Reply to 'Digoxin and beta-blockers in patients with heart failure'. Letter regarding the article 'Clinical outcomes with digoxin vs. beta-blocker for heart rate control in permanent atrial fibrillation with heart failure'.

Abstract

We thank Dr. Čulić for his comment on our research letter about clinical outcomes with digoxin versus beta-blocker for heart rate control in atrial fibrillation with heart failure.1 It has indeed been suggested in the literature that sex and age differences in the outcomes may exist both with digoxin or beta-blocker use when treating patients with heart failure. Considering our main finding that among matched patients with permanent atrial fibrillation and heart failure, there was no statistically significant difference in the risk of all-cause death, cardiovascular mortality and major clinical events between those treated with digoxin or beta-blocker, we think it is worth presenting an additional analysis about interaction possibly related to sex (Table 1) and age below or above 75 (Table 2) for the matched analysis that we previously described (n = 540).1 There was no statistical interaction when comparing digoxin (n = 270) versus beta-blocker (n = 270) regarding sex and age for clinical outcomes, including cardiovascular death, sudden death and cardiovascular death related to heart failure. There was generally a trend for a higher benefit (with lower hazard ratios) for beta-blocker use versus digoxin use in women than in men, although this was neither significant in subgroup of men or women and for the interaction analysis. Considering the direct comparison of digoxin and of beta-blocker (and no comparison with patients neither treated with digoxin nor with beta-blocker), we cannot speculate on whether the trend would be related to a lower benefit with beta-blocker in men or to a possible increased risk with digoxin in women. Regarding age, the trend was generally for a higher benefit (with lower hazard ratios) for beta-blocker use versus digoxin use in older patients, although this was neither significant in subgroup of patients <75 or ≥75 years old and for the interaction analysis. Dr. Čulić appropriately mentions that the somewhat limited sample size of the study may result in relatively wide confidence intervals for our results. We thus performed an additional analysis in the larger unmatched cohort of patients with permanent atrial fibrillation and heart failure (n = 937) with a multivariable Cox model for adjustment of possible confounders (using the same covariables than those for the propensity matching analysis). There was similarly no statistical interaction when comparing digoxin versus beta-blocker regarding sex and age for clinical outcomes. We thus conclude that the results of our recent analysis reporting a lack of statistical difference for the risk of major clinical outcomes in patients with permanent atrial fibrillation and heart failure between those treated with digoxin or beta-blocker would apply similarly in men and in women and regardless of younger or older age.