By Cara Pellegrini, MD
Assistant Professor of Medicine, UCSF; Cardiology Division, Electrophysiology Section, San Francisco VA Medical Center
Dr. Pellegrini reports no financial relationships relevant to this field of study.
SOURCE: Chao TF, et al. Rate-control treatment and mortality in atrial fibrillation. Circulation 2015;132. [Epub ahead of print].
National guidelines emphasize the importance of rate control in the long-term management of atrial fibrillation (AF). Yet, there are limited data to support whether use of rate control agents impacts survival in AF patients, and there are no evidence-based data to guide choice of rate control agent. Chao et al have performed a large observational population study utilizing a Taiwanese nationwide AF cohort culled from a database that houses detailed healthcare information from > 99% of Taiwan’s population. They compared mortality rates across AF patients who were receiving a single atrioventricular (AV) nodal blocking agent — 43,879 on beta-blockers (BBs), 18,466 taking calcium channel blockers (CCBs), and 38,898 receiving digoxin — with a 168,678 patient reference group who were not taking any rate control agents. Patients with combinations of AV nodal agents were excluded from the study. Propensity matching was performed to try to minimize confounding.
The mean age of patients was 70 ± 13 years and 56% were male. There were significant differences between groups with regard to age, sex, comorbidities, medications, degree of urbanization, and income level. Significantly more patients receiving digoxin had heart failure and there were fewer receiving antiarrhythmic medications in that group. Over a follow-up of 4.9 ± 3.7 years, about one-third of patients died. After adjustment for baseline characteristics, there were significant differences in mortality, with those receiving BBs having a 24% lower risk of death compared to no agent, those on CCBs having a 7% lower risk, and those taking digoxin displaying a 12% excess risk of mortality compared to those on no rate control agent. There appeared to be a dose effect, as risks were proportional to percentage of time using the drug; those receiving BBs more frequently had a lower mortality risk than those with less frequent usage, and the highest mortality was observed among those with the highest usage of digoxin. Propensity matching did not change results substantively. The authors concluded that AF patients receiving BBs or CCBs had lower risk of mortality compared to those not taking rate-control drugs, with the lowest mortality rate in the BB group, while digoxin use was associated with a higher risk of mortality.
The biggest limitation of this study is obviously its observational, non-randomized nature. As mentioned, the groups differed in multiple ways at baseline and very possibly these differences, which may have impacted the selection of rate control agents, played a much larger role than the agents themselves in the mortality differences observed. The authors attempted to control for this with the propensity analysis, which aims to account for the differences among participants that determine which treatment they receive, thereby making the groups more comparable. The similar findings after performing propensity matching are somewhat reassuring. Perhaps more convincing is the dose effect observed. If it were aspects of their heart failure that were poorly adjusted for in the analysis that made patients who happened to be receiving digoxin perform worse, why was there such a good match between digoxin exposure and severity of outcome? Was it really all mediated by an aspect of heart failure that both made more digoxin exposure more likely and the patient more likely to die sooner, or perhaps did the digoxin have something to do with it?
Additional limitations of this study include the absence of data on left ventricular ejection fractions, which could have helped adjust for heart failure differences more granularly, as well as data on type of AF — paroxysmal or persistent — which also could have impacted outcomes. The dosages of the rate control agents were not provided. Were higher doses of BBs needed to achieve the positive outcomes observed? Most notably, there was no indication of how well these agents did at controlling heart rates in the study population; it certainly would have been interesting to see how differences in heart rate might have related to (or perhaps mediated) the mortality associations observed.
There is biologic plausibility for this study’s findings. BBs were the most efficacious agent at heart rate lowering in AF patients in the large AFFIRM trial, and have many pleiotropic effects that could positively impact life expectancy. Another study, RATAF, sought to compare the heart rate control attained by various AV nodal blocking agents, and found diltiazem to be the most effective, giving support to the idea of CCBs’ mortality impact via good heart rate control. Other studies have been quite mixed with regard to the potential harm or lack thereof in digoxin use for patients with AF. Clearly, a randomized trial would be most helpful. In its absence, I would still individualize treatment choice based on a patient’s comorbidities, tolerances, and other factors. In the absence of other indications for digoxin, I would avoid it for AF rate control.