Peroral Digoxin for Controlling Heart Rate in Atrial Fibrillation

Summary

A systematic review 1 included 45 studies with a total of 2 059 subjects. Seven studies with a total of 389 subjects compared digoxin versus placebo; of them 3 studies (n=69) used peroral digoxin with a study duration from 10 days to 4 weeks; 2 studies administered peroral digoxin only once; and 2 studies used intravenous digoxin for rate control in atrial fibrillation. Two of the 3 studies using peroral digoxin more than once, reported a significant reduction in heart rate at rest with digoxin. One study evaluating digoxin during exercise did not find a significant heart rate reduction and another study suggested a difference, but no measure of statistical significance was provided, and the third study did not find any reduction of heart rate with digoxin during exercise.

A post hoc analysis of the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial 2 included 4 060 subjects. The AFFIRM trial enrolled patients with atrial fibrillation (AF) considered at high risk for stroke, and randomized them to rate control vs. rhythm control over a 4-year period with a mean follow-up of 3.5 years. The AFFIRM trial was designed to compare rhythm control to rate control and did not, therefore, randomize patients to digoxin therapy. The association between digoxin and mortality was assessed by using Cox proportional hazards models adjusting for clinical characteristics and comorbidities. Analyses were conducted in all patients and in subsets according to the presence or absence of heart failure (HF). Digoxin was associated with a 41% increase in deaths from any cause (estimated hazard ratio, EHR 1.41, 95% CI 1.19 to 1.67), after controlling for other medications and risk factors, and that an increase in deaths occurred regardless of gender or the presence or absence of underlying heart failure. Digoxin was also associated with a 35% increase in deaths from cardiovascular causes (EHR 1.35, 95% CI 1.06 to 1.71), and a 61% increase in deaths from arrhythmias (EHR 1.61, 95% CI 1.12 to 2.30). Routine monitoring of digoxin levels was not mandated nor recorded in the AFFIRM trial, and it was not possible to assess whether serum digoxin levels were predictive of mortality outcomes. No specific digoxin dosing recommendations were provided by the AFFIRM protocol and individual doses were not available.

Another post hoc analysis of the AFFIRM study was performed. 4060 patients with paroxysmal and persistent AF were randomized to rate (n = 2027) vs. rhythm (n = 2033) control strategies in the AFFIRM study. Of these, 1377 received digoxin as initial therapy and 1329 received no digoxin at baseline. Propensity scores for digoxin use were estimated for each of these 2706 patients and used to assemble a cohort of 878 pairs of patients receiving and not receiving digoxin, who were balanced on 59 baseline characteristics. Matched patients had a mean age of 70 years, 40% were women, and 11% non-white. During the 3.4 years of the mean follow-up, all-cause mortality occurred in 14 and 13% of matched patients receiving and not receiving digoxin, respectively (HR with digoxin use 1.06, 95% CI 0.83 to 1.37). Among matched patients, digoxin had no association with all-cause hospitalization (HR 0.96, 95% CI 0.85 to 1.09) or incident non-fatal cardiac arrhythmias (HR 0.90, 95% CI 0.37 to 2.23).