Results of the Digoxin Trial
Results of the Digoxin Trial
ABSTRACT & COMMENTARY
The main inclusion criteria were a diagnosis of heart failure and LV ejection fraction of 45% or less, determined by radionuclear, cath, or echo techniques. Patients could be eligible with a chest x-ray showing pulmonary congestion and a low EF. A small subset of individuals with an ejection fraction of greater than 45% and heart failure were also enrolled. The primary outcome was mortality. A variety of secondary outcomes were evaluated, including any cardiovascular death, worsening heart failure, as well as hospitalization for any cause of worsening heart failure.
Approximately 3400 patients were randomized to each arm of the main trial; baseline characteristics were well-matched. Seventy-eight percent were male, the mean age was 63, and the mean ejection fraction was 29%. Most patients were NYHA class II (53-54%), with approximately 30% in NYHA class III. Two-thirds had a history of a prior myocardial infarction, and 27% had current angina pectoris. Almost half were hypertensive, and 28% had diabetes; 71% had an ischemic etiology. Almost 95% of the patients were treated with an ACE inhibitor; more than 40% received a nitrate and more than 80% a diuretic.
The patients were started on 0.25 mg of digoxin or placebo. By the end of the study, 30% and 32% of surviving patients had discontinued the study drug (digoxin or placebo); 10% and 16% of individuals were given open-label digoxin because of clinical indications. Serum digoxin concentrations were within the normal range throughout the study in the large majority of patients. Digoxin toxicity was suspected in two-fold more in the digoxin group but was uncommon.
The overall mortality rate in the main trial (EF < 45%) was 35%, with no difference between digoxin vs. placebo. In the ancillary trial of subjects with preserved LV function, the overall mortality rate was 23% at study completion for both groups. Thus, the primary end point of all-cause mortality was not affected by digoxin in either the low EF or normal EF groups. Death or hospitalization for heart failure was significantly reduced by digoxin, however. There was a 28% reduction in hospitalization for worsening heart failure and a 15% reduction in either death or hospitalization in the digoxin patients (P < 0.001). Of interest, similar results were noted in the high ejection fraction group, with an 18% reduction in either end point (NS). Digoxin decreased all hospitalizations by 6%. However, there was an increase in mortality in digoxin vs. placebo in those patients who did not have worsening heart failure (15% vs 13%). The authors conclude that digoxin "had no effect on overall mortality . . . but did reduce the overall number of hospitalizations and 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."
An editorial on the same issue by Milton Packer takes a rather even-handed approach, and points out that both advocates and critics of digoxin therapy will find something in this study. He suggests that over the next decade, the use of digoxin will become increasingly uncommon because newer effective therapies (e.g., ACE inhibitors, beta-blockers) will decrease the necessity for digoxin treatment, which (based on these data) is no longer imperative in patients with heart failure. (The Digitalis Investigation Group. N Engl J Med 1997;336:525-533. Packer M. N Engl J Med 1997;336:575-576.)
COMMENT BY JONATHAN ABRAMS, MD
This long awaited study has been greeted with somewhat of a "so what" and does not completely resolve the controversy regarding digoxin therapy. Clearly, there was an increased risk of death from non-heart failure causes that is not well defined. This approaches 11% of the study cohort and is significant because it completely neutralized the benefit of digoxin in reducing deaths from heart failure. It is reassuring that digoxin toxicity was a minor problem, as suggested by the clinical experience of the past two decades.In a limited subset analysis, patients were analyzed as to whether there were differences in event rates that might be related to NYHA class, ejection fraction, cardiac silhouette, and cause of heart failure. This assessment suggests that the sicker hearts benefited the most from digoxin. For instance, there was a 32% reduction in death or hospitalization due to worsening heart failure in those with a baseline ejection fraction of less than 25%, compared to a 20% decrease in those with an ejection fraction of 25-45%. A greater reduction in the risk ratio was found for those with cardiomegaly, a non-ischemic etiology of heart failure, or a high NYHA class.
Overall, there was a 25% reduction in the risk of hospitalization or death due to heart failure, which the authors emphasize in the manuscript. The DIG trial does not provide information about how to identify individuals who have an increased mortality from other cardiovascular causes, presumed to be arrhythmias (15% digoxin group vs 13% placebo group). Prior analyses of post-MI studies indicate that digoxin is a risk factor for subsequent mortality, with causation being unclear. Confounding morbidity may be an important factor, but specific risk factors have not been identified in this trial or in previous studies.
The recently completed RADIANCE and PROVED withdrawal trials have been reassuring regarding digoxin in the treatment of heart failure but did not completely resolve the controversy regarding efficacy and safety of the drug. At least it can be said that digoxin has no overall effect on mortality, unlike a wide variety of other inotropic drugs studied over the past few years that have increased observed death rates.
In conclusion, this trial supports the use of digoxin for sicker patients with a significantly depressed ejection fraction (e.g., < 30%), which is the practice of many experienced cardiologists and appears to be supported by older clinical trial data. There seems little usefulness in prescribing digoxin for subjects with a low NYHA class, only moderate depression of LV function, and who are doing well. Digoxin was used in addition to ACE inhibitor therapy and diuretics in most of these patients, and this is appropriate for the treatment of heart failure today.
It is intriguing that digoxin appeared to be of greater benefit in the non-ischemic patients, representing a minority of the study; other data, including the recent PRAISE trial, have also suggested that drug interventions may be more effective in CHF patients without coronary artery disease. Digoxin should be strongly considered for patients with an ejection fraction under 30% who remain symptomatic on conventional heart-failure therapy; digoxin probably should not be considered if the ejection fraction is 35% or greater, or the patient is NYHA class II.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.