Electrographic Flow Mapping Electrogram Validation in Patients With Persistent Atrial Fibrillation (FLOW EVAL-AF)
Phase: NA
Conditions: Persistent Atrial Fibrillation, Longstanding Persistent Atrial Fibrillation, Atrial Fibrillation, Persistent, Arrhythmias, Cardiac
Sponsor: Ablacon, Inc.

 
 
 
 
Title: FLOW Mapping Electrogram VALidation in Patients with Persistent Atrial 
Fibrillation (FLOW EVAL-AF) 
NCT06260670 
 
 
 
 
CP-004 Investigational Protocol 
Rev A 
21 December 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsored By 
 
Ablacon, Inc. 
4800 Wadsworth Blvd., Suite 310 
Wheat Ridge, CO 80033 USA 
 
 

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PRIMARY STUDY CONTACT 
 
Sponsor and Study 
Management 
Ablacon, Inc.  
4800 Wadsworth Blvd., Suite 310 
Wheat Ridge, CO 80033 USA 
Report Author/Contact 
Melissa Kong, MD, FHRS 
Chief Clinical Officer 
Ablacon, Inc. 
Phone: (650) 556-4563 
Email: melissa.kong@ablacon.com  
Principal Investigators 
David E. Haines, MD  
Professor, Oakland University William Beaumont School of Medicine 
Director, Heart Rhythm Center, Department of Cardiovascular 
Medicine 
Beaumont Hospital Royal Oak, Royal Oak, MI  
Philipp Sommer, MD 
Professor, Herz-und Diabeteszentrum NRW 
Ruhr-Universitaet Bochum, Bad Oeynhausen, Germany 
Contract Research 
Organization (CRO) 
Brommet Clinical Research (Netherlands/Belgium)  
Contact: Leo Brommet  
Email: lbrommet@ziggo.nl     
Data 
Management/Biostatistics 
Sun Clinical Consulting  
Contact: Felice Sun  
Email: felice@sunclinicalconsulting.com     
 
 
 

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TABLE OF CONTENTS 
 
1.0 
PROTOCOL SUMMARY ............................................................................................................. 4 
2.0 
BACKGROUND ............................................................................................................................. 5 
2.1 
Mapping and ablation of persistent atrial fibrillation .................................................................. 5 
2.2 
Ablamap® mapping system .......................................................................................................... 5 
2.3 
Electrographic Flow Consistency ................................................................................................. 7 
2.4 
Preliminary Clinical Data of Ablamap® ....................................................................................... 7 
3.0 
STUDY DESIGN ............................................................................................................................. 8 
3.1 
Objectives ...................................................................................................................................... 8 
3.2 
Study Endpoint .............................................................................................................................. 8 
3.3 
Design ........................................................................................................................................... 8 
3.4 
Study Population ........................................................................................................................... 8 
3.5 
Subject Selection ........................................................................................................................... 8 
4.0 
STUDY METHODS ........................................................................................................................ 9 
4.1 
Baseline Data ................................................................................................................................ 9 
4.2 
Study Procedure ............................................................................................................................ 9 
5.0 
SIGNAL ANALYSIS .................................................................................................................... 11 
5.1 
EGF Maps ................................................................................................................................... 11 
5.2 
Comparison of EGF Maps and HD Grid Maps .......................................................................... 11 
5.3 
Statistical Analysis ...................................................................................................................... 12 
6.0 
REFERENCES .............................................................................................................................. 12 
7.0 
STUDY DEFINITIONS ................................................................................................................ 13 
8.0 
STUDY ABBREVIATIONS......................................................................................................... 13 
 
 
 

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1.0 
PROTOCOL SUMMARY  
Sponsor 
Ablacon, Inc. 
Study Name 
FLOW EVAL-AF 
Study Title 
Electrographic flow mapping electrogram validation in patients with persistent 
atrial fibrillation 
Clinical Document 
No/Revision  
Version 1.0  
Clintrials.Gov 
Identification 
NCT05093868 
Objectives 
To correlate electrogram morphology of atrial fibrillation measured by a high-
density regional mapping to low density global electrographic flow mapping 
generated by the Ablamap® software 
Procedure 
10 subjects with persistent atrial fibrillation 
 
Test Devices 
Ablamap® Software v.9.0.2 (With Abbott FIRMap Catheter) 
Study Design 
Prospective, observational, single center pilot trial 
 
Clinical Site 
Herz-und Diabeteszentrum NRW, Ruhr-Universitat Bochum, Bad Oeynhausen, 
Germany 
Study Endpoint 
Successful acquisition of global EGF maps from each of the right and left atrial 
chambers, and simultaneous high density electrogram acquisitions from at least 
3 sites in each chamber. 
Primary Outcome 
Descriptive correlation of electrogram patterns using traditional high density 
regional mapping versus low density global EGF mapping using a novel 
mapping software. 
 

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2.0 
BACKGROUND 
2.1 
Mapping and ablation of persistent atrial fibrillation 
It is hypothesized that initiation and propagation of atrial fibrillation (AF) is 
dependent, at least in part, on rapid atrial stimulation from focal sources. It is 
debated whether the mechanism of arrhythmogenesis at these foci is abnormal 
automaticity, triggered activity, or reentry. However, after activation emerges 
from these “driver” sites, fibrillatory conduction ensues resulting in the 
disorganized conduction pattern of AF.1,2   
Conventional mapping systems can either achieve high spatial resolution by 
sequential tachycardia beats following a fixed intra-atrial activation pattern (as in 
macroreentrant atrial flutter), or high temporal resolution with very low spatial 
resolution achieved through multielectrode basket catheters. Activation mapping 
in AF with commercially available mapping systems has been unsuccessful in 
identifying driver sites because atrial activation patterns change on a beat-to-beat 
basis precluding the use of sequential mapping approaches, and real-time 
mapping with basket electrodes lacks sufficient resolution to delineate the 
complex patterns of conduction.2,3 
2.2 
Ablamap® mapping system 
Electrographic Flow (EGF) mapping (Ablamap®, Ablacon, Inc, Wheat Ridge, 
CO) is a unique method to assess dominant patterns of intra-atrial conduction 
during ongoing atrial fibrillation and has been previously described.4-6 EGF 
mapping reconstructs global atrial wavefront propagation in near real-time. 
Recordings from a multielectrode basket catheter are analyzed for electrical 
wavefront activation over sequential 2-second segments during a 60 second 
acquisition period. Patterns of reproducible wavefront activation are used to 
identify driver sources for AF. Multiple sources are often identified in patients 
with persistent AF.7 It is anticipated that substrate modification of these source 
regions will eliminate the AF drivers and result in a favorable response to catheter 
ablation as shown in a previously published retrospective analysis.8 
 
 

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Figure 1: FIRMap basket mapping catheter (left) captures 64 unipolar electrograms 
(center). After undergoing biharmonic spline interpolation based on Green’s function, 
the moving image is produced (right).  
 
 
 
Figure 2: The transformed data are divided into 2 second segments and activation 
vectors are produced (center). Multiple segments are compared, and dominant activation 
wavefronts (vector flows) are identified (right).  
 
 
 
 
 
 
 
 
 
 

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Figure 3: The 
EGF maps are 
summated over multiple segments and a composite map identifying reproducible sources 
(red dots, right) are identified. It is hypothesized that these source areas are the locations 
of microreentry, triggered or rotational activity that account for the persisting activation 
and re-activation of atrial fibrillation wavefronts. Flow consistency of the wavefront 
activation is weighted on a color scale of blue (low consistency) to maroon (high 
consistency). 
 
2.3 
Electrographic Flow Consistency 
In addition to the identification of AF driving sources, EGF mapping allows for 
the quantification of local and global electrographic flow consistency (EGFC), 
which measures the overall magnitude and temporal consistency of wavefront 
patterns.9 Regions of low EGFC are therefore associated with areas of chaotic or 
slowed conduction and conduction block.  
In the context of AF, a well-established correlation exists between bipolar low 
voltage areas detected on high density electroanatomic mapping and the presence 
of scar tissue as revealed by late gadolinium-enhanced cardiac magnetic 
resonance imaging, a surrogate marker for atrial fibrosis. Areas of atrial scar, as 
identified from bipolar voltage maps, have also been associated with worse 
outcomes, and larger low voltage areas obtained during SR mapping have been 
associated with the presence and progression of AF.10,11 This study aims to extend 
this understanding by investigating the correlation between bipolar voltage maps 
and EGFC in multiple rhythms to correlate areas of delayed versus healthy 
conduction.  
2.4 
Preliminary Clinical Data of Ablamap® 
The FLOW-AF study (NCT 04473963) was a prospective, randomized controlled 
multi-center study to evaluate the reliability of the CE-marked EGF algorithm 
technology (Ablamap®, Ablacon, Inc, Wheat Ridge, CO), which identified AF 
sources and guided ablation therapy in patients with persistent atrial fibrillation. 
In total, 85 patients with persistent or long-standing persistent AF indicated for 
redo ablation were enrolled in the FLOW-AF study. In this population, EGF 

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mapping identified AF sources for ablation in 60% of the patients. Source 
elimination by means of radiofrequency ablation was achieved in 95.0% (19/20 
patients). AF-free survival at 12-months was improved among patients 
randomized to PVI+EGF-guided source ablation (68%) versus PVI-alone (17%; p 
= 0.042); freedom from AF/AT/AFL at 12-months was 51% versus 14% 
(p=0.103), respectively. Freedom from adverse safety events was 97.2%. Two 
adverse safety events occurred (decompensated heart failure and arteriovenous 
fistula), both of which were adjudicated by an independent Clinical Events 
Committee as related to the procedure but not related to EGF mapping/ablation. 
EGF-guided ablation of AF sources seems to be an efficacious adjunct to PVI in 
non-paroxysmal AF patients undergoing redo-ablation. Publication of the FLOW-
AF trial is expected in the first quarter of 2024. 
In addition, several sites in the EU have been and continue to perform 
commercial cases using the CE-marked Ablamap® software, and over 172 
additional patients have been treated with ablation using EGF-guidance outside of 
the FLOW-AF randomized clinical trial. 
 
3.0 
STUDY DESIGN 
3.1 
Objectives 
To identify driver sources in subjects with ongoing AF using EGF mapping and 
describe the activation patterns observed from concomitant high density (HD) 
mapping of those regions.  
 
3.2 
Study Endpoint 
Successful acquisition of global EGF maps from each of the right and left atrial 
chambers and simultaneous high density electrogram acquisitions from at least 3 
sites in each chamber. 
3.3 
Design 
Prospective, observational, single center pilot trial. 
3.4 
Study Population 
Subjects with persistent or longstanding persistent AF that are scheduled for 
elective catheter ablation of AF (De Novo and Redo). 
3.5 
Subject Selection 
3.5.1 Subject Identification 
All subjects who are scheduled for catheter ablation of AF, including those 
with prior history of AF catheter ablation, were considered. Screening was 
performed by physician staff at the time of procedure scheduling. 
 

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3.5.2 Inclusion Criteria 
Subjects will be eligible to participate if the following criteria are met: 
- 
Scheduled to undergo elective catheter ablation of AF 
- 
History of persistent or longstanding persistent AF  
- 
Able to provide written informed consent prior to the procedure 
- 
Age ≥18 years 
 
3.5.3 Exclusion Criteria 
Subjects will not be eligible to participate if any of the following criteria 
are met: 
- 
Presence of a permanent pacemaker or other transvenous 
pacing/defibrillation leads 
- 
Presence of a prosthetic mitral heart valve 
- 
Known reversible causes of AF 
- 
Any cerebral ischemic event (strokes or transient ischemic attacks) 
which occurred during the 6-month interval preceding the consent date 
- 
History of thromboembolic event within the past 6 months or evidence 
of intracardiac thrombus at the time of the procedure 
- 
Unable to provide own informed consent 
 
3.5.4 Informed Consent  
- 
Written informed consent was obtained from the subject by the 
research coordinator or investigator within 30 days of the procedure.   
 
4.0 
STUDY METHODS 
4.1 
Baseline Data 
Subjects will undergo baseline evaluation in accordance with hospital’s standards. 
4.2 
Study Procedure 
4.2.1 Catheter Ablation Procedure  
- 
During the study, subjects with PeAF or long-standing PeAF are 
prospectively enrolled at the Heart and Diabetes Center NRW in Bad 
Oeynhausen, Germany.   
- 
All subjects should be able to provide written informed consent and 
should be at least 18 years of age.  
- 
All procedures are performed under sedation after obtaining informed 
consent.   
- 
All subjects included in this analysis will undergo 3-dimensional 
electroanatomic mapping with an Ensite mapping system (Abbott, Abbott 
Park, IL) and Ablamap®.  

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- 
Pulmonary vein isolation (PVI) ablation or PVI touch-up should be 
performed according to standard hospital ablation procedures, using an 
irrigated tip radiofrequency ablation catheter. 
- 
Ablation catheter power and temperature settings are at the operator’s 
discretion.  
- 
Intravenous heparin should be administered for systemic anticoagulation 
to maintain an activated clotting time (ACT) > 300 seconds prior to 
insertion of the 64-pole basket mapping catheter.  
 
4.2.2 High-Density Voltage Mapping and EGF Mapping  
- 
All subjects should first undergo high-density voltage mapping using the 
16-pole grid mapping catheter (HD-Grid, Abbott, Abbott Park, IL) 
followed by baseline EGF mapping in their presenting rhythm: AF or SR.  
- 
PVI is then performed in standard fashion at the physician’s discretion. 
- 
For any ablation of PVs, confirmation of PVI (entrance or exit block) 
should be performed after a mandatory minimum 20-minute wait after the 
last RF application. PV reconnections should be ablated when necessary. 
- 
By necessity, the workflow will vary depending on the subject's presenting 
rhythm (SR or AF).  
o If subjects present in SR, they undergo both EGF mapping and high-
density bipolar voltage mapping in SR first, followed by PVI. Post-
PVI, AF should be induced and EGF mapping and high-density 
bipolar voltage mapping in AF is then be performed. Cardioversion 
back to SR should be performed at the end of the procedure. 
o If subjects present in AF, they undergo EGF mapping and high-density 
bipolar voltage mapping in AF first, followed by PVI. Post-PVI, if the 
subject remained in AF, cardioversion should be performed followed 
by EGF mapping and high-density bipolar voltage mapping in SR.  
 
4.2.3 EGF Mapping  
- 
EGF mapping should be performed both pre- and post-PVI using the 
Ablamap® software (Ablacon, Inc., Wheat Ridge, CO). 
- 
Unipolar electrograms (EGMs) are recorded using a commercially 
available 64-electrode basket mapping catheter (FIRMap™, Abbott 
Laboratories, Abbott Park, IL) connected to a proprietary, CE-marked 
recording system (EP Map, Herdecke, Germany). 
- 
EGF mapping is performed by obtaining 1-minute recordings from the 64-
pole basket catheter placed in multiple standardized positions within each 
atrium. 
- 
In the LA, there are typically 2 standardized basket positions: 1) 
posterosuperior LA with the dome of the basket aiming toward the left 

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PVs and LA appendage (LAA); 2) lateral LA with basket dome pointing 
toward LAA and the mitral valve. 
- 
In the right atrium (RA), there are typically 3 standardized basket 
positions: 1) superior vena cava (SVC)/RA junction with basket position 
halfway into the SVC; 2) central RA with basket dome pointing to SVC 
with vertical catheter shaft orientation and basket expanded to fill RA; 3) 
anterolateral RA with basket dome pointing to RA appendage and 
tricuspid valve and catheter deflected anterior and lateral from SVC.  
- 
If additional rhythm changes occurred spontaneously, EGF mapping 
should be conducted in the new rhythm without requiring accompanying 
voltage maps.  
 
4.2.4  Procedure Completion 
- 
Due to time considerations and other practical considerations, voltage 
maps and EGF maps can be omitted from the protocol at the physician’s 
discretion.  
- 
Adjunctive ablations can be performed at physician’s discretion, after all 
mapping is completed. This includes EGF-identified source ablations. 
- 
Before concluding the procedure, any subjects who are in AF are 
cardioverted to SR.   
- 
At the end of the procedure, heparin is discontinued. Catheters and sheaths 
are removed, and hemostasis is achieved per standard protocol. 
- 
The de-identified raw electrogram signal data should be downloaded onto 
portable media. These anonymized data should be securely transmitted 
electronically to the technical staff at Ablacon, Inc. for analysis. 
  
5.0 
SIGNAL ANALYSIS 
5.1 
EGF Maps 
- 
Unipolar electrogram signals from the basket catheter are analyzed using the 
Ablamap® software for each 1-minute recording to generate an EGF Summary 
Map. EGFC scores are calculated from all EGF summary maps. EGFC is 
computed from the Euclidean length of the vector field estimates over time. 
This provides a measure of the overall magnitude of flow averaged over all 
basket electrodes in arbitrary units (AUs). 
- 
Additionally, an overall EGFC score is computed for each atrium of each 
subject, by averaging the positional EGFCs within each atrium.  
5.2 
Comparison of EGF Maps and HD Grid Maps 
- 
The EGF patterns observed on Ablamap® and their EGFC scores are 
compared with the unipolar and bipolar voltage maps observed on HD grid 
maps from those same regions. 

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5.3 
Statistical Analysis 
- 
Continuous variables are reported as mean ± standard deviation and where 
appropriate as median ± interquartile range. For all statistical tests, the null 
hypothesis is rejected at the level of P < 0.05.  
- 
P-values for group comparisons are computed using two-tailed t-tests for 
continuous variables and chi-squared tests for proportions, as appropriate.  
- 
T-tests are paired when compared across the same subjects and independent 
when compared among different subjects.  
- 
Analyses are performed by a biostatistician and data scientist using both SAS 
software for Windows version 9.3 and SciPy version 1.10.1.  
 
6.0 
REFERENCES 
1. 
Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications 
for management. Circulation 2011;124:2264-74. 
2. 
Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE 
expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart 
Rhythm 2017;14:e275-e444. 
3. 
Stiles MK, Sanders P, Lau DH. Targeting the Substrate in Ablation of Persistent Atrial 
Fibrillation: Recent Lessons and Future Directions. Front Physiol 2018;9:1158. 
4. 
Bellmann B, Lin T, Ruppersberg P, et al. Identification of active atrial fibrillation sources 
and their discrimination from passive rotors using electrographical flow mapping. Clin Res 
Cardiol 2018;107:1021-32. 
5. 
Bellmann B, Zettwitz M, Lin T, et al. Velocity characteristics of atrial fibrillation sources 
determined by electrographic flow mapping before and after catheter ablation. Int J Cardiol 
2019;286:56-60. 
6. 
Swerdlow M, Tamboli M, Alhusseini MI, et al. Comparing phase and electrographic flow 
mapping for persistent atrial fibrillation. Pacing Clin Electrophysiol 2019;42:499-507. 
7. 
Haines DE, Kong MH, Ruppersberg P, et al. Analysis of Behavior of AF Sources with 
Electrographic Flow Mapping. Heart Rhythm 2021;18:1626-7. 
8. 
Szili-Torok T, Kis Z, Bhagwandien R, et al. Functional Electrographic Flow Patterns in 
Patients with Persistent Atrial Fibrillation Predict Outcome of Catheter Ablation. J 
Cardiovasc Electrophysiol 2021. 
9. 
Szili-Torok T, Neuzil P, Langbein A, et al. Electrographic Flow-Guided Ablation in Redo 
Patients with Persistent Atrial Fibrillation (FLOW-AF): Design and Rationale. Heart 
Rhythm O2 2023. 
10. 
Teh AW, Kistler PM, Lee G, et al. Electroanatomic remodeling of the left atrium in 
paroxysmal and persistent atrial fibrillation patients without structural heart disease. J 
Cardiovasc Electrophysiol 2012;23:232-8. 
11. 
Lin Y, Yang B, Garcia FC, et al. Comparison of left atrial electrophysiologic abnormalities 
during sinus rhythm in patients with different type of atrial fibrillation. J Interv Card 
Electrophysiol 2014;39:57-67. 
 
 
 

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7.0 
STUDY DEFINITIONS 
Persistent AF 
Arrhythmic episodes lasting > 7 days or requiring cessation 
with pharmacological or direct current cardioversion 
between 48 hours to 7 days duration. 
 
Longstanding Persistent AF 
Persistent AF that has been continuous for greater than 12 
months. 
 
 
8.0 
STUDY ABBREVIATIONS 
ACT 
Activated Clotting Time  
LA 
Left Atrium 
AF 
Atrium Fibrillation 
LAA 
Left Atrial Appendage 
AU 
Arbitrary Units 
PVI 
Pulmonary Vein Isolation 
 
EGF 
ElectroGraphic Flow 
SAC 
Source Activity 
EGFC 
ElectroGraphic Flow 
Consistency 
SR 
Sinus Rhythm  
EGM 
Electrograms 
SVC 
Superior Vena Cava 
HD 
High Density 
RA 
Right Atrium