Digitalis for treatment of congestive heart failure in patients in sinus rhythm

Digitalis for treatment of congestive heart failure in patients in sinus rhythm – Cochrane For Clinicians: Putting Evidence Into Practice

William E. Cayley, Jr.

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. William E. Cayley, Jr., M.D., M.Div., presents a clinical scenario and question based on the Cochrane Abstract, along with the evidence-based answer and a full critique of the abstract.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available at

Clinical Scenario

A 63-year-old man with a history of congestive heart failure (CHF) and an ejection fraction of 25 percent presents with dyspnea on moderate exertion. He has a regular heartbeat, basilar crackles, and 3+ pitting edema on both legs.

Clinical Question

Should we prescribe digitalis for treatment of CHF in patients in normal sinus rhythm?

Evidence-Based Answer

Adding digitalis to treatment with angiotensin-converting enzyme (ACE) inhibitors and diuretics will reduce hospitalization rates and improve clinical status in patients in normal sinus rhythm with left ventricular systolic dysfunction (LVSD) and symptoms of CHF on moderate or mild exertion (New York Hospital Association [NYHA] class II or III). However, the addition of digitalis to ACE inhibitor or diuretic therapy will not reduce the risk of death. The incremental benefit of adding digitalis to regimens already including ACE inhibitors, beta blockers, and spironolactone (Aldactone) is unclear.

Practice Pointers

The most recent guidelines on evaluation and management of heart failure from the American College of Cardiology and the American Heart Association (2) include a new staging system (see the accompanying table) and emphasize management of CHF. Risk factor reduction is recommended in patients at risk for heart failure who are asymptomatic and have structurally normal hearts (stage A), and ACE inhibitors and beta blockers are recommended in patients with asymptomatic LVSD (stage B). Digitalis is advised for use only in patients who need symptom control in stage C (equivalent to NYHA class II or III) or stage D (equivalent to NYHA class IV). (3)

This Cochrane review combines data from 11 studies–the large Digitalis Investigators Group (DIG) trial (4) and 10 smaller trials–to assess the effect of digitalis on three patient-oriented end points: mortality rates, hospitalization rates, and clinical outcomes. Most patients in these studies had NYHA class II or III heart failure and an ejection fraction of 25 to 30 percent, and also were taking diuretics and ACE inhibitors.

Meta-analysis of the eight studies that addressed mortality found no evidence that treatment with digitalis decreased the risk of death. Combined data from the DIG study and three smaller, shorter studies found that digitalis reduced hospital admissions (25.4 versus 33.1 percent, P < .001); approximately 13 patients would need to be treated with digitalis to prevent one hospitalization over the three- to five-year study period of the DIG trial. Meta-analysis of the 10 smaller studies that addressed clinical outcomes found a 71 percent relative reduction in risk of clinical deterioration at three months of digitalis therapy, but the precise meaning of "clinical deterioration" varied between studies.

There have been no new major studies of digitalis in heart failure since this Cochrane review was revised in May 2001, but a retrospective review of the original DIG data suggests that lower serum digitalis concentrations may be most beneficial. When patients in the DIG study were grouped according to serum digitalis concentration (SDC) after the first month of therapy, patients with an SDC of 0.5 to 0.8 ng per mL had lower rates of death and hospitalization than the control patients, and patients with an SDC of 1.2 ng per mL or greater had a higher rate of death than control patients. (5)

Recent research has also highlighted the importance of beta blockers in NYHA class II to IV heart failure, and spironolactone in NYHA class IV heart failure. Although approximately 60 to 70 percent of the patients in the major studies of metoprolol, (6) carvedilol, (7) and spironolactone (8) were taking digitalis, no retrospective or prospective information has been published on the impact of the addition of digitalis to therapy with ACE inhibitors, beta blockers, and spironolactone.

Heart Failure Classification Systems

NYHA functional classes ACC/AHA stages

I. Asymptomatic LVSD A. Asymptomatic high risk

II. Symptoms with moderate exertion B. LVSD without symptoms

III. Symptoms with mild exertion C. LVSD and symptomatic

heart failure

IV. Symptoms at rest D. End-stage heart failure

NYHA = New York Hospital Association; ACC = American College

of Cardiology; AHA = American Heart Association; LVSD = left

ventricular systolic dysfunction.


(1.) Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of congestive heart failure in patients in sinus rhythm. Cochrane Database Syst Rev 2003:CD002901.

(2.) Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001;38:2102-12.

(3.) Kasper EK. What’s new in the ACC/AHA guidelines for the evaluation and management of chronic heart failure in adults. Adv Studies Med 2003;3:14-21. Accessed September 2003 at: http://

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

(5.) Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz, HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289:871-8.

(6.) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-7.

(7.) Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-8.

(8.) Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.

RELATED ARTICLE: Cochrane abstract.

Background. Digitalis glycosides have been used clinically to treat CHF for more than 200 years. In recent years, several trials have been conducted to address concerns about the efficacy and potential toxicity of digitalis. Although a systematic review of the literature was published recently, an update is required to include more current trials.

Objectives. To examine the effectiveness of digitalis glycosides in treating CHF in patients with normal sinus rhythm and the effect of digitalis in patients taking diuretics, ACE inhibitors, and beta blockers; patients with varying severity and duration of disease; patients with prior exposure to digitalis compared with no prior exposure; and patients with diastolic versus systolic dysfunction.

Search Strategy. The authors (1) searched electronic databases from 1966 to 2000. Dissertation Abstracts and annual meeting abstracts of the American Heart Association, American College of Cardiology, and European Society of Cardiology were searched from 1996 to 2000. In addition, reference lists provided by Glaxo Wellcome Inc. were searched.

Selection Criteria. The authors included randomized, placebo-controlled trials of 20 or more adult patients with symptomatic CHF who were studied for seven weeks or more. They excluded trials in which the prevalence of atrial fibrillation was 2 percent or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of heart failure (e.g., acute ischemic heart disease, myocarditis) was present.

Data Collection and Analysis. Selected articles were reviewed by one of the coauthors and validated by staff from the central office of the Heart Collaborative Review Group in Bristol, U.K.

Primary Results. Eleven articles meeting the defined criteria were identified, and eight, four, and 10 of these trials had end points of mortality, hospitalization, and clinical status, respectively. The data show that there is no evidence of a difference in mortality rates between treatment and control groups, although digitalis therapy is associated with lower rates of hospitalization and clinical deterioration.

Reviewers’ Conclusions. The literature indicates that digitalis has a useful role in the treatment of patients with CHF who are in normal sinus rhythm.

These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in The Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (

William E. Cayley, Jr., M.D., M.Div., is assistant professor at the University of Wisconsin Eau Claire Family Practice Residency Program, Eau Claire.

Address correspondence to William E. Cayley, Jr., M.D., University of Wisconsin Eau Claire Family Practice Residency, 807 S. Farwell, Eau Claire, WI 54701 (e-mail: Reprints are not available from the author.

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