Increased mortality among patients taking digoxin—analysis from the AFFIRM study

We thank Dr. Horowitz for his interest in our publication and for raising thoughtful points of discussion. Dr. Horowitz proposes that the results of our AFFIRM substudy should suggest that high doses of digoxin are inappropriate in atrial fibrillation, while lower doses are safe and beneficial. Unfortunately, this hypothesis cannot be confirmed by our data. While a growing body of literature supports the association between high serum digoxin levels and increased mortality, purported salutary effects with lower doses remain contentious. The only data to support this assertion come from a substudy of the Dig trial [1] in which the main intention-to-treat analysis failed to demonstrate a mortality reduction with digoxin. Although a post-hoc analysis suggested a potential survival benefit with low serum levels of digoxin [2], this observational study is subject to several limitations. For example, beta blockers, which may attenuate digoxin's neurohormonal effects, were not widely prescribed to treat patients with heart failure. It remains uncertain whether such results would be reproducible in the current era. Moreover, the Dig trial included a very different population than AFFIRM [3], as only patients with an ejection fraction <40% and sinus rhythm were enrolled. Results cannot, therefore, be extrapolated to a population with atrial fibrillation and predominantly preserved left ventricular function in whom digoxin's potentially advantageous neurohormonal or inotropic properties may be expected to be of little value. Importantly, our findings do not exclude the possibility that the judicious use of digoxin may be safe in certain subpopulations of patients with atrial fibrillation, such as those with heart failure. On the whole, the AFFIRM real world experience is alarming in that the association between digoxin and mortality was of large magnitude and coherent across various analyses. At a minimum, it appears reasonable to conclude that the widespread use of digoxin should be questioned in patients with atrial fibrillation. Furthermore, these results are consistent with findings from a large prospective cohort study [4]. In light of the concerns raised by this and other studies, it appears reasonable to discourage rate control with digoxin as a single first line agent, especially when other safe and inexpensive alternatives such as beta blockers or calcium blockers are readily available.

Matthew G. Whitbeck,M.D, Paul Khairy,M.D*, and Claude S. Elayi,M.D University of Kentucky: Lexington, KY; US Centre Hospitalier Universite de Montreal: Montreal, Canada* 1. The 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. 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(7):871-8. 3. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ,Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC,Dalquist JE, Corley SD, Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347(23):1825-33 4 .Hallberg P, Lindb?ck J, Lindahl B, Stenestrand U, Melhus H, RIKS-HIA group. Digoxin and mortality in atrial fibrillation: A prospective cohort study. Eur J Clin Pharmacol 2007; 63(12):1201-2.

Conflict of Interest:

None declared

10th December, 2012

Re: Whitbeck et al : Increased mortality among patients taking digoxin - analysis from the AFFIRM study.

The report by Whitbeck et al(1) demonstrates that the use of digoxin in AFFIRM was associated with a significant increase in all-cause mortality, and it is therefore suggested that the widespread use of digoxin in such patients should be questioned. Perhaps a more appropriate conclusion would be that utilization of digoxin except in low doses may be inappropriate in atrial fibrillation.

The data available on the digoxin treatment regimes utilized in AFFIRM are very limited. No details are available, critically, related to monitoring of serum digoxin concentrations other than the generality that serum levels of digoxin were encouraged to be >1.0 ng/ml.

The authors quote the results of the DIG trial(2) to suggest that digoxin has a neutral effect on mortality "but only in the setting of strict monitoring of serum drug levels". However, the data from the DIG trial have served to demonstrate that digoxin reduces mortality in concentrations below 1 ng/ml, and increases mortality in higher concentrations(3). These findings have led to a downwards adjustment of the therapeutic range for digoxin worldwide.

If indeed most patients in AFFIRM had serum digoxin concentrations >1 ng/ml, the associated increase in mortality is therefore hardly surprising.

Given that the premise for such aggressive dosing with digoxin was presumably a desire for strict rate control, which turns out to be in no way obligatory(4), it might be appropriate for the authors to reconsider the relevance of their conclusions to current patterns of utilization of digoxin.

J D Horowitz MBBS, PhD, FRACP Director, Cardiology/Clinical Pharmacology Queen Elizabeth Hospital Professor of Cardiology University of Adelaide

References

1. Whitbeck MG et al. Increased mortality among patients taking dioxin-analysis from the AFFIRM study. 2012

2. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med, 336:525-533, 1997.

3. Adams KF Jr et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol. 39:946-543, 2002.

4. Van Gelder IC et al. Rate control versus electric rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Eng J Med. 347:1834-1940, 2002.

Conflict of Interest:

None declared