Conditions: Arrhythmia, Cardiac
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
The purpose of this study is to test if catheter ablation is better than medication therapy at treating arrhythmias originating from the upper and/or lower chambers of the heart in order to allow the heart to beat properly.

Detailed description:

Arms:
arm 1: Catheter ablation procedure of atrial and/or ventricular arrhythmias. arm 2: Medical management using antiarrhythmic drugs per standard of care of treating physician.

Interventions: intervention 1: Catheter Ablation intervention 2: Anti-Arrhythmics
Intervention descriptions: intervention 1: Catheter ablation of atrial or ventricular arrhythmia. The technique and type of ablation will be at the discretion of the treating electrophysiologists. intervention 2: Anti-Arrhythmic drugs that are deemed to be appropriate for the given participants's arrhythmia by the treating physician.

Protocol document:
Prot_SAP_001.pdf: 
1 
Catheter Ablation of Arrhythmias to Improve CRT Response: The ABLATE-CRT Study 
Principal Investigator: Dhanunjaya Lakkireddy, MD 
Co-investigators: Mohammad-Ali Jazayeri, MD; Venkat Vuddanda, MD; Yong Mei Cha, MD; 
Paul Freidman, MD; Andrea Natale, MD; Madhu Reddy, MD; Vijay 
Swarup, MD; Moussa Mansour, MD; Emile Daoud, MD; Gery Tomassoni, 
MD 
Version 2 
Participating Institutions: 
University of Kansas Hospital, Kansas City, KS 
Texas Cardiac Arrhythmia Institute, Austin, TX 
Arizona Heart Rhythm Institute, Phoenix, AZ  
Massachusetts General Hospital, Boston, MA  
Mayo Clinic, Rochester, MN 
The Ohio State University Medical Center, Columbus, OH 
Baptist Health Lexington, Lexington, KY 
Funding:  Biosense Webster 
NCT03035227
Document Date: March 29, 2017


2 
Table of Contents 
1. Protocol Summary: ............................................................................................................................ 3
2. Background and Significance ............................................................................................................... 3
3. Hypothesis and Objectives ................................................................................................................... 5
4. Study Population, Study Inclusion & Exclusion Criteria: ...................................................................... 5
5. Participating Centers ............................................................................................................................ 6
6. Study Design and Analysis: ................................................................................................................. 6
7. Data Collection .................................................................................................................................... 9
8. Statistical Analysis: ........................................................................................................................... 10
9. Data Safety Monitoring Board ........................................................................................................... 11
10. Subject Consent ............................................................................................................................... 11
11. Patient Safety:.................................................................................................................................. 12
12. Funding: .......................................................................................................................................... 12
13. References ....................................................................................................................................... 14


3 
1. Protocol Summary:
Cardiac resynchronization therapy (CRT) is an effective therapy for heart failure patients. Often 
arrhythmias such as atrial fibrillation/flutter (AF/AFL), supraventricular tachycardia (SVT), 
premature ventricular contractions (PVC) and ventricular tachycardia (VT) impair 
synchronization of the atrial and ventricular contractions. These arrhythmias therefore interfere 
with optimization of heart failure therapy using CRT. This study proposes to evaluate if catheter 
ablation of cardiac arrhythmias such as AF, AFL, SVT, PVC or VT will result in improved 
biventricular synchrony and thus improve ejection fraction. This will be a prospective, 
randomized study with intention to treat. A total of 189 patients will be enrolled for the study, 
126 in the catheter ablation arm and 63 in the medical therapy arm. The consented patients will 
be enrolled into either catheter ablation or medical therapy arms. Patients enrolled to the catheter 
ablation arm will undergo ablation of the respective arrhythmia and will be followed up for a 
period of 1 year after procedure. Patients randomized to the medical therapy arm will have their 
medications titrated/added to improve bi-ventricular optimization. Those patients who do not 
respond to medication therapy after 3 months have the option to be crossed over to the catheter 
ablation arm at physician’s discretion.  Patients who are non-responders to CRT are defined as 
those with biventricular pacing <94% and ejection fraction improvement less than 5% for at least 
3 months post CRT implantation. Patients that continue in the medical management arm will 
remain in the study for 1 year after they have signed the informed consent. If the patient crosses 
over to the treatment arm, they will be followed for one year post procedure. Primary and 
secondary outcomes will be compared between the catheter ablation and medical therapy arm. 
2. Background and Significance
Heart failure is a chronic condition that is associated with high mortality, morbidity and 
decreased quality of life. The estimated prevalence of heart failure in the United States is about 
2.2% and is estimated in the elderly to approach 8.4% (1). Complications of chronic heart failure 
also include adverse effects on the conduction pathways of the heart and particularly delays in the 
onset of ventricular contractions (2). This is evident in nearly 30% of patients with chronic heart 
failure (3,4). This abnormal conduction may further exacerbate the dyssynchrony between the 
two ventricles and may lead to further impairment of cardiac output. The conduction 
abnormalities in heart failure lead to poor quality of life and higher mortality (5-8). 
Cardiac resynchronization therapy (CRT) is designed to circumvent the dyssynchronous 
contraction of the ventricles by simultaneously pacing both the right and left ventricles together. 
CRT is also referred to as biventricular or “Bi-V” pacing. The depolarization of both  ventricles 
by means of simultaneous pacing results in improvement of global mechanical contractility and 
decreases mitral regurgitation. Multiple studies have demonstrated the benefit of CRT therapy in 


4 
patients with heart failure and widened QRS complex. In patients with a left bundle branch block 
and heart failure, CRT therapy resulted in improvement of ejection fraction by 11.9 ± 5.1 % (9). 
In addition, other markers of heart failure such as left ventricular end diastolic volume and left 
ventricular end systolic volume also showed improvement. There was a 35% decrease in 
mortality with the use of CRT devices, and patients who were implanted with CRT devices had 
less severe symptoms and greater quality of life (10).  
Cardiac resynchronization therapy is an effective therapy for patients with heart failure and a 
prolonged QRS complex who remain in sinus rhythm (2,11). Irregular heart rhythms such as AF 
and PVCs can prevent optimization of the synchrony between the ventricles and undermine the 
effects of CRT. Atrial arrhythmias prevent optimization of the atrial and ventricular function, and 
the high ventricular rate prevents optimal biventricular capture by the device (11). Medications to 
control heart rate and rhythm may impart negative inotropic effects and thereby worsen heart 
failure. This approach is suitable when the AF burden is low to intermediate (12). Alternatively, 
for patients with permanent atrial fibrillation, atrio-ventricular (AV) nodal ablation can be done 
to prevent the supraventricular arrhythmia from disrupting optimal biventricular pacing (12). This 
approach has been shown to be superior to medical therapy and decreases the overall and 
cardiovascular mortality compared to medical management of AF (11).  
Several studies have evaluated optimal biventricular pacing time and have concluded that 
mortality was inversely proportional to the time spent in biventricular pacing (13). Patients with 
AF and biventricular pacing <98.5% of the time had a higher mortality rate compared to those 
who had biventricular pacing >98.5% of the time (13). Therefore every effort should be made to 
improve the biventricular pacing to as close to 100% as possible. In fact, when atrio-ventricular 
nodal ablation was performed in an atrial fibrillation population, the % biventricular pacing was 
96 ± 6% which was significantly higher than patients treated with AV nodal blocking 
medications (87 ± 14 %) (11).  
Radiofrequency ablation (RFA) is an effective treatment for atrial fibrillation and is increasingly 
being used in patients with symptomatic recurrences while on anti-arrhythmic medications. RFA 
of AF has also been shown to improve left ventricular ejection fraction and heart failure 
symptoms (14). Furthermore AF ablation has been shown to improve ejection fraction when 
compared to atrio-ventricular nodal ablation and biventricular pacing in heart failure patients 
(15). There was greater improvement in ejection fraction, functional capacity and quality of life 
in the AF ablation group (15). Besides AF, ventricular arrhythmias such as PVCs also decrease 
optimization of the CRT response (16). Ablation of the PVC foci has been shown to improve 
CRT response (16). Our group has shown that ablation of the PVC foci increased biventricular 


 
5 
pacing to 98 ± 2% from a baseline 76 ± 12% (16). There was also improvement in left ventricular 
ejection fraction and other heart failure echocardiographic parameters (16). A previous study of 
86 consecutive patients that had either a pacemaker or ICD at the time of RFA for symptomatic 
AF was both safe and efficacious (17). RFA is routinely done in patients with atrial fibrillation, 
atrial flutter, ventricular tachycardia, and supraventricular tachycardia and concomitant cardiac 
implantable electronic devices without any issues. Based on the above studies and evidence, we 
hypothesize that ablation of atrial and/or ventricular arrhythmias is likely to improve 
biventricular pacing in patients with suboptimal CRT response, as compared to medication 
therapy.  
3. Hypothesis and Objectives 
We hypothesize that catheter ablation of atrial and/or ventricular arrhythmias is superior to 
medical management for optimization of CRT response in CRT non-responders.  
Objectives: 
1. To evaluate if catheter ablation of atrial and/or ventricular arrhythmias will help improve 
patient’s biventricular pacing percentage. 
2. To evaluate if catheter ablation of atrial and/or ventricular arrhythmias will result in 
greater improvement in patients’ ejection fraction compared to medical management at 3 
months and if the effect will be sustained at 12 months follow-up. 
3. To evaluate if  quality of life is improved after catheter ablation of atrial and/or 
ventricular arrhythmias in patients with CRT devices compared to medical management. 
4. Study Population, Study Inclusion & Exclusion Criteria: 
Consecutive patients who have a previously implanted CRT and are non-responders to CRT 
therapy (as defined by Bi-V pacing less than 94% and one of the following arrhythmias: atrial 
fibrillation, atrial flutter, supraventricular tachycardia, premature ventricular contractions and/or 
ventricular tachycardia) presenting to the participating institutions will be screened for the 
inclusion and exclusion criteria. Those subjects meeting the following criteria will be asked to 
participate in the study.  
Inclusion Criteria:  
 Between ages 18-80 years old 
 Heart failure patients with CRT-D or CRT-P greater than 3 months 
 Bi-ventricular pacing less than 94% of the time 
 3 months after CRT-D or CRT-P implantation an EF improvement less than 5% 


 
6 
 Presence of one of the following arrhythmias and eligible for catheter ablation: 
o Atrial fibrillation 
o Atrial flutter 
o Supraventricular tachycardia 
o Premature ventricular contraction burden greater than 10% in a 24-hour 
period 
o Ventricular tachycardia 
 
Exclusion Criteria: 
 Estimated survival less than one year 
 Patient unable to make scheduled follow up visits at treating center 
 Participating in another investigational study 
5. Participating Centers 
This will be a multicenter open-label randomized control study. The principal coordinating site 
will be the University of Kansas Hospital, Kansas City, Kansas. The remaining centers include: 
Massachusetts General Hospital, Boston, Massachusetts, Arizona Heart Rhythm Institute, 
Phoenix, Arizona, Texas Cardiac Arrhythmia Institute, Austin, Texas, Mayo Clinic, Rochester, 
Minnesota, The Ohio State University Medical Center, Columbus, Ohio, and Baptist Health 
Lexington, Lexington, Kentucky.  
6. Study Design and Analysis: 
This will be an open-label randomized control study. Patients will be screened for participation in 
the study during their visits to the cardiology clinic. Patients who are non-responders to CRT 
defined as biventricular pacing less than 94% and ejection fraction improvement less than 5% for 
at least 3 months post CRT implantation will be included in the study if they meet all other 
inclusion and have no exclusion criteria. The study design is illustrated in Figure 1. Patients will 
be considered enrolled into the study after they sign the informed consent form. Once patients are 
enrolled they will be randomized, by sealed envelope, to either continued medical management 
or ablation. Patients enrolled into the ablation arm will undergo catheter ablation of atrial or 
ventricular arrhythmia within 3 months of signing the informed consent form. The technique and 
type of ablation will be at the discretion of the treating electrophysiologists. The medical 
treatment arm consists of the use of antiarrhythmic drugs that are deemed to be appropriate for 
the given arrhythmia by the treating physician. All patients will then be followed for a period of 1 
year after randomization. Standard of care follow up visits will be conducted at 3, 6 and 12 


7 
months post treatment (either ablation or randomization for medical treatment arm). Those 
patients in the medical therapy arm will be crossed over to the ablation arm if they become 
severely symptomatic or have worsening cardiovascular function after 3 months of medical 
management. Patients will be enrolled in a 2:1 ratio to the catheter ablation arm and medical 
therapy arms respectively.  


 
8 
Figure 1: ABLATE-CRT Study Design 
 
 
CRT – Non-responder (% of Bi-V 
pacing <94%and one of the 
following arrhythmias: 
AF/AFL/SVT/PVC/VT 
Medical Therapy (63) 
Catheter Ablation (126) 
x 
NYHC  
x 
Physical exam 
x 
Device Interrogation  
x 
QoL: SF-36 & KCCQ score 
x 
6 minute walk test 
)
Crossover to ablation therapy if patients 
cannot tolerate medical therapy 
x
NYHC  
x
Physical exam 
x
QoL: SF-36 & KCCQ score 
x
Device Interrogation 
x
6 minute walk test 
3 months 
+/- 14 Days 
x
NYHC 
x
Physical exam 
x
Echo 
x
Device Interrogation 
x
NYHC 
x
Physical exam 
x
Echo 
x
Device Interrogation 
12 months 
+/- 30 Days 
x
NY
x
NYHC 
x
Physical Exam  
x
QoL: SF-36 & KCCQ score 
x
6 minute walk test 
x
Echo 
x
NYHC 
x
Physical Exam  
x
QoL: SF-36 & KCCQ score 
x
6 minute walk test 
x
Echo 
6 months 
+/- 30 Days 


9 
Primary and Secondary Endpoints 
Primary Endpoints 

EF improvements greater than 5%

Bi-ventricular pacing improvement  greater than 5%

Cardiovascular mortality
Secondary Endpoints – the following will be reported as observational endpoints 

All-cause mortality

Hospital admissions for heart failure exacerbation

NYHA class change

6 minute walk test

QoL assessment: SF-36 and KCCQ score changes
7. Data Collection
The Cardiovascular Research Institute will be the coordinating site for the study. REDCap will be 
the electronic data capture used for this project. All coordinators will have an account created and 
forms will be available to them during the study. A project manager (PM) with the help of the PI 
will create the study worksheets and create the CRFs. The PM will assist the database manager 
(DM) with updating REDCap and providing computer support for outside centers. All data will 
be submitted via REDCap including de-identified patient data that is to be used as source.  
Participant’s data will be de-identified and a code will be assigned. The code will consist of site 
number, patient number and patient initials.  The coordinator at that site will have access to the 
code, and the linking list will be destroyed at the completion of the project.  
The coordinating center will monitor patient records using REDCap. Charts will be reviewed on 
a regular basis for discrepancies. 
The following data points will be collected: 
A. Baseline demographics (age, sex, height, weight, BMI, NYHA class). 
B. Co-morbidities (including but not limited to HTN, DM, CVA, TIA, HF, CRF, GI 
bleeding, intracranial bleeding, device implantations, infections, history of other 
arrhythmias, CAD, h/o of Lariat procedure, CABG, PCI or other procedures). 
C. Family history of AF and other arrhythmias will be collected.  


 
10
D. Medications used in the past and current medications and their adverse effects will be 
collected.  
E. Social and other personal history including but not limited to smoking, alcohol usage, 
other nonprescription medications and amount of coffee intake will be recorded.  
F. Physical examination findings (hepatomegaly, jugular venous pressure, hepatojugular 
reflux, ascites, heart sounds, murmur, rales, peripheral edema, BP, HR, weight, 
height, BMI) 
G. Laboratory variables including but not limited to sodium (Na), potassium (K), 
magnesium (Mg), phosphorus, complete blood count (CBC), comprehensive 
metabolic profile (CMP), lipid profiles, basic natriuretic levels (BNP) and coagulation 
profile.  
H. 6 minute walk test. 
I. CRT device interrogation – Percent of bi-ventricular pacing and percent of arrhythmia 
burden. 
J. Kansas City Cardiomyopathy Questionnaire (KCCQ) and SF-36 forms 
K. Echocardiogram parameters including the left atrial size, Cardiac CT parameters 
including the PV anatomy, size of the PV and left atrial appendage size, MRI 
parameters including the myocardial structure, scar data and other significant imaging 
that will be helpful to test the hypothesis.  
L. Procedural variables for the index ablation (type of ablation, use of general anesthesia, 
procedure length, fluoroscopy time, radiation time, complications during procedure, 
ablation time, type of catheters used or other changes on the device/ICD parameters). 
M. Adverse events related to the procedure and medical treatment including but not 
limited to bleeding from the groin site, infections, pericardial effusion, myocardial 
rupture, mortality and other complications. 
N. Length of stay and number of hospitalizations during the study.  
O. Cost associated with the procedure.  
P. Quality parameters including but not limited to success of ablation procedure, 
ancillary staff utilization, nursing staff utilization and use of other resources.  
Q. Follow up visit history and all changes to the management plan will be recorded.  
R. Mortality data will be collected.  
8. Statistical Analysis: 
To observe a minimum 5% difference in the ejection fraction or biventricular pacing, with a two 
tailed hypothesis and power of 80% and α of 0.05, we need to enroll 48 and 96 patients 
respectively to the medical and catheter ablation arms respectively. Assuming a dropout rate of 


 
11
about 10% during the follow up period, the final enrollment should be aimed at 53 and 106 
patients in the medical and catheter ablation therapy arms respectively. The total number of 
subjects analyzed may be 189 subjects. The above estimate is provided assuming an EF of 30 ± 
10% in the medical therapy group and post ablation if the EF were to improve to 35 ± 10% in the 
ablation group (5% improvement in the mean EF).  
Standard statistical tools will be utilized. IBM SPSS Statistics for Windows, Version 21.0. 
(Armonk, NY: IBM Corp) will be used to analyze the data. Continuous data will be presented as 
the mean value ± SD, and categorical data will be presented as n (%). The catheter ablation and 
medical therapy arms will be compared on an intention to treat basis. Categorical variables will 
be compared using chi square or Fisher’s exact test and continuous variables will be compared 
using t-test or Mann-Whitney U test as and when appropriate. Univariate and multivariate 
analysis will be performed to detect factors affecting the outcomes between the two groups. A ‘p’ 
value <0.05 will be considered statistically significant.  
9. Data Safety Monitoring Board 
To meet the study’s ethical responsibility to its subjects, an independent data safety monitoring 
Board (DSMB) will monitor results during the study. The board consists of 2 general 
cardiologists and 1 statistician who have no formal involvement or conflict of interest with the 
subjects or the investigators. Records will be reviewed after the first 30 patients and then 
routinely after every 30 patients.  The study will be stopped if the major complication rates (ie. 
Stroke, cardiac perforation, cardiac tamponade requiring surgery) exceed 15% at each given time 
points. All participant sites will have to upload their data in REDCap within 7 days of the time 
point. All adverse events will have to be reported within 48 hours. 
 
10. Subject Consent 
Participation of the subjects is voluntary and all participants will sign a written informed consent 
before participating in the study. The principal investigator or research staff will fully inform the 
subjects of the risks and benefits of participation in the study and will obtain their consent before 
enrollment into the study. Patients will be screened for enrollment into the study during standard 
of care office visits in the cardiology outpatient clinic. Patients will be given all the details of the 
study and will be asked for their voluntary participation. The patients may provide the consent 
anytime between their preoperative visit and the day of the procedure before the procedure 
actually begins in order to participate in the study. 


12
11. Patient Safety:
Risks: Catheter ablation, standard of care, will be done on patients randomized to this group and 
also the crossover patients. This is an invasive procedure and the risks from catheter ablation 
include a small risk for bleeding, hematomas, cardiac perforation, stroke, myocardial infarction 
and rarely death.  These risks are the same for this standard of care procedure. Patients in the 
medical therapy arm not responding to medical therapy will have the chance to be crossed over to 
the catheter ablation arm and these patients will have similar risks if they undergo catheter 
ablation. Patients will sign a separate informed consent form outlining the risks of the procedure. 
Benefits to the subjects: 
Participation of subjects in this study is voluntary and there are no direct benefits to these study 
subjects. The knowledge gained from this study may help benefit future patients undergoing CRT 
implantations to help maximize their ejection fraction and decrease morbidity. Additionally it 
will greatly help the research community at large in understanding the benefits versus risks of 
catheter ablation of atrial and ventricular arrhythmias in patients with CRT-D devices. 
Records Retention 
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by Biosense Webster, whichever is longer.  
If the investigator withdraws from the study (e.g. relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g. another investigator, another institution, 
IRB). Notice of such transfer will be given in writing to Biosense Webster.  
12. Funding:
Funding provided by Biosense Webster.


 
13
Study Assessments and Procedures 
Time and Events Schedule 
Procedure 
Baseline 
Randomization 
Procedure 
3 Month      
(+/- 14 Days)  
6 Month      
(+/- 30 Days) 
12 Month 
(+/- 30 Days) 
Eligibility  Assessments 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
Study Assessments 
 
 
 
 
 
 
New York Heart Class 
Assessment 
X 
 
X 
X 
X 
X 
Physical Exam 
X 
 
X 
X 
X 
X 
Device Interrogation 
X 
 
X 
X 
X 
X 
SF 36 
X 
 
 
X 
X 
X 
KCCQ Score 
X 
 
 
X 
X 
X 
6 Minute Walk Test 
X 
 
 
X 
 
X 
Echocardiogram 
X 
 
 
 
X 
X 
Procedural Variables 
 
 
X 
 
 
 
Adverse Events 
Assessment 
 
X 
X 
X 
X 
X 


 
14
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6. 
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Shamim W, Francis DP, Yousufuddin M et al. Intraventricular conduction delay: a 
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8. 
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Zareba W, Klein H, Cygankiewicz I et al. Effectiveness of Cardiac Resynchronization 
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Gasparini M, Leclercq C, Lunati M et al. Cardiac resynchronization therapy in patients 
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13.
Hayes DL, Boehmer JP, Day JD et al. Cardiac resynchronization therapy and the
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14.
Jones DG, Haldar SK, Hussain W et al. A randomized trial to assess catheter ablation
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Khan MN, Jais P, Cummings J et al. Pulmonary-vein isolation for atrial fibrillation in
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Lakkireddy D, Di Biase L, Ryschon K et al. Radiofrequency ablation of premature
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Lakkireddy D, Patel D, Ryschon K, et al. Safety and efficacy of radiofrequency energy
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