By Joshua Moss, MD

Associate Professor of Clinical Medicine, Cardiac Electrophysiology, Division of Cardiology, University of California, San Francisco

Dr. Moss reports he is a consultant for Abbott, Biosense Webster, and Boston Scientific.

SYNOPSIS: A rhythm control strategy implemented less than one year after atrial fibrillation diagnosis was associated with significant reduction in adverse cardiovascular outcomes when compared to usual care.

SOURCE: Kirchhof P, Camm AJ, Goette A, et al. Early rhythm control therapy in patients with atrial fibrillation. N Engl J Med 2020;383:1305-1316.

The landmark AFFIRM randomized trial1 has long been cited as evidence that rhythm control therapy is not superior to rate control for atrial fibrillation (AF), but treatment for AF has evolved since its publication. The potential adverse effects of antiarrhythmic drugs (particularly amiodarone) and the importance of therapeutic anticoagulation regardless of treatment strategy are better appreciated, and a mortality benefit has been associated with catheter ablation in patients with cardiomyopathy.

Kirchhof et al sought to assess whether modern rhythm control therapy for AF would reduce the risk for cardiovascular complications. The authors randomized 2,789 adults (nearly half women) at 135 centers in 11 countries with AF diagnosed less than one year before to early rhythm control vs. “usual care,” in which rhythm control therapies were added only to mitigate symptoms after adequate rate control was achieved. Patients had to be older than age 75 years or have other risk factors for stroke similar to those in the widely used CHA2DS2-VASc score. The first primary outcome was a composite of death from stroke, hospitalization, or cardiovascular causes with exacerbated heart failure or acute coronary syndrome. The second primary outcome was nights spent in the hospital annually. The authors also assessed several secondary outcomes, including quality of life and cognitive function.

Patients were enrolled a median of 36 days after the first diagnosis of AF. In the rhythm control arm, about 87% of patients received an antiarrhythmic drug initially (19.6% amiodarone) and 8% underwent ablation. By two years, about 46% of patients were on an antiarrhythmic drug (11.8% on amiodarone) and 19% had undergone ablation; sinus rhythm was found in 82%. The mean CHA2DS2-VASc score was 3.4, and 88% of patients remained on oral anticoagulants at two years.

In the usual care arm, 96% of patients were managed initially without any rhythm control therapy. By two years, about 8% were on an antiarrhythmic drug (2.8% on amiodarone) and 7% had undergone ablation; sinus rhythm was found significantly less often (in 61%). The mean CHA2DS2-VASc score was 3.3, and 91% of patients remained on oral anticoagulants at two years.

The trial ended early for efficacy after a median of 5.1 years of follow-up. There were 3.9 first primary outcome events for every 100 person-years in the rhythm control arm, significantly less than the 5.0 events for every 100 person-years in the usual care arm (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = 0.005). Significant differences were not found in nights spent in the hospital nor in secondary outcomes. Both left ventricular function and cognitive function remained stable at two years. More than 70% of patients in both groups were asymptomatic at years one and two.

Overall safety outcomes did not differ significantly between groups. However, stroke and death rates were lower in the rhythm control group (stroke significantly so at 2.9% vs. 4.4%). Meanwhile, serious adverse events were more common: more toxic effects of drug therapy (0.7% vs. 0.2%), drug-induced bradycardia (1% vs. 0.4%), bleeding and tamponade related to ablation (0.7% vs. 0.1%), and hospitalization for AF (0.8% vs. 0.2%). The authors concluded that a rhythm control strategy implemented less than one year after an AF diagnosis vs. usual care was associated with significant reduction in adverse cardiovascular outcomes.

COMMENTARY

A critically important study in 2002, AFFIRM simply is no longer representative of modern approaches to AF management. As in the Kirchhof et al study, rhythm control was achieved primarily with antiarrhythmic drugs. However, amiodarone was used at some point in > 60% of patients, compared with 12% of patients at two years in the Kirchhof et al study. That is a dramatic difference, especially considering that more than 25% of rhythm control patients in AFFIRM experienced an adverse event or clinical finding prompting discontinuation of a drug. Only 63% of patients were in sinus rhythm at five years in the AFFIRM rhythm control arm, and only about 70% of patients in that arm continued anticoagulation (with warfarin, the only choice of oral agent at the time). Stroke rate was ~1% per year, and most strokes occurred in patients in whom warfarin had been stopped or in whom the INR was subtherapeutic.

The Kirchhof et al study is more representative of current rhythm control techniques, with less amiodarone use, more consistent thromboembolic prophylaxis with more reliable oral anticoagulants, and addition of catheter ablation as a treatment option. By two years, substantially more patients in the rhythm control arm had undergone catheter ablation than were on amiodarone (19% vs. 12%), and even 7% of patients in the usual care arm had an ablation. The outcomes in the Kirchhof et al study reflect the changes in care that have evolved over the past 18 years: sinus rates were higher, serious adverse events related to antiarrhythmic drug therapy occurred in only 37 out of 2,789 patients (2% in the rhythm control arm and 0.6% in the usual care arm), and overall stroke rates were lower (3.7% vs. 8.2% in AFFIRM). With these overall improvements in mind, early rhythm control also was associated with a significant reduction in the primary outcome of death from stroke, cardiovascular causes, and hospitalization with acute coronary syndrome or exacerbated heart failure. Considering the individual components of the composite outcome, the hazard ratio for death from cardiovascular causes was 0.72 (0.52-0.98) and 0.65 for stroke (0.44-0.97). Death from cardiovascular causes was rare in this population, but using an early rhythm control strategy in 100 patients over about three years could prevent such a death compared to usual care.

As always, limitations must be considered. Overall, about 7% of patients withdrew, and researchers lost about 7% of subjects to follow-up. Catheter ablation, although used more than amiodarone, still accounted for a relatively small proportion of patients treated (even though this has been shown in other trials to be superior to drug therapy for maintenance of sinus rhythm). Nevertheless, no longer should rate and rhythm control be considered equivalent in a typical patient with recent-onset AF, even when asymptomatic. With shared decision-making about the potential risks of antiarrhythmic drugs and/or catheter ablation, early restoration and maintenance of sinus rhythm should be strongly considered.

REFERENCE

  1. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-1833.