Prof Juan Carlos Kaski, St George's, University of London, UK

In subjects with atrial fibrillation (AF) who are at an increased risk of falling, anticoagulation is often regarded as problematic and not infrequently avoided, in many cases, despite a clear indication for its use. Recommendations in this specific group of patients are based on expert consensus but not on objective trial data. Recently, the ENGAGE AF–TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48) trial specifically assessed the “relative efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation judged to be at increased risk of falling”. (1) – The identification of patients at risk of falling was rather subjective in the study and may have introduced a degree of selection bias.

The authors performed a pre-specified analysis comparing patients with versus without increased risk of falling. This was a large study with 900 patients (4.3%) considered to be at increased risk of suffering a fall. These patients were found to be older (median, 77 vs. 72 years; p < 0.001), and had more comorbidities including the following: a history stroke/transient ischemic attacks, diabetes mellitus, and ischemic heart disease. As expected, patients at increased risk of falling had more fractures as a result of falling (adjusted hazard ratio [HR]: 1.88; 95% confidence interval [CI]: 1.49 to 2.38; p < 0.001), major bleeding (HR: 1.30; 95% CI: 1.04 to 1.64; p 1⁄4 0.023). These patients also had more life-threatening bleeding (HR: 1.67; 95% CI: 1.11 to 2.50; p 1⁄4 0.013), and increased all-cause mortality (HR : 1.45; 95% CI: 1.23 to 1.70; p < 0.001).  Ischemic events such as stroke (HR: 1.16; 95% CI: 0.89 to 1.51; p 1⁄4 0.27) were not higher in these subjects. The authors reported that “treatment with edoxaban resulted in a greater absolute risk reduction in severe bleeding events and all-cause mortality compared with warfarin”. (1)

A critical assessment of the study results (1) by Elaine M. Hylek and Darae Ko, (2) highlighted the fact that patients at increased risk of falling were not randomised and the optimal choice of anticoagulant for patients who are prone to falling cannot be definitively answered by this study. Hylek and Ko however agree that “biologically, the non-vitamin K oral anticoagulants (NOACs) should have an advantage as their mode of action does not affect factor VII”.

The findings of ENGAGE AF–TIMI 48, if confirmed in further large, multicentre studies may trigger a paradigm change in the management of AF in real life clinical practice. This as a result of the main findings in the study (1) that the use of edoxaban was associated with a greater absolute reduction in severe bleeding events and mortality.


  1. Steffel J et al. J Am Coll Cardiol 2016; 68:1169–78
  2. Hylek EM and Ko D. J Am Coll Cardiol 2016; 68:1179–80