Subacute Care/Hospital Forum

Digoxin: No Effect on Mortality, But Fewer Hospitalizations

A placebo-controlled trial of digoxin indicates that the glycoside has no effect on mortality in patients with chronic heart failure and normal sinus rhythm according to a recent report in the New England Journal of Medicine. However, the drug reduced hospitalizations both overall (6%) and for worsening heart failure (26.8%).¹

Approximately 6,800 patients at 302 clinical centers in the United States were studied. All patients, who had left ventricular ejection fractions of 0.45 or less, were randomly assigned to digoxin or placebo. All patients were receiving diuretics and ACE inhibitors-the median dose of digoxin was 0.25 mg/day, and patients were followed an average of 37 months.

A total of 34.8% of patients on digoxin died, compared with 35.1% of those on placebo. Deaths from cardiovascular causes were also similar between the two groups (29.9% in digoxin recipients and 29.5% in those taking placebo).

Despite digoxin's lack of reduction of mortality, the drug provided other benefits. Fewer patients taking digoxin were hospitalized for worsening heart failure (risk ratio of 0.72, with 910 hospitalizations in the digoxin group versus 1,180 hospitalizations in the placebo patients). Hospitalizations for all causes were 6% lower in the digoxin group than in the placebo group.

At one month, 88% of patients had serum digoxin concentrations in the therapeutic range, with only 2% of patients with supratherapeutic levels. While 11.9% of digoxin patients had suspected digoxin toxicity during the trial, some 7.9% of placebo patients did as well. Only 2.0% of digoxin patients were hospitalized for actual or possible digoxin toxicity.

The authors concluded, "Digoxin had no effect on overall mortality in patients receiving diuretics and angiotensin-converting-enzyme inhibitors, but it did reduce the overall number of hospitalizations and the combined outcome of death or hospitalization attributable to worsening heart failure. In clinical practice, digoxin therapy is likely to affect the frequency of hospitalization, but not survival." (reprints: R. Gorlin, Mt. Sinai Med. Ctr., Box 1018, 1 Gustave L. Levy Pl., New York, NY 10029.)

In an accompanying editorial, Milton Packer (reprints: Columbia U., New York, NY 10032) evaluated the impact of this landmark study on clinical medicine. He notes that digoxin advocates will point to these study results: Digoxin is safe and effective; digoxin-treated patients were hospitalized less often; and digoxin is the first inotropic agent for heart failure that is not associated with an increased risk of death.

However, opponents will also find much fodder in the report: Patients in the digoxin group had an increased risk of death from arrhythmias; digoxin increased the risk of hospitalization from cardiac causes other than heart failure; and the study confirms fears about adverse effects of the drug even when it is within therapeutic ranges.

He writes: "For most patients with heart failure, digitalis remains an effective, safe, and inexpensive choice for the relief of symptoms, despite its inability to alter the natural course of the disease. To the extent that symptom relief has driven most of the drug's clinical use, the results of the trial should not lead most physicians to change their prescribing patterns."

Packer concludes, "Although the new data indicate that digitalis is neither as good as hoped nor as bad as feared, both advocates and opponents [of its use] will undoubtedly find much in the trial to fuel their arguments. The ... trial changes one fundamental aspect of the treatment of heart failure: digoxin's inability to substantially influence morbidity and mortality eliminates any ethical mandate for its use and effectively relegates it to being prescribed for the treatment of persistent symptoms after the administration of drugs that do reduce the risk of death and hospitalization (such as [ACE] inhibitors and beta-adrenergic blockers)."

L. Michael Posey, Academics Editor

References

1. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336:525-33.

2. Packer M. End of the oldest controversy in medicine: are we ready to conclude the debate on digitalis? [editorial] N Engl J Med 1997; 336:575-6.