Elsevier

American Heart Journal

Volume 206, December 2018, Pages 94-104
American Heart Journal

Trial Design
A randomized clinical trial of early invasive intervention for atrial fibrillation (EARLY-AF) - methods and rationale

https://doi.org/10.1016/j.ahj.2018.05.020Get rights and content

Background

The ideal management of patients with newly diagnosed symptomatic atrial fibrillation (AF) remains unknown. Current practice guidelines recommend a trial of antiarrhythmic drugs (AAD) prior to considering an invasive ablation procedure. However, earlier ablation offers an opportunity to halt the progressive patho-anatomical changes associated with AF, as well as impart other important clinical benefits.

Objective

The aim of this study is to determine the optimal initial management strategy for patients with newly diagnosed, symptomatic atrial fibrillation.

Methods/Design

The EARLY-AF study (ClinicalTrials.gov NCT02825979) is a prospective, open label, multicenter, randomized trial with a blinded assessment of outcomes. A total of 298 patients will be randomized in a 1:1 fashion to first-line AAD therapy, or first-line cryoballoon-based pulmonary vein isolation. Patients with symptomatic treatment naïve AF will be included. Arrhythmia outcomes will be assessed by implantable cardiac monitor (ICM). The primary outcome is time to first recurrence of AF, atrial flutter, or atrial tachycardia (AF/AFL/AT) between days 91 and 365 following AAD initiation or AF ablation. Secondary outcomes include arrhythmia burden, quality of life, and healthcare utilization.

Discussion

The EARLY-AF study is a randomized trial designed to evaluate the optimal first management approach for patients with AF. We hypothesize that catheter ablation will be superior to drug therapy in prevention of AF recurrence.

Section snippets

Background

Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice, affecting approximately 1–2% of the population.1 Beyond stroke reduction the contemporary management of AF is centered on symptomatic improvement, with consequent reduction in AF-related emergency room visits and hospitalizations, as well as improved exercise capacity and quality of life.2., 3., 4., 5.

Contemporary guidelines recommend AADs as the “first-line” therapy for the maintenance of sinus rhythm.

Study design

The EARLY-AF study (ClinicalTrials.gov #NCT02825979) is a multicenter prospective, open label randomized clinical trial with blinded adjudication of endpoints (PROBE design). Patients with untreated AF will be randomized in a 1:1 ratio to either first-line antiarrhythmic therapy or first-line AF ablation using cryothermal energy. Randomization will be performed with concealed allocation using permuted block randomization according to a computer-generated sequence with a block size of 4 and 8

Assessments

All patients will be followed for a minimum of 12 months after the index ablation procedure or medication initiation. This duration is based on the 2017 expert consensus statement for reporting outcomes in clinical trials of AF ablation, as well as the knowledge that most recurrences transpire during the first year after ablation.19., 33., 34., 35., 36.

Table III details the planned visits and procedures. For both groups, a one-week post treatment telephone call will occur followed by scheduled

Data collection and management

The Cardiovascular Research Methods Centre (CRMC) at the University of Ottawa Heart Institute will coordinate the study. The support staff at the CMRC will be composed of a full-time study coordinator, data manager, and biostatistician. The center will specifically be responsible for the randomization process, and for receiving, editing, processing, analyzing, and storing data generated in this trial.

A unique subject number not derived from personal identifiers will be utilized for subject

Sample size calculation

The sample size was estimated using data from previous studies and from Steering Committee experience. From RAAFT Study21 we know that 1-year freedom from any recurrence of symptomatic AF or asymptomatic AF lasting longer than 30 seconds was 37% in AAD arm and 87% in RF ablation arm. Both Namdar et al37 and Tanner et al38 showed that freedom from any documented episode of AF, atrial flutter or atrial tachycardia of ≥30 s duration on average of 15 months of follow-up was 78% in patients

Discussion

Despite the presence of three prior trials comparing first-line AAD to ablation therapy for AF, the magnitude of benefit of ablation in this setting is still unknown. RAAFT-2 showed a significant reduction in AF recurrence in the ablation arm [HR 0.56; 95%CI 0.35–0.90; P = .02], but the magnitude in difference between the 2 groups was not clinically impactful [17.6% reduction in arrhythmia recurrence from 72.1% in the AAD group to 54.5% in the ablation group].21 Furthermore, the MANTRA PAF

Competing interests

Dr. Andrade reports grants and personal fees from Medtronic, grants from Baylis, personal fees from Biosense-Webster; Dr. Champagne has nothing to disclose; Dr. Deyell reports grants from Biosense-Webster; Dr. Essebag reports personal fees from Biosense, Abbott, and Medtronic; Dr. Lauck has nothing to disclose; Dr. Morillo personal fees from Abbott (SJM), Boston Scientific, Bayer, Daiichi Sankyo, Medtronic, grants from Bayer, Pfizer; Dr. Sapp reports grants from Biosense-Webster, personal fees

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      Randomised controlled trials (RCTs) have shown the efficacy of CA as first-line treatment, with one meta-analysis of six RCTs finding that first-line CA reduced arrhythmic recurrences when compared with anti-arrhythmic drugs [14,15]. Delivering ablation earlier in treatment of AF may be more effective in maintaining sinus rhythm, has the potential to retard the progression of electro-anatomical changes associated with AF, and may reduce overall health care utilisation [14–16]. One (1) study in the US identified an increase in the proportion of patients undergoing early ablation from 5% in 2010 to 10.5% in 2016 [17].

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      A noteworthy point is that randomized clinical trials and a meta-analysis of recent trials have shown that catheter ablation compared with antiarrhythmic drugs is associated with reductions in recurrence of atrial arrhythmias and hospitalizations, with no difference in major adverse events.81 Recent studies, namely the East AF Network (EAST AFNET) trial and the Early Aggressive Invasive Intervention for Atrial Fibrillation (EARLY-AF) trial, have suggested that early rhythm control of AF may be beneficial in many patients with AF.82,83 Current guidelines recommend catheter ablation as a treatment option for patients with heart failure with reduced ejection fraction and AF, as catheter ablation has been shown to decrease mortality and heart failure hospitalizations, as well as increase left ventricular ejection fraction in these patients.81,84

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      Last, whether early cardioversion of recent-onset atrial fibrillation improves long-term cardiovascular outcomes remains to be seen. Early cardioversion in the ED may serve as a bridge to continued rhythm control with maintenance antidysrhythmic drug therapy or left atrial ablation, treatment strategies that are being investigated in the ongoing Early Aggressive Invasive Intervention for Atrial Fibrillation (EARLY-AF) trial.74 In conclusion, there is a paucity of high-level evidence to inform the pharmacologic cardioversion of recent-onset atrial fibrillation and atrial flutter within a 4-hour ED visit.

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      Clinical guidelines recommend CA in symptomatic patients with AF refractory to at least 1 AAD.10,11 Although CA has increasingly been used as a first-line therapy in patients with paroxysmal AF,30 it remains likely that patients were prescribed an AAD before CA.10,11 In addition, studies evaluating AAD prescription patterns demonstrated that patients treated by cardiac electrophysiologists were more likely to be prescribed an AAD, who in turn may be more likely to proceed with CA.31,32

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      In these series, temperatures warmer than –36°C for superior PVs and warmer than –33°C for inferior PVs predicted ineffective PVI with >95% specificity (positive predictive value 80% for superior PVs and 82% for inferior PVs).22,23 As such, we consider lesions that fail to achieve a temperature colder than –35°C after 60 seconds ineffectual.24,25 The permanence of cryoablation lesions is a function of tissue temperature and time (ie, freezing duration).26,27

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    Trial Registration number: ClinicalTrials.gov NCT02825979.

    Protocol version: 3.0.

    Funding source: The EARLY-AF study was funded by a peer-reviewed grant from the Canadian Arrhythmia Network [grant number SRG-15-P15-001], with additional financial support from Medtronic. Drs. Andrade and Deyell are supported by Michael Smith Foundation for Health Research Career Scholar Awards. Dr. Essebag is supported by a Clinical Research Scholar Award from Fonds de recherché du Quebec-Santé (FRQS). All authors are Investigators of the Cardiac Arrhythmia Network of Canada (CANet), a Networks of Centres of Excellence.

    Role of the funding source: The funding sources had no role in the design of this study and will not have any role in data collection, study execution, data analyses and interpretation, writing of the report, or decision to submit the report for publication.

    Authors contributions: JGA, MWD, GAW, and AV conceived the study, and were involved in the drafting of the peer-reviewed grant, the study protocol, and the manuscript. JC, VE, SL, CM, JS, and AS served on the steering committee for the trial and have provided critical revision of the peer-reviewed grant, the study protocol, and the manuscript.

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