PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Int J Cardiol. Author manuscript; available in PMC 2010 July 22.
Published in final edited form as:
Int J Cardiol. 2009 July 24; 136(1): 91–92.
doi:  10.1016/j.ijcard.2008.06.083
PMCID: PMC2904633
NIHMSID: NIHMS133470

Low-Dose Digoxin and Reduction in Mortality and Morbidity in Heart Failure

Ali Ahmed, MD, MPH and Finn Waagstein, MD

We thank Drs. van Veldhuisen and de Boer for their insightful comments regarding our recent report based on the Digitalis Investigation Group (DIG) trial [1]. We agree that digoxin should continue to play an important role in the management of heart failure [2, 3]. However, unfortunately digoxin continues to be underutilized in clinical practice [4]. This may be due to a lack of scientific discussion at national meetings, a lack of industry promotion, and an overemphasis on mortality over hospitalization as outcomes [5]. This latter reason is particularly ironic as hospitalization due to worsening heart failure, common in heart failure, is reduced by digoxin regardless of serum concentrations or daily dosages [6]. The introduction of beta-blockers since the DIG trial may also have contributed to the underuse of digoxin [5].

Most heart failure patients are older adults and we agree that beta-blockers are safe and well tolerated in elderly systolic heart failure patients [710]. In the SENIORS trials, nebivolol significantly reduced the primary combined end point of all-cause mortality or cardiovascular hospitalization in elderly heart failure patients, but had no significant effect on individual components of that composite end point [7]. In the MERIT-HF trial, metoprolol extended release was as effective in the elderly as in the younger heart failure patients [9]. However, heart failure patients enrolled in major beta-blocker trials were over a decade younger than typical heart failure patients seen in clinical practice [4, 10].

Mortality and morbidity in contemporary heart failure patients receiving beta-blockers and other neurohormonal antagonists remain high and many subsequent clinical trials using other interventions have failed to further improve outcomes. Yet, the role of digoxin in these patients is often questioned as the DIG trial was conducted before the beta-blocker era of heart failure therapy. Although this issue can only be definitively resolved with a large randomized clinical trial of digoxin in contemporary heart failure patients receiving beta-blockers, data from post-hoc analysis of beta-blocker trials suggest that digoxin and carvedilol may be equally effective in the presence or absence of each other. Digoxin reduced the combined endpoint of all-cause death or all-cause hospitalization in patients receiving carvedilol (relative risk {RR}, 0.64; 95% confidence interval {CI}, 0.52 to 0.79) and placebo (RR, 0.82; 95% CI, 0.71 to 0.99) [11]. Carvedilol, on the other hand, had similar effect on combined endpoint in patients receiving (RR, 0.63; 95% CI, 0.52 to 0.75) and not receiving (RR, 0.80; 95% CI, 0.64 to 1.00) digoxin [11]. A plausible explanation of this synergy may be that by reducing digoxin-induced serious arrhythmias, beta-blockers enhance the effectiveness of digoxin, and by providing inotropic support, digoxin improves the tolerability for beta-blockers.

All major beta-blocker trials in heart failure excluded patients with diastolic heart failure, who constitute nearly half of all elderly heart failure patients. Data from the DIG ancillary trial suggest that digoxin may play a role in the management of diastolic heart failure [12]. The effects of digoxin in these patients were very similar to those of candesartan, the only other drug tested in diastolic heart failure in a large randomized clinical trial [5, 12]. Digoxin was better tolerated and patients receiving digoxin had fewer adverse effects than those receiving candesartan [5]. Digoxin is also inexpensive, an important consideration for millions of heart failure patients in the developing world, whose left ventricular ejection fraction often cannot be known.

The safety and effectiveness of digoxin in elderly heart failure patients has been documented in a post-hoc analysis of the DIG trial [13]. Findings from that analysis suggest that the use of digoxin in low doses (≤0.125 mg/day) was a strong predictor of low serum concentrations, which was significantly associated with reduced mortality and hospitalization in these patients [13]. However, in frail elderly heart failure patients with impaired kidney function, even a lower daily dose (0.125 mg every other day) may be preferable [13].

For a definite resolution of the role of digoxin in contemporary heart failure patients, a second multicenter randomized clinical trial of digoxin is warranted. This trial should be designed to include equal representations of men and women, whites and non-whites, and systolic and diastolic heart failure patients. However, there may not be enthusiasm in the industry to fund such a trial. We therefore hope that public international funding would be made available to support a definitive trial of digoxin in contemporary heart failure in the greater public health interest.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Contributor Information

Ali Ahmed, University of Alabama at Birmingham and VA Medical Center, Birmingham, AL, USA.

Finn Waagstein, Sahlgrenska University, Göteborg, Sweden.

References

1. Ahmed A, Pitt B, Rahimtoola SH, et al. Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial. Int J Cardiol. 2008;123:138–146. [PMC free article] [PubMed]
2. Gheorghiade M, van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation. 2006;113:2556–2564. [PubMed]
3. van Veldhuisen DJ. Low-dose digoxin in patients with heart failure. Less toxic and at least as effective? J Am Coll Cardiol. 2002;39:954–956. [PubMed]
4. Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and framework for future research. Circulation. 2005;112:3958–3968. [PubMed]
5. Ahmed A, Young JB, Gheorghiade M. The underuse of digoxin in heart failure, and approaches to appropriate use. CMAJ. 2007;176:641–643. [PMC free article] [PubMed]
6. 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;27:178–186. [PMC free article] [PubMed]
7. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS) Eur Heart J. 2005;26:215–225. [PubMed]
8. Dobre D, van Veldhuisen DJ, Mordenti G, et al. Tolerability and dose-related effects of nebivolol in elderly patients with heart failure: data from the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial. Am Heart J. 2007;154:109–115. [PubMed]
9. Deedwania PC, Gottlieb S, Ghali JK, Waagstein F, Wikstrand JC. Efficacy, safety and tolerability of beta-adrenergic blockade with metoprolol CR/XL in elderly patients with heart failure. Eur Heart J. 2004;25:1300–1309. [PubMed]
10. Ahmed A, Dell'Italia LJ. Use of beta-blockers in older adults with chronic heart failure. Am J Med Sci. 2004;328:100–111. [PubMed]
11. Eichhorn EJ, Lukas MA, Wu B, Shusterman N. Effect of concomitant digoxin and carvedilol therapy on mortality and morbidity in patients with chronic heart failure. Am J Cardiol. 2000;86:1032–1035. A10-1. [PubMed]
12. 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;114:397–403. [PMC free article] [PubMed]
13. Ahmed A. Digoxin and reduction in mortality and hospitalization in geriatric heart failure: importance of low doses and low serum concentrations. J Gerontol A Biol Sci Med Sci. 2007;62:323–329. [PMC free article] [PubMed]