Significant bivariate associations of AF with increased risk for both all-cause, cardiovascular, and HF mortality and all-cause and HF hospitalizations in patients with advanced chronic systolic HF suggest that AF remains an important prognostic marker in these patients. However, data from propensity-matched patients, who were well balanced in 74 baseline characteristics, demonstrate that AF had no intrinsic association with total or cause-specific mortality, but had an independent association with HF hospitalization. These findings are important as hospitalization due to worsening HF is a major cause of hospitalization for patients with HF, and in the US it is the leading cause for hospitalization for Medicare beneficiaries 65 years and older. Further, the lack of an intrinsic association of AF with mortality may in part explain the lack of superiority for rhythm control strategy relative to rate control in these patients.17
Atrial fibrillation is characterized by irregular cardiac rhythm, which along with an uncontrolled heart rate, may cause significant haemodynamic abnormalities leading to worsening HF and hospitalization. Atrial fibrillation is also associated with structural and functional pathologies such as a dilated left atrium with impaired contraction, impaired left ventricular filling, and activation of vasoconstrictive neurohormones.4,18,19
However, little is known about the individual contribution of an abnormal cardiac rhythm or an uncontrolled heart rate to the haemodynamic instability in HF patients with AF that may lead to HF or all-cause hospitalizations. An irregular cardiac rhythm alone, in the presence of controlled ventricular rate, may cause acute adverse haemodynamic events in AF.20
However, whether an irregular rhythm alone, in the presence of normal heart rate, may also lead to increased HF hospitalization is unknown. Findings from a recent large randomized clinical trial of rhythm vs. rate control for AF in systolic HF suggest that fewer patients in the rate control group required hospitalization, highlighting the importance of a rate control strategy.17
Although uncontrolled heart rate may also lead to adverse haemodynamic consequences, heart rate in matched patients with AF was well controlled and was well balanced. Therefore, the observed association of AF and HF hospitalization cannot be explained by baseline uncontrolled heart rate or baseline differences in heart rate. However, it is plausible that heart rate varied between patients with and without AF during follow-up. Heart failure patients with AF may have an inappropriate tachycardic response to physical activities or other stresses which could lead to acute decompensation with resultant increases in HF hospitalization. This notion is supported by our subgroup analyses that demonstrated that AF-associated increased HF hospitalization was only observed among patients not receiving bucindolol, a beta-blocker (Figure
). In the BEST, patients receiving bucindolol were less likely to have tachycardia.13
Beta-blockers are currently recommended as the drug of choice for control of ventricular rate in HF patients with AF.21
This is particularly important as beta-blockers, when added to digitalis, may have a synergistic effect in controlling ventricular rate both at rest and during physical activities.22–24
Over 90% of patients in our study were receiving digoxin, and among these patients, AF-associated increase in HF hospitalization was only seen in patients who were not receiving bucindolol. Interestingly, although AF had no overall association with mortality, in the subgroup of patients not receiving bucindolol, AF seemed to be associated with increased mortality, but had no significant association among those receiving bucindolol.
Despite an increased unadjusted bivariate association, findings from our study suggest that AF may not have an intrinsic association with mortality and that the bivariate association was likely due to differences in prognostically important baseline covariates. This is consistent with the findings from a recent large randomized clinical trial of rhythm vs. rate control for AF in systolic HF, where rhythm control did not reduce the primary endpoint of cardiovascular mortality.17
The authors of that study speculated that the failure of the rhythm control strategy may have been due to the fact that AF in HF may not have an intrinsic association with mortality,17
a contention which is supported by findings from our study. It was further speculated that the benefit of rhythm control may have been cancelled by harmful effects of anti-arrhythmic therapies. The proportion of patients receiving anti-arrhythmic drugs was low in our study and was well balanced in our matched cohort.
Previous studies have demonstrated a lack of an independent association between AF and mortality.4,25
However, our study is distinguished from those studies by the use of propensity-score matching in which patients with and without AF were well balanced in 74 important demographic, clinical, subclinical, and biochemical covariates. Further, our subgroup analysis provided insight into the role of beta-blockers in HF patients with AF.
There are several limitations in the current study. Despite an excellent post-match balance in 74 baseline covariates, it is possible that there were imbalances in unmeasured covariates. In fact, our sensitivity analysis suggests that our findings may be rather sensitive to an unmeasured confounder. However, sensitivity analysis cannot determine whether an unmeasured covariate exists or not. Furthermore, for an unmeasured covariate to be a confounder, in addition to being associated with the exposure (AF), it must also be a near-perfect predictor of outcomes (HF hospitalization) and not be strongly correlated with any of the 74 measured covariates used in our propensity model. We were able to match 75% of patients with AF and any effect due to loss of participants during matching would be minimal. Further, we were able to reproduce our key findings in the pre-match dataset adjusting for propensity score.
Interestingly, despite same sample size, we observed discordant findings after risk adjustment using a traditional multivariable model and propensity score. Multivariable regression adjustments may not ensure that the distribution of the confounders is balanced between groups, which may lead to extrapolations beyond the data.7
Results of this study based on advanced systolic HF patients may not be generalizable to patients with mild to moderate HF and those with diastolic HF, who constitute half of all HF patients. It is possible that some patients without baseline history of AF may have developed AF during the follow-up period. However, this regression dilution is known to underestimate true associations.26
Atrial fibrillation is a marker of increased mortality and hospitalization in advanced systolic HF and remains a useful tool to identify patients at risk of poor outcomes. Atrial fibrillation seems to have an intrinsic association with hospitalization due to worsening HF, which was worse in patients not receiving bucindolol. Despite the overall lack of an intrinsic association of AF with mortality, it appears to increase mortality in those not receiving bucindolol. These data provide additional arguments that HF patients with AF should be treated with beta-blockers in the absence of an absolute contraindication.