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Therapeutics

Digoxin reduced hospitalizations in patients with heart failure and normal sinus rhythm

ACP J Club. 1997 Sep-Oct;127:34. doi:10.7326/ACPJC-1997-127-2-034

Related Content in the Archives
Withdrawal of digoxin after treatment of chronic heart failure lead to clinical deterioration and worsening heart failure


Source Citation

The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997 Feb 20;336:525-33.


Abstract

Objective

To determine the effect of digoxin on mortality and hospitalization for heart failure in patients with heart failure and normal sinus rhythm.

Design

Randomized, double-blind, placebo-controlled trial with mean 37-month follow-up.

Setting

302 clinical centers in the United States and Canada.

Patients

The main trial included 6800 patients (mean age 63 y, 78% men) with heart failure, left ventricular ejection fraction (LVEF) ≤ 0.45, and a normal sinus rhythm. Most patients were receiving angiotensin-converting enzyme (ACE) inhibitors and diuretics. 988 patients with heart failure and a LVEF > 0.45 were enrolled in an ancillary trial. Patients were included whether they had already been treated with digoxin.

Intervention

Patients were stratified by center and LVEF. In the main trial, 3397 patients were allocated to digoxin and 3403 to placebo. The initial digoxin dose was based on the patient's age, sex, weight, and renal function. Investigators were allowed to modify the dose and were encouraged to give patients ACE inhibitors. Patients were assessed at 4 and 16 weeks and every 4 months thereafter.

Main outcome measures

The primary outcome was total mortality. Secondary outcomes were mortality from cardiovascular causes and worsening heart failure; hospitalization for worsening heart failure; and hospitalization for other causes, particularly digoxin toxicity.

Main results

Mortality (overall and from cardiovascular causes) did not differ between groups. 1181 deaths occurred in the digoxin group compared with 1194 deaths in the placebo group (34.8% vs 35.1%, P = 0.8). Compared with the placebo group, the digoxin group had lower rates of hospitalizations overall (P < 0.006), for worsening heart failure (P < 0.001), and for cardiovascular causes (P < 0.001) (Table). More patients in the digoxin group were hospitalized for digoxin toxicity than in the placebo group (P < 0.001). Subgroup analyses suggested a greater benefit among patients at high risk (i.e., those with lower LVEF, enlarged hearts, and more severe New York Heart Association [NYHA] functional class). Ancillary trial results were consistent with the main trial.

Conclusion

Digoxin did not affect mortality but reduced hospitalizations in patients with heart failure and normal sinus rhythm.

Source of funding: In part, Glaxo Wellcome.

For article reprint: Dr. R. Gorlin, Mount Sinai Medical Center, Box 1018, 1 Gustave L. Levy Place, New York, NY 10029-6574, USA. FAX 212-722-2543.


Table. Digoxin vs placebo*

Hospitalization Digoxin EER Placebo CER RRR (95% CI) ARR |EER - CER| NNT (CI)
Total 64% 67% 4.1% (0.8 to 7.4) 3% 36 (20 to 196)
For worsening heart failure 27% 35% 23% (17 to 28) 8% 13 (10 to 18)
For cardiovascular causes 50% 54% 8% (4 to 12) 4% 22 (15 to 47)

*Abbreviations defined in Glossary; RRR, ARR, NNT, and CI calculated from data in article.


Commentary

Drug therapy in patients with congestive heart failure has been extensively studied. The Study of Left Ventricular Dysfunction (SOLVD) trial (1) showed that the ACE inhibitor enalapril reduced mortality and hospitalizations. The Evaluation of Losartan in the Elderly (ELITE) trial (2) suggested that treatment with an angiotensin II inhibitor caused reductions in morbidity and mortality. These issues were examined for the use of digoxin in this study of 6800 patients with heart failure, sinus rhythm, and an LVEF of ≤ 45%. Digoxin or a placebo was added to an ACE inhibitor (94%) and diuretics (82%). Mortality did not differ between the 2 groups. Previous studies with inotropic agents actually showed increased mortality.

There was a 25% reduction in the number of hospitalizations for worsening heart failure with digoxin. In comparison, in the SOLVD trial, enalapril caused a 30% reduction in hospitalization (but also reduced mortality). As with ACE inhibitors, the benefit of digoxin treatment seemed to be greatest in patients with lower LVEFs, cardiomegaly, or NYHA class II or IV.

Digoxin also decreased hospitalizations for worsening heart failure in an ancillary trial of 988 patients who had LVEF > 45%. The mechanism for this benefit was not discussed.

This study confirms the suggestion of clinical benefit with digoxin use shown as far back as 1982 in the first randomized, but small, trial of digoxin compared with placebo (3).

Robert Weiss, MD
Androscoggin Cardiology AssociatesAuburn, Maine, USA


References

1. The SOLVD Investigators. N Engl J Med. 1991;325:293-302.

2. Pitt B, Segal R, Martinez FA, et al. Lancet. 1997;349:747-52.

3. Lee DC, Johnson RA, Bingham JB, et al. N Engl J Med. 1982;306:699-705.