Dr Rachel Bastiaenen, PhD, St George’s University of London, UK

Digoxin has been widely used in the rate control of atrial fibrillation (AF) and as a positive inotrope in heart failure, but it is hampered by drug interactions and a relatively narrow therapeutic window. Over time the prescription of digoxin has declined and guidelines have downgraded it to a second-line agent. This is due to multiple factors including increased use of newer drugs such as beta-blockers and ACE inhibitors with a strong evidence base for clinical effectiveness. It is also partly due to safety concerns after reports of digoxin associated increases in mortality.

The largest randomized controlled trial of digoxin in 6800 patients with heart failure by the Digitalis Investigation Group (DIG) demonstrated neutral effects on mortality and a reduction in hospital admissions overall compared to placebo, as well as decreased mortality among those with low serum digoxin concentration (1).

Subsequent observational studies have produced multiple conflicting results. One recent meta-analysis including 19 studies comprising 326,426 patients found digoxin use was associated with increased all-cause mortality (HR 1.21, 95%CI 1.21-1.39; p <0.01). In this meta-analysis digoxin use was associated with 29% increased mortality in patients with AF and 14% increased mortality in patients with heart failure (2). However a subsequent meta-analysis including 52 studies comprising 621,845 patients demonstrated a neutral effect on mortality in randomized controlled trials (RR 0.99, 95%CI 0.93-1.05; p=0.75) and a lower rate of hospital admissions across all study groups (RR 0.92, 95%CI 0.89-0.95; p <0.001). Although the mortality risk associated with digoxin across all groups was higher in unadjusted analyses, this effect was reduced by propensity matching and meta-regression confirmed that baseline differences between groups had a significant impact. Digoxin is particularly prone to prescription bias as clinicians tend to use it in sicker patients and statistical adjustment of observational data cannot remove all confounding factors (3).

So should we prescribe digoxin for our heart failure and AF patients or not? Some argue that contemporary randomized controlled trials in the era of the newer drugs are required before that question can be adequately answered. When prescribing digoxin close monitoring of plasma levels should be performed and physicians should be aware of potential drug interactions including amiodarone.

References

  1. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–33.
  2. Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: A systematic review and meta-analysis of the literature. Eur Heart J 2015;36(28):1831-8.
  3. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ : British Medical Journal. 2015;351:h4451.
Cardio Debate Expert Comments

Digoxin is one of the oldest drugs in cardiovascular medicine and it has been traditionally used in patients with atrial fibrillation (AF) and heart failure (HF). In the last 20 years, however, the use of this pharmacological agent has declined markedly.  In the most recent International guidelines for HF (European Society of Cardiology 2012, ASHF 2013), however,  it is  clearly stated that for patients with HF and reduced left ventricular ejection fraction (LVEF) ≤40%, who are in sinus rhythm, ‘digoxin may be used’.  Interestingly, the results of the Digitalis Investigation Group (DIG) trial, represent a strong influence regarding current recommendations. The DIG Study assessed the effect of digoxin on clinical outcomes in 6800 patients with HF. Despite the lack of beneficial effects in patients with atrial fibrillation, the study reported that digoxin is effective for long-term heart rate control at rest (albeit not during exercise).

More recently, the AFFIRM trial concluded that digoxin is associated with an increase in all-cause mortality, and that these findings should call into question the widespread use of digoxin in patients with AF. In this population, other drugs, beta-blockers in particular, have been shown to have more beneficial effects

Contrary to the AFFIRM Study, during the past 2016 ESC Congress in London, a presentation from Fauchier  at the “Highlights” session, suggested that digoxin use "as a rate-control drug has been proposed in patients with HF and AF or in sedentary patients with AF, but is no longer a class 1 indication in recent HF guidelines." He added that past studies examining risk of all-cause and CV mortality in AF patients using this drug "have reported conflicting results, with most not being able to take into account the severity of possible associated heart failure."

In my view, digoxin is still useful in patients with HF and EF <40% and in sinus rhythm; not as an inotropic drug, but as a neuro-hormonal modulator, when given in low doses. Low-dose digoxin may still be useful but well designed, large, trials are still required to examine this question thoroughly and comprehensively. Only when these studies are carried out we will gain insight as to whether the use of digoxin in patients with AF is useful, useless or dangerous.

In 1785, William Withering wrote about digoxin, “… After all, in spite of opinion, prejudice or error, TIME will fix the real value upon the discovery, and determine whether I have imposed upon myself and others, or contributed to the benefit of science and mankind”

As we read in this commentary by Dr Bastiaenen, it is clear that after more than 200 years, time has not fixed the role of digoxin as a therapeutic agent, especially in atrial fibrillation.

The best available evidence on clinical outcomes for the use of digoxin in atrial fibrillation comes from observational studies or from post-hoc analyses of clinical trials designed to answer other questions. Thus, the evidence is controversial. Some studies have shown increase in mortality if patients receiving digoxin in atrial fibrillation and others have not.

What should clinicians do regarding possible risks with digoxin in patients with atrial fibrillation?

Digoxin should not be the first choice to treat atrial fibrillation for several reasons.

First, since digoxin exerts its rate-controlling effects via enhancement of vagal tone, a mechanism that is easily overcome by exercise and other high catecholamine states. Therefore, patients on digoxin do not have an excellent rate control.

Second, it is also known that digoxin has a narrow therapeutic window, and that adverse effects, including mortality, are related to higher serum levels and thus safety continues to be an important problem.

Finally, should a clinician never use digoxin for rate control in atrial fibrillation? Such a recommendation cannot be made on the basis of this kind of observational data. There are still some clinical scenarios, such as patients with heart failure and atrial fibrillation, difficult rate control and patients with low blood pressure in which this agent may be useful.

In conclusion, I will agree with Dr. Bastiaenen that based on the potential risks and benefits, as well as the presence of alternative drugs, there is a limited role for digoxin in the management of patients with atrial fibrillation. The proper role of digoxin is less certain in other subgroups of patients, such as those with both atrial fibrillation and systolic congestive heart failure or after a myocardial infarction.

After the first scientific description o­f Purple Foxglove derived digitalis made by William Withering in 1775, the drug reigned ­undisputed for more than two centuries. Interestingly, the first randomized trial with the use of this agent aiming to clarify the role of digoxin in the management of heart failure (HF) was published only in 1997.  It showed no benefit regarding mortality albeit its use was associated with a decrease in hospitalization rate. Since the publication of these data, digoxin was no longer considered to be first line therapy in HF.

The situation is even more ­­surprising regarding its use in atrial fibrillation (AF) as despite the widespread use of digoxin for rate control for many decades, there have been no controlled randomized studies to elucidate the effect of digoxin on clinical outcomes. All the evidence available in this regard has derived from observational studies, cohort analyses or post-hoc subgroup analyses. Of importance, several retrospective analysis, meta-analysis and systematic reviews have shown an increased in mortality rates in AF patients -with or without HF- receiving treatment with digoxin [1]–[9]. In addition, the lack of efficacy of digoxin in the control of exercise induced tachycardia [10] and the high hospitalization rate related to adverse effects of digoxin [11] have both contributed to the reduced use of this agent in clinical practice. However, the situation is not that clear as several studies failed to demonstrate a negative association between digoxin and clinical outcomes albeit they confirmed the drug’s adverse effects [12], [13]. One extensive meta-analysis [14] recently discussed in “Cardio-Debate” by Dr Bastiaenen, addresses these issues. How should the clinician interpret these controversial findings? Differences in patient selection, study design, type of analysis performed and statistical method used can explain the discrepancies. None of the recent studies has clearly assessed the impact of digoxin serum level on the clinical results. It therefore is quite difficult to establish whether the guilty part is digoxin (with a narrow therapeutic window and many known adverse effects) or the patient – elderly subjects with heart failure and other major comorbidities. From a clinical perspective, until a more definitive answer is obtained regarding the risks associated with the use of digoxin, patients considered to require treatment with this agent should be characterised carefully and closely monitored, including the assessment of digoxin plasma levels, as emphasized in Dr. Bastiaenen’s paper. Albeit the time to attend digoxin’s funeral has not yet come, the “old lady” seems to be approaching retirement at a fast pace.

References

[1]     M. P. Turakhia, P. Santangeli, W. C. Winkelmayer, X. Xu, A. J. Ullal, C. T. Than, S. Schmitt, T. H. Holmes, S. M. Frayne, C. S. Phibbs, F. Yang, D. D. Hoang, P. M. Ho, and P. A. Heidenreich, “Increased Mortality Associated With Digoxin in Contemporary Patients With Atrial Fibrillation,” J. Am. Coll. Cardiol., vol. 64, no. 7, pp. 660–668, 2014.

[2]     J. V. Freeman, J. Yang, S. H. Sung, M. a. Hlatky, and A. S. Go, “Effectiveness and safety of digoxin among contemporary adults with incident systolic heart failure,” Circ. Cardiovasc. Qual. Outcomes, vol. 6, no. 5, pp. 525–533, 2013.

[3]     M. G. Whitbeck, R. J. Charnigo, P. Khairy, K. Ziada, A. L. Bailey, M. M. Zegarra, J. Shah, G. Morales, T. Macaulay, V. L. Sorrell, C. L. Campbell, J. Gurley, P. Anaya, H. Nasr, R. Bai, L. Di Biase, D. C. Booth, G. Jondeau, A. Natale, D. Roy, S. Smyth, D. J. Moliterno, and C. S. Elayi, “Increased mortality among patients taking digoxin--analysis from the AFFIRM study,” Eur. Heart J., vol. 34, no. 20, pp. 1481–1488, 2013.

[4]     A.-J. Ouyang, Y.-N. Lv, H.-L. Zhong, J.-H. Wen, X.-H. Wei, H.-W. Peng, J. Zhou, and L.-L. Liu, “Meta-Analysis of Digoxin Use and Risk of Mortality in Patients With Atrial Fibrillation,” Am. J. Cardiol., vol. 115, no. 7, pp. 901–906, 2015.

[5]     T.-F. Chao, C.-J. Liu, T.-C. Tuan, S.-J. Chen, K.-L. Wang, Y.-J. Lin, S.-L. Chang, L.-W. Lo, Y.-F. Hu, T.-J. Chen, C.-E. Chiang, and S.-A. Chen, “Rate-Control Treatment and Mortality in Atrial FibrillationCLINICAL PERSPECTIVE,” Circulation, vol. 132, no. 17, pp. 1604–1612, 2015.

[6]     M. Vamos, J. W. Erath, and S. H. Hohnloser, “Digoxin-associated mortality: a systematic review and meta-analysis of the literature,” Eur. Heart J., vol. 36, no. 28, pp. 1831–1838, 2015.

[7]     Y.-G. M. Wang, Zhi-Quan MD; Zhang, Rui MD; Chen, Man-Tian MD; Wang, Qun-Shan MD; Zhang, Yi MD; Huang, Xiao-Hong MD; Wang, Jun MD; Yan, Jian-Hua MD; Li, “Digoxin Is Associated With Increased All-cause Mortality in Patients With Atrial Fibrillation Regardless of Concomitant Heart Failure: A Meta-analysis.,” J. Cardiovasc. Pharmacol., vol. 66, no. 3, pp. 270–275, 2015.

[8]     J. B. Washam, S. R. Stevens, Y. Lokhnygina, J. L. Halperin, G. Breithardt, D. E. Singer, K. W. Mahaffey, G. J. Hankey, S. D. Berkowitz, C. C. Nessel, K. A. A. Fox, R. M. Califf, J. P. Piccini, and M. R. Patel, “Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in,” Lancet, vol. 385, no. 9985, pp. 2363–2370, 2015.

[9]     S. Virgadamo, “Digoxin: A systematic review in atrial fibrillation, congestive heart failure and post myocardial infarction,” World J. Cardiol., vol. 7, no. 11, p. 808, 2015.

[10]   P. Isabelle C. Van Gelder, MD, PhD; Anne H. Hobbelt, MD; Bart A. Mulder, MD and P. Michiel Rienstra, MD, “Rate Control in Atrial Fibrillation Many Questions Still Unanswered,” Circ. 2015;1321597-1599., vol. 132, pp. 1597–1599, 2015.

[11]   B. D.S., L. M.C., S. N., and R. C.L., “Emergency hospitalizations for adverse drug events in older Americans,” N. Engl. J. Med., vol. 365, no. 21, pp. 2002–2012, 2011.

[12]   S. Chamaria, A. M. Desai, P. C. Reddy, B. Olshansky, and P. Dominic, “Digoxin Use to Control Ventricular Rate in Patients with Atrial Fibrillation and Heart Failure Is Not Associated with Increased Mortality,” vol. 2015, 2015.

[13]   M. Gheorghiade, G. C. Fonarow, D. J. van Veldhuisen, J. G. F. Cleland, J. Butler, A. E. Epstein, K. Patel, I. B. Aban, W. S. Aronow, S. D. Anker, and A. Ahmed, “Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial,” Eur. Heart J., vol. 34, no. 20, pp. 1489–1497, 2013.

[14]   O. J. Ziff, D. A. Lane, M. Samra, M. Griffith, P. Kirchhof, G. Y. H. Lip, R. P. Steeds, J. Townend, and D. Kotecha, “Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data,” Bmj, p. h4451, 2015.