Early Rhythm Control in Patients With Atrial Fibrillation and High Comorbidity Burden

Background: The randomized EAST-AFNET4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial-Atrial Fibrillation Network) demonstrated that early rhythm control (ERC) reduces adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. The effectiveness and safety of ERC in patients with multiple cardiovascular comorbidities is not known.

Methods: These prespecified subanalyses of EAST-AFNET4 compared the effectiveness and safety of ERC with usual care (UC) stratified into patients with higher (CHA₂DS₂-VASc score ≥4) and lower comorbidity burden. Sensitivity analyses ignored sex (CHA₂DS₂-VA score).

Results: EAST-AFNET4 randomized 1093 patients with CHA₂DS₂-VASc score ≥4 (74.8±6.8 years, 61% female) and 1696 with CHA₂DS₂-VASc score <4 (67.4±8.0 years, 37% female). ERC reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome in patients with CHA₂DS₂-VASc score ≥4 (ERC, 127/549 patients with events; UC, 183/544 patients with events; hazard ratio [HR], 0.64 [0.51-0.81]; P < 0.001) but not in patients with CHA₂DS₂-VASc score <4 (ERC, 122/846 patients with events; UC, 133/850 patients with events; HR, 0.93 [0.73-1.19]; P=0.56, P_interaction=0.037). The primary safety outcome (death, stroke, or serious adverse events of rhythm control therapy) was not different between study groups in patients with CHA₂DS₂-VASc score ≥4 (ERC, 112/549 patients with events; UC, 132/544 patients with events; HR, 0.84 [0.65, 1.08]; P=0.175), but occurred more often in patients with CHA₂DS₂-VASc scores <4 randomized to ERC (ERC, 119/846 patients with events; UC, 91/850 patients with events; HR, 1.39 [1.05-1.82]; P=0.019, P_interaction=0.008). Life-threatening events or death were not different between groups (CHA₂DS₂-VASc score ≥4, ERC, 84/549 patients with event, UC, 96/544 patients with event; CHA₂DS₂-VASc scores <4, ERC, 75/846 patients with event, UC, 73/850 patients with event). When female sex was ignored for the creation of higher and lower risk groups (CHA₂DS₂-VA score), the P_interaction was not significant for the primary efficacy outcome (P=0.25), but remained significant (P=0.044) for the primary safety outcome.

Conclusions: Patients with recently diagnosed atrial fibrillation and CHA₂DS₂-VASc score ≥4 should be considered for ERC to reduce cardiovascular outcomes, whereas those with fewer comorbidities may have less favorable outcomes with ERC.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT01288352. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20. URL: https://www.isrctn.com/; Unique identifier: ISRCTN04708680.