For two decades, randomized trials and systematic reviews have largely demonstrated that rate control is better than rhythm control for atrial fibrillation. These findings were somewhat surprising considering that pathophysiology-based models suggest that rhythm control should reduce cerebrovascular events better than rate control. The prior body of evidence found the contrary to be true — rhythm control did not reduce the risk of cerebrovascular events and actually increased the rate of hospitalizations and adverse events. Recently, however, newer rhythm control agents and advances in radiofrequency ablation have renewed interest in how we prioritize rhythm control.
The AF-NET trial randomized 2,789 older adults with atrial fibrillation diagnosed in the past year to early rhythm control therapy or usual care. The unblinded study included adults more than 75 years of age with a history of cerebrovascular disease and adults more than 65 years of age with at least two risk factors for cerebrovascular disease (mean age 70 years, mean CHA2DS2-VASc score 3.4). Nearly 90 percent of participants in both groups received oral anticoagulation throughout the trial and 30 percent presented with symptomatic atrial fibrillation. Per the study design, adequate power would have been achieved at 695 events to detect a 20 percent difference in cardiovascular death or hospitalization; however, the trial was stopped after 565 events due to benefit.
About 95 percent of participants in the rhythm control group underwent therapeutic intervention, most commonly with flecainide, amiodarone, or ablation, with 65.1 percent continuing rhythm control therapy and 82.1 percent achieving sinus rhythm at two years. In the usual care group, 14.6 percent required rhythm control for symptoms and 60.5 percent were in sinus rhythm at two years. The rhythm control group had fewer composite occurrences of cardiovascular death, stroke, or hospitalization from heart failure or acute coronary syndrome than the usual care group (3.9 per 100 person-years vs. 5 per 100 person-years, hazard ratio 0.79, 96% CI 0.66-0.94). Atrial fibrillation-related symptoms were similar at two years. There were more serious adverse events related to antiarrhythmic strategy in the rhythm control group compared to the usual care group (4.9% vs. 1.4%, NNH= 28), including major bleeding from ablation procedures and drug-induced bradycardia.
The bottom line is that early rhythm control increased the risk of major procedural bleeding and bradycardia compared to rate control with no improvement in symptom control and a modest improvement in cardiovascular outcomes. The small absolute magnitude of benefit of early rhythm control in terms of cardiovascular prevention needs to be weighed against cost and simplicity of treatment if patients are anticoagulated anyway.
Important limitations to this trial include lack of blinding, multiple endpoints with changes in follow-up time, and early cessation of the trial, which is an established risk for overestimating benefit and underestimating harm. This final factor may have resulted in underestimation of the true harms of the rhythm control strategy given that major bleeding and other complications were more common in the rhythm control group. Before mechanistic reasoning leads us back to an early rhythm control strategy, clinicians must carefully balance the known risks, potential benefits, and real cost of an early rhythm control strategy.
For more information, see the topic Rate Control for Atrial Fibrillation in DynaMed.
EBM Focus articles provide concise summaries of clinical trials most likely to inform clinical practice curated by the DynaMed editorial team.