Use of digoxin in heart failure with reduced ejection fraction
- Wilson S Colucci, MD
Wilson S Colucci, MD
- Section Editor — Heart Failure
- Professor of Medicine
- Boston University School of Medicine
- Lynne Sylvia, PharmD
Lynne Sylvia, PharmD
- Senior Clinical Pharmacy Specialist, Tufts Medical Center
- Clinical Professor, Northeastern University, School of Pharmacy
Digitalis has been used for over 200 years to treat patients with heart failure (HF). Evidence from clinical trials supports the use of digoxin (the most widely used formulation of digitalis) to improve symptoms and reduce hospitalization in patients with HF with reduced left ventricular ejection fraction (LVEF ≤40 percent; HFrEF), particularly in patients with more advanced symptoms, but a survival benefit was not demonstrated [1,2]. (See 'Evidence' below.)
The use of digoxin in treating HFrEF will be reviewed here. The use of digoxin in this setting should be considered in the context of comprehensive management of HFrEF . (See "Overview of the therapy of heart failure with reduced ejection fraction".)
MECHANISM OF ACTION
Digoxin acts by inhibiting the Na-K-ATPase pump, thus reducing the transport of sodium from the intracellular space in myocytes  as well as noncardiac cells to the extracellular space . This mechanism contributes to digoxin’s hemodynamic, neurohumoral, and electrophysiologic effects .
Hemodynamic effects — In myocytes, increased intracellular sodium (resulting from Na-K-ATPase inhibition by digoxin) reduces sodium-calcium exchange (which normally causes calcium extrusion from the cell), leading to a rise in the intracellular calcium concentration. This results in improved isolated myocyte contractile performance (increased shortening velocity) and improved overall left ventricular (LV) systolic function [4,6].
Several small trials have examined the short-term hemodynamic efficacy of digoxin in patients with systolic HF using invasive monitoring [7-9]. These studies showed that the administration of 1 mg of intravenous digoxin resulted in an acute improvement in cardiac output, LV stroke work index, mean pulmonary capillary wedge pressure (PCWP), pulmonary artery diastolic pressure, and right atrial pressure, either at rest or with exercise.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Gheorghiade M, van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation 2006; 113:2556.
- Ambrosy AP, Butler J, Ahmed A, et al. The use of digoxin in patients with worsening chronic heart failure: reconsidering an old drug to reduce hospital admissions. J Am Coll Cardiol 2014; 63:1823.
- WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128:e240.
- Smith TW. Digitalis. Mechanisms of action and clinical use. N Engl J Med 1988; 318:358.
- Gheorghiade M, Ferguson D. Digoxin. A neurohormonal modulator in heart failure? Circulation 1991; 84:2181.
- McMahon WS, Holzgrefe HH, Walker JD, et al. Cellular basis for improved left ventricular pump function after digoxin therapy in experimental left ventricular failure. J Am Coll Cardiol 1996; 28:495.
- Gheorghiade M, St Clair J, St Clair C, Beller GA. Hemodynamic effects of intravenous digoxin in patients with severe heart failure initially treated with diuretics and vasodilators. J Am Coll Cardiol 1987; 9:849.
- Gheorghiade M, Hall V, Lakier JB, Goldstein S. Comparative hemodynamic and neurohormonal effects of intravenous captopril and digoxin and their combinations in patients with severe heart failure. J Am Coll Cardiol 1989; 13:134.
- Ribner HS, Plucinski DA, Hsieh AM, et al. Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: a hemodynamic-hormonal study. Am J Cardiol 1985; 56:896.
- Arnold SB, Byrd RC, Meister W, et al. Long-term digitalis therapy improves left ventricular function in heart failure. N Engl J Med 1980; 303:1443.
- Ferguson DW, Abboud FM, Mark AL. Selective impairment of baroreflex-mediated vasoconstrictor responses in patients with ventricular dysfunction. Circulation 1984; 69:451.
- Schobel HP, Oren RM, Roach PJ, et al. Contrasting effects of digitalis and dobutamine on baroreflex sympathetic control in normal humans. Circulation 1991; 84:1118.
- Ferguson DW, Berg WJ, Sanders JS, et al. Sympathoinhibitory responses to digitalis glycosides in heart failure patients. Direct evidence from sympathetic neural recordings. Circulation 1989; 80:65.
- Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311:819.
- Cohn JN, Johnson GR, Shabetai R, et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. The V-HeFT VA Cooperative Studies Group. Circulation 1993; 87:VI5.
- Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 1986; 73:257.
- Alicandri C, Fariello R, Boni E, et al. Captopril versus digoxin in mild-moderate chronic heart failure: a crossover study. J Cardiovasc Pharmacol 1987; 9 Suppl 2:S61.
- Krum H, Bigger JT Jr, Goldsmith RL, Packer M. Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure. J Am Coll Cardiol 1995; 25:289.
- van Veldhuisen DJ, Man in 't Veld AJ, Dunselman PH, et al. Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT). J Am Coll Cardiol 1993; 22:1564.
- Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37:2129.
- Lee DC, Johnson RA, Bingham JB, et al. Heart failure in outpatients: a randomized trial of digoxin versus placebo. N Engl J Med 1982; 306:699.
- Guyatt GH, Sullivan MJ, Fallen EL, et al. A controlled trial of digoxin in congestive heart failure. Am J Cardiol 1988; 61:371.
- Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. The Captopril-Digoxin Multicenter Research Group. JAMA 1988; 259:539.
- Double-blind placebo-controlled comparison of digoxin and xamoterol in chronic heart failure. The German and Austrian Xamoterol Study Group. Lancet 1988; 1:489.
- DiBianco R, Shabetai R, Kostuk W, et al. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 1989; 320:677.
- Fleg JL, Rothfeld B, Gottlieb SH. Effect of maintenance digoxin therapy on aerobic performance and exercise left ventricular function in mild to moderate heart failure due to coronary artery disease: a randomized, placebo-controlled, crossover trial. J Am Coll Cardiol 1991; 17:743.
- Uretsky BF, Young JB, Shahidi FE, et al. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol 1993; 22:955.
- Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993; 329:1.
- Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336:525.
- Adams KF Jr, Gheorghiade M, Uretsky BF, et al. Patients with mild heart failure worsen during withdrawal from digoxin therapy. J Am Coll Cardiol 1997; 30:42.
- Adams KF Jr, Gheorghiade M, Uretsky BF, et al. Clinical predictors of worsening heart failure during withdrawal from digoxin therapy. Am Heart J 1998; 135:389.
- Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991; 325:1468.
- Rich MW, McSherry F, Williford WO, et al. Effect of age on mortality, hospitalizations and response to digoxin in patients with heart failure: the DIG study. J Am Coll Cardiol 2001; 38:806.
- Davies RF, Beanlands DS, Nadeau C, et al. Enalapril versus digoxin in patients with congestive heart failure: a multicenter study. Canadian Enalapril Versus Digoxin Study Group. J Am Coll Cardiol 1991; 18:1602.
- Alicandri C, Fariello R, Boni E, et al. Ibopamine vs. digoxin in chronic heart failure: a double-blind, crossover study. J Cardiovasc Pharmacol 1989; 14 Suppl 8:S77.
- Packer M. Vasodilator and inotropic drugs for the treatment of chronic heart failure: distinguishing hype from hope. J Am Coll Cardiol 1988; 12:1299.
- Sullivan M, Atwood JE, Myers J, et al. Increased exercise capacity after digoxin administration in patients with heart failure. J Am Coll Cardiol 1989; 13:1138.
- Tanabe Y, Takahashi M, Momotsu T, et al. Effect of digoxin on exercise performance in mildly symptomatic patients with idiopathic dilated cardiomyopathy and sinus rhythm. Jpn Heart J 1994; 35:301.
- Ahmed A, Rich MW, Fleg JL, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation 2006; 114:397.
- Rubinow A, Skinner M, Cohen AS. Digoxin sensitivity in amyloid cardiomyopathy. Circulation 1981; 63:1285.
- Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005; 112:2047.
- DiDomenico RJ, Bress AP, Na-Thalang K, et al. Use of a simplified nomogram to individualize digoxin dosing versus standard dosing practices in patients with heart failure. Pharmacotherapy 2014; 34:1121.
- Bauman JL, DiDomenico RJ, Viana M, Fitch M. A method of determining the dose of digoxin for heart failure in the modern era. Arch Intern Med 2006; 166:2539.
- Adams KF Jr, Ghali JK, Herbert Patterson J, et al. A perspective on re-evaluating digoxin's role in the current management of patients with chronic systolic heart failure: targeting serum concentration to reduce hospitalization and improve safety profile. Eur J Heart Fail 2014; 16:483.
- Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289:871.
- Goldberger ZD, Goldberger AL. Therapeutic ranges of serum digoxin concentrations in patients with heart failure. Am J Cardiol 2012; 109:1818.
- Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J 2006; 27:178.
- Adams KF Jr, Patterson JH, Gattis WA, et al. Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis. J Am Coll Cardiol 2005; 46:497.
- Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002; 347:1403.
- MECHANISM OF ACTION
- Hemodynamic effects
- Neurohumoral effects
- Electrophysiologic effects
- Our approach
- - Worsened symptoms with digoxin withdrawal
- - Symptomatic benefit from digoxin
- When to avoid
- Evaluation for contraindications and cautions
- Baseline and follow-up testing
- Digoxin dosing
- - Standard initial dose
- - Nomogram-based method
- Digoxin level
- - When to check digoxin levels
- - Target level
- - How to monitor levels and adjust digoxin dose
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS