Editor’s Note: Commentary based on Mohanty S, Mohanty P, Di Biase L, et al. Results From a Single-Blind, Randomized Study Comparing the Impact of Different Ablation Approaches on Long-Term Procedure Outcome in Coexistent Atrial Fibrillation and Flutter (APPROVAL). Circulation 2013;127:1853-60.

Background

Catheter-based ablation has become first-line therapy in the management of typical atrial flutter (AFL), with a long-term efficacy exceeding 90%.¹ However, because AFL and atrial fibrillation (AF) frequently co-exist,² this presents an interesting clinical conundrum especially on the long-term use of anticoagulation and anti-arrhythmic drugs (AAD). AFL ablation requires creation of bidirectional block across the cavo-tricuspid isthmus (CTI) region whereas the most frequent strategy for AF ablation is pulmonary vein isolation (PVI). Previous smaller, non-randomized studies have shown comparable efficacy of PVI alone versus PVI combined with CTI ablation in achieving long term arrhythmia control in patient manifesting both AF and AFL. The objective of the APPROVAL study was to compare the impact of different ablation approaches on long-term arrhythmia recurrence and quality of life (QoL) in patients with coexistent AF and AFL in a prospective randomized design.³

Methods

The study enrolled patients at five centers. To participate in the study, subjects needed to have paroxysmal AF refractory to at least one AAD and also manifest ECG-documented typical AFL. Exclusion criteria included age (<18 or >85), history of prior ablation, contraindication to anticoagulation, or left atrial size >5cm. Participating patients were randomized on a 1:1 basis to undergo either both AF and AFL ablation (group 1), or AFL ablation alone (group 2). In group 1, CTI ablation was only performed if the patients manifested typical flutter during the procedure (spontaneous or induced). The primary end point was freedom from arrhythmia after a 12-week blanking period. Arrhythmia recurrences were documented by 12-lead ECG and 7-day Holter monitoring performed at three, six, nine, and 12 months post ablation. Secondary end points were QoL, hospitalizations, and complications. QoL was assessed by multiple (n=4) surveys that were administered at baseline and 1 year follow-up. The estimated sample size for the study was 350 subjects in order to provide adequate power to show a 15% difference between the two strategies for the primary end-point.

Results

Three hundred and sixty subjects were enrolled and all subjects successfully underwent the ablation procedure as per the arm to which they were randomized. In group 1, the majority of patients (n=124; 68%) did not undergo CTI ablation for AFL. Mean age of the population was 61±11 years and all subjects were relatively healthy.  Freedom from arrhythmias both on and off AADs was significantly lower in group 1 than group 2 (69 vs. 26% and 64 vs. 19%, respectively; p<0.001 for both comparisons). Within group 1, arrhythmia recurrences were not statistically different in patients that received AF ablation alone versus those that had additional AFL (CTI) ablation (68 vs. 71%; p=0.657). Hospitalizations were significantly higher in patients randomized to group 2 (30.9% vs. 6.6%; p <0.001). Consistent with this observation, some subsets of QoL (anxiety and depression) were significantly worse at one year in patients randomized to group 2. Multi-variate analysis revealed that freedom from arrhythmia was an independent predictor of improvement in multiple QoL scales.

Conclusion

Based on these observations the authors conclude that in patients with coexistent AF and AFL, the strategy of either AF ablation alone or combined with AFL ablation results in lower arrhythmia recurrence rates and improved patient QoL than performing AFL ablation alone.

Commentary/Perspective

The coexistence of AF and AFL is well recognized and extensively described.⁴ Although catheter ablation is highly effective for patients manifesting typical AFL, up to 50% of these patients can develop AF within two years of undergoing AFL ablation.⁵  The occurrence of AF post AFL ablation is even higher in patients who manifest both arrhythmias clinically. In the past, a “hybrid” approach, (CTI ablation combined with AAD) has been utilized to treat patients with co-existent AFL and AF. However this approach has been shown to be ineffective in controlling AF long term.⁶ The APPROVAL study provides further evidence of the ineffectiveness of AFL ablation alone in patients manifesting dual arrhythmias (AF and AFL). This is not unexpected, because the pulmonary veins (PVs) are the most common source of triggers in patients experiencing AF.⁷ Clearly, AFL ablation alone does nothing to address PV triggers. This however makes it difficult to explain why 26% of patients randomized to undergo CTI ablation alone in APPROVAL study remained free of AF. Mechanistically, this would suggest that AFL and/or the CTI region was the source / driver of AF in these patients. However, we know that non-PV locations serve as the source of AF triggers only in a small minority of patients (2-3%)⁶ with paroxysmal AF.  An alternative explanation for this observation is that the true burden of paroxysmal AF in these 26% of patients may not have been adequately captured by the intermittent monitoring strategy used in the APPROVAL study. Ideally, to estimate the true change in burden of paroxysmal AF post ablation, it is important to also assess AF burden pre-ablation, which was not done in this study. An important finding in this study is that the long-term freedom from arrhythmia recurrences was similar amongst patients who underwent combined AF and AFL ablation versus those who had only AF ablation. This observation would strongly imply that much like AF, AFL too is mechanistically dependent on PV triggers. It is conceivable that PV triggers propagate from the left to the right atrium through preferential conduction via the coronary sinus (CS) musculature in vicinity of the CS ostium (os). This pattern of propagation could set up unidirectional block in CTI region resulting in counter clockwise atrial flutter similar to what has been observed with rapid pacing and/or programmed stimulation from the CS os.  Another interesting observation in this study pertains to QoL. While the beneficial effect of any intervention on QoL has to be treated with some skepticism, the patient blinded nature of the APPROVAL trial, gives credence to the notion that being consistently arrhythmia-free over a longer period of time translates into improvement in patient well-being. The APPROVAL study adds to the growing evidence on the critical role of PVs in patients with co-existent AF and AFL. However, it still remains unclear whether for patients manifesting AFL alone, is CTI ablation sufficient? In a series of 80 patients undergoing typical AFL ablation at our center, over a mean follow-up period of 29.6±21.7 months, 40 subjects (50%) demonstrated new onset AF.⁷ These data were confirmed by a recent study that assessed the incidence of AF via implantable loop recorders following catheter ablation of AFL.⁸ Furthermore, in a recent study of 126 veterans undergoing typical flutter ablation, we found that despite undergoing successful AFL ablation, these patients remained at an elevated risk for AF and stroke.⁹ These observations make a strong case for exploring the utility of prophylactic PV isolation in patients manifesting typical AFL only.¹⁰ We are currently conducting a prospective randomized multicenter study (REDUCE AF) to specifically address this hypothesis.¹¹ We hope that this study may further help refine our treatment strategy for patients with typical AFL who may not clinically manifest AF initially.

References

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11. Pulmonary Vein Isolation to Reduce Future Risk of Atrial Fibrillation in Patients Undergoing Typical Flutter Ablation: REDUCE AF trial. http://www.ClinicalTrials.gov. NCT01710150.

Keywords: Atrial Fibrillation, Atrial Flutter, Catheter Ablation, Coronary Sinus, Stroke

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