Congestive heart failure has been recognized as a syndrome of anatomic, functional and biologic alterations that interact together in a complex manner over a prolonged period. Initially, this syndrome was viewed predominantly as a problem of salt and water retention caused by abnormalities of renal blood flow. Over time, however, physicians began to recognize that congestive heart failure was associated with reduced cardiac output and excessive peripheral vasoconstriction.¹ Recognition of this association provided the rationale for the use of inotropic agents and intravenously administered vasodilators to improve cardiac output.

Despite these therapeutic developments, it became apparent that at some point, congestive heart failure would progress independent of the patient's hemodynamic status. Thus, the neurohormonal model evolved.¹ According to this model, heart failure progresses as a result of overexpression of biologically active molecules that exert toxic effects on the heart and circulation.^2,3

Pathophysiology

Following an initial index event that results in a decline of ventricular contractility, most patients remain asymptomatic or minimally symptomatic for some time. The initial event may be abrupt, such as a myocardial infarction, or it may have a gradual onset, as in the case of hypertension or volume overload. The index event may also be a hereditary condition such as a genetic cardiomyopathy.

Many compensatory mechanisms, including the sympathetic nervous system and salt-and water-retaining systems, become activated in the setting of a depressed cardiac output.^4,5 The compensatory systems can maintain left ventricular function for days to months. However, when patients become overtly symptomatic, they begin to experience a striking increase in morbidity and mortality. The transition to symptomatic heart failure is accompanied by further activation of the neurohormonal system, including the sympathetic nervous system and a series of adaptive changes in the myocardium, collectively referred to as “left ventricular remodeling.”⁶

Epidemiology of Congestive Heart Failure and Evolution of Treatment

Congestive heart failure continues to be a major health problem. Despite significant advances in the prevention and treatment of cardiovascular diseases, the incidence and prevalence of congestive heart failure have been increasing in recent years. Contributing factors include increased survival in patients with coronary artery disease (especially myocardial infarction), an aging population and significant advances in the control of other potentially lethal diseases.

In the past two decades, the treatment of congestive heart failure has evolved and is now directed at the attenuation of neurohormonal activation using angiotensin-converting enzyme (ACE) inhibitors, beta blockers⁷ and, more recently, spironolactone (Aldactone).⁸ Because neurohormonal antagonists have been shown to prolong survival in patients with congestive heart failure,^8–11 the role of digoxin (Lanoxin) has become less certain.

Controversy over an Old Drug

In 1785, Withering published an account of digitalis (dried leaves of the purple foxglove) and some of its medical uses.¹² Although digoxin continues to be viewed as beneficial in patients with heart failure and atrial fibrillation, its role in patients with heart failure and sinus rhythm has been increasingly challenged. Mackenzie and Christian, two eminent clinicians and coeditors of Oxford Medicine, debated this issue in 1922. Mackenzie advocated the use of digitalis only in heart failure with associated atrial arrhythmias, whereas Christian argued that digitalis was effective irrespective of an irregular pulse. In 1938, Cattell and Gold first showed a direct inotropic effect of digitalis on cardiac muscle.

For many more years, digitalis continued to be an important part of heart failure management. The detrimental aspects of digoxin therapy were not considered important until excess mortality was reported in survivors of myocardial infarction who received digitalis.^13,14 Uncontrolled observations that the withdrawal of digoxin produced no ill effects also raised concerns about the efficacy of the drug.^15,16

Trials of Digoxin in Heart Failure

The role of digitalis in the treatment of heart failure has continued to be controversial and has been studied in clinical trials over the years. This role was recently addressed by the Digitalis Investigation Group (DIG)¹⁷ in a large multicenter trial sponsored by the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs. The trial involved patients in 302 centers in the United States and Canada.

Over the past decade, randomized double-blind, placebo-controlled trials and other new findings, such as the successful use of lower dosages, have revived interest in the use of digoxin in the treatment of heart failure. One study¹⁸ demonstrated that compared with placebo, digoxin improved signs and lessened symptoms in patients with heart failure who had normal sinus rhythm and were receiving maintenance diuretic therapy. The benefits of digoxin were greatest in patients with more severe heart failure, a third heart sound gallop, left ventricular enlargement and a depressed left ventricular ejection fraction.

In 1993, trials conducted in the Prospective Randomized Study of Ventricular Failure and Efficacy of Digoxin (PROVED)¹⁹ and the Randomized Assessment of Digoxin on Inhibitors of Angiotensin-Converting-Enzyme (RADIANCE)²⁰ study examined the effects of withdrawal of digoxin in patients with stable, mild to moderate heart failure (New York Heart Association [NYHA] functional classes II and III) and left ventricular systolic dysfunction (left ventricular ejection fraction of 35 percent or less). Both trials showed that digoxin prevented clinical deterioration and hospitalizations, and improved exercise tolerance and left ventricular function in patients, but had no survival benefit in patients who had congestive heart failure (Table 1).^19,20

In the DIG trial,¹⁷ patients with heart failure and sinus rhythm were randomized to receive digoxin (N = 3,397) or placebo (N = 3,403). The investigators were strongly encouraged to also give ACE inhibitors to patients in the trial. No difference was found in all-cause mortality between patients who were treated with digoxin and those who were given placebo. However, the patients

who received digoxin had significantly fewer hospital admissions when the drug was given in addition to diuretics and ACE inhibitors (Table 2).¹⁷ Compared with the placebo group, the digoxin-treated group had 270 fewer patients who required hospital admission for worsening heart failure (P <0.001). Furthermore, there were 626 fewer hospital admissions in patients with worsening heart failure as the primary diagnosis (1,927 in the digoxin group versus 2,553 in the placebo group). The trial showed little evidence of risks related to digoxin therapy.

Digoxin-Induced

Neurohormonal Modulation

In the past, digoxin was considered to be solely a positive inotropic agent. In patients with heart failure, digoxin exerts its positive inotropic effect by inhibiting sodium-potassium adenosine triphosphatase (ATPase). Inhibition of this enzyme in cardiac cells results in an increase in the contractile state of the heart. In recent years, it has been shown that digoxin exerts a positive inotropic effect at higher dosages (0.25 mg or more per day); however, at lower dosages (less than 0.25 mg per day), this drug exerts a mainly neurohormonal effect and has little inotropic activity.²¹

The neurohormonal effect of digoxin was first demonstrated in a small study in 1987.²² The study findings showed that digoxin reduced plasma norepinephrine levels; these results were validated in other studies.^23,24 The explanation for this effect was that digoxin improves impaired baroreceptor reflexes in heart failure.²⁵

Digoxin may also lower plasma renin levels,²⁴ either because of a direct renal effect or secondary to inhibition of sympathetic activity. By inhibiting sodium-potassium ATPase in the kidney, digoxin decreases renal tubular reabsorption of sodium, thereby increasing delivery of sodium to the distal tubules and suppressing renin secretion.

Digoxin in Patients with Mild to Moderate Heart Failure

In the DIG trial,¹⁷ digoxin therapy was most beneficial in patients with ejection fractions of 25 percent or lower, patients with enlarged hearts (cardiothoracic ratio of greater than 0.55) and patients in NYHA functional class III or IV. The findings of the DIG trial also indicated that digoxin was clinically beneficial in subgroups of patients with less severe forms of heart failure.

Using direct clinical measures of heart failure, the PROVED¹⁹ and the RADIANCE²⁰ trials showed definite clinical improvement in patients who were treated with digoxin, even patients with mild heart failure.

Based on the study findings, digoxin therapy may be effective in patients with mild or moderate heart failure,²⁶ although the magnitude of the effect may be quite modest.

Digoxin in Patients with Preserved Left Ventricular Systolic Function

Much has been learned about the effective treatment of patients who have congestive heart failure associated with left ventricular systolic dysfunction. In contrast, little is known about how best to treat patients with preserved left ventricular systolic function.

As many as 30 percent of patients with congestive heart failure have a normal or nearly normal left ventricular ejection fraction. In these patients, congestive heart failure is often described as “left ventricular diastolic dysfunction.” Left ventricular diastolic dysfunction is considered to be a diagnosis of exclusion (or assumption) in patients with congestive heart failure and preserved left ventricular systolic function.

Diagnostic tools such as radionuclide angiography and Doppler echocardiography have made it possible to identify patients who have normal or nearly normal left ventricular systolic function but abnormal left ventricular filling parameters. The majority of patients with congestive heart failure who have only diastolic dysfunction have no identified diagnosis. Most of these patients are elderly or have a history of hypertension. Some patients have coronary artery disease without extensive scar tissue. Such patients also commonly have diabetes mellitus.

APPROACH TO PATIENTS WITH DIASTOLIC DYSFUNCTION

In patients with diastolic dysfunction, appropriate measures include the diagnosis and treatment of myocardial ischemia (if present) and the aggressive treatment of hypertension (if needed). Digitalis therapy has been considered inappropriate in these patients. In some patients, treatment with diuretics and nitrates could reduce pulmonary congestion.

In the DIG trial,¹⁷ a subgroup of nearly 1,000 patients with a left ventricular ejection fraction of 45 percent or greater experienced a reduction in congestive heart failure end points similar to patients with a left ventricular ejection fraction of 25 to 45 percent. One group of investigators²⁷ suggested that this effect may be the result of digoxin's ability to reduce neurohormonal activities. However, they concluded that information about the effect of digoxin in patients with congestive heart failure and preserved left ventricular systolic function is limited and does not warrant routine use of the drug in this setting until the results of more studies are available.

At present, the consensus is that digoxin therapy is probably inappropriate in patients with preserved left ventricular systolic function. In addition, digoxin therapy may not be useful in patients with congestive heart failure and a high cardiac output syndrome such as anemia or thyrotoxicosis.

Adverse Effects of Digoxin

Adverse reactions to digoxin are usually dose dependent and occur at dosages higher than those needed to achieve a therapeutic effect. The actual incidence of digoxin toxicity may be lower than is historically reported.²⁸ Adverse reactions are less common when digoxin is used in the recommended dosage range and careful attention is given to concurrent medications (Table 3) and medical conditions.

The principal manifestations of digoxin toxicity include cardiac arrhythmias (ectopic and reentrant cardiac rhythms and heart block), gastrointestinal tract symptoms (anorexia, nausea, vomiting and diarrhea) and neurologic symptoms (visual disturbances, headache, weakness, dizziness and confusion). Most adult patients with clinical toxicity have serum digoxin levels greater than 2 ng per mL (2.6 nmol per L). Conditions such as hypokalemia, hypomagnesemia or hypothyroidism may predispose patients to have adverse reactions even at lower serum digoxin concentrations.²⁹

Dosages of Digoxin

Although some investigators advocate the use of serum levels to guide digoxin dosing, little evidence supports this approach.³⁰ The serum level of digoxin may be used to assist in evaluating a patient for toxicity, but not to determine the efficacy of the drug.

When digoxin was considered to be mainly an inotrope, higher dosages (greater than 0.25 mg per day) were generally used, and the incidence of toxicity was much higher. In the PROVED and RADIANCE trials, the mean digoxin dosage was 0.375 mg per day. However, a study of a subset of patients in the RADIANCE trial³¹ showed that increasing the digoxin dosage from a mean of 0.2 mg per day to 0.39 mg per day did not significantly improve heart failure symptoms, exercise time or serum norepinephrine levels.

When lower dosages are used, the side effects of digoxin, especially ventricular arrhythmias, decrease. Use of lower dosages is particularly important in the elderly, because digitalis toxicity may be difficult to recognize in this patient population.³² It is generally agreed that digoxin should be given in a dosage of 0.125 to 0.25 mg per day. Dosages higher than 0.25 mg per day are probably unwarranted.

Renal function plays a major role in the pharmacokinetics of digoxin and is an important factor in determining the dosage. Medications such as quinidine, amiodarone (Cordarone) and verapamil (Calan) can increase the serum digoxin concentration. Thus, safe and effective dosing requires recognition of concomitant disease states and medications that could change digoxin pharmacokinetics, along with a recognition of digoxin toxicity.³³

Digoxin in Acute Myocardial Infarction

Digoxin has been reported to have detrimental effects following myocardial infarction.^13,14,34 The drug may increase myocardial oxygen consumption³⁵ by augmenting contractility and inducing peripheral or coronary vasoconstriction.³⁶ It may also provoke ventricular arrhythmias and increase infarct size.³⁷

Because myocardial stunning may be present for weeks after an infarction, digoxin therapy should be avoided in the acute phase after myocardial infarction, unless its use is strongly indicated. For example, digoxin may be indicated to control the ventricular rate in patients with atrial fibrillation when rate control cannot be achieved with beta blockers or calcium channel blockers, or when the use of these medications is contraindicated.

Digoxin and Other Medications for Congestive Heart Failure

ACE inhibitors, beta blockers and spironolactone have been shown to improve survival in patients with heart failure. Consequently, the role of digoxin in the treatment of heart failure remains secondary (Table 4), despite renewed interest in its use. Digoxin has been shown to reduce the morbidity associated with congestive heart failure but to have no demonstrable effect on survival.

In the absence of a survival benefit, the goal of digoxin therapy is to improve quality of life by reducing symptoms and preventing hospitalizations. Digoxin should be used routinely, in conjunction with diuretics, ACE inhibitors, beta blockers and spironolactone, in all patients with severe congestive heart failure and reduced systolic function. It also should be added to the therapy of patients with mild to moderate congestive heart failure if they have not responded adequately to an ACE inhibitor or a beta blocker.^30,38 If digoxin acts primarily by reducing neurohormonal activation, its value is in question in patients with heart failure who are already being treated with beta blockers.