Atrial fibrillation (AF) is the most common cardiac arrhythmia (a condition associated with an irregular heartbeat). Clinical studies show that advanced-generation catheter ablation techniques have superior success in preventing recurrence of arrhythmias in AF compared to drugs. However, in the early period following ablation treatment, recurrence of atrial arrhythmia can be common. Dr Jason Andrade and colleagues at the University of British Columbia, Canada, are exploring the true prevalence of Early Recurrence of Atrial Tachyarrhythmia (ERAT), its causes, and what the presence of ERAT following ablation treatments may indicate for patients with AF worldwide.
The heart has four chambers: two atria (upper chambers) and two ventricles (lower chambers). During a normal heart rhythm, electrical signals generated in the sinus node cause the atria to contract. Consequently, these signals are transmitted through the atrioventricular node to the ventricles, causing ventricular contraction. In atrial fibrillation (AF), an irregular heart rhythm exists where abnormal electrical impulses (mostly arising in the pulmonary veins or surrounding areas) cause chaotic atrial contraction and insufficient filling of the ventricles with blood. Atrial fibrillation may occur suddenly and intermittently (paroxysmal AF), or it may be more chronic (persistent AF). Patients may experience a reduced quality of life and, if inadequately treated, AF is associated with increased risk of thromboembolism (obstruction of a blood vessel caused by a blood clot), congestive cardiac failure, and death.
A global health burden
With a prevalence of 2% of the population, AF presents a significant global health burden. Atrial fibrillation therapeutics include antiarrhythmic drugs or Pulmonary Vein Isolation (PVI) using catheter ablation, among others. Ablation is the destruction of the cardiac tissue that causes abnormal signals associated with AF. During PVI, the connections between the pulmonary vein and the left atrium are targeted to prevent transmission of abnormal signals. The goal of such treatment is to prevent the arrhythmias caused by these signals and provide symptom relief for the patient. As AF is a progressive disease, early effective treatment may reduce pathology and improve long-term outcomes.
In a recent clinical study, Dr Jason Andrade and colleagues from the University of British Columbia, explored the outcomes following antiarrhythmic drug initiation or catheter ablation, as the first treatment for atrial fibrillation. The multicentre ‘Early Aggressive Invasive Intervention for Atrial Fibrillation’ (EARLY-AF) clinical trial reported a significant reduction in arrhythmia recurrence, and improved quality of life with cryoablation compared to antiarrhythmic drugs as a first line treatment for patients with paroxysmal AF. Published in the New England Journal of Medicine, their study provides vital evidence for the longer-term benefits of catheter ablation in the relief of arrhythmias.
However, Early Recurrence of Atrial Tachyarrhythmias (ERAT) is common following catheter ablation procedures, being reported in up to 60% of patients. ERAT has been shown to be a predictor of late recurrences and ‘treatment failure’, although a significant proportion of patients with ERAT do not go on to experience late recurrences. Several mechanisms may be responsible for ERAT, and Andrade’s research provides a much-needed understanding of these mechanisms as well as the clinical significance of this initial recurrence.
“The timing of onset of Early Recurrence of Atrial Tachyarrhythmia (ERAT) has significant prognostic value for predicting late recurrences.”
Catheter ablation and ERAT
Catheter ablation can be realised using radiofrequency energy (RFCA) and cryoablation. RFCA uses radiofrequency generated heat, whereas cryoablation uses extreme cold to injure the cardiac tissue. Both technologies aim to isolate the areas causing arrhythmia, eg, the pulmonary veins. Following the procedure, rhythm monitoring via non-invasive methods or an implanted cardiac device helps detect any recurrence of arrhythmia. ERAT is acknowledged as being transient and therefore any such recurrence within three months (known as the ‘blanking period’) of the procedure is not considered an indicator of unsuccessful treatment. The length of the blanking period has been debated and while widely accepted as being three months, recent research by Andrade and colleagues using the CIRCA-DOSE trial data now suggests this could be reduced to five weeks.
But what causes ERAT and what are the underlying mechanisms responsible? Andrade suggests different mechanisms maybe at play depending on how long after the ablation ERAT occurs.
Ablation causes acute cellular injury leading to an inflammatory response at the site of the injury. This direct cellular injury and the release of inflammatory proteins (called cytokines) and neurotransmitters, such as catecholamines, can be thought of as a transient irritation to the tissue resulting in arrhythmia episodes. Alterations to the autonomic nervous system have also been reported to affect atrial muscle tone, leading to early recurrence of arrhythmias. In a majority of cases the ERAT provoked by the early healing phase will resolve with time.
“The CIRCA-DOSE trial revealed approx 60% of patients developed ERAT following their AF treatment, with most episodes being asymptomatic.”
However, a significant minority of patients with ERAT will continue to experience arrhythmia on follow-up. These later recurrences represent treatment failure, and usually indicate a reconnection between the pulmonary vein and left atrium allowing abnormal signals to be conducted and thus recurrence of arrhythmia.
Being able to accurately differentiate ‘treatment failure’ from ‘delayed success’ would allow for earlier intervention, which should improve patient outcomes.
Although our understanding of ERAT has advanced in the last decade, varied prevalence of ERAT following ablation has been reported. It is thought the true incidence of ERAT has been underestimated due to the use of non-invasive cardiac monitoring to detect ERAT as opposed to continuous monitoring. In addition, no study has compared RFCA and cryoballoon ablation techniques and the resultant ERAT prevalence. To complicate matters, the three-month blanking period is widely debated.
The CIRCA-DOSE trial was designed to address these gaps and provide valuable information about the clinical outcomes of patients with ERAT. A second goal was to gather information to redefine the blanking period so it may be more reflective of clinical outcomes.
The CIRCA-DOSE trial
From 2014 to 2019, Andrade and colleagues conducted the CIRCA-DOSE clinical trial in eight centres in Canada. An aim of this study was to determine the prevalence of ERAT in patients undergoing ablation using advanced-generation catheter techniques. The researchers also looked at the clinical outcomes of patients with ERAT. A total of 346 patients with paroxysmal AF who had been unsuccessfully treated for AF with antiarrhythmic drugs were randomised to either undergo radiofrequency ablation or cryoballoon ablation (a short two-minute procedure or the standard four-minute procedure). Patients were monitored for signs of arrhythmias via a cardiac monitoring device and were followed for 12 months.
“The study provides vital insight into the prognostic value of ERAT, associated clinical outcomes, and when patients may benefit from further intervention.”
The CIRCA-DOSE trial revealed that 61% of patients developed ERAT following their AF treatment procedures with most episodes being asymptomatic. Interestingly, this prevalence and its association with late recurrences did not differ between the radiofrequency or cryoballoon ablation techniques; both techniques were effective at treating AF.
In half of the patients with ERAT, the onset occurred within 30 days of the procedure. Patients where ERAT occurred slightly later, eg, in the second and third months post ablation, were at higher risk of developing late recurrences than those with ERAT onset in the first month. Specific analysis showed that ERAT episodes occurring later than 38 days after catheter ablation was a strong predictor of late recurrence. The timing of onset therefore has significant prognostic value for predicting late recurrences. Andrade hypothesises that ERAT occurring in the first month predominantly reflect the inflammation and remodelling mechanisms, whereas ERAT in the later months may indicate pulmonary vein reconnection. Without ERAT, patients were far less likely to experience late recurrences of arrhythmias with 74% of such patients having no late recurrences after 12 months. A major strength of the CIRCA-DOSE trial was the use of a more reliable continuous rhythm-monitoring system, and the study suggests a redefined and more clinically appropriate blanking period of five weeks as opposed to the much-debated three months.
Clinical implications
The study provides vital insight into the prognostic value of ERAT, the associated clinical outcomes, and when patients may benefit from further intervention. However, Andrade recommends that the need for further intervention should not be based on ERAT alone but should also take the patient’s symptoms and quality of life into consideration. Importantly, this research also gives patients and the scientific community an understanding of what may be expected following such therapies and in the pathway to recovery.
Can you tell us about current or future research plans into the use of advanced-generation catheter ablation techniques in patients with persistent AF?
We continue to evaluate the natural history of atrial fibrillation and explore the importance of catheter ablation in altering the disease trajectory and improving patient outcomes, providing a more complete picture of how we provide cardiac care for arrhythmia patients. Specifically, we are working to determine the appropriate timing of intervention, as well as the optimal ablation techniques to ensure that we are able to help patients live better, more fulsome lives with their atrial fibrillation. Our goal is to provide clear evidence that better informs treatment choices, enabling clinicians to better support patients when participating in shared decision-making. Ultimately, we want to see that our patients are happier, healthier, and living longer, better lives with these chronic conditions.
References
- Andrade, J, (2012) Early Recurrence of Atrial Tachyarrhythmias Following Radiofrequency Catheter Ablation of Atrial Fibrillation. PACE, 35 (1), 106–116. doi.org/10.1111/j.1540-8159.2011.03256.x
- Andrade, J, (2014) Incidence and Significance of Early Recurrences of Atrial Fibrillation After Cryoballoon Ablation: Insights From the Multicenter Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP AF) Trial. Circ Arrhythm Electrophysiol, 7 (1), 69–75. doi.org/10.1161/CIRCEP.113.000586
- Andrade, J, (2021) Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation. NEJM, 384, 305–315. doi.org/10.1056/NEJMoa2029980
- Steinberg, C, (2021) Prevalence and outcome of early recurrence of atrial tachyarrhythmias in the Cryoballoon vs Irrigated Radiofrequency Catheter Ablation (CIRCA-DOSE) study. Heart Rhythm, 18 (9), 1463–1470. doi.org/10.1016/j.hrthm.2021.06.1172
- Andrade, J, (2021) Cryoballoon Ablation as Initial Treatment for Atrial Fibrillation. Journal of the American College of Cardiology, 78 (9), 914–930. doi.org/10.1016/j.jacc.2021.06.038
10.26904/RF-139-2139904844
Research Objectives
Dr Andrade is the principal investigator of several multi-centre randomised clinical trials on cryoablation (the CIRCA-DOSE study and the EARLY-AF program).
Funding
Heart and Stroke Foundation of Canada
Bio
Jason Andrade is the Director of Electrophysiology at Vancouver General Hospital. He is an associate professor of medicine at the University of British Columbia, co-chair of the Canadian Cardiovascular Society AF Guidelines, and chair of the Canadian Heart Rhythm Society Device Committee. Dr Andrade has authored over 200 publications.
Contact
2775 Laurel St
Room 9159, 9th Floor
Vancouver BC V5Z 1M9
Canada
E: Jason.andrade@vch.ca
T: +1 604 875 5069
W: Jason Andrade | VCH Research Institute (vchri.ca)
