Beware Digoxin for Atrial Fibrillation

[[{"type":"media","view_mode":"media_crop","fid":"59319","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_6759991910597","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"7503","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"height: 349px; width: 250px; float: right;","title":" ","typeof":"foaf:Image"}}]]Digoxin was first isolated in 1930 from the foxglove plant and has had been used for many years in the treatment of atrial arrhythmias as well as for heart failure indications. While it has long been a staple in the cardiac pharmacopeia, there is increasing evidence that digoxin may be associated with higher mortality in heart failure patients. Specifically, prior studies have demonstrated that higher serum concentrations of digitalis are associated with higher mortality in patients with HF and LVEF ≤45%.¹ The authors suggest targeting a digoxin level between 0.5-0.8 ng/mL. A recent analysis presented at the American College of Cardiology Scientific Sessions 2017 posed the same question about the impact of digoxin levels on mortality among patients with atrial fibrillation. Data was obtained from the ARISTOTLE trial of apixaban vs warfarin.

The ARISTOTLE trial randomized 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke to apixaban or warfarin with the addition of digoxin left to the discretion of the investigator. Of the total number of patients, 17,897 (98%) had serum digoxin levels during the study. At the beginning of the trial, approximately 25% of patients had heart failure and 33% were already taking digoxin. Propensity score matching was used to compare patients who were and weren’t on digoxin. Renal function was factored into all analyses.

The risk of death in patients with atrial fibrillation in the trial was directly proportional to serum digoxin level with every 0.5 ng/mL increase in digoxin level, increasing the risk of death by 19%. A digoxin level of >1.2 ng/mL was associated with an increase in mortality of 56%. Additional “prevalence” analysis was conducted to compare those who started digoxin during the trial with propensity-matched controls. Starting digoxin during the course of the trial increased the risk of all-cause death by 78% as well as the risk of sudden death. These findings were true regardless of the presence of heart failure or left ventricular dysfunction. The authors even attempted to match all variables, such as in which setting digoxin was started (ie, hospital or office-based) in order to account for confounding with “sicker” patients receiving digoxin. There was no interaction with apixaban and digoxin, and apixaban was superior to warfarin, regardless of the use of digoxin.

Digoxin is used in nearly 30% of patients with atrial fibrillation worldwide, even though no randomized clinical trials exist to assess its use in this setting.³ And so, while the current study is subject to the limitations of a post-hoc non-randomized observational analysis, the significant findings suggest important clinical conclusions for the physician treating atrial fibrillation, regardless of the presence of heart failure:

 ^► Digoxin should be used sparingly for rate control or symptom management in atrial fibrillation.

 ^► Serum digoxin levels are associated with a linear increase in mortality with every 0.5 ng/ml increasing death by 19%.

 ^► If treatment is started, attempt to keep digoxin levels ≤1.1 ng/ml, after which mortality has a dramatic increase.

 ^► There may be an increase in sudden death due to a proarrhythmic effect of digoxin.

References:

• Rathore et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289:871-878. doi:10.1001/jama.289.7.871. https://www.ncbi.nlm.nih.gov/pubmed/?term=JAMA.+2003%3B289%3A871-878.
• Lopes R, et al. Digoxin and Mortality in Patients with Atrial Fibrillation with and without Heart Failure: Does Serum Digoxin Concentration Matter?" Presented at the 2017 American College of Cardiology Scientific Sessions on  March 19, 2017; abstact 411-10, at 10:45 a.m. ET in the Main Tent (Hall D).
• Washam JB, Stevens SR, Lokhnygina Y, et al; ROCKET AF Steering Committee and Investigators.  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 Atrial Fibrillation (ROCKET AF). Lancet. 2015;385:2363-70. doi: 10.1016/S0140-6736(14)61836-5. Epub 2015 Mar 6.