Exciting researches continue to swirl around the niche of atrial fibrillation and its management. The year 2020 marked the advent of cryoablation as a first line therapy for paroxysmal AF through two well-conducted randomized trials. The EAST AFNET trial once again addressed the debate of rate vs. rhythm control in AF, while the role of NOACs in elderly and patients with prosthetic valves was explored in ELDER-CARE and RIVER trials respectively.

1. EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention) Trial

A rhythm-control strategy is superior to usual care in improving cardiovascular (CV) outcomes at 5 years among patients with a recent diagnosis of AF and concomitant CV conditions.

Patients were randomised 1:1 to early rhythm control therapy or usual care, stratified by sites. Patients in both groups received treatment for cardiovascular conditions, anticoagulation, and rate control according to guidelines.

Patients in the early rhythm control group received antiarrhythmic drugs or catheter ablation (chosen by the local study teams). Rhythm control therapy was escalated when recurrent atrial fibrillation was documented clinically or by ECG, including monitoring with patient-operated ECG devices.

Patients in the usual care group were initially managed with rate control. Rhythm control therapy was only used to mitigate severe atrial fibrillation-related symptoms despite optimal rate control, following current guidelines.

The primary outcome, CV death, stroke, hospitalization for HF, or acute coronary syndrome (ACS), for rhythm control vs. usual care, was 3.9 vs. 5.0/100 person-years (P-Y) (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.66-0.94, p = 0.005)

The results of this trial are different from other similar trials such as CABANA-AF, AFFIRM, and RACE.

One difference is the population enrolled – recent onset (within 12 months) in EAST-AFNET 4 vs. more sustained AF in the other trials. There was also a reasonably high rate of AF ablation (8% at enrollment, 20% by 5 years) in the current trial.

"The risk of severe cardiovascular complications and death in patients with atrial fibrillation is highest in the first year after diagnosis, suggesting that early therapy could be most beneficial," said principal investigator Professor Paulus Kirchhof of the University Heart and Vascular Centre UKE Hamburg, Germany and University of Birmingham, UK. "Furthermore, atrial fibrillation causes atrial damage within a few weeks of disease onset. Early rhythm control therapy could reduce or prevent this damage, making it more effective."

Source: Kirchhof P, Camm AJ, Goette A, et al., Early Rhythm-Control Therapy in Patients With Atrial Fibrillation. N Engl J Med 2020;383:1305-16. DOI: 10.1056/NEJMoa2019422

2. EARLY AF and STOP-AF trials

Current guidelines for atrial fibrillation (AF) recommend antiarrhythmic drugs as initial therapy before considering catheter ablation. However, findings from two clinical trials indicate that cryoablation as first-line treatment is superior to drug therapy for the prevention of atrial arrhythmia recurrence in patients with paroxysmal AF.

a) Both trials included patients with untreated paroxysmal AF who were randomly assigned to catheter ablation with a cryoballoon or to antiarrhythmic drug therapy.

b) The EARLY-AF trial, which was presented at the virtual AHA Scientific Sessions 2020 showed that after 1year, atrial tachyarrhythmia recurrence occurred in 42.9% of the patients who underwent ablation versus 67.8% of the patients receiving drug therapy (HR 0.48, 95% CI 0.35–0.66, P < 0.001).

c) Cryoballoon ablation was also associated with lower recurrence of symptomatic atrial tachyarrhythmia (11.0% versus 26.2%) and a significant reduction in AF burden.

d) The STOP AF showed that initial success of the ablation procedure was achieved in 97% of patients, and procedure-related serious adverse events were uncommon.

e) The percentage of patients with treatment success at 12 months (freedom from initial failure of the procedure or atrial arrhythmia recurrence after day 90) was higher with ablation than with drug therapy (74.6% versus 45.0%; P < 0.001).

Sources: Journal: NEJM

1. EARLY AF: Andrade JG, Wells GA, Deyell MW, et al. Cryoablation or drug therapy for initial treatment of atrial fibrillation. N Engl J Med. 2020

2. STOP-AF Wazni OM, Dandamudi G, Sood N, et al., on behalf of the STOP-AF First Trial Investigators. Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation. N Engl J Med 2020

3. RIVER (Rivaroxaban vs. Warfarin in AFib Patients With Bioprosthetic Mitral Valves) trial

Rivaroxaban is non-inferior to warfarin for prevention of thromboembolic events among patients with AF/AFL and bioprosthetic mitral valve.

Patients were randomized in a 1:1 open-label fashion to either rivaroxaban 20 (15 mg daily if creatinine clearance was 30-49) or warfarin with an international normalized ratio (INR) goal of 2-3.

The mean time to the primary outcome (death, major adverse cardiac events, major bleeding) for rivaroxaban vs. warfarin was 347.5 vs. 340.1 days (p < 0.0001 for noninferiority, p = 0.1 for superiority)

This is one of the first trials to directly evaluate the role of a direct OAC (DOAC) in patients with mitral valve disease and atrial arrhythmias. Historically, these patients have been treated with warfarin.

Although this trial has limitations (open-label design, etc.), these findings are likely to be practice-changing.

The only caveat is that it is unclear if the mitral valve surgery was for rheumatic heart disease, in particular mitral stenosis, where warfarin is still recommended as the OAC of choice.

Source: Guimarães HP, Lopes RD, de Barros e Silva PG, et al., on behalf of the RIVER Trial Investigators. Rivaroxaban in Patients With Atrial Fibrillation and a Bioprosthetic Mitral Valve. N Engl J Med 2020;Nov 14 DOI: 10.1056/NEJMoa2029603

4. ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation) trial

The ELDERCARE-AF trial showed that very low dose edoxaban (15 mg) was superior to placebo in reducing stroke or systemic embolism among Japanese AF patients ≥80 years of age.

This Phase 3 multicenter, randomized, double-blind, placebo-controlled trial examined a once-daily 15 mg dose of edoxaban vs placebo in elderly Japenese patients (≥80 years) with nonvalvular AF (in whom standard oral anticoagulants were not recommended).

The results of this trial indicate that very low dose edoxaban (15 mg) was superior to placebo in reducing stroke or systemic embolism among Japanese AF patients ≥80 years of age. The primary safety endpoint of major bleeding was similar, although bleeding was overall higher with edoxaban, primarily GI bleeding. Mortality rates were high and similar between the two arms. Trial discontinuation rates were quite high (nearly one-third).

These were all very elderly patients with a high proportion of frail patients; nearly one-third had sustained a fall within the year prior to enrollment. The dose of edoxaban used in this trial is one-fourth the usual stroke prophylaxis dose approved for AF (60 mg).

Typically, when estimated glomerular filtration rate is <50, the dose is reduced to 30 mg daily for this indication. The current trial suggests that an even lower dose may be efficacious and could be considered in selected elderly patients.

Source: NEJM: Okumura K, Akao M, Yoshida T, et al., Low-Dose Edoxaban in Very Elderly Patients With Atrial Fibrillation. N Engl J Med 2020;383:1735-45 DOI: 10.1056/NEJMoa2012883