Ablating Rotors and Focal Beat Sources of Atrial Fibrillation to Improve Outcome: The CONFIRM Trial

Case Description

Recently, a 47-year-old gentleman visited us in San Diego for a ‘final opinion’ on his extremely burdensome atrial fibrillation (AF). His AF symptoms had been getting worse over the past few years, and the resulting palpitations and dizziness had required regular (roughly monthly) emergency room visits for cardioversion. Medications were unable to control his symptoms, and he had undergone three prior AF ablation procedures with little improvement in his symptoms.

At this clinic visit, he asked us if there were “any other options.” We answered that one had just become available. Under specific IRB consent, we offered ablation guided by a new computational mapping system developed in our laboratory to identify localized sources that cause AF in any individual patient. During this mapping, a localized AF source (“electrical rotor”) was found — unexpectedly — in the right atrium. As part of our protocol, we targeted this rotor for ablation. To the great surprise of everybody in the laboratory, ablation at only this right atrial rotor terminated AF to sinus rhythm in 5.5 minutes, and AF could not be reinduced. The total ablation time for the case was under 10 minutes. The next month was the “best [he had] had in years,” and he went on to have no AF on follow-up using an implanted continuous ECG monitor. The success of the approach of Focal Impulse and Rotor Modulation (FIRM) ablation for AF in this patient led to the CONFIRM trial, as we summarize here, and to the initiation of clinical programs for FIRM ablation at several institutions beyond our initial study group.

Background

Great strides have been made in ablation therapy for atrial fibrillation.^1-3 Approaches for AF ablation vary between laboratories, yet their cornerstone is pulmonary vein isolation (PVI)^2,4 based on the pioneering observations of Haïssaguerre et al that ectopic beats within PVs may trigger episodes of AF.¹ Nevertheless, the efficacy and time efficiency of percutaneous and surgical ablation remain suboptimal and demonstrate a 70–80% ‘ceiling’ in efficacy.^2,5 With wider adoption of rigorous monitoring, it is increasingly clear that many patients may experience ‘silent’ AF post ablation even with no symptoms.⁶ Accordingly, recent reports show one-year elimination of AF off-medications at 50–60% for a single ablation procedure,^2,5,7 and 60–80% after up to three procedures,^2,8-10 with potentially long procedural times even at experienced centers.

These limitations of AF ablation may reflect multiple factors. What is often considered first is that current tools may fail to create durable ablation lesions,² evidenced by pulmonary vein reconnection^11,12 and gaps in linear atrial lesions¹³ in patients with recurrent AF post ablation. This has led to several technologies to improve lesion durability. However, another very important limitation of AF ablation is that current techniques only target the triggering beats of AF, in sharp contrast to all other arrhythmias in which ablation is centered on the main ‘driving’ or sustaining mechanism.^2,14-16 Unfortunately, few technologies have improved our understanding of AF-sustaining mechanisms.

The CONFIRM (Conventional Ablation with or without Focal Impulse and Rotor Modulation) trial was designed to test the hypothesis that ablation directed at the sustaining mechanisms for AF in any given patient would improve the success of conventional ablation. To address our hypothesis, we have developed a novel computational mapping approach over the past 10 years to identify localized sources for AF, in the form of electrical rotors¹⁷ or focal impulses.^15,18 Such localized sources were first reported in animal studies of AF, but there had been little or no^19-21 evidence for their existence in human AF prior to our work. In our approach, when such sources are identified, ablation is directed at them (Focal Impulse and Rotor Modulation, FIRM-guided therapy).

CONFIRM Trial Design

This report summarizes the CONFIRM trial abstract, presented as a Late-Breaking Clinical Trial at the 32nd Scientific Sessions of the Heart Rhythm Society in San Francisco, California in May 2011.²² CONFIRM was conducted prospectively by five investigators at three sites. Dr. Narayan is Professor of Medicine and Co-Director of Electrophysiology at the University of California, San Diego (UCSD) and Director of EP at the San Diego Veterans Affairs Medical Center, Dr. Krummen is Associate Professor of Medicine at UCSD and Associate Director of the VA EP Laboratory, and Dr. Sehra is staff Electrophysiologist at the San Diego VA. The San Diego team is pictured in Figures 1 and 2. Dr. Shivkumar is Professor of Medicine and Director of Electrophysiology at the University of California, Los Angeles (UCLA). Dr. Miller is Professor of Medicine and Director of Electrophysiology at the Indiana University Hospitals.

As presented,²² we enrolled 103 patients undergoing AF ablation for standard indications, aged 62±9 years (range 40–82 years), with the only exclusion criteria being inability or unwillingness to consent to FIRM mapping and ablation. Subjects had enlarged left atria (diameter 44±8 mm) and preserved left ventricular ejection fractions (56±12%), although patients with heart failure were enrolled (LVEF range 20% to 79%). Approximately two-thirds of patients had persistent AF.

In all patients we recorded AF widely from the atria using commercially available multipolar basket catheters (Constellation^®, Boston Scientific, Natick, MA) prior to ablation. Figure 3A shows basket catheters placed simultaneously in both atria in a patient in the CONFIRM trial (some patients were studied using only one basket, moved sequentially from right to left atrium).

Patients were divided into two groups. Subjects in the active group, termed FIRM-Guided, underwent computational mapping of AF during their procedure. Computational mapping involves analysis of simultaneous multielectrode recordings of AF using algorithms and methods developed in our laboratory using grants from the National Institutes of Health and the Doris Duke Charitable Foundation (2001-present). This approach performs physiologically guided analyses^23-26 employing concepts such as regional conduction slowing that may enable localized reentry,²⁷ and has been licensed from the University of California and further developed by Topera Medical Inc. (RhythmView^™, Topera Medical, Inc., San Diego, CA). When computational maps revealed localized electrical rotors or focal impulses that are sustained (tens of minutes, i.e., thousands of cycles), those sites were directly ablated by FIRM prior to any other ablation or PV isolation. FIRM ablation was applied for <10 minutes at each source, and the composite endpoint was AF termination or AF slowing >10% (greater than the previously used ≈3% cutpoint that predicts good long-term outcomes²⁸). Typically, less than 3–5 minutes of FIRM ablation were required to achieve termination. If AF terminated, it was aggressively reinduced and AF maps were recomputed. This process was permitted for <30 minutes of FIRM ablation (typically 10–15 minutes). FIRM-Guided patients then underwent conventional ablation, as described below.

Subjects in the control (FIRM-Blinded/conventional) group also underwent basket recordings of AF, but these data were not used to guide ablation and were processed offline. These patients proceeded directly to conventional ablation, including standard wide-area circumferential ablation (WACA) and a left atrial roof line in persistent AF patients. Patients with documented atrial tachycardias had appropriate ablation, but no other targets (e.g., fractionated electrograms²⁹ or ganglionated plexi³⁰) were ablated.

All patients were followed in clinic and a three-month blanking period² was used. Notably, repeat procedures were not permitted, and we reported only the outcome of this single procedure. Recurrent AF was detected rigorously using implanted continuous ECG recorders with AF autodetection algorithms (Reveal XT, Medtronic, Minneapolis, MN) or clinically indicated pacemakers or defibrillators (84% of FIRM-Guided versus 23% of FIRM-Blinded subjects). Other patients were followed using external event monitors or Holter monitors.

CONFIRM Trial: Acute Results

Computational maps in AF revealed localized sources in nearly all patients (97%), in both FIRM-Guided and FIRM-Blinded groups. Notably, patients typically had more than one concurrent source (2.0±1.1), each of which remained stable over time. Overall, 77% of sources were rotors and 23% were focal impulses. Approximately one-quarter of localized sources lay in the right atrium.

Figure 3B illustrates an example of a rotor location in the inferoposterior left atrial wall during AF, outside the WACA line set delivered in our laboratory, in a patient with persistent AF. Figure 3C illustrates the counterclockwise rotor, color coded from red to blue (cycle length ≈190 ms) that persisted for 45 minutes prior to ablation. An ablation catheter was advanced transseptally, and FIRM ablation at this rotor terminated AF to sinus rhythm in <1 minute prior to pulmonary vein isolation or any other ablation. Sustained AF could not be reinduced. The patient then underwent planned conventional ablation (WACA).

In FIRM-Guided subjects, 88% achieved the acute efficacy endpoint of AF termination or substantial AF slowing with FIRM ablation alone (prior to any other ablation such as PVI) in 6.6±4.9 minutes of FIRM ablation.

CONFIRM Trial: Long-Term Results

Figure 4 shows that the single-procedure elimination of AF at two years was 84.5% in FIRM-Guided subjects, compared to 50.5% in FIRM-Blinded subjects. Notably, implantable devices were used to detect recurrent AF in 84% of FIRM-Guided but only 23% of FIRM-Blinded subjects. The higher intensity of monitoring in the FIRM-Guided subjects compared to the FIRM-Blinded subjects may theoretically underestimate the treatment impact of FIRM-Guided ablation.

The final results from the CONFIRM trial will describe longer follow-up in a larger cohort of patients.

Conclusion

In the CONFIRM trial, localized electrical rotors and focal impulse sources were highly prevalent during human AF, revealed using a novel computational mapping system. FIRM-Guided ablation of patient-specific AF mechanisms acutely terminated or slowed AF, and significantly augmented freedom from AF (84% at 2 years) compared with conventional ablation alone (50%). Thus, these results provide an approach to rise above the previous ceiling for success of AF ablation. Of note, two-thirds of patients in the CONFIRM trial had more difficult to treat persistent AF.

By detecting the actual sustaining mechanisms for AF in each patient, these results offer a novel treatment paradigm for AF that may increase the efficacy of ablation. Ongoing studies at multiple centers will determine whether this successful and simplified approach to AF ablation may reduce procedure times and complication rates, and whether populations can be identified in whom FIRM alone may be effective without PVI.

Disclosures:This study was funded by grants from the National Institute of Health (HL 70529, HL 83359, HL 103800) and Doris Duke Charitable Foundation to SMN. It has resulted in intellectual property owned by the University of California and licensed to Topera Inc., who are commercializing this system as RhythmView^™. Dr. Narayan is a cofounder and equity holder in Topera. Topera has not sponsored any research including the CONFIRM trial. Dr. Narayan has received honoraria from Medtronic, St. Jude Medical, and BIOTRONIK. Dr. Shivkumar is a member of Topera Medical’s Scientific Advisory board. Dr. Miller reports honoraria from Medtronic, St. Jude Medical, Biosense Webster, Stereotaxis, and BIOTRONIK, and is a member of Topera Medical’s Scientific Advisory Board.

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