Trial DesignA randomized clinical trial of early invasive intervention for atrial fibrillation (EARLY-AF) - methods and rationale
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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Cited by (22)
An Observational Study of Clinical and Health System Factors Associated With Catheter Ablation and Early Ablation Treatment for Atrial Fibrillation in Australia
2022, Heart Lung and CirculationCitation Excerpt :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].
Racial and Ethnic Differences in the Management of Atrial Fibrillation
2021, CJC OpenCitation Excerpt :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
Pharmacologic Cardioversion of Recent-Onset Atrial Fibrillation and Flutter in the Emergency Department: A Systematic Review and Network Meta-analysis
2020, Annals of Emergency MedicineCitation Excerpt :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.
Population-Level Sex Differences and Predictors for Treatment With Catheter Ablation in Patients With Atrial Fibrillation and Heart Failure
2020, CJC OpenCitation Excerpt :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
Cryoablation for atrial fibrillation
2020, Heart Rhythm O2Citation Excerpt :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
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.