Digoxin Eric J. Eichhorn and Mihai Gheorghiade After 200 years of use, digitalis still appears to have a place in our armamentarium for heart failure and atrial fibrillation despite the proven survival benefits with ACE inhibitors and g-blockers. Digoxin ther- apy is inexpensive and well tolerated and may result in considerable savings. Digoxin is the only oral inotrope that does not increase mortality in heart failure patients, particularly if low doses are being used. Digoxin therapy should be used in patients with systolic heart failure who continue to have signs and symptoms despite therapeutic doses of ACE inhibitors or diuretics or in patients with atrial fibrillation with or without heart failure for rate control. Copyright 2002, Elsevier Science (USA). All rights reserved. ince 1785 when Sir William Withering pub- lished his treatise on the use of the foxglove,! physicians have used digitalis preparations to treat edematous states and chronic heart failure. Digitalis preparations have been used, perhaps for as much as a millennium, to teat medical condi- tions including dropsy.2? According to the writ- ings of Withering, digitalis was believed to slow heart rate, particularly in patients with an irregu- lar pulse, and increase diuresis.” It has only been. in the early 20th century that digitalis prepara- tions were considered useful in patients with heart failure and sinus rhythm2+ Beginning with 1927, many studies in animals and humans demonstrated the positive inotropic properties of digitalis in normal as well as failing myocardium.*"? However, in the 1970s and 1980s, several studies, many of which did not assess left ventricular function, failed to show clinical benefit or improved exercise tolerance with digoxin.247 This lack of clinical benefit combined with a high incidence of digoxin intox- ication?4829 brought its utility into question. ‘As newer therapies emerged in the 1980s such as vasodilators, angiotensin-converting enzyme ‘Progress in Cardiovascular Diseases, Vol. 44, No. 4, (January/February) 2002; pp 251-266 (ACE) inhibitors, and newer inotropic agents, the interest in digoxin and its utility faded into the background temporarily.*! ‘There was renewed interest in digoxin in the late 1980s when therapies with newer inotropes and vasodilators (except for hydralazine-isosor- bide dinitrate combination) were shown to worsen survival.2? In the late 1980s and early 1990s, several ran- domized placebo-controlled trials demonstrated the utility of digoxin in patients with chronic heart failure and sinus rhythm.??*° In 1997, a large digoxin mortality trial demonstrated no ef- fect of digoxin on all-cause mortality and a de- crease in hospitalizations for heart failure.>" These recent trials?”28.1 form the basis for the recent approval of digoxin by the US Food and Drug Administration under current regulations for the treatment of heart failure. Digoxin remains one of the most commonly prescribed drugs. Effects of Digoxin (Table 1) Mechanism of Action The primary mechanism of action of digoxin is its ability to inhibit membrane-bound alpha subunits of sodium-potassium ATPase2*> and thereby promote sodium-calcium exchange, which in- creases intracellular calcium concentration that is From the Cardiac Catheterization Laboratory and De- partment of Intamal Medicine (Division of Cardiology), Dalas Veterans Administration Hospital and University of ‘Texas Southwestem Medical Center, Dallas, TX: and ‘Northwestern University Medical School, Chicago, ILL. ‘Address requests for reprints to Mihai Gheorghiade, MD, Northwastern University Medical School, 201 East Huron St, Galter 10-240, Chicago, IL 60611; e-mail, ‘m-gheorghiade@northwostern.edu ‘Copyright 2002, Elsevier Science (USA). Al rights reserved. (0039-0820/02/4404-0001835.000 251252 EICHHORN AND GHEORGHIADE Table 1. Effects of Digitalis in Systolic Heart Failure at Therapeutic Concentrations Hemodynamic effects Increase CO and decrease PCWP and systemic vascular resistance At rest During exercise Alone or in combination with ACE inhibitors or systemic vasodilators During chronic therapy Increase left ventricular ejection traction Neurohormonal effects: \Vagomimetic action Improves baroreceptor sensitivity Decreases norepinephrine serum concentration Decreases activation of renin-angiotensin system May directly increase aldosterone release Directs sympathoinhibitory effect ‘At high doses increases sympathetic CNS outflow Decreases cytokine concentrations Increases release ANP and BNP Electrophysiologic effects: 'S-A node: decreases automaticity’; severe sinoatrial block in patients with sinus node disease ‘Atrium: no effact or decreases refractory period ‘AV node: decreases conduction velocity; increases effective refractory period; advanced heart block in patients with AV node disease; increases antegrade conduction in accessory AV pathways Ventricle: no effect; at higher doses or during ischemia “Cholinergic and antiadrenergic effects. ‘Abbreviations: CO, cardiac outpt BNP, brain natriuretic peptide; AV, atrioventricular. available to the contractile proteins. This results in the increase in the force of myocardial contrac- tion, Both inotropic and arrhythmogenic effects of digoxin are related to its effects on the sodium pump. The inhibition of the sodium pump may also improve baroreceptor sensitivity in the heart failure model and explain some of the neuroendo- crine effects of digitalis preparation. Hasenfuss et aP> showed that in dogs the positive inotropic effects of cardiac glycosides is obtained with little oxygen wasting, suggesting that digoxin is a met- abolically efficient drug. Hemodynamic Effects Digitalis preparations do not alter cardiac output in normal control subjects.»*>* This effect is likely ow- ing to an increase in systemic vascular resistance in normal subjects produced by digitalis that prevents the increase in contractility from translating into in- creased cardiac performance." In patients with systolic-heart failure and sinus rhythm, it improves left ventricular ejection fraction222+* and reduces pulmonary capillary wedge pressure while increas- ing cardiac output both at rest and during exercise ‘The combination of digoxin with an ACE inhibitor PCWP, pulmonary capillary wedge pressure; ANP, atrial natriuretic polypeptide; or a systemic vasodilator results in an improvement in cardiac performance greater than that resulting from the administration of either agents alone.‘ Because during chronic heart failure-therapy there is no up-regulation of digitalis-binding sodium-potas- sium ATPase sites,¢7* the improvements in hemo- dynamics are sustained.'°2 In heart failure when hemodynamics are normalized with vasodilators and diuretic therapy, no further improvement is achieved after the acute administration of digoxin.*® Neuroendocrine Effects Systolic heart failure results in activation of com- pensatory neurohormonal systems (renin-an giotensin system, adrenergic nervous system, vasopressin, cytokines, endothelins).°° Neuro- hormonal activation results in short-term hemo- dynamic effects (vasoconstriction, positive ino- tropy, positive chronotropy, and salt and water retention) but may have long-term deleterious ological effects (pathological growth and remod- cling, cell death, phenotypical alterations).%° The way we currently view heart failure chronic treat- ment is not to stimulate the dysfunctional pump with pharmacological manipulations (inotropes,DIGOXIN IN CHF vasodilators) but rather to decrease or remove the stimuli for progressive pump dysfunction, the of- fending neurohormones. This strategy has proved beneficial with both ACE inhibitors and B-block- ers, which have been shown to improve symptoms and survival 2151 Digoxin preparations modulate the neurohor- monal abnormalities noted in heart failure, and this may account for its long-term beneficial ef- fects. In the low-output heart failure model, there is attenuation of the carotid sinus baroreceptor discharge sensitivity.>> This may be the result of augmentation of sodium-potassium ATPase pump activity. Digitalis restores baroreceptor sensitivity most likely by decreasing the sodium pump activity.*°4 This improvement in barore- ceptor function may result in decreased activa- tion of the sympathetic nervous system, By reducing sympathetic activity, digoxin may in- directly reduce plasma renin and vasopressin release.*° In patients with heart failure, digoxin increases heart rate variability, °°°° an index of baroreflex activity, and decreases serum norepi- nephrine concentrations and plasma renin ac- tivity.26253° A low dose of digoxin that has no effect on cardiac contractility or hemodynamics decreases cardiac norepinephrine spillover in patients with severe heart failure.®* Digitalis also has a direct sympathoinhibitory effect.2 However, at higher doses or during ischemia, digitalis may cause adrenergic stimulation. Digitalis has been shown to have parasympatho- mimetic properties related to stimulation of the central vagal nucleus and sensitization of car- diac tissues to the effects of exogenous acetyl- choline.’ It recently has been shown that digi- talis reduces tumor necrosis alpha factor ¢ production and increases ANP and BNP re- Tease.*? 253 The improvement in the hemodynamic and neurohormonal profile in heart failure in re- sponse to digoxin may be related to its effects on the sodium pump. It is not clear whether the beneficial effect of digoxin seen in patients with systolic heart failure is related to its hemo- dynamic effects, neurohormonal effects, or both. However, the rapidity with which patients deteriorate when digoxin is discontinued sug- gests that its hemodynamic effects are impor- tant, particularly for relatively short-term ther- apy.*728 This immediate hemodynamic benefit is not seen with ACE inhibitors or B-blocker therapy. Electrophysiological Effects The electrophysiological effects of digoxin are re- lated to inhibition of the sodium pump and its effect on autonomic nervous system.'® Adminis- tration of nontoxic doses of digitalis causes slow- ing of sinus rate mostly in heart failure. Digitalis has a predominant parasympathomimetic action, on atrial myocardium, and it slows conduction and prolongs atrioventricular (AV) node refracto- riness.1® There are practically no electrophysio- logical effects in Purkinje fibers and ventricular muscle.!* Toxic doses predispose atrial fibers to auto- ‘matic impulse initiation that does not depend on the autonomic nervous system, high-grade AV block that is cholinergically mediated, and an in- ‘crease in rate of spontaneous diastolic repolariza- tion leading to the occurrence of rapid spontane- ‘ous rhythms of Purkinje fibers.2® Although it is clear that digitalis intoxication may produce lethal ventricular arrhythmias 162° therapeutic doses of digoxin do not appear to in- crease arrhythmias in the absence of isch- emia.2258 Table 2. Comparisons of the Systemic Availability and Equivalent Doses for Oral Preparations of Digoxin Product Absolute Bioavailability Equivalent Doses (ua) Among Dosage Forms Digoxin tablets 60-80% 62.5 125 250 ‘500 Digoxin elixir pediatric 70-85% 625 125 250 500 Digoxin CAPS 90-100% 50 100 200 400 Digoxin injection/1V 100% 50 100 200 400 ‘Adapted from Physicians’ Desk Reference (ed 53), 1999, page 1160.254 Table 3. Times to Onset of Pharmacological Effect and to Peak Effect of Preparations of Digoxin Time to Onset Time to Peak Product of Effect” Effect Digoxin tablets o5-2h 26h Digoxin elixir pediatric 0.5-2 h 26h Digoxin caps 05-2h 26h Digoxin injection/V 5-30 min 4h “Documented for vontricular response rate in aria brilafion, inatople “effets, and’ electrocardlographic Aadpted trom Physi om 1908, page 1760 18' Desk Reference (ed 53), Pharmacokinetics (Tables 2 and 3) The half-life of digoxin elimination is 36 to 48 hours in patients with normal renal function, The half-life in anuric patients is 3.5 to 5 days Digoxin is not removed by peritoneal or hemodi- alysis or during cardiopulmonary bypass. When the therapy starts with a maintenance dose (oral and intravenous loading is rarely indicated), a steady-state blood concentration is achieved in EICHHORN AND GHEORGHIADE approximately 7 days in a patient with normal renal function. Rapid intravenous loading can cause vasoconstriction.©* Clinical Effects Chronic Systolic Heart Failure The majority of double-blind trials examining the effect of digoxin in patients with systolic heart failure and sinus rhythm have noted an improve- ment in clinical status (Table 4.2229 In the Cap- topril-Digoxin Multicenter trial,2? 300 patients with mild 10 moderate heart failure who were re- ceiving a diuretic were randomized to captopril, digoxin, or placebo. Digoxin reduced the inci- dence of hospitalization and emergency room vis- its for heart failure and improved left ventricular ejection fraction. However, digoxin did not im- prove exercise tolerance. In the Milrinone Multicenter Trial, 230 pa- tients receiving diuretics and digoxin were ran- domized to milrinone, digoxin, the combination, or placebo. Digoxin therapy improved ejection Table 4. Double- With Heart Failure , Randomized, Placebo-Controlled Studies of Digoxin in Patients Concomitant Therapy ‘Worsening Mortality Digoxin oo OF HESS (%) Study Duration No.of FC Concentration ———— Reference Design (wooks) Patients (NYHA) EF (%) (ng/ml) DV 1&7 Og P Oy P Dossseta e777 —= in patients with mild heart failure, digoxin increased exercise time and reduced the plasma norepinephrine concentra- tions and renin activity at 6 months of therapy. The Prospective Randomized Study of Ven- ticular Failure and the Efficacy of Digoxin (PROVED)** and the Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE) trials ex- amined the effects of digoxin withdrawal in pa- tients with stable heart failure. The two trial designs were similar except that the RADIANCE trial included ACE inhibitors and diuretics as, background therapy, whereas in the PROVED trial, patients were receiving only diuretics. Af- ter a stabilization period, the patients were ran- domized to continuing digoxin or placebo for 12 weeks. Patients continuing digoxin main- tained their exercise ability, whereas patients randomized to placebo (and thus withdrawn from digoxin) but continuing on ACE inhibi- tors and diuretics (RADIANCE) or diuretics alone (PROVED) had a deterioration in their exercise tolerance. In both trials, when digoxin was discontinued, there was an increase in worsening heart failure, heart rate, body weight, and a decrease in ejection fraction, (Table 5). In the RADIANCE trial, the patients withdrawn from digoxin had a sixfold increase in worsening of heart failure as evidenced by heart failure— related hospitalizations, emergency care visits, or the need for concomitant heart failure ther- apy. This occurred despite patients being main- tained on therapeutic doses of diuretics and ACE inhibitors. When PROVED and RADI- ANCE data are examined together, it appears that the lowest rate of deterioration of less than 5% was observed in patients receiving digoxin, diuretics, and ACE inhibitors and the highest in patients receiving diuretics alone (39%). In pa- tients receiving diuretics and ACE inhibitors or diuretics and digoxin, the rate was 25% and 19%, respectively (Fig. 1).° Digitalis Investigation Group (DIG) Trial The DIG tial?! was the first large trial in which the ‘main objective was to assess all-cause mortality in patients with heart failure and sinus rhythm, Im- portantly, this was not a withdrawal trial because more than 50% were not digoxin users before the study. There were 7,788 patients randomized to a mean dose of 0.25 mg of digoxin or placebo with a background therapy of ACE inhibitors and diuret- ics. Of these patients, 988 had a left ventricular ejection fraction greater than 45%. A majority of,256 o=46) |MeceborDnrete & ACE O83) Digedwbturte vez) Be 8 Probability of ‘Treatment Fallure bigot & ACE (288) 90 30 60 Days of Followup Fig 1. Probability of treatment failure in patients re- ceiving diuretics, diuretics and ACE inhibitors, digoxin ‘and diuretics, and triple therapy with digoxin, diuretics and an ACE inhibitor.® patients were NYHA class Il and III, and approxi- mately 70% had coronary artery disease. Mortality. In the patients with reduced systolic function (6,800 patients) at 37 months of follow-up, all- cause mortality was 35% with no difference be- tween placebo and digoxin groups (Fig 2). The cardiovascular mortality was 30% for both groups. There was a reduction in death or hospitalization owing to worsening heart failure in the digoxin gtoup (P< .001) (Fig 3). A reduction in death caused by pump failure was offset by an increase in deaths for other causes that included deaths presumed to result from arrhythmias. Hospitalizations: There was a 25% reduction in numbers of hospi- talizations for worsening heart failure in the erat tom Any Cae) & Fig 2. All-cause mortality in the digoxin and placebo groups." EICHHORN AND GHEORGHIADE Fig 3. Death of hospitalization caused by worsening heart failure in the digoxin and the placebo group.*! digoxin group (910 v 1,180 patients). Digoxin was associated with a 28% reduction in the risk of a patient having at least one hospitalization and 6.5% reduction in total hospitalizations. Total hospitalizations were decreased, particularly in the patients with a very low ejection fraction (525%), with increased cardiothoracic ratio on. chest radiograph, or in functional class 111 or IV (Table 6). The results of the DIG study are con- sistent with the results of the PROVED and RADIANCE study and other studies regarding digoxin’s ability to reduce heart failure hospital- ization 22272800 Therapy for Worsening Heart Failure. In the DIG study as seen in other studies,?728°° there was also a reduction in need for increasing or adding new therapies for worsening heart fail- ure in the digoxin group. A higher proportion of patients had to be switched to open-label digoxin in the placebo group for worsening heart failure The DIG trial showed that digoxin hasa neutral effect on mortality and a decrease in the rate of worsening heart failure in patients already receiv- ing diuretics and ACE inhibitors. These benefits were seen in patients withdrawn from digoxin and patients receiving digoxin for the first time. Atrial Fibrillation Chronic atrial fibrillation is a common arrhythmia that can occur in patients with or without heart failure. Digoxin has been shown to slow the rest- ing ventricular rate in most patients with atrialDIGOXIN IN CHF 257 ‘Table 6. Subgroup Analyses of Mortality and Hospitalization During the First 2 Years After Randomization Risk of AllCause Mortality or All-Cause Risk of HF-Related Mortality or Hospitalization HF-Related Hospitalization” Variable A Placebo Digoxin Relative Risk Placebo Digoxin Relative Riskt Al patients (EF = 0.45) 6,801 604 593 0.94 (0.88-1.00) 204 27 (0.69 (0.63-0.76) NYHA W/L 4671 548 541 0.96 (0.88-1.04) 242 178 0.70 (0.62-0.80) EF 0.25-0.45 4\543 568 sn 0.99(0.91-1.07) 244 190 0.74 (0.66-0.84) CTR = 0.55 4455 561 569 0,98 (0.91-1.06) 239 180 0.71 (0.63-0.81) NYHA tIVIV 2.224 719 696 0.88 (0.80-0.97) 402 295 0.65 (0.57-0.75) EF <025 2.258 677 637 0.84 (0.76-0.93) 394 270 0.61 (0.53-0.71) CTR > 055 2.946 687 650 0.85 (077-094) 308 287 0.65 (0.57-0.75) EF > 0.45¢ ‘987871 585 1.04 (0.88-1.23) 179 136 0.72 (0.53-0.99) ‘Adapted from Physicians’ Desk Reference (ed 53), 1999, page 1161, “Number of {Relative risk (8596 confidence interval. 401G Ancilary Study. with an event during the first 2 years per 1000 randomized patients. ‘Abbreviations: HF, heart failure; EF, ejection fraction; CTR, cardiothoracic ratio. fibrillation.*7® Because it canbe taken once a day, is well tolerated, is inexpensive, and allows for measurement of plasma concentration if intoxica- tion is suspected, it remains an important drug for rate control in atrial fibrillation®; however, dur- ing exercise and in patients with increased sym- pathetic activity, digoxin alone does not control ventricular response unless large doses that are likely to produce intoxication are used,*7® Al- though B-blockers and non-dihydropyridine cal- cium channel blockers have been advocated alone to control rate, usually the doses used have been large, causing significant side effects, particularly in patients with systolic heart failure.® It is prob- ably prudent to recommend that in atrial fibrilla- tion with a rapid ventricular response, digoxin should be combined with B-blockers. Non-diby- dropyridines such as diltiazem or verapamil may also be used in patients with preserved systolic function. Digoxin does not appear to restore sinus rhythm in patients with atrial fibrillation without heart failure.7° Once a patient is converted to si- nus rhythm, digoxin therapy may not be neces- sary unless the patient has systolic heart failure. Digoxin Serum Concentration The development of the radioimmuno-assay (RIA) for digoxin by Dr. Thomas Smith and co- workers in 1969 was a landmark in digitalis ther- apy.°7! Radioimmuno-assay cross-reacts with digitalis-like immuno-reactive substances that may be present in renal failure, hepatic failure, pregnancy, and hypertensive states.”! Specimens for serum digoxin concentrations should be col- lected in the postdistribution period (at least 8 hours after the last dose) preferably immediately before the next dose. In the DIG trial, the use of a nomogram (Table 7) resulted in a serum digoxin concentration of approximately 1 ng/mL. Serum concentrations should be obtained only under special conditions (Table 8). Digoxin intoxication is a clinical and not a serum concentration diag- nosis because significant overlap in serum con- centrations of digoxin exists between patients who are intoxicated versus the ones whoare not." Digoxin Intoxication Digoxin intoxication (Table 9) usually occurs at doses that are higher than those needed to achieve a therapeutic effect.'#2°42 The incidence of digoxin intoxication increases in situations where digoxin excretion by the kidneys is impeded. This is most often seen in elderly and heart failure patients who have poor renal perfusion due to reduced stroke volume.'® The serum concentra- tion of digoxin is not only dependent on the dose administered but is also related to concurrent medications (Table 10) and conditions (Table 1D. The incidence and severity of digoxin intoxica- tion has decreased substantially in recent years.72 In the DIG trial, the incidence of hospitalization258 EICHHORN AND GHEORGHIADE Table 7. Usual Daily Maintenance Oral Dose Requirements (cg) of Digoxin for Eatimated Peak Body Stores of 10 peg/kg Lean Body Weight Corrected Cor Sokg § 80kg70kg BO Kg «GOK ~—«100Kg No. of Days Before mulminper70kg 1101 1321 16411761) 198 ©2001 ‘Steady Slate Achievedt ° e25t 125 125 125 175 (1875 OD 10 125 125 125 1e75 0187501875810 20 125 125 we75 18751875250 16 30 125 1875 18751875250 250 4 40 125 18751875 250 250 250 13 50 1975 1875 250 250 250 250 12 60 1875 1875 250 250 250 375 1" 70 1675 250 250 250 250 375 10 80 1875 250 250 250 375 375 8 20 1875 250 250 250 375 500 8 100 250 250 250 375 375 500 7 Seated ome se mre ose cotn eens cree Te ra Bi oraret ecnateace i or ah tae tona ta canata ae a Clearance in infants or children. tifno loading dose administered. #825 nq ~0.0625 ma, ‘Adapted from Phy for suspected digoxin toxicity was 2% in patients taking digoxin compared with 0.9% in patients taking placebo.” In patients with life threatening intoxication that includes ventricular tachycardia or ventricular fibrillation or ingestion of a very high dose of digoxin resulting in a very high se- rum concentration, purified antidigoxin Fab frag- ments from digoxin-specific antisera, an antidote, is usually administered (Table 12)."? In patients treated with digoxin immune Fab fragments, mea- surements of unbound digoxin concentration should be determined. Digoxin in Chronic Heart Failure: Remaining Questions The DIG trial generated the hypothesis that digoxin has a bidirectional effect: increased mor- Table 8. Digoxin Serum Concentrations Indications for measurement: ‘Suspected digoxin intoneaton Compliance Conditons ikely to ater sem concentrations Gables 10 and 13) Sampling: ust Deore the next scheduled doset “Goncentratons are 10% t0 25% lower when sampleg at 24 vorsus 8 hours ator he dose, Ave meee sar oo wihin'® hours afer the dose, 1.73 m? body surface area. For adults, if only serum kg body weight) may be estimated in men as (140, wysicians’ Desk Reference (ed 53), 1999, page 1170. tality from presumed arrhythmias and decreased mortality from progressive heart failure, The re- maining questions should be examined with the notion of improving the safety profile of digoxin without decreasing its beneficial effects. Digoxin Dose The DIG study found no effect of digoxin on all- cause mortality; however, a preliminary analysis suggests a relationship between baseline serum digoxin concentrations and risk of death.’ In this empirical observation, the risk of death increased significantly above a digoxin level of 1.0 ng/ml. While this relationship is not cause and effect be- cause a higher plasma concentration may only reflect worse cardiac and renal function at base- line, a similar relationship between serum digoxin concentrations and mortality was observed in the Prospective Randomized Milrinone Survival Eval- uation (PROMISE) trial’> where a serum digoxin concentration greater than 1.1 ng/ml. was associ- ated with a 38% excess mortality rate. In addition, digoxin is known to be arrhythmogenic at higher plasma concentrations.%82° This may be of most concern when higher doses of digoxin are used in patients with advanced coronary artery disease and ongoing ischemia where arrhythmogenesis is enhanced even at therapeutic doses.’ The hy-DIGOXIN IN CHF Table 9. Manifestations of Digoxin Intoxication 1. Cardiac disturbances ‘Arrhythmias due to increased automaticity Premature ventricular depolarization ‘Accelerated junctional (nodal) rhythm Unifocal or multifocal ventricular bigeminy Ventricular tachycardia Ventricular fibrilation Bidirectional ventricular tachycardia ‘Arrhythmias due to decreased conduction velocity ‘and ERP Asystole Sinoattial block First or second (Wenckebach) AV block, advanced or complete heart block ‘Acceleration of conduction via accessory pathway in WPW ‘Muttifocal or paroxysmal atrial tachycardia with block Idioventricular rhythm; AV dissociation 2. Gastrointestinal symptoms ‘Anorexia Nausea Vomiting Diarrhea ‘Abdominal pain Intestinal ischemia/infarction 3. Central nervous system ‘Visual disturbances (blurred or yellow vision) Headache ‘Weakness Dizziness Apathy Confusion Mental disturbances (anxiety, depression, delirium, ‘hallucination) 4, Other Gynecomastia (especially with spironolactone) ‘Thrombocytopenia Severe hyperkalemia ‘Abbreviations: ERP, effective iod; WPW, Wolfe-Parkinson-White syndrome; AV, atrioventricular. pothesis generated by the DIG and PROMISE studies that an increase in the serum concentra- tion within therapeutic range correlates with an increase in mortality should be examined in the light of the dose-dependent effects of digoxin on hemodynamics, neurohormones, and clinical sta- tus. A very low dose of digoxin that has no hemo- dynamic effect has a significant effect on reducing cardiac norepinephrine spillover in patients with severe heart failure. In two separate studies, lat- ton® and Gheorghiade have shown that an in- crease in serum digoxin concentration within the therapeutic range does not improve the neurohor- monal profile. Because reduction in worsening heart failure is seen with low-dose digoxin®® and higher doses may provide little or no additional hemodynamic? or neurohormonal‘?4> benefit (but do offer a higher risk of arrhythmia), a dose that results in a serum concentration of 0.7 to 1.0 ng/mL may be preferable. Who Benefits? Although in the DIG trial all subgroups appeared to derive benefit from digoxin in terms of a reduc- tion in worsening heart failure, the benefits appear to be greater in patients with a left ventricular ejection fraction =25%, noncoronary artery dis- ease-related heart failure, or functional class HILIV (Table 6).2" These findings are consistent with previous results that suggest that the worse the heart failure, the lower the ejection fraction; the greater the impairment in myocardial relax- ation, the greater the benefit from digoxin.1!2331 Patients were equally benefited if they were digoxin naive or were withdrawn from digoxin. In RADIANCE and PROVED trials, findings support the use of digoxin therapy in patients with left ventricular systolic dysfunction even when only a few signs or symptoms of heart failure are present.*! Safety and Efficacy in Patients With Coronary Artery Disease The majority of patients with heart failure in the United States have coronary artery disease.? Acute hypoxemia predisposes to development of the manifestation of digitalis intoxication.2607679 Myocardial ischemia itself may cause inhibition of sodium-potassium ATPase”®”’ and render myo- cardial tissue more sensitive to the arrythmogenic effects of digitalis even at lower serum concentra- tion. Studies by Lynch et al’*7 using a dog model with a chronic left anterior descending coronary occlusion resulting in significant left ventricular dysfunction showed that animals randomly as- signed to digoxin with a serum concentration in the therapeutic range had a significant excess mortality when an episode of ischemia induced by a transient occlusion of the left circumflex coro- nary artery was superimposed, In some studies, digitalis has been reported to increase the early postdischarge mortality ob-260 EICHHORN AND GHEORGHIADE Table 10. Drug Interaction With Digoxin rug Non-potassium-sparing diuretics tntravenous calcium Quinidine, verapamil, amiodarone, propafenone, itraconazole, alprazolam, spironolactone Erythromycin, clarithromycin, tetracycline Propantheline, diphenoxylate Antiacids, anticancer drugs, bran, cholestyramine, kaolin-pectin, metoclopramide, neomyocin, sulfasalazine, Rifampin Thyroid medications ‘Sympathomimetics Succinylcholine Bradrenergic blockers, ondihydropiridines, calcium channel blockers, flecanide, disopyramide, bepridil ACE inhibitions Nonsteroidal anti-inflammatory agents Mechanism of Action Hypokalemia, hypomagneser ‘promotes sodium pump. inhibition Increases myocyte calcium Reduction in digoxin clearance and decrease in volume of distribution Increase digoxin absorption by inactivating intestinal bacterial metabolism Increased digoxin absorption by decreasing gut motility Decrease digoxin absorption Increases nonrenal clearance of digoxin Increases metabolic state Increases automaticity Extrusion of potassium from cells Decrease sinoatrial or ‘atrioventricular node conduction May decrease renal function Decrease renal function Effects Increase in the risk of arrhythmias Increase in the risk of arrhythmias Increase in serum digoxin concentration Increase in serum digoxin concentration Increase In serum digoxin concentration Decrease serum digoxin concentration Decreases serum digoxin concentration Decrease serum digoxin concentration Increase in the risk of arrhythmias Increases the risk of arthythmias Increase the risk of sinoattial and atrioventricular block Increase serum digoxin concentration Increase serum digoxin concentration served in patients who survived a myocardial infarction (Table 13).**#* In contrast, in other studies of patients with coronary artery disease, regression analysis failed to show digitalis to be an independent predictor of mortality.* In the DIG trial,?! 70% of patients had coro- nary artery disease. At the time of enrollment, approximately 29% of patients had angina pec- toris and 63% had a history of previous myocar- dial infarction, Hospitalization for myocardial infarction, unstable angina, and ventricular ar- thythmias including cardiac arrests were almost identical in the digoxin and the placebo group. When the digoxin effects on prespecified sub- groups were examined, it appeared that the re- duction in hospitalizations and mortality due to worsening heart failure was lower in patients with coronary artery disease. Similar results were scen in the RADIANCE and PROVED tri- als.8> Because during ischemia the presence of di- goxin may have a proarrhythmic effect that is related to catecholamine release," its benefi- cial effects on chronic heart failure may be offset by a malignant arrhythmia, It is possible that B-blocker therapy may prevent digoxin-in- duced arrhythmias during ischemia.””7° Safety When Used With Nonpotassium Sparing Diuretics Thiazide and loop diuretics are the most com- mon cause of hypokalemia and possible hypo- magnesemia. This increases automaticity and promotes sodium pump inhibition by digoxin.'* This increases the arrhythmogenic effects of digoxin, particularly in patients with cardiac isch- emia and heart failure.'® Magnesium suppresses digitalis-induced arrhythmias and hypomag- nesemia predisposed to digitalis intoxication." Because digitalis affects potassium homeostasis as well, combination therapy with a nonpotassium sparing diuretic may induce serious arrhythmias, High normal concentrations of potassium and magnesium should be maintained in patients re- ceiving digoxin and nonpotassium sparing diuret- ies.DIGOXIN IN CHF Table 11. Causes of Altered Responsiveness to Cardiac Glycosides Digitalis resistance ‘Apparent. Tablets not taken as prescribed Inadequate bioavailability of tablets Inadequate intestinal absorption Increased metabolic degradation (og. bygut flora) True end-organ resistance: Infancy With respect to control of ventricular response in the presence of arial fibration or atrial flutter: A. Fever B. Elevated sympathetic tone from all causes, including uncontrolled congestive heart failure . Hyperthyroicism Digitalis Sensitivity Apparent: ‘Unsuspected use of digitalis (Change from poorly absorbed tablets to well absorbed tablets Decreased renal excretion Drug-drug interactions (eg, quinidine) ‘True end-organ sensitivity to toxic effects: ‘Advanced myocardial disease ‘Active myocardial ischernia Electrolyte imbalance (especially hypokalemia) ‘Acid-base imbalance ‘Concomitant drug administration (69, catecholamines) Hypothyroidism Hypoxemia (especially in setting of acute respiratory failure) Atered autonomic tone (eg, vagotonic states) From Smith et al.'® Interaction With Aldosterone Antagonist Agents Aldosterone antagonist diuretics may protect against digoxin-induced arrhythmias, Aldosterone has been shown to reduce serum and tissue potassium and ‘magnesium levels” and to cause the release of nor- epinephrine from the myocardium.® Aldosterone has also been shown to enhance the peripheral vaso- constrictor effects of digoxin and decrease atrial con- tractlity.” Digitalis preparations may indepen- dently stimulate aldosterone production. Thus, an aldosterone antagonist such as spironolactone might increase the safety of digoxin while maintain- ing its beneficial effect in preventing progressive heart failure. The use of spironolactone in patients with moderate to severe heart failure has recently been found to improve survival in the RALES trial.°! Although the beneficial effects of spironolactone 261 ‘may be related to its antifibrotic and neurohormonal effects, prevention of electrolyte depletion, particu- larly in patients receiving digoxin, may also be ben- ficial. Although the results of the RALES trial have not been completely analyzed, it appears that spi- ronolactone was particularly beneficial in patients receiving digoxin.! Role in Patients Receiving B-Blockers Previous studies of digoxin when added toan ACE inhibitor have shown benefits in hemodynam- ics,*243 exercise tolerance,” and hospitaliza- tion?”21 without an adverse effect on mortality.®* The role of digoxin in heart failure patients re- ceiving B-blocking agents is not known. A recent retrospective analysis of 1,509 patients with heart failure in 4 United States studies and 1 Australia/ New Zealand study of carvedilol demonstrated no additional benefit of digoxin in terms of death and hospitalization.° However, despite identical rates of death and hospitalization in the digoxin and no digoxin groups, the digoxin patients had more severe heart failure at baseline. Despite a lack of data in patients receiving B-blockers for heart failure, digoxin may provide 12, Therapy of Digoxin Intoxication General measures: iscontique digoxin Discontinue other drugs that increase digoxin serum ‘concentration or potentiate its action Bradyarrhythmias: 1, Asymptomatic; HR > 40 bpm; serum digoxin ‘concentration < 5 ng/dL. ‘Serum potassium <5 mg/dL: monitor 2. Symptomatic: ‘A. Atropine: 0.5 mg IV or more BB. Fab fragments if not responding to atropine or potassium > § ng/dl. and/or serum digoxin concentration > 5 ng/mL. Ventricular arrhythmia: 1. Correct hypomagnesemia and hypokalemia ‘A.V potassium may increase the AV block and ‘should be given slowly only when there is severe hypokalemia. 2. Fab fragments for life-threatening arrhythmias, Overdose: 1, Fab 2. Emesis" or gastric lavage 3, Glucose and insulin or dialysis for life-threatening ‘hyperkalemia “i ingestion less than 30 minutes and patient is awake. ‘Abbreviations: HR, heart rate; AV, atrioventricolar.262 EICHHORN AND GHEORGHIADE Table 13. Retrospective Studies: Digoxin Use and Mortality in Postinfarction Patients Reference Mortality Risk Postinfarction studies Moss et al, 1981 Higher mortality among patients on digoxin overall, but differences compared with those not on digoxin are not significant. Statistically significant excess in retrospectively identified subgroup of patients with heart failure and coupiet \VPDs. This subgroup comprised only 8.4% of total population. Bigger et al, 1985 \Nonsigrificant higher mortality with digoxin overall and in the subgroup identified by Moss et al. ‘Sweeney et al, 1991 ‘Significant excess in sudden death in group receiving digitalis. Overall mortality ‘ot provided. Byington and Goldstein, 1985 _Nonsignificant higher mortality with digoxin overall and in several subgroups. ‘examined, Muller et al, 1986 Madsen et al, 1984 Nonsignificant higher mortality with digoxin overall Nonsignificant higher mortality with digoxin overall and in several subgroups ‘examined, Leor et al, 1995 Higher mortality with digoxin. ‘Abbreviation: VPD, ventricular premature depolarization. 'Nonsignificant refers to a comparison not achieving statistical significance. ‘Adapted from Yusuf et al safe inotropic support during f-blocker up-titra- tion when ventricular function may deteriorate from adrenergic withdrawal and prevent worsen- ing-heart failure during chronic therapy. In clinical trials conducted to date, beneficial effects of B-blockers were seen in patients already receiv- ing digoxin. B-blocker therapy may enhance the safety and therefore efficacy of digoxin by pre- venting malignant arrhythmias,” particularly in patients with heart failure caused by coronary ar- tery disease. Digoxin Effects on Heart Failure With Preserved Systolic Function Itis estimated that 20 to 40% of patients admitted with heart failure have preserved systolic func- tion. It appears that mortality and readmission rates are substantial and similar to those patients with systolic dysfunction.* In the ancillary DIG trial that studied close to 1,000 patients with heart re and preserved systolic function, digoxin Table 14. Indications for Digoxin Therapy © Systolic heart failure and signs and symptoms in spite of therapeutic doses of ACE inhibitors and uretics «Atrial fibrilation with a rapid ventricular response in patients with or without heart failure prevented hospitalizations from worsening heart failure without an increase in mortality. The role of digoxin in patients with heart failure and pre- served systolic function remains to be determined, Indication for Digoxin Therapy (Table 14) After 200 years of use, digitalis still appears to have a place in our armamentarium for heart fail- ure and atrial fibrillation despite the proven sur- vival benefits with ACE inhibitors and B-block- ers. Digoxin therapy is inexpensive and well tolerated and may result in considerable savings.°° Digoxin is the only oral inotrope that does not increase mortality in heart failure patients, partic- ularly if low doses are being used. Digoxin therapy should be used in patients with systolic heart fail- ure who continue to have signs and symptoms despite therapeutic doses of ACE inhibitors or diuretics or in patients with atrial fibrillation with or without heart failure for rate control. 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