Reconsidering the Role for Digoxin in the Management of Acute Heart Failure Syndromes

The use of digitalis preparations for treatment of cardiac maladies has been debated for centuries. Controversy regarding their effect on mortality has been the primary issue, given their relatively narrow toxic-therapeutic ratio. This led to the Digitalis Investigation Group trial, organized and conducted by the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs. The trial, which involved patients with chronic heart failure and in sinus rhythm, demonstrated that, although digoxin did not affect survival, it was effective at reducing hospitalizations of patients receiving standard therapy—consisting of diuretics and angiotensin-converting enzyme (ACE) inhibitors—for heart failure.¹ As a result, the US Food and Drug Administration granted regulatory approval to digoxin for the treatment of heart failure and atrial fibrillation in 1997.²

However, available data from registries and clinical trials of heart failure suggest that digoxin use has decreased considerably, from approximately 80% to <30% in the last 10 years.^{2 - 3} Several factors may have contributed to this decreased use of digoxin. Digoxin has received little attention at large cardiology meetings; has not been promoted by the pharmaceutical industry, given the very low cost of this generic drug; and has been supplanted by the introduction of life-saving therapies for heart failure including β-blockers, angiotensin-receptor blocking agents, aldosterone-blocking agents, and cardiac resynchronization therapies. Moreover, retrospective studies of the Digitalis Investigation Group trial raised serious safety concerns, particularly for women, which may have further contributed to the decreased use of digoxin.⁴

Forgetting a drug is not necessarily a tragedy. In the last decade, however, registries and trials of acute heart failure syndromes resulting in hospitalization have shown mortality and rehospitalization rates as high as 15% and 30%, respectively, within 90 days of discharge.^{3 ,5} This high event rate occurred in patients already receiving evidence-based therapies, including loop diuretics, β-blockers, ACE inhibitors, and angiotensin-receptor blockers.⁵ Although the main reason for heart failure–related admission and readmission results from hemodynamic instability due to a high left ventricular filling pressure, low cardiac output, or both, every new agent tested to date known to improve hemodynamics in acute heart failure syndromes has not been shown to be either efficacious or safe.⁶ In the last 15 years, only nesiritide has been approved by the Food and Drug Administration for acute heart failure syndromes, even though safety issues for nesiritide were raised after it was approved, including renal function impairment and, more importantly, mortality.⁷ The most recently evaluated agent, rolofylline, an adenosine-blocking agent, did not demonstrate clinical benefit and showed an increase in central nervous system events.⁸ With this background, the role of digoxin in acute heart failure syndromes should be reexamined.

What would be an ideal agent for treatment of acute heart failure syndromes? Such a drug should (1) improve hemodynamics without adversely affecting heart rate or blood pressure or increasing myocardial oxygen demand and without reducing coronary perfusion; (2) prevent further neurohormonal activation, favorably modulate the existing neurohormonal milieu, or both; (3) be applicable in the context of known evidence-based therapies, such as ACE inhibitors and β-blockers; (4) help control ventricular rate in atrial fibrillation; (5) have a formulation for intravenous use during the acute phase of heart failure and an oral formulation for long-term use; (6) importantly, improve symptoms and signs, decrease rehospitalization rate, improve survival, or all 3; and (7) be affordable for the millions of patients with heart failure throughout the world. This last point is particularly important because many patients with heart failure cannot afford newer, much more expensive drugs.

Digoxin has many of these properties. It improves hemodynamics acutely, both at rest and with exercise.² These hemodynamic effects are additive when digoxin is used with other vasoactive agents.² Digoxin has beneficial neurohormonal actions, does not impair renal function, and has a neutral or beneficial effect on heart rate and blood pressure.² The intravenous form can easily be switched to the oral form, which is taken once a day. Digoxin is inexpensive, and therapeutic serum concentrations can be monitored. In relatively low doses resulting in serum concentration of less than 1 ng/mL, digoxin appears to reduce hospitalizations and cardiovascular mortality,⁹ particularly in patients with severe signs and symptoms or a very depressed ejection fraction.² In addition, digoxin also has been demonstrated to be safe and possibly effective in reducing hospitalizations even in patients with preserved ejection fraction.²

What are some remaining questions? Digoxin has not been well studied in acute heart failure syndromes. Past studies were conducted before the use of β-blocker therapy. Worse outcomes in women have been suggested but also refuted.^{4 ,10} Although the drug has a relatively narrow toxic-therapeutic ratio, it has been shown that low-dose digoxin is both effective and safe.^{9 - 10}

The net clinical benefit of digoxin in acute heart failure syndromes should be reevaluated, given the unacceptably high postdischarge hospitalization rates and subsequent increasing economic costs, despite standard therapies including ACE inhibitors and β-blockers. This is particularly important given the negative results in terms of efficacy, safety, or both with newer therapies that include both vasodilators and inotropic agents. It is not feasible for the pharmaceutical industry to support a trial of a generic drug, but this is certainly a clinical situation in which the National Heart, Lung, and Blood Institute can make a critically important contribution to the health of hundreds of thousands of US residents and millions of persons worldwide. Because little data exist on the use of intravenous or oral digoxin in acute heart failure syndromes, a large outcome study should be preceded by a smaller study that would first assess the clinical, hemodynamic, and neurohormonal effects of digoxin in patients admitted with acute heart failure syndromes who are in sinus rhythm and already receiving standard therapy. It is time to remember a forgotten drug.