Rhythm control therapy beneficial in AF with heart failure when initiated early

Starting rhythm control therapy with antiarrhythmic drugs or ablation within a year following diagnosis of atrial fibrillation (AF) in patients with heart failure (HF) helps improve cardiovascular outcomes, and this clinical benefit is seen across ejection fraction (EF) ranges, according to subgroup analysis of the EAST-AFNET4 trial.

“As expected, patients treated by early rhythm control therapy were more likely to present in sinus rhythm at the 2-year follow-up when compared with usual care. Also, the proportion of patients with AF was higher in this analysis than in the overall cohort of the EAST-AFNET4 trial. This is in line with previously published data, as HF is believed to contribute to recurrent AF and to atrial cardiomyopathy in patients with AF,” the investigators said. [N Engl J Med 2018;379:492; N Engl J Med 2020;383:1305-1316; Europace 2016;18:1455-1490; JAMA 2014;311:498-506]

“The early timing of rhythm control therapy in this study could have amplified [its] clinical benefit … compared with usual care. It is also possible that the early initiation … led to an improved efficacy of antiarrhythmic drug therapy as compared with other trials testing antiarrhythmic drugs for rhythm control … in patients with HF,” the investigators said. [Circulation 2021;143:1377-1390; N Engl J Med 2008;358:2667-2677]

The present subanalysis of EAST-AFNET4 included 798 HF patients with AF (median age 71.0 years, 37.6 percent female) randomized to receive early rhythm control therapy (ERC; n=396) or the current strategy of delayed, symptom-directed rhythm control (usual care; n=402).

In the usual care group, 5.8 percent patients received rhythm control medication at randomization while 19.6 percent did at the 2-year follow-up. Meanwhile, catheter ablation was performed in 88 patients in the ERC group and 52 in the usual care group.

Most of the patients in the cohort had preserved EF (HFpEF; n=442; left ventricular [LV]EF ≥50 percent, mean 61 percent), while the others had mid-range EF (n=211; LVEF 40–49 percent, mean 44 percent) or reduced EF (n=132; LVEF <40 percent, mean 31 percent).

Over a median follow-up of 5.1 years, the composite primary outcome of cardiovascular death, stroke, or hospitalization for HF worsening or acute coronary syndrome occurred with significantly lower frequency in the ERC than the usual care group (5.7 vs 7.9 per 100 patient-years; hazard ratio [HR], 0.74, 95 percent confidence interval [CI], 0.56–0.97; p=0.03), regardless of HF status (p=0.63 for interaction). [Circulation 2021;doi:10.1161/CIRCULATIONAHA.121.056323]

Safety outcomes were similar. While ERC seemed to result in a lower incidence of the composite of death, stroke, or serious adverse events related to rhythm control therapy compared with usual care (71 [17.9 percent] vs 87 [21.6 percent]), the difference was not statistically significant (HR, 0.85, 95 percent CI, 0.62–1.17; p=0.33).

LVEF improved equally in both groups at 2 years (change, 5.3 percent with ERC vs 4.9 percent with usual care; p=0.43).This result, according to the investigators, might be attributed to the possibility that rhythm control therapy given to patients in the usual care group led to improved left ventricular function.

“The majority of patients were treated with antiarrhythmic drugs, with amiodarone (in HFrEF), and flecainide, dronedarone or amiodarone (in HFpEF) as the main agents. Approximately 17 percent of patients randomized to early rhythm control were treated with AF ablation in the first 2 years after randomization,” the investigators said. [Europace 2016;18:1609-1678; Eur Heart J 2021;42:373-498]

“This suggests that the clinical benefit found in [the present analysis] can be achieved using antiarrhythmic drugs as initial therapy. It is worthwhile to note that flecainide was used in a relatively high number of patients without safety concerns,” they continued, adding that all treatments were given in accordance with international AF guidelines, enabling the safe use of antiarrhythmic drugs in this population.

Meanwhile, catheter ablation of AF improves quality of life and reduces arrhythmia recurrence to a higher extent compared with antiarrhythmic drug therapy, with signals that there may be clinical benefit, especially in patients with reduced left ventricular function. [N Engl J Med 2018;379:492; Circulation 2016;133:1637-1644; Circ Arrhythm Electrophysiol 2019;12:e007731; J Am Coll Cardiol 2017;70:1949-1961]

“In view of the clinical benefit of catheter ablation compared with antiarrhythmic drug therapy seen in the CABANA heart failure subanalysis, it is tempting to speculate that early rhythm control using catheter ablation could convey even larger clinical benefit than the treatment pattern chosen by the investigators of the EAST-AFNET4 trial,” according to the investigators. [Circulation 2021;143:1377-1390]

“Alternatively, antiarrhythmic drugs may be sufficient to achieve early rhythm control therapy due to the lower risk of recurrent AF. The value of catheter ablation for early rhythm control awaits testing in a controlled clinical trial,” they added.