:107-77. Reproduced by permission.)

In randomized studies, 53'58'60'61'63'65'68"71'78'79worsening of heart failure occurred in an average of 24% of patients in whom digoxin was discontinued or was not started. In the group in whom digoxin was continued or was started, worsening of heart failure occurred in an average of 5% of patients (Fig. 27). The beneficial clinical effects of digitalis therapy in heart failure are listed in Table 7.

G.A. Belier: Drs. Rahimtoola and Tak provide extensive literature documentation relevant to the beneficial clinical effects of oral digoxin therapy in patients with heart failure. Interestingly, this mild inotropic agent, which has been in our therapeutic armamentarium for more than 200 years, is the only inotropic agent that has not increased overall mortality when administered to patients with heart failure. Recently, the multicenter randomized trial evaluating the efficacy and safety of vesnarinone was discontinued due to increased mortality in patients receiving the drug. Similarly, increased mortality was observed in patients receiving the oral form of phosphodiesterase inhibitors (e.g., milrinone) and patients receiving catecholamine agonists (e.g., pirbuterol). In the absence of atrial fibrillation, digoxin should be used primarily in patients with heart failure and a left ventricular ejec-

828

Curr Probl Cardiol, December 1996

TABLE 8. Pharmacokinetic data: adults

Availability (oral; %) Urinary excretion (%) Bound in plasma (%) Clearance (ml/min/kg)

Digitoxin

Digoxin

>90 32 _+ 15 97 + 0.5 0.055 + 0.018

70 + 13 (tablets) 60 + 11 25 _+ 5 CL = (0.88 CLr 4- 0.33) + 52% (heart failure) CL = (1.0 CLcr 4- 0.33) + 52%

0.54 + 0.14 6.7 -+ 1.7 days >10

V = (3.12 CLer + 30%) 39 + 13 hours >0.8 (inotropic effect)

(no heart failure) Volume of distribution (L/kg)

Half-life Effective concentrations (ng/ml) Toxic concentrations 10% Probability* 50% Probability* 90% Probability*

1.7 ng/ml 2.5 ng/ml 3.3 ng/ml

*of digoxin-inducedarrhythmias. From Gilman AG, Rail TW, Mies S, Taylor P, editors. Goodman & Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990:1675. Reproduced by permission. tion fraction (LVEF) of < 0 . 4 5 who remain s y m p t o m a t i c after optimal vasodilator and diuretic therapy. Digoxin should usually be avoided in p a t i e n t s with s y m p t o m s of heart failure attributed to diastolic dysfunction when the LVEF is normal, and a b n o r m a l myocardial compliance due to left ventricular hypertrophy is j u d g e d to be t h e d o m i n a n t p a t h o p h y s i o l o g i c finding for the heart failure state.

Digitalis in Acute Myocardial Infarction The beneficial and possible harmful effects of digitalis in experimental animal studies and clinical acute myocardial infarction was completely reviewed in 1975. 88 In 1970, Constant, 89 after reviewing the world literature, concluded that no clinical study had shown an increased incidence of arrhythmia when digitalis had been administered to patients with acute myocardial infarction. In 1976, in a randomized double-blind study, Reicansky et al.90 found no difference in the incidence of arrhythmias between digoxin-treated and control patients. Lown et al. 91 found that almost 90% of patients with acute myocardial infarction tolerated a full dose of acetylstrophanthidin; this is evidence to suggest that in clinical acute myocardial infarction, there is no significant enhancement of sensitivity to the drug. Most patients have left ventricular dysfunction after an acute myocardial infarction whether they have clinical heart failure o r n o t . 9z94 Ouabain has been shown to improve the left ventricular dysfunction during both the acute and convalescent phases of acute myocardial infarction in patients who were not in clinical heart failure (Figs. 28 and 2 9 ) . 95,96 Whereas diuretCurr Probl Cardiol, December 1996

829

TABLE 9. Dosages, time of effect, and fate of digoxin and digitoxin in human beings Digoxin Average digitalizing dose Oral IV Average daily maintenance dose Oral IV Onset of action Oral IV Maximal effect Oral IV Intestinal absorption Plasma protein binding Disposition half time Route of elimination

Enterohepatic circulation "Therapeutic" plasma concentration

Digitoxin

0.75-1.25 mg 0.5-1.0 mg

0.8-1.2 mg

0.125-0.5 mg 0.25 mg

0.05-0.3 mg

1.5-6 hr* 5-30 min

3-6 hr

4-6 hr 1.5-4 hr

6-12 hr

<40%-100%t (75%) 25%

90%-100%

1.6 days Renal excretion of unchanged drug: limited hepatic metabolJsm Small 0.5-2.0 ng/ml

95% 7 days Hepatic degradation of molecule: renal excretion of metabolites Large 10-35 ng/ml

*Dependent on relation of dose to meals, gastric emptying time, and type of preparation. l'Nearly 100% of encapsulated digoxin solution is absorbed from a normal enteric tract: 75% of a tablet with high bioavailability is absorbed by a normal enteric tract. Absorption may be poor with certain tablets or when there is gastrointestinal malabsorption. From Hoffman 8F, Bigger JT Jr. Digitalis and allied cardiac glycosides. In: Gilman AG, Rail TW, Nies AS, Taylor P, editors. Goodman and Gilmans's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990:814-39. Reproduced by permission.

ics reduce only ventricular filling pressures, 97digitalis reduces filling pressure and increases stroke work both at rest and on exercise (Fig. 30). 8s Studies fr0m 1950 to 195798-1°1showed that administration of digitalis to patients with myocardial infarction did not result in an increased mortality. Two retrospective studies 1°2,1°3suggested that patients with acute myocardial infarction who received digitalis after myocardial infarction had a higher mortality than those who had not received the drug. In these studies, patients taking digoxin were a high-risk group (had more heart failure and arrhythmias), left ventricular function was not quantitated, important risk factors for mortality were not evaluated, and some of the patients died of recurrent myocardial infarction. Moreover, in four large studies of patients with high-risk coronary artery disease or acute myocardial infarction, 1°41°7 a statistically significant increase in mortality, independent of other highrisk factors, was not demonstrated. In other words, the increased mortality was a result of the known predictors of increased mortality such as heart failure or arrhythmias. 830

Curr Probl Cardiol, December 1996

TABLE 10. Dosage regimen of digoxin~

Tablet

Gelatin capsule (Lanoxicaps)

Injection

Rapid digitalization*

Slow digitalization

0.5 mg initially (2 divided doses of 0.25 mg 3-4 hours apart) Followed by 0.25 mg 4-12 hours apart up to 3-4 doses 0.4 mg initially (2 divided doses of 0.2 mg 3-4 hours apart) Followed by 0.2 mg 4 to 12 hours apart up to 3 doses 1.0 mg intravenously in divided doses over 24 hrt

0.125-0.5 mg once daily for 1 week

0.125-0.25 mgt once daily Average: 0.25-0.375 mg once daily

0.1-0.4 mg once daily for 1 week

0.1-0.2 mg once daily

Maintenance

*Considerable caution is needed in those already receiving digitalis therapy, those with increased sensitivity to digitalis toxicity (Table 8), and in those receiving medications that interact with digoxin. tSee section entitled Value of Digoxin Blood Levels(page 841 ). :l:lntravenous preparations to be given slowly over a period of 15 to 30 minutes. §Specificmanufacturer's product information and the PDRshould be consulted before prescribing.

D. McCall: The authors have done a great job of laying to rest the old concept that administration of digoxin in the setting of an acute myocardial infarction results in increased mortality. Although digoxin is safe in the context of an acute myocardial infarction, little is known of the drug's long-term effect on ventricular function following such an event. Recently, Jugdutt et al. (J Am Coil Cardiol 1 9 9 6 ; 2 7 : 1 7 8 7 ) examined the effect of 6 weeks of dJgoxJn administratJon after experimental infarction in the dog. They found that left ventricular contractility and systolic thickening were higher in the digoxin-treated animals at 6 weeks compared with these parameters in the control animals. On the other hand, in those animals treated with digoxin there was more infarct expansion and thinning and more aneurysm formation despite the fact that there was less global left ventricular dilatation and increase in LV mass. These elfects on left ventricular remodeling were present to a greater degree in transmural infarctions than in nontransmural infarctions. Although these effects on left ventricular remodeling are interesting, more studies need to be done before any firm conclusion can be drawn regarding the effect of digoxin on this i m p o r t a n t d e t e r m i n a n t of l e f t v e n t r i c u l a r f u n c t i o n f o l l o w i n g a myocardial infarction.

Curr Probl Cardiol, December 1996

831

G.A. Belier: For the most part, digoxin should be avoided in the management of patients with mild to moderate left ventricular dysfunction in the acute or subacute phase of acute myocardial infarction unless supraventricular arrhythmias are encountered. The majority of these patients respond adequately to intravenous furosemide and vasodilators. Early administration of an angiotensin-converting enzyme inhibitor has been shown to enhance survival and attenuate left ventricular remodeling after acute infarction. Nitrates have also proven beneficial with respect to prevention of progressive left ventricular dilation consequent to a large infarction. Digoxin may certainly prove useful in the subsequent management of such patients should the constellation of symptoms and signs of ischemic cardiomyopathy develop.

Pharmacokinetics, Bioavailability,and Dosage of Digitalis

Digoxin Digoxin is the most frequently prescribed digitalis preparation. Absorption of digoxin after oral administration depends on the type of preparation used and varies from <40% to 90%. i08 The Food and Drug Administration now requires that all digoxin tablets marketed in the United States must have an in vitro dissolution rate of >90% in 15 minutes and 265% in 1 hour. 1°9 Digoxin excretion is predominantly renal and, under most circumstances, is roughly proportional to the glomerular filtration rate (GFR). "° Digoxin/digitoxin pharmacokinetics are summarized in Table 8; dosages, time of effect, and fate of digoxin/digitoxin are summarized in Table 9; and methods of administration of digoxin are summarized in Table 10. NOTE: Specific manufacturer's'product information and the PDR should be consulted before prescribing. The half-life of digoxin does not vary with the route of administration and is ~1.6 days or 36 to 48 hours, m-m Usual maintenance dose is 0.25 to 0.375/day; also see the section entitled Value of Digoxin Blood Levels (page 841). Adjustment of maintenance doses of 0.25 mg/day to compensate for altered renal function and digoxin excretion is important. When it is administered intravenously, the onset of action is 5 to 30 minutes, and a maximal effect occurs in 1.5 to 4 hours, m Average digitalizing dose is 0.5 to 1.0 mg for intravenous use. Digoxin is widely distributed in body tissues, as evidenced by a large volume of distribution (5 to 8 L/kg; Table 8). It readily binds to heart and skeletal muscle, whereas adipose tissue contains little digoxin. Digoxin is eliminated primarily via the kidney; therefore, its dosage has to be titrated against renal function. Severe renal impairment will prolong the half-life of digoxin to ~4 to 5 days and thus extends the period required to reach 832

Curr Probl Cardiol, December 1996

TABLE 11. Drug interactions with digoxin Digoxin blood levels Decreased

Increased

Antacids Kaolin-pectin Cholestyramine Bran Phenytoin Propafenone PAS Sulfasalazine Neomycin Cathartics

Quinidine Amiodarone Propafenone Flecainide Verapamil Nicardipine Tiapamil Spironolactone Triamterene Indomethacin Cyclosporine

TABLE 12. Increased sensitivity to digitalis toxicity Electrolyte abnormalities Hypokalemia Hypercalcemia Hypomagnesemia Hyponatremia Acid/base changes Resulting from changes in K÷ and Ca2÷ Hypothyroidism Advanced pulmonary disease Cor pulmonale Hypercapnia Hypoxemia Renal failure (including "elderly" patients) Very early phase of acute myocardial infarction* Concomitant drug administration Sympathomimetics Catecholamines Antiarrhythmics *Has been demonstratedonly in experimentalanimals.

steady state up to 3 weeks. The maintenance digoxin dose required to replace daily losses will vary from - 3 7 % of the total body content in patients with normal renal function to nonrenal losses averaging - 1 4 % in patients who are essentially anephric. A reasonable approximation of daily percentage of loss of digoxin is as follows: C L in ml/min 14 + 5

where C L = creatinine clearance. Parenteral (IV) loading and maintenance dose recommendations are ~75% Curr Probl Cardiol, December 1996

833

TABLE 13. Circumstances in which digitalis toxicity is suspected New gastrointestinal symptoms New neurologic symptoms Any change in cardiac rhythm Stable patient "not doing well" Concomitant use of drugs that increase digoxin blood levels (see Table 11)

TABLE 14. Frequency of symptoms associated with digoxin intoxication

Definite (%) Nausea Vomiting Anorexia Dizziness Fatigue Visual disturbances Syncope Abdominal pain Diarrhea Headache Delirium

52 48 34 14 14 9 6 6 2 0 0

Possible (%) 30 30 27 19 16 5 3 4 2 2 1

Nontoxic (%) 27 27 18 23 11 7 2 0 2 0 0

From Mahdyoon H, Battilana G, Rosman H, Goldstein S, Gheorghiade M. The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988. Am Heart J 1990;120:1189-94. Reproduced by permission.

of the oral dosages. 114Rapid IV administration of any digitalis preparation can cause transient systemic arterial and coronary vasoconstriction; therefore it should be administered as a slow infusion over a 15- to 30-minute period, is With daily maintenance therapy, a steady state is reached when daily losses are matched by daily intake. Approximately 10% of the population carries gut flora capable of metabolizing digoxin into inactive digoxin reduction products; 115 antibiotic therapy in these persons can result in potentially important alterations in the state of digitalization. Specific recommendations for digoxin dosage have been developed on the basis of the pharmacokinetic principles (Tables 8 through 10). In clinical practice, there is usually no need to use a loading dose in most patients in heart failure. Digitalization with digoxin can be achieved over a period of about a week in patients with normal renal function by administration of the daily maintenance dose (e.g., 0.25 mg daily [slow digitalization]), especially in outpatient practice (Table 10).

Digitoxin Digitoxin is the most slowly excreted of the available cardiac glycosides. It differs from digoxin only by absence of a hydroxyl group at C-12.Absorp834

Curr Probl Cardiol, December 1996

TABLE 15. Arrhythmias induced by digitalis toxicity

Enhanced impulse formation Atrial premature depolarization Atrial tachycardia Accelerated junctional rhythm Ventricular premature depolarization, especially multiform and repetitive during atrial fibrillation Bidirectional or fascicular ventricular tachycardia Impaired impulse conduction SA nodal block AV nodal block Enhanced impulse formation and impaired impulse conduction Atrial tachycardia with block A-V block with junctional tachycardia

tion of digitoxin is more complete (90% to 100%) than that of digoxin, because digitoxin is more lipid soluble (Table 8). Gastrointestinal absorption of digitoxin is essentially complete. About 97% of the serum or plasma content of this drug is bound to albumin at clinically relevant concentrations, in contrast to digoxin, which is only ~25% bound to plasma proteins. For digitoxin, half-lives usually range within 20% of the mean value of 4 to 6 days, and relatively little variation in the body pool would be expected among individual patients receiving a given maintenance dose of the drug. Digitoxin is almost totally metabolized in the liver to primarily cardiac inactive metabolites. Digoxin has also been identified as a metabolite but is quantitatively unimportant, n6 Excretion of digitoxin is via the feces (71%) and urine (29%). The half-life of elimination is 7 days. Average digitalizing dose is 0.80 to 1.2 mg; daily dose is usually 0.05 to 0.3 m g n3 (Table 9).

Ouabain Ouabain is the most rapid acting of the cardiac glycosides commonly available; onset of action is 5 to 10 minutes, with a peak effect of 30 minutes to 2 hours, n4 It is poorly absorbed from the gastrointestinal tract and is not available for oral use. Complete digitalization dose is 0.010 to 0.015 mg/kg body weight or 0.3 to 0.5 mg intravenously infused slowly over a 15- to 30-minute period or can be given in divided doses. Its half-life is ~21 hours in normal persons; in those with impaired renal function, clearance is prolonged. It is excreted principally by the kidneys; its gastrointestinal excretion is significant even after intravenous administration. It has limited use in everyday clinical practice because we now know that IV digoxin also has a fairly rapid onset of effect and of peak effect. Curr Probl Cardiol, December 1996

835

TABLE 16. Frequency of arrhythmias associated with digoxin intoxication

Definite (%) Atrioventricular block (11 or III) Atrioventricular block

Possible (%)

Nontoxic (%)

33

5

5

33

12

0

26 21 19 16 12

2 6 1 12 1

2 26 0 19 0

7 3 2

4 1 1

5 0 0

(I) Sinus bradycardia Junctional rhythm Sinus pause (>2 sec) Ventricular ectopy Atrial fibrillation with rate <50 Ventricular tachycardia Ventricular fibrillation Paroxysmal atrial tachycardia

From Mahdyoon H, Battilana G, Rosman H, Goldstein S, Gheorghiade M. The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988. Am Heart J 1990;120:1189-94. Reproduced by permission.

Interactions with Digitalis Glycosides Any drug or clinical condition that decreases the GFR will inhibit digoxin elimination and increase serum digoxin levels. The contribution of tubular secretion to overall digoxin clearance is minimal; nevertheless, agents that significantly inhibit this process (e.g., spironolactone) can predispose the patient to increased plasma digoxin levels and to the risk of digoxin toxicity. 117Acute vasodilator therapy during heart failure has been shown to increase digoxin clearance without altering GFR, suggesting an increase in tubular secretion. This would be expected to lower serum digoxin levels. Hypokalemia may result from concurrent administration of loop diuretics and other oral diuretics. One consequence is an increased myocardial uptake of digitalis, potentiating its electrophysiologic effects and predisposing the patient to toxicity. Drugs that interact with digoxin are shown in Table 11. Any drug that lowers serum potassium concentrations may predispose patients to digitalis toxicity. Conditions/disorders that hinder drug absorption (e.g., malabsorption syndrome), and those that increase distribution of drug (e.g., pregnancy, hyperthyroidism) or increase elimination (e.g., diarrhea, ACE inhibitors) reduce serum digoxin levels. Conversely, conditions that facilitate drug absorption, decrease distribution of drug, or have decreased elimination (e.g., renal failure, aging) will increase serum digoxin levels.

Digitalis Glycosides and Pregnancy Both digoxin and digitoxin cross the placenta, and serum concentrations of digoxin are similar in the newborn and mother at term. "8 Fetal deaths asso836

Curr Probl Cardiol, December 1996

TABLE :1.7. Potassium administration In suspected digitalis toxicity

Indications Serum potassium <4.0 mEq/L VPCs: ventricular tachycardia SVT with AV block Serum potassium <3.0 mEq/L First-degree AV block Relative contraindication Serum potassium >5.0 mEq/L (particularly if AV block is present) Concurrent with chronic cardiac glycoside therapy Indications Serum potassium <3.5 mEq/L Combines diuretic/cardiac glycoside therapy Use particular caution with the following Concurrent administration of Potassium-sparing diuretics ~-Blockers ACE inhibitors Nonsteroidal antiinfiammatory drugs Chronic renal insufficiency (GFR <20 ml/min) Hyporeninism (type IV RTA: diabetes mellitus) GFR, Glomerular filtration rate; RTA,tubular acidosis; ACE, angiotensin-converting enzyme; AV, atrioventricular; SVT, supraventricular tachycardia; VPCs,ventricular premature complexes. From Kelly RA, Smith W. Digitalis glycosides. In: Hosenpud JD, Greenberg BH, editors. Congestive heart failure. New York: Springer-Verlag, 1994:354-79. Reproduced by permission.

ciated with maternal digitalis toxicity have been reported, u9 The serum digoxin concentration in pregnant women is reduced by as much as 50% when compared with that of nonpregnant women, because of an increase in renal blood flow and clearance, n8

Digitalis Toxicity The incidence of digitalis toxicity was much lower in the 1980s t2° (B. Massie, personal communication) than in an earlier era. t21-124A retrospective review from Henry Ford Hospital in Detroit showed the incidence of definite digitalis toxicity was 0.8% for the years 1980 through 1988, and the diagnosis could not be excluded in another 4%; the mortality from digitalis toxicity was 1.1%.12° In another study, from the San FranciscoVA Medical Center (B. Massie, personal communication), the estimated incidence of digitalis toxicity in patients taking digoxin was <1% per year for the years 1980 through 1986; deaths did not occur in the patients with digitalis toxicity. Digitalis toxicity would be reduced even further or could possibly be eliminated by attention to clinical situations of increased bioavailability, increased sensitivity for digitalis toxicity, and awareness of digitalis toxicCurr Probl Cardiol, December 1996

837

TABLE 18, Calculation of the optimal dose of digoxin-specific antibody fragments

Step 1"

Determine the total body load (TBL) of digitalis by using dose ingested: TBL (mg) x F, an absorption variability constant, where F = 0.8 for digoxin tablets and 1.0 for capsules, elixir, or digitoxin Digoxin serum level: TBL (mg) = serum level (ng/ml) x volume of distribution (5.6 L/kg for digoxin x weight [kg]) x 1 / 1 0 0 0 :

Step 2:

Determine equimolar dose of digoxin-specific antibody fragments by using FAB dose (no. of vials) =TBL (mg)/O.6 mg FAB per vial

From Hickey AR et al. J Am Coil Cardiol 1991;17:590-8. Reproduced by permission.

ity, as well as by judicious determinations of digoxin blood levels (see Value of Blood Levels). Increased bioavailability increases the potential for digitalis toxicity. Factors associated with increased sensitivity for digitalis intoxication are listed in Table 12. Circumstances in which digitalis toxicity should be suspected are listed in Table 13. Value of digoxin blood levels is discussed later in this chapter.

Clinical Manifestations The major manifestations of digitalis intoxication include gastrointestinal and central nervous system symptoms and disturbance of cardiac rhythm. The clinical manifestations include: 1. Gastrointestinal symptoms. Anorexia is often an early manifestation of digitalis toxicity. 123 Nausea and vomiting occur as a result of central nervous system mechanisms. 125These symptoms may be caused also by cardiac failure or by associated illnesses and thus in clinical practice are often difficult to attribute solely to digitalis toxicity. 2. Neurologic symptoms. These manifest as headache, fatigue, malaise, neurologic pain, disorientation, confusion, delirium, and seizures. Visual symptoms such as scotomas, flickering, halos, and changes in color perception are also common.lZl,123As with gastrointestinal symptoms, it is often difficult in clinical practice to determine whether this is a consequence of digitalis toxicity or of associated illnesses. The frequency of various symptoms caused by digitalis toxicity in the 1980s is shown in Table 14. 3. Cardiac rhythm disturbances. Digitalis is usually said to be known to induce nearly every known arrhythmia. These include atrioventricular junctional tachycardia, unifocal or multifocal ectopic ventricular beats 838

Curr Probl Cardiol, December 1996

TABLE 19. Circumstances in which estimating digoxin blood levels is useful Digoxin toxicity is suspected Clinical response to therapy is less than optimal In those with increased sensitivity to digitalis toxicity During pregnancy Concomitant use of drugs that increase or decrease digoxin blood levels Presence of conditions/disorders that alter drug absorption, distribution, or elimination

TABLE 20. Advantages of digitalis therapy in heart fai!ure Stood test of time (in use 220 years) Given orally, once daily Easily tolerated Side effects infrequent Has multiple actions: all mild or moderate (see Table 1) Has multiple beneficial clinical effects (see Table 7) Is inexpensive Reduces costs of treating heart failure

and ventricular tachycardia, and sinoatrial and A-V b l o c k 126'127 (Table 15). Ectopic impulse formation can result either from the ability of digoxin to potentiate phase 4 depolarization (an effect that occurs more readily at low serum potassium levels) or from the development of delayed afterdepolarization.128,129 Ectopic impulse formation can occur in the atria, particularly at high serum concentrations, in His-Purkinje tissue, or in the ventricles. The most c o m m o n manifestation of digitalis toxicity is an increase in the frequency of ventricular premature depolarizations of any structure, with either fixed or varying coupling Intervals to preceding supraventricular depolarizations.123 Bidirectional and fascicular tachycardias may occur and are very suggestive of digitalis toxicity. Ventricular fibrillation is rarely the first electrophysiologic manifestation of digitalis toxicity. The probability of digoxin-induced arrhythmias at various toxic concentrations is shown in Table 8. Although no one electrocardiographic abnormality is pathognomonic of digoxin toxicity, the combination of enhanced automaticity and impaired conduction (e.g., AV block accompanied by an accelerated junctional pacemaker) is highly suggestive of toxicity even in patients with serum levels of 1 to 2 ng/ml. The frequency of different arrhythmias caused by digitalis toxicity in the 1980s is shown in Table 16. 4. Other. Allergic skin reactions are rare but have been reported. 13° GyCurr Probl Cardiol, December 1996

839

necomastia is occasionally induced in men 131 and sexual dysfunction has been reported. 132 [] G.A. Belier: Ventricular bigeminy is a characteristic toxic arrhythmia in patients with chronic heart disease and digitalis excess. We showed that ventricular bigeminy or trigeminy and atrioventricular junctional escape rhythm were the most common rhythm disturbances seen in 34 "definitely toxic" patients as evaluated in a prospective study of digitalis intoxication (Belier GA, et al. Digitalis intoxJcation: a prospective clinical study with serum level correlations. N Engl J Med 1971;284:989-97).

[]

Treatment Successful treatment of digitalis toxicity is enhanced by early recognition and appropriate treatment. Early treatment of the mild and the more common manifestations of digitalis toxicity requires temporary discontinuation of the drug. Hypokalemia, if present, is treated with administration of K ÷ (Table 17). Ectopic arrhythmias may need treatment with phenytoin or lidocaine? ° Occasionally ~-adrenergic blockers may be needed; it is wise initially to use one with a short duration of action (e.g., esmolol). Directcurrent countershock should be avoided if at all possible; if it becomes necessary for a life-threatening arrhythmia that has not responded to other therapy, lower energy levels should be employed. 8° Reversal of Toxicity with Specific Antibody. The development of digoxin antibodies in the late 1960s was a major therapeutic advance in the treatment of digitalis toxicity.S°'133-135A large multicenter study with digoxin-specific antibody (Fab) fragments to treat life-threatening intoxication enrolled patients from 21 medical centers over a 10-year period. 136The investigators found that 80% of patients given Fab for life-threatening digoxin-induced arrhythmias or hyperkalemia had complete resolution of all signs and symptoms of digitalis toxicity. Clinical improvement occurred within 1 hour of completion of Fab fragment infusion in the majority of patients who derived benefit from therapy. About 10% of patients did not improve with Fab; the majority were thought either to have had something other than digitalis toxicity or to have been already moribund at the time therapy was initiated. Use of digoxin-specific antibody fragments should be guided by clinical evaluation. It is clearly indicated in those with advanced or potentially lifethreatening digitalis toxicity. 8°Marked hyperkalemia as a result of digitalis 840

Curr Probl Cardiol, December 1996

excess is strong indication for the use of Fab. 8°Its use should be considered seriously also in those in whom excretion of digitalis is impaired. Digoxinspecific antibody fragments probably should not be used routinely for less threatening symptoms of digitalis intoxication including anorexia, nausea, vomiting, or visual disturbances .80However, clinical judgment is important, and specific antibody fragments may be needed in moderately to severely ill patients and in those with increased sensitivity to digitalis toxicity. Patientrelated factors that should be taken into account in all instances include age, serum electrolyte levels, renal function, underlying cardiac, pulmonary, or thyroid disease, and concomitant drug therapy. It must be emphasized that antidigoxin Fab fragments will also reverse the inotropic and antiarrhythmic effects of digoxin 8° and transiently will increase serum digoxin blood levels. Digitalis therapy can be restarted several days after use of Fab fragments if indicated. The dosage of digoxin-specific antibody fragments is based on the total body stores of digoxin (or digitoxin), which can be estimated by using either the ingested dose or the serum level of digoxin. The serum concentration will be a reliable estimate of total body digoxin load only if measured at least 6 hours after ingestion (i.e., after the distribution phase); plasma levels from before then will overestimate total body stores. Determination of the appropriate dose of Fab is performed in a step-wise manner (Table 18). The recommended dose of Fab in cases in which the amount ingested or the serum concentration or both is not known is 12 mg (20 vials). 136 Adverse responses to digoxin-specific antibody fragments are uncommon. However, in one multicenter study involving its use in 150 patients, adverse effects were reported in 10% of patients and included, in order of decreasing frequency, marked hypokalemia, exacerbation of symptoms of congestive heart failure (presumably caused by the abrupt loss of the beneficial effects of digitalis), and mild hypotension. 137

Value of Digoxin Blood Levels The availability of assays to measure serum digoxin levels has led to a better understanding of the relation between the plasma concentration of the drug and its therapeutic/toxic levels. It is often stated that there is a narrow margin between the therapeutic and toxic digoxin levels; however, this is not correct. Toxicity was quite uncommon in clinical practice in the 1980s (see Digitalis Toxicity). Judicious use of digitalis in appropriate doses (Tables 8 through 10), early suspicion of toxicity (Table 13), and determining digoxin blood levels (vide infra) will reduce the incidence of toxicity to even lower levels. For everyday clinical practice, the therapeutic range is from a favorable Curr Probl Cardiol, December 1996

841

clinical effect of the drug to just short of toxicity; digoxin blood levels in these circumstances usually range from _>0.8 ng/ml to _<1.9 ng/ml (1 ng/ml = 1.28 nmol/L). The graph of Lewis 138 (Fig. 31) suggests that the "best," that is, most therapeutic benefit with the lowest incidence of toxicity may be in the range of serum digoxin level of 1.0 to 1.5 ng/ml. Three studies 58'61'69demonstrated that patients had significant clinical and other benefits; in these studies, digoxin doses were higher than is routinely clinically employed, and serum digoxin levels were >1.0 ng/ml. 58,61,69 In the PROVED trial, 78 the serum digoxin level was 1.2 _+0.05 ng/ml, and in the RADIANCE trial, 79 the serum digoxin level was 1.2 _+0.03 ng/ml. In both trials, the average digoxin dose was 0.375 mg/day. Gheorghiade et al. 138a recently showed that for patients in heart failure, increasing the digoxin dose from 0.25 mg to 0.375 mg/day resulted in increasing the digoxin blood levels to >1.0 ng/ml but <1.5 ng/ml led to a further increase of left ventricular ejection fraction and further reduction of the elevated neurohormones. In those with very mild heart failure or asymptomatic left ventricular dysfunction, for prophylaxis against recurrent supraventricular tachyarrhythmias and for control of ventricular rate in atrial fibrillation, particularly in those in whom the ventricular rate is not very rapid before initiation of drug therapy (e.g., in the elderly), digoxin blood levels of 0.7 to 1.0 ng/ml may be clinically adequate. In clinical practice, blood digoxin level should be maintained at <1.5 ng/ml; however, it is probably clinically prudent to keep the digoxin blood level at about 1.0 ng/ml, with a range of 0.8 to 1.2 ng/ml. Use of ACE inhibitors increases elimination of digoxin, and thus, patients may need a higher dose of digoxin to obtain the same blood level and clinical benefit. In clinical practice, estimating serum digoxin levels is helpful in several clinical circumstances (Table 19): • When digoxin toxicity is suspected (Table 13); • When clinical response to therapy is less than optimal; • In those with increased sensitivity to digitalis toxicity (Table 12); • During pregnancy; • With concomitant use of drugs that increase or decrease digoxin blood levels (Table 11); and • In the presence of conditions/disorders that alter drug absorption or increase distribution or elimination (see Interactions with Digitalis Glycosides).

Overview The advantages of using digitalis therapy are summarized in Table 20. Digitalis is not merely a mild inotropic agent (Table 1). In clinical deci842

Curr Probl Cardiol, December 1996

sion making, the recommendation for use of digitalis can be judged by considering the following factors, which have been described in detail earlier (Clinical Studies): • In most studies, the addition of digitalis to diuretic or the discontinuation of digitalis from combined digitalis plus diuretic showed that diuretics as a single agent was inferior to a combination of digitalis and diuretic therapy. In most of these studies, placebo or baseline was diuretic(s) as single-drug therapy. • ACE-inhibitor therapy is not satisfactory as single-drug therapy even for the treatment of mild heart failure. 139 • Digitalis as single drug for heart failure has not been carefully evaluated. Such therapy is very unlikely to be able to control the salt and water retention associated with heart failure. • The combination of digitalis and diuretic was shown to be better than or as good as ACE-inhibitor and diuretic therapy in several studies. • The combined use of digitalis and ACE inhibitor has additive effects. • Triple therapy (digitalis, diuretic, and ACE inhibitor) was superior to either combinedACE inhibitor/diuretic therapy or combined digitalis/ diuretic therapy. 79,84.14° • Digitalis has multiple actions (Table 1) and multiple beneficial clinical effects (Table 7). Thus patients in heart failure (NYHAFC II, III, and IV) should receive digitalis therapy, that is, they should be treated with digitalis, diuretic, and ACE inhibitor unless there is a contraindication to their use. It must be emphasized that the improvement in survival with ACE inhibitor in patients with N Y H A F C II, III, and IV has been demonstrated only when ACE inhibitor was added to digitalis and diuretic therapy. 79,84A4°Patients in heart failure after myocardial infarction are benefited by ACE-inhibitor therapy.141 Patients in heart failure after myocardial infarction should also receive digitalis therapy; in fact, they should receive digita!is, diuretic, and ACE inhibitor unless there is a contraindication to their use. More recently carvedilol, a nonselective 13-receptor antagonist that also blocks al-receptors and exerts antioxidant effects, was shown to be of benefit (reduce mortality) when added to digitalis, diuretics, and ACE-inhibitor therapy. 142However, this particular trial has been critiqued with regard to an improvement in survival 143because • It combines the data of four studies of efficacy and safety; • There were a small number of deaths; • The trial had a run-in period during which patients died but were not included in the analysis, and others were not randomized because of worsening of heart failure during this period; and Curr Probl Cardiol, December 1996

843

• There were few patients with severe heart failure. Moreover, there were several subgroups of patients in whom the benefit was not statistically significant. Thus we must await the results of other 13blocker trials 143before we are able to accurately define the role of ~-blockers in the treatment of patients with heart failure for improving survival. Patients who are asymptomatic but have significant left ventricular systolic dysfunction (for example, reduced left ventricular ejection fraction of <0.40) are benefited with use of ACE-inhibitor therapySS; however, in the SOLVD Prevention Trial, 85 33% of patients were in NYHAFC II. Patients after myocardial infarction are benefited with ACE-inhibitor therapy. 86,144-146 Most patients after myocardial infarction have left ventricular systolic dysfunction.92-94In most patients with coronary artery disease who have irreversible left ventricular systolic dysfunction, the dysfunction is the result of previous myocardial necrosis. Digitalis produces a rapid and profound attenuation of sympathetic nerve activity even before the hemodynamic effects are observed; that is, there may be a dissociation between the neuroendocrine and hemodynamic effects (see Vasodilatation [p. 793] and Baroreflex action [p.796]). Thus digitalis can be expected to be of benefit in patients with left ventricular dysfunction even in the absence of a potential hemodynamic benefit. Actually, digitalis improTes left ventricular systolic dysfunction even in those who were asymptomatic after myocardial i n f a r c t i o n 95'96 (see Digitalis in Acute Myocardial Infarction, p. 829) and improves left ventricular function even in those with normal left ventricular size and function (seeActions of Cardiac Glycosides, p.787). Moreover, digitalis has multiple actions (Table 1) and multiple clinical benefits (Table 7). For all of these reasons, it would be expected to be of benefit in asymptomatic patients with significant left ventricular systolic dysfunction, and these patients should receive combined digitalis and ACE-inhibitor therapy.

Addendum A recent study (McMahon WS, et al. J A m Coll Cardiol 1996;28:495505) examined the cellular basis for improved LV pump function with digoxin in pacing-induced experimental LV failure. Digoxin treatment improved LV pump function, enhanced isolated myocyte contractile performance, and normalized myocyte action potential characteristics.

D. McCall: Drs. Rahimtoola and Tak have provided the readers of Current Problems in Cardiology with an outstanding review of the use of digitalis in patients with congestive heart failure. The authors make a strong case, based on a carefully referenced review of all available literature, for the continued use of these 844

Curr Probl Cardiol, December 1996

drugs in this increasingly more common clinical syndrome. This monograph carefully details the indications for the use of digitalis in heart failure and the clinical benefits of its administration, together with clear descriptions of appropriate dosing schedules. As such, this issue will prove invaluable to Cardiologists, Internists, and House Officers alike. In addition, the monograph is so clearly written that it should be recommended to medical students interested in the area of heart failure. The careful and detailed annotation of this monograph, in addition, make it an invaluable reference source on this important and interesting topic.

G.A. Belier: Drs. Rahimtoola and Tak have written a superb and timely review of the use of digoxin in the 1990s for patients with congestive heart failure. They provide convincing evidence from a review of the literature for the beneficial clinical and hemodynamic effects of oral digoxin therapy in patients with heart failure. Several clinical trials have shown that withdrawal of digoxin results in deterioration of clinical status. Digoxin should always be used with caution and with knowledge of the risk factors associated with cardiac toxicity (renal dysfunction, hypokalemia, hypomagnesemia, hypothyroidism, severe pulmonary disease, etc.). The drug should not be administered to patients with heart failure, left ventricular hypertrophy and an ejection fraction of >45% unless for control of the ventricular response to atrial fibrillation. Furthermore, digoxin is rarely necessary for first-line treatment of acute heart failure in patients with an acute myocardial infarction. Further research is warranted to identify those risk variables that may be associated with potentially lethal arrhythmias in patients receiving maintenance digoxin and whose serum digoxin levels are in the normal therapeutic range.

References 1. Rahimtoola SH. Digitalis andWilliamWithefing:the clinical investigator [editorial]. Circulation 1975;52:969-71. 2. Withering W. An account of the foxglove, and some of its medical uses. London: GGJ and J Robinson, 1785. (Special Edition Copyright 1979, Classics of Medicine Library, Division of Gryphon Editions, Ltd., Birmingham, AL). 3. Smith TW. Digitalis: mechanisms of action and clinical use. N Engl J Med 1988;381:358-65. 4. Smith TW, Braunwald E, Kelly RA. The management of heart failure_ In: Braunwald E, editor. Heart disease: a textbook of cardiovascular medicine. 4th ed. Philadelphia: Saunders, 1992:464-519. 5. Wiggers CJ, Stimson B. Studies on cardiodynamic action of drugs. III. The mechanism of cardiac stimulation by digitalis and g-strophanthin. J Pharmacol Exp Ther 1927;30:251-69. 6. Cattell M, Gold H. The influence of digitalis glycosides on the force of contraction of mammalian cardiac muscle. J Pharmaco] Exp Ther 1938;62:116-25. 7. Sonnenblick EH, Williams JF Jr, Glick G, Mason DT, Braunwald E. Studies on digitalis. XV. Effects of cardiac glycosides on myocardial force-velocity relations in the nonfailing human heart. Circulation 1966;34:532-9. Curr Probl Cardiol, December 1996

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