Assumption versus evidence: the case of digoxin in atrial fibrillation and heart failure

Despite development of new and innovative medical therapies, still millions of patients with chronic heart failure (HF) with reduced ejection fraction and/or atrial fibrillation (AF) are treated with cardiac glycosides (overall 122 millions of patients defined daily dose prescriptions 2013 in Germany).1 Randomized evidence for efficacy of this treatment strategy is, however, sparse. For HF with reduced ejection fraction (HFrEF), the only randomized controlled outcome trial (RCT) of reasonable size is the DIG trial.2 Although the DIG Trial could not demonstrate a benefit on total mortality in the overall trial population, hospitalization for worsening of HF was significantly reduced. Moreover, subgroup analysis suggested a benefit on total mortality in patients with low plasma levels of digoxin.3,4 Randomized controlled outcome trials prospectively investigating the impact of digoxin on mortality and morbidity in patients with AF are not available. In the very recent past, quite a number of cohort studies, post hoc analyses of RCTs (initiated to investigate other treatments), and meta-analyses,5–11 which are all liable to prescription bias as randomization was not targeting digoxin therapy,12 retrospectively investigated whether digoxin treatment would eventually increase mortality in AF. These analyses surely are invaluable sources to generate important hypotheses to be investigated in prospective RCTs, which are costly, time consuming, and in need of high resources. However, it is very important to interpret their results with caution, and potential sources of bias require careful assessment and discussion. The AFFIRM study originally investigated survival outcome of patients with AF randomized to treatment for either rate (defined as therapy with beta blocker, calcium-channel blocker, digoxin, and combinations of these drugs) or rhythm control (antiarrhythmic drug use upon discretion of the treating physician).13 Rhythm control did not offer advantages over rate control. In a first post hoc analysis of …