Author + information
- Renato D. Lopes, MD, PhD, MHS∗ (, )
- Roberto Rordorf, MD,
- Gaetano M. De Ferrari, MD,
- Sergio Leonardi, MD, MHS and
- Lars Wallentin, MD, PhD
- ↵∗Department of Cardiology, Duke Clinical Research Institute, Duke University School of Medicine, 2400 Pratt Street, Durham, North Carolina 27705
We thank Dr. Aloia and Dr. Chen and colleagues for their comments about our recent publication exploring the association between digoxin and mortality in patients with atrial fibrillation (AF) (1).
In our study, digoxin use was independently associated with a higher risk of death in chronic users with higher serum digoxin concentration (≥1.2 ng/ml), and in those who recently started digoxin. Based on these findings, we recommended that digoxin should generally be avoided in patients with AF, especially when other treatments such as beta-blockers or calcium-channel blockers can be used to alleviate symptoms. We also suggest that monitoring serum digoxin concentration is important and that clinicians should target levels <1.2 ng/ml.
Dr. Aloia raises appropriate concerns about potential confounding differences in baseline characteristics between patients on versus off digoxin at baseline. These differences in baseline characteristics may explain the potential harm associated with digoxin use in our unadjusted analysis. However, in our prevalence analysis, after comprehensive adjustment, using a Cox regression model with overlap propensity score weighting, we did not find a significant association between digoxin use and higher risk of death. Importantly, we found a 56% higher risk of death in patients with baseline serum digoxin concentration levels ≥1.2 ng/ml. These results were fully adjusted for measured variables, including medical history, AF characteristics, concomitant medications, indicators of renal function (serum creatinine and estimated creatinine clearance), uric acid, and prognostic biomarkers (N-terminal pro–B-type natriuretic peptide, troponin I and T, and growth differentiation factor 15). We believe these data are compelling and make it prudent to be cautious with the use of digoxin in patients with AF.
In our analysis there was a continuous association between serum digoxin concentration and mortality, with a 19% higher risk of death for each 0.5-ng/ml increase in serum digoxin concentration. We therefore appreciate that Dr. Chen and colleagues further emphasized the very uncertain evidence base for digoxin cutoff levels currently used by many physicians in clinical practice, including the type, size, and timing of the study (2) and the quality of the data used to define those levels. In our study, the risk of death was independently related to serum digoxin concentration, with the highest risk in patients with a concentration ≥1.2 ng/ml. Our results support the opinion of Dr. Chen and colleagues that the current threshold level for digoxin should be revised. More recent and robust data should be used to define a more accurate and contemporary cutoff for use in clinical practice (1,3).
In our incidence analysis, which included new digoxin users who were not using digoxin at baseline, we found a 78% higher risk of death in patients starting digoxin when compared with patients who did not. For this type of analysis, which addresses potential survival bias that the baseline analysis may not be able to address, a risk-set matching approach was implemented longitudinally. For this adjustment, covariates, both baseline and time dependent, measured before matching were incorporated via a time-dependent propensity model for digoxin initiation and estimated using Cox proportional hazards regression. We accounted for geographic region, clinical setting where digoxin was initiated (heart failure hospitalization, other hospitalization, or out of hospital), and heart failure status. Finally, we discussed some aspects of our findings that are consistent with a potential causal relationship between digoxin and mortality, including the early mortality among patients starting digoxin (“new users”) and the associated higher rates of sudden death of these patients.
We believe that our analyses are the most comprehensive and current evaluations of digoxin and mortality in patients with AF, and we addressed several gaps that were not clarified before, including novel data on serum digoxin concentration. We also discussed the limitations of our study, including the lack of randomization, a broad definition of heart failure, and the lack of serum digoxin concentration for patients who started digoxin (“new users”). Therefore, putting our results in perspective and in the absence of randomized data on the efficacy and safety of digoxin in patients with AF, our study provides important contemporary information to help physicians in the decision-making process regarding digoxin use in clinical practice.
Please note: Dr. Lopes has received Research grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, and Pfizer Inc; and consulting fees/honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Medtronic, Merck & Co., Pfizer, and Portola. Dr. Rordorf has received speaking fees from Medtronic and St. Jude Medical. Dr. De Ferrari has received a research grant from Amgen; advisory board and speaking fees from Amgen, Merck, and Sigma-Tau; and steering committee support for Boston Scientific. Dr. Leonardi has received research grant from AstraZeneca; and honoraria from The Medicine Company, Chiesi, Daiichi-Sankyo, and AstraZeneca. Dr. Wallentin has received research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck/Schering-Plough, Pfizer Inc., and Roche Diagnostics; and consulting fees/honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Pfizer Inc.
- 2018 American College of Cardiology Foundation
- Lopes R.D.,
- Rordorf R.,
- De Ferrari G.M.,
- et al.
- Adams K.F. Jr..,
- Butler J.,
- Patterson J.H.,
- et al.