Attaining sinus rhythm mediates improved outcome with early rhythm control therapy of atrial fibrillation: the EAST-AFNET 4 trial

Figure 1. CONSORT diagram of the analyses. (A) Objective 1: Population analysis for the mediator analysis at the 12-month visit and follow-up time for future events (landmark analysis). (B) Objectives 2 and 3: Population analysis for the effect of atrial fibrillation ablation as a component of early rhythm control.

Figure 2. Strong mediating and moderating effect of sinus rhythm at 12 months on the first primary outcome of the EAST-AFNET 4 trial. The presence of sinus rhythm at 12 months explains about 81% of the effect of early rhythm control on the first primary outcome, a composite of cardiovascular death, stroke, or hospitalization for heart failure, or acute coronary syndrome. This can be appreciated in the first horizontal line in the graph (natural effect). There is hardly any effect of early rhythm control in patients who are not in sinus rhythm at the 12-month visit, visible in lack of a controlled direct effect in patients not in sinus rhythm at 12 months. Atrial fibrillation recurrence at any time up to the 12-month visit, in contrast, only explains 31% of the effect of early rhythm control, due to the small differences between the effects of the two subgroups (controlled effect in patients without AF recurrence and patients with AF recurrence). The analysis is adjusted for baseline characteristics that may confound the treatment effects on the mediator or the mediator effect on the outcome. Total effect indicates the adjusted treatment effect on the outcome; natural direct effect…

Figure 3. Time to recurrent atrial fibrillation and number of patients with recurrent atrial fibrillation in patients randomized to early rhythm control by rhythm status at 12 months. (A) The survival curves show the time to recurrent atrial fibrillation from randomization to 12 months in patients randomized to early rhythm control who were in sinus rhythm at 12 months and for patients who were not in sinus rhythm at 12 months. Patients who reached a primary outcome event or died in the first 12 months were not included. Recurrent atrial fibrillation was documented by triggered visits due to atrial fibrillation in the telemetric echocardiography or by an unscheduled visit due to clinically documented atrial fibrillation. (B) The tabulated data show the proportion of patients without recurrent atrial fibrillation and with recurrent atrial fibrillation who were in sinus rhythm at the 12-month visit: 58.3% (105/180) of patients not in sinus rhythm at 12 months had a scheduled or unscheduled visit due to recurrent atrial fibrillation, while only 28.5% (288/1009) of those in sinus rhythm at 12 months had such a visit.

Figure 4. Association of atrial fibrillation ablation and primary outcome for all patients: results of an adjusted Cox model with ablation as a time-dependent predictor and its interaction with treatment, and random effect for centre (n = 2789, events = 565).

Figure 5. Association of early, late, or no atrial fibrillation ablation and primary outcome for patients randomized to early rhythm control: results of an adjusted Cox model with two time-dependent variables for early and late ablation as predictors and random effect for centre (n = 1395, events = 249).