Conditions: Ventricular Tachycardia Premature Ventricular Contraction Stroke
Keywords: Radiofrequency ablation anticoagulation Direct oral anticoagulants Aspirin Ventricular arrhythmia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 246
Healthy volunteers: no

Brief summary:
The purpose of this study is to learn if taking a drug called direct oral anticoagulant after an ablation procedure keeps blood clots from forming and lowers the chance of having a stroke in patients with ventricular tachycardia or arrhythmia (VT).

Detailed description:
Ventricular tachycardia (VT) or fast heart rhythm is a condition where the lower chambers (ventricles) of the heart beat too fast. This condition can be life threatening because these ventricles are the main pumping chambers of the heart. The fast heartbeat is caused by electrical impulses that travel incorrectly in your heart.

One way to treat VT is to have a catheter ablation procedure. A catheter ablation is a procedure that creates scar tissue in the heart to interrupt the electrical impulses that create irregular heart rhythms.

It is possible that the ablation procedure might cause a blood clot to form. The blood clot can stop blood flow to the brain and cause a stroke. When blood flow is interrupted to a certain part of the brain, that part does not receive enough oxygen. As a result of the stroke the affected areas of the brain are unable to function normally.

Direct oral anticoagulant (DOAC) is a blood thinning drug, also called an anticoagulant. It interferes with the body's natural blood clotting ability by inactivating a specific enzyme that the body needs to form blood clots.

Participation in this study will last about 30 days.

Arms:
arm 1: Participants will be asked to take standard dose approved for stroke prophylaxis arm 2: Participants will be asked to take 81 milligrams by mouth once per day.

Interventions: intervention 1: DOAC intervention 2: Aspirin
Intervention descriptions: intervention 1: DOAC is a blood thinning drug, also called direct oral anticoagulant. These group of drugs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of stroke prophylaxis in atrial fibrillation and deep vein thrombosis and pulmonary embolism, which are blood clots in the veins or lungs. intervention 2: Aspirin works by reducing substances in the body that cause pain, fever, and inflammation. Aspirin is used to treat pain, and reduce fever or inflammation.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
1 
 
COVER PAGE 
 
 
OFFICIAL TITLE: SafeTy and Efficacy of Periprocedural Direct Oral Anticoagulant 
versus Aspirin Use for Reduction Of the RisK of CErebrovascular Events in Patients Undergoing 
Ventricular Tachycardia Radiofrequency Catheter Ablation (STROKE-VT) 
 
NCT#02666742 
 
 
Version: 13 / October 1st,2018 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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SafeTy and Efficacy of Periprocedural Direct Oral Anticoagulant versus Aspirin Use for 
Reduction Of the RisK of CErebrovascular Events in Patients Undergoing Ventricular 
Tachycardia Radiofrequency Catheter Ablation (STROKE-VT) 
 
 
 
 
Principal Investigators 
 
Dhanunjaya Lakkireddy, MD 
Kansas City Heart Rhythm Research Foundation 
6709 W. 119th Street, Suite 121 
Overland Park, KS 66209 
913-575-2157 
dlakkireddy@gmail.com 
 
Andrea Natale, MD 
Texas Cardiac Arrhythmia Institute 
St. David’s Medical Center 
Austin, TX 
 
 
Version: 13 / October 2018 
 
 
 


 
 
 
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INTRODUCTION 
Considerable research has sought to overcome the limitations of available anticoagulant and 
antithrombotic agents. This includes efforts to develop agents that target specific factors of the 
coagulation process, which in turn may improve efficacy and increase the therapeutic index. 
Warfarin acts through inhibition of multiple areas on the coagulation caseade and the direct oral 
anticoagulants (DOACs) like (Dabigatran/Rivaroxaban/Apixaban/Edoxaban) .Factor Xa is a 
primary target since this factor plays a pivotal role in the coagulation cascade at the junction of 
the intrinsic and extrinsic pathways of the coagulation system. Inhibition of FXa is expected to 
exert anticoagulant and antithrombotic effects by decreasing the conversion of prothrombin to 
active thrombin, thereby diminishing thrombin-mediated activation of the coagulation process, 
including fibrin formation and platelet activation [1].  DOAC helps to anticoagulated and 
potentially decrease the risk of systemic thromboembolism .  
Overall Risk/Benefit Assessment 
Atrial fibrillation (AF) is associated with 5 times increased risk of cerebrovascular events 
compare to patients in Sinus rhythm [2]. Even in patients undergoing Radiofrequency Ablation 
(RFA) for atrial fibrillation, the incidence of symptomatic cerebrovascular events (CVE) was 
2.3% and 41% of those are from transient ischemic attacks and 25% are from ischemic CVEs, 
despite being on anticoagulation. The incidence of asymptomatic CVEs rises to 14% after the 
ablation for AF, detected by Flair enhancement MRI . Multiple trials have shown that the 
asymptomatic CVEs and/or micro infarcts can increase the odds of having dementia. The 
incidence of stroke immediately after ablation for left ventricular arrhythmias has ranged from 0 
to 2.7% to 7.5% depending on the case series , but there aren’t many studies to quantify this 
problem clearly. Interestingly, the amount of tissue ablated in the ventricles is not any smaller 
than what is done in the left atrium. Even though the stunning phenomenon that is seen with the 
left atrial appendage may not be relevant to the ventricular tachycardia ablation, the extensive 
endothelial denudation and subclinical thrombus formation at the sites of ablation is clearly 
under appreciated. No active strategies to prevent post ablation systemic thromboembolization 
are available in patients undergoing left ventricular arrhythmia ablation especially on the left 
side.  Similar to AF, the projected incidence of asymptomatic CVEs may be much higher than 
the incidence of symptomatic CVEs given the multiple reasons like heat generated from the 


 
 
 
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ablation, possibility of necrosis of myocardium from ablation and manipulation of the left side of 
the heart, but currently there are no studies that have focused on the incidence of asymptomatic 
CVEs. It has been therefore recommended to perform cardioversion or ablation only at 
therapeutic levels of anticoagulation to decrease the risk of thromboembolism and stroke. So far, 
there are no trials evaluating the efficacy of unfractionated heparin or newer direct thrombin or 
factor Xa inhibitors in preventing or reducing symptomatic and also asymptomatic CVEs post- 
left ventricular arrhythmia ablation. Given the high incidence of symptomatic CVEs and 
possibility of higher incidence of asymptomatic CVEs which has many prognostic implications, 
this issue warrants further studies. 
 
Use of oral anticoagulation after left ventricular arrhythmia ablation is not standard of care at this 
point and is anecdotally used in high risk patients with LV aneurysms and those with severe LV 
dysfunction. Even when used post ablation anticoagulation with warfarin is fraught with several 
practical issues including the time to therapeutic range and the need for bridging with 
unfractionated or low molecular weight heparin with implications to prolonged length of stay 
and increased bleeding complications. So, the novel non VKA agents probably are a better fit for 
this specific situation. Early experience with all four currently available agents (Dabigatran, 
Rivaroxaban , Apixiban and Edoxaban) for periprocedural anticoagulation seems to be safe and 
efficacious.  DOAC is a direct oral inhibitor of Prothrombin/factor Xa inhibitor and thereby 
mediates its anticoagulation effect . In the recently published double blind randomized clinical 
trial  DOAC was found to be superior to warfarin in decreasing the risk of stroke and also had 
fewer complications of bleeding and death in patients with atrial fibrillation/flutter . 
 
We believe that peri-procedural  DOAC use for left ventricular arrhythmia ablation will provide 
effective anticoagulation without increasing bleeding complications and may decrease the 
incidence of both symptomatic and asymptomatic cerebrovascular events, TIAs and strokes. 
 
Magnetic resonance imaging (MRI) is the most commonly used imaging test to detect acute 
ischemic stroke and asymptomatic CVEs. There is a natural apprehension about the use of MRI 
scanning in patient with Cardiac Implantable Electrical Devices (CIEDs) . However, there are 
protocols in place showing MRI examination of patients with CIEDs with minimal or no side 


 
 
 
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effects . There is increasing data on the safety of the use of MRI in CIED patients which perhaps 
led to the participating institutions routine use of MRI in defining ventricular scar prior to RF 
ablation to optimize the treatment strategy and outcomes. The potential for adverse effects on the 
CIED during MRI of the head is far lower than imaging the chest as the device will not be in the 
direct MRI field as it is with head scanning. When performed with appropriate monitoring the 
post left ventricular arrhythmia ablation MRI scanning of the brain can be safe and help us 
examine an important issue that has not been well defined. 
Research Hypothesis  
We hypothesize that periprocedural anticoagulation with  DOAC (an oral anticoagulation agent 
with rapid onset of action) for left ventricular arrhythmia ablation decreases symptomatic and 
asymptomatic cerebrovascular events compared to use of Aspirin only.   
Study Rationale 
Ventricular tachycardia (VT) is a complex arrhythmia with high mortality rate. ICDs have shown 
improvement in survival when placed for primary or secondary prevention in such patients, but 
they are not a cure for VT and they don’t prevent recurrences. In addition, painful ICD shocks, 
not only impair quality of life and psychological health , but they are also associated with 
increased all-cause mortality. Antiarrhythmic therapy, even though moderately effective, with 
time and progressive remodeling recurrent VT and subsequent ICD therapies are common. 
Radiofrequency catheter ablation has emerged as an important therapeutic option to prevent VT 
recurrences and reduce the frequency of ICD shocks . Catheter ablation provides potential 
curative treatment in 77-95% of post MI patients presenting with monomorphic VT and around 
60% in patients with VT arising from non-ischemic cardiomyopathy . With advancement in 
technology and newer saline irrigation catheters, the risks are very minimal, with high success 
rates . In a nationwide sample of 4653 patients who underwent ablation in the United States 
between 2002 and 2011 for post-myocardial infarction VT, the overall in-hospital complication 
rate was 11 percent with in-hospital mortality of 1.6 percent . The number of catheter ablations 
that are being performed for left ventricular arrhythmias continues to grow and varies from 
region to region and hard to quantify . Both retrograde transaortic approach and trans-septal 
approach are possible routes for endocardial radiofrequency ablation (RFA) with embolic risk 
associated with thrombus formation on the ablation catheters and sheaths, micro thrombus 


 
 
 
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formation at the ablation site during the procedure and after ablation as well. [3].Over the last 
decade left ventricular arrhythmia ablation techniques have evolved from being more focal 
targeted sites to the addition of extensive substrate modification targeting active channels as 
represented by mid diastolic potentials, late activation potentials etc. in the scar and scar border. 
This will change the surface area of the ventricular endocardium ablated significantly. The 
extensive denudation of the ventricular endocardium can obviously become a site of thrombus 
formation and subsequent embolization. Often times patients with Cardiomyopathy (CM) 
undergoing left ventricular arrhythmia ablation have poor LV function and have large segments 
of akinesis/dyskinesis/aneurysms making them more prone for stasis and thrombus formation. 
Treating them with periprocedural anticoagulation has a potential to significantly decrease the 
risk of systemic thromboembolization as measured by symptomatic and asymptomatic 
cerebrovascular events. 
STUDY END POINTS: 
Primary Objectives 
Primary end point: To estimate the new symptomatic (Stroke and TIA) and asymptomatic CVEs 
(brain MRI lesions) and systemic thromboembolism in patients undergoing left ventricular 
arrhythmia ablation with a novel oral anticoagulant ( DOAC) when compared to aspirin only.  
Secondary Objectives:  
• To estimate the impact of  DOAC on major peri-procedural bleeding in patients 
undergoing left ventricular arrhythmia ablation when compared to ASA. Assessment 
done up to 30 days post procedure. 
• To estimate the impact of  DOAC on minor peri-procedural bleeding in patients 
undergoing left ventricular arrhythmia ablation when compared to ASA. Assessments 
completed at 1week post procedure and up to 30 days post procedure.  
Institutional Review Board/Independent Ethics Committee 
Before initiation of the study, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials/process 
(eg, advertisements), and any other written information should be provided to subjects. The 


 
 
 
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investigator or sponsor should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects, and any updates.  
The investigator should provide the IRB/IEC with reports, updates, and other information (eg, 
expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
Informed Consent 
Investigators must ensure that subjects or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
Investigators must: 
a) Provide a copy of the consent form and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. 
The language must be non-technical and easily understood. 
b) Allow time necessary for subject or subject's legally acceptable representative to 
inquire about the details of the study. 
c) Obtain an informed consent signed and personally dated by the subject or the 
subject's legally acceptable representative and by the person who conducted the 
informed consent discussion.  
d) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed 
consent form and any other information to be provided to the subjects, prior to the 
beginning of the study, and after any revisions are completed for new information. 
e) If informed consent is initially given by a subject’s legally acceptable representative 
or legal guardian, and the subject subsequently becomes capable of making and 
communicating their informed consent during the study, then consent must 
additionally be obtained from the subject. 
f) Revise the informed consent whenever important new information becomes available 
that is relevant to the subject's consent. The investigator, or a person designated by 


 
 
 
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the investigator, should fully inform the subject or the subject's legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the subject's willingness to continue participation in the study. 
This communication should be documented.  
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
INVESTIGATIONAL PLAN 
Study Design and Duration 
This is a multicenter, randomized, prospective study to determine, if  DOAC can be used 
periprocedural in patients undergoing a scar left ventricular arrhythmia ablation. Patients will be 
screened from both the clinic setting and upcoming EP lab schedule. The patient’s chart will be 
reviewed and those that meet inclusion/exclusion will be approached for the study. For this 
study, we intend to enroll 52 consecutive subjects who are undergoing a scar left ventricular 
arrhythmia ablation at participating institutions if they meet all other inclusion criteria and do not 
have any exclusion criteria. Patients will be randomized in a 1:1 fashion. 
  
 Figure 1 shows the use of ASA or  DOAC for left ventricular arrhythmia ablation.  
 
Patients undergoing left ventricular arrhythmia ablation will be consented and randomized to 
either ASA 81 mg or 100 mg daily or  DOAC twice daily. Patients randomized to ASA will 
continue or start ASA 81 mg or 100 mg by mouth daily, and continue up to 30 days after the 
procedure. Patients randomized to  DOAC group will stop the ASA if they are currently taking 
it;  DOAC 5 twice daily will be started 3 hours after hemostasis and continue for 30 days post 
procedure.  
 
The drugs to which they are assigned to will be continued at least for 30 days post left ventricular 
arrhythmia ablation. All subjects will be followed from baseline to 30 days post procedure. At 
this time they will have completed the study and can stop either  DOAC and/or Aspirin at the 
physician’s discretion. 


 
 
 
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Figure 1 Therapy initiation protocol for procedures. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* In case of any two of the following: age ≥ 80 yrs, body weight ≤ 60 kg, or serum creatinine ≥1.5  
mg/dL a dose of  DOAC at a reduced dose will be initiated. 
 
Initial Evaluation for left ventricular 
arrhythmia Ablation 
Start  DOAC daily3 hours post hemostasis 
and continue for 30 days post procedure. 
• 
If patient is already on ASA 81 mg or 100 
mg, it will be continued at the same dose 
before and after LV arrhythmia ablation. 
• 
It patient is on ASA 325 mg it will be 
reduced to 81 mg or 100 mg PO daily. 
LV Arrhythmia Ablation 
Continue ASA 81 mg or 100 mgPO daily 3 
hours post hemostasis and continue for 30 
days post procedure. 
 DOAC Arm 
 
Aspirin Arm 
(81 mg or 100 mg PO 
Daily 
• 
If patient is on ASA 81 mg or 100 mg or 325 
mg, stop ASA immediately.  
 


 
 
 
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Baseline Visit: 
Baseline visit will be conducted within 30 days prior to procedure (unless noted). This visit will 
include: 
• A physical exam and medical history will be performed that includes:  height, weight, 
BMI, NYHC evaluation, blood pressure, pulse, review of systems. 
• Labs: Chemistry, CBC, Coagulation, Pregnancy test  
• Echo: EF, LA size, Mitral Regurgitation, Aortic Regurgitation, Mitral Stenosis, Aortic 
Stenosis within 3 months of the procedure 
• ECG, MRI, TEE, CT, Device interrogation – most recent within 6 months 
• Procedural variables 
 
Oral Anti-Coagulation/Anti-Platelet Regimen: 
The initiation and stopping of the antiplatelet and  DOAC regimens will be based on Figure 1. If 
subjects are on Aspirin 325 mg, the dose will be changed to 81mg daily. Once vascular access is 
obtained for ablation, the patient will be started on unfractionated heparin intravenously to 
maintain the ACT levels ≥ 300 msec during the procedure, as deemed appropriate by the 
operator. Subjects randomized to the  DOAC group will be started on oral  DOAC at the standard 
dose of 5 mg twice daily and continued for 30 days post procedure beginning 3 hours after 
hemostasis. In case of any two of the following: age ≥ 80 yrs, body weight ≤ 60 kg, or serum 
creatinine ≥1.5 mg/dL a dose of  DOAC at reduced dose will be initiated for those randomized to 
the  DOAC arm. For drug interactions occurring with  DOAC, the concomitant use of the 
medications per the USPI should be avoided or dose should be adjusted accordingly.  
 
Ablation Protocol 
A standard left ventricular arrhythmia ablation protocol that is approved at the participating 
institution and which is in place will be followed. Endocardial ablation, access to the left 
ventricle is gain via trans-septal approach which is preferred access or via retrograde transaortic 
approach. When deemed necessary by the operator epicardial access will be obtained and used 
for mapping and ablation. Left ventricular arrhythmia ablation is performed targeting the clinical 
VT. A voltage map is created to assess the scar and scar border. If the VT is hemodynamically 


 
 
 
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stable it will be mapped and ablated using activation and entrainment mapping. If the VT is 
unstable, pace making, and substrate modification should be done in the target region. The non-
clinical VTs are also targeted at the discretion of the operator. Substrate modification including 
ablation of potential sites of interest with mid diastolic and LAVA potentials should also be 
targeted. Standard definition for identifying the scar, scar border, pace match, induction protocol 
and substrate characteristics apply. Programmed stimulation will be repeated after the ablation to 
look for any inducible Ventricular Tachycardia. Hemodynamic support is used at the discretion 
of the operator.  DOAC will be restarted only after the hemodynamic support has been removed 
and hemostasis has been achieved.  
Hemostasis after procedure is defined as complete absence of any access site bleeding with ACT 
< 200 seconds and no further need for manual or artificial compression. 
 
Cerebral MRI (as adopted from ) 
Study subjects will be screened for new asymptomatic CVEs, within 24 hours after the ablation 
procedure and again at 1month post procedure with 1.5 T MRI. A baseline is not done to 
minimize the number of imaging studies. The Flair sequencing has the ability to delineate a new 
embolic lesion from an old infarct. This will help reduce the patient exposure to repeated testing.  
The imaging protocol includes a sagittal T1-weighted spin echo sequence to obtain a better 
definition of the anterior and posterior cerebral commissures. The parameters of the T1-weighted 
spin echo sequence were as follows: repetition time/echo time 400/13; slice thickness 5 mm; 
distant factor 0%; field of view 230 mm; matrix 192×256; and acquisition time 59 seconds. An 
axial fluid-attenuated inversion recovery (FLAIR) sequence was then used. The parameters of 
the FLAIR sequence were as follows: repetition time/echo time 8500/112; TI 2500 ms; slice 
thickness 5 mm; distant factor 30%; field of view 240 mm; matrix 154×256; and acquisition time 
3.24 seconds. A diffusion-weighted (DW) sequence, with the use of a single-shot spin echo with 
echo-planar imaging technique that combined the motion-probing gradient before and after the 
180° pulse with echo-planar imaging readout, was obtained; The parameters of the DW sequence 
were as follows: repetition time/echo time 3200/99; slice thickness 5 mm; distant factor 30%; 
field of view 230 mm; matrix 128×128; bandwidth 1502 Hz; gradient strength 22 mT; duration 
of diffusion gradients 31 ms; gradient separation 42 ms in 3 orthogonal directions; and 


 
 
 
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acquisition time 43 seconds. For each DW sequence, the apparent diffusion coefficient map will 
be obtained. 
 
On the post ablation MRI, an acute embolic lesion was defined as a focal hyper intense area 
detected by diffusion weighted sequence (DWI) with or without addition of delayed Fluid-
attenuated inversion recovery (FLAIR) positive sequence. The size and localization of the focal 
lesions will be analyzed certified by radiologist blinded to the clinical status. 
 
Subjects who have the Cardiac electrical implantable devices who are undergoing MRI 
examination will follow standard protocol which are in place in the institution.  
 
Neurology Evaluations 
Patients will undergo a NIHSS and EQ5D prior to procedure (within 24 hours) and post (12-48 
hours). If changes in the NIHSS score of greater than 3 a neurologist will be consulted, and the 
patient will be evaluated and treated based on their recommendation. Asymptomatic 
Cerebrovascular emboli are defined as cerebral infarct present on MRI or CT scan for which no 
corresponding symptoms were documented [2]. Symptomatic Cerebrovascular emboli were 
defined as an episode of neurological dysfunction associated with a focal cerebral infarction in 
the region correlating with the dysfunction. . 
 
Study Population 
For entry into the study, the following criteria MUST be met. 
Inclusion Criteria 
A. Signed Written Informed Consent 
 
Before any study procedures are performed, subjects will have the details of the study 
described to them, and they will be given a written informed consent document to read. Then, 
if subjects consent to participate in the study, they will indicate that consent by signing and 
dating the informed consent document in the presence of study personnel. 
B. Target Population 


 
 
 
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• Patients undergoing radiofrequency catheter ablation for left ventricular arrhythmias 
secondary to ischemic cardiomyopathy and non-ischemic cardiomyopathy. Patients with 
normal heart VT, i.e. no clinical evidence of cardiomyopathic process will be excluded 
from the study.  
• Patients undergoing radiofrequency catheter ablation for left sided VT based on initial 
clinical suspicion.  
C. Age and Reproductive Status 
• 
Males and Females, ages 18 to 80 years 
• 
Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to the start of study drug. 
• 
Women must not be breastfeeding 
• 
WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with  DOAC plus 5 half-lives of  DOAC (3 days) plus 30 days (duration of 
ovulatory cycle) for a total of 33 days post-treatment completion. 
• 
Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with  DOAC plus 5 half-lives 3 
days) plus 90 days (duration of sperm turnover) for a total of 93 days post-treatment 
completion. 
• 
Azoospermia males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements.  However, they must still undergo pregnancy 
testing as described in this section. 
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly. 


 
 
 
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At a minimum, subjects must agree to the use of one method of highly effective contraception as 
listed below: 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectable, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject 
or male subject’s WOCBP partner. Female partners of male subjects participating in the 
study may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug  
• 
IUDs, such as ParaGard 
• 
Tubal ligation 
• 
Vasectomy. 
• 
Complete Abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence. 
Exclusion Criteria 
A. Target Disease Exceptions  
• History or CVA/TIA in last 3 months 
• Cardiac surgery or neurosurgery within 3 months of the intended procedure date 


 
 
 
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B. Medical History and Concurrent Diseases 
• Ongoing ischemia or a prior coronary intervention requiring continued dual 
antiplatelet therapy 
• Any active bleeding 
• Severe hypersensitivity reaction to DOACs (including drug hypersensitivity, such as 
skin rash and anaphylactic reactions, such as allergic edema) 
• Prosthetic heart valves; the safety and efficacy of DOACs have not been studied in 
patients with prosthetic heart valves. 
• History or bleeding and clotting disorders 
• Requires dual anti-platelet therapy 
• Contraindications to Aspirin therapy 
• Contraindication to oral anticoagulation 
•  Patients who have a continuing need for oral anticoagulation (i.e. patients with AF; 
DVT or a mechanical valve) Evidence of intracardiac thrombus 
• Patient with Creatinine Clearance of < 40 cc/min 
C. Sex and Reproductive Status 
See Section on WOCBP above  
D. Prohibited Treatments and/or Therapies 
• Participation in another investigational study related to oral anticoagulation, drug and/or 
device intervention. 
• Claustrophobic patients 
• ICD generator placement before the year 2000 
• Has an ICD and is pacing dependent without underlying rhythm upon interrogation at 
baseline 
• Patient has abandoned leads 


 
 
 
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E. Other Exclusion Criteria 
• Prisoners or subjects who are involuntarily incarcerated. 
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness. 
• Patients with abnormal troponins or any evidence of a recent MI 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study can be used. It is imperative that subjects fully 
meet all eligibility criteria. 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause. 
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal: 
• 1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 4 week minimum for transdermal products 
• 8 week minimum for oral products 
Other parenteral products may require washout periods as long as 6 months. 


 
 
 
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Discontinuation of Subjects from Treatment 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons: 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• 
Any clinical adverse event, laboratory abnormality, or inter-current illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject. 
• 
Pregnancy 
− Instruct WOCBP to contact the investigator or study staff immediately if they suspect 
they might be pregnant (eg, missed or late menstrual period) at any time during study 
participation. Institutional policy and local regulations should determine the 
frequency of on-study pregnancy tests for WOCBP enrolled in the study. 
− The investigator must immediately notify BMS if a study subject becomes pregnant. 
• 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness. 
All subjects who discontinue should comply with protocol-specified follow-up procedures 
outlined above. The only exception to this requirement is when a subject withdraws consent for 
all study procedures or loses the ability to consent freely (ie, is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness). If a subject withdraws 
before completing the study, the reason for withdrawal must be documented appropriately. 
TREATMENTS 
Study Treatment: DOAC or Warfarin  
Definition of Investigational Product: A pharmaceutical form of an active substance or placebo 
being tested or used as a reference in a clinical study, including products already with a 
marketing authorization but used or assembled (formulated or packaged) in a way different from 


 
 
 
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the authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form. In this protocol, the investigational product is  DOAC. 
 Definition of Non-Investigational Product: Other medications used in the study as support or 
escape medication for preventative, diagnostic, or therapeutic reasons as components of a given 
standard of care. In this protocol, the non-investigational products are none. 
Method of Assigning Subjects to a Treatment 
All subjects who have signed the study ICF and meet all inclusion and no exclusion criteria will 
be randomized in a 1:1 into one of the two study arms (1) Aspirin 81 mg or 100 mg or (2)  
DOAC recommended dose. For study purposes, subjects are considered enrolled in the study 
once they have signed the consent form and are randomized and stratified by individual sites. 
Selection and Timing of Dose for Each Subject 
 DOAC should not be used if a patient has an allergy or has had active pathological bleeding 
where the use of the agent is contraindicated. Similarly, patients who are allergic and 
contraindicated to ASA should not use ASA. 
If a dose of  DOAC is not taken at the scheduled time, the dose should be taken as soon as 
possible on the same day and then continue with twice daily administration as before.   The dose 
should not be doubled to make up for a missed dose.  DOAC can be taken with or without food. 
 DOAC is not recommended in patients with severe hepatic impairment. These patients will not 
meet the inclusion/exclusion criteria.  
Dose Modifications 
Dose modification per investigator recommendations and per current guidelines. 
Concomitant Treatments 
Prohibited and/or Restricted Treatments 
Co-administration of the maintenance dose of  DOAC is not recommended with drugs that 
increase the risk of bleeding (eg, other anticoagulants, heparin, thrombolytic agents, NSAIDs, 
SSRIs, serotonin norepinephrine reuptake inhibitors).  


 
 
 
20 
 
Other Restrictions and Precautions 
 DOAC should be discontinued 48 hours prior to elective surgery or invasive procedures. If 
surgery or invasive procedures cannot be delayed, exercise appropriate caution taking into 
consideration an increased risk of bleeding. This risk of bleeding should be weighed against the 
urgency of intervention. 
Use  DOAC with caution when co-administered with nonsteroidal anti-inflammatory drugs 
(NSAIDs), including ASA. 
Treatment Compliance 
Patient compliance will be reported by patient interview to assure no medications were missed. 
The  DOAC bottle will be returned to the study coordinator at their 1 month follow up visit. 
 
 


 
 
 
21 
 
 
STUDY ASSESSMENTS AND PROCEDURES 
Study Schematic 
Time and Events Schedule 
Procedure 
Baseline 
(Within 30 
days of the 
procedure) 
Randomization 
(Within 48 prior 
to procedure) 
Prior to 
Procedure 
(Within 24 
hours of 
procedure) 
Day of 
Procedure 
24-48 hours 
Post-
Procedure 
Discharge 
Day 30 
(+/- 7 
days) 
Follow-
Up 
Eligibility 
Assessments 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria  
X 
 
 
 
 
 
 
Study Assessments: 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
X 
X 
X 
X 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
Adverse Events 
Assessment 
X 
X 
X 
X 
X 
X 
X 
Evaluation of 
Bleeding Events 
X 
 
X 
X 
X 
X 
X 
Laboratory Tests 
X 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
Ablation Procedure 
 
 
 
X 
 
 
 
Device Interrogation 
 
 
X 
 
X 
X 
X 
Cerebral MRI 
 
 
 
 
X 
 
X 
Neurology Evaluation 
NIHSS 
 
 
X 
 
X 
 
X 
EQ5D Survey 
 
 
X 
 
X 
 
X 
Randomization 
 
X 
 
 
 
 
 
Dispense Study Drug 
 
 
 
X (3 hours 
post 
hemostasis 
 
 
 
Drug Compliance 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
22 
 
Schedule of Events  
Baseline (to be completed within 30 days prior to the procedure) 
• Informed Consent 
• Medical History including medication review 
• Inclusion/Exclusion Criteria reviewed 
• Physical Exam  
• Vital Signs 
• Adverse Event Assessment 
• Evaluation of Bleeding events – including TIMI evaluation 
• Laboratory tests (including Chemistry, CBC, Pregnancy Test) 
• Pregnancy Test (if applicable) 
Randomization  
• Adverse Event Assessment 
• Randomization 
Prior to Procedure (within 24 hours of procedure) 
• Vital Signs 
• Adverse Event Assessment 
• Evaluation of Bleeding events – including TIMI evaluation 
• Device Interrogation 
• Neurology Evaluation – NIHSS 
• EQ5D Survey 
Day of Procedure 
• Physical Exam  
• Vital Signs 
• Adverse Event Assessment 
• Dispense Study Drug  
• Evaluation of Bleeding events – including TIMI evaluation 
• Ablation Procedure 


 
 
 
23 
 
Post Procedure (within 24-48 hours) 
• Physical Exam  
• Vital Signs 
• Adverse Event Assessment 
• Evaluation of Bleeding events – including TIMI evaluation 
• Device Interrogation 
• Cerebral MRI 
• Neurology Evaluation – NIHSS 
• EQ5D Survey 
Discharge 
• Physical Exam  
• Vital Signs 
• Adverse Event Assessment 
• Evaluation of Bleeding events – including TIMI evaluation Device Interrogation 
Day 30 Follow up (+/- 7 days) 
• Physical Exam  
• Vital Signs 
• Adverse Event Assessment 
• Evaluation of Bleeding events – including TIMI evaluation 
• Device Interrogation 
• Cerebral MRI 
• Neurology Evaluation – NIHSS 
• EQ5D Survey 
Safety Assessments 
STROKE VT 
Non-CABG Surgery Related Bleeding Events Criteria 


 
 
 
24 
 
TIMI Major Bleeding Events 
Any Symptomatic Intracranial Hemorrhage, or clinically overt signs of hemorrhage (including 
imaging) associated with a drop in hemoglobin of >5 g/dL (or when the hemoglobin concentration is 
not available, an absolute drop in hematocrit of >15% or Fatal Bleeding (bleeding that directly results 
in death within 7 days post procedure) 
TIMI Minor Bleeding Events 
Any clinically overt sign of hemorrhage (including imaging) that is associated with a fall in 
hemoglobin concentration of 3 to < 5 g/dL (or, when hemoglobin concentration is not available, an 
absolute drop in hematocrit of 9 to < 15%) 
TIMI Bleeding Events Requiring Medical Attention 
Any bleeding event that requires medical treatment, surgical treatment, or laboratory evaluation and 
does not meet criteria for a major or minor bleeding event, as defined above 
Insignificant Bleeding Events (ie, TIMI Minimal Bleeding Event) 
A reported blood loss or bleeding event episode not meeting any of the above criteria 
Clinically Significant Bleeding Events 
The composite endpoint of TIMI major bleeding event, TIMI minor bleeding event, or bleeding event 
requiring medical attention is considered clinically significant for the TIMI scale 
Not a TIMI Bleeding Event 
 
Primary End Point Assessment  
Incidence of periprocedural embolic events –TIA/CVA/other systemic embolic events 
immediately after the left ventricular arrhythmia ablation up to 30 days post left ventricular 
arrhythmia ablation.  
The incidence of new asymptomatic cerebrovascular events as documented by MRI at 24-48 
hours post procedure and at 30 days after the left ventricular arrhythmia ablation. 
 
Secondary End Point Assessments 
A. Major bleeding events as defined above using TIMI criteria 
B. Minor Bleeding events as defined by the TIMI criteria 


 
 
 
25 
 
C. Cardiovascular mortality 
D.  All-Cause mortality 
E. Any other adverse events occurring during the study period 
 
ADVERSE EVENTS 
An Adverse Event [AE] is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AEs). The causal relationship can be one of the following: 
• Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
• Not Related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more adverse events).  
Serious Adverse Events 
Serious Adverse Event (SAE) is any untoward medical occurrence at any dose that:  
• results in death 


 
 
 
26 
 
• is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE*: below for exceptions) 
• results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event, defined as a medical event that may not be immediately 
life-threatening or result in death or hospitalization but, based on appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed above. Examples of such 
events include but are not limited to intensive treatment in an emergency department or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.  
• 
Potential drug-induced liver injury (DILI) is also considered an important medical event--
see the DILI section below for a definition of a potential DILI event. 
• 
Suspected transmission of an infectious agent (eg, pathogenic or non-pathogenic) via the 
study drug is an SAE.  
• 
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, 
these events must be handled as SAEs. 
*NOTE: The following hospitalizations are not considered SAEs:  
• 
A visit to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a life-
threatening event) 
• 
Elective surgery planned before signing consent 
• 
Admissions as per protocol for a planned medical/surgical procedure 
• 
Routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
• 
Medical/surgical admission other than remedying ill health state that was planned before 
study entry. Appropriate documentation is required in these cases 
• 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason) 
• 
In this study, the following adverse events are to be reported to BMS, regardless of whether 
these reports are classified as serious or unexpected: 


 
 
 
27 
 
Potential or suspected cases of liver injury including but not limited to liver test 
abnormalities, jaundice, hepatitis or cholestasis. 
 
Serious Adverse Event Collecting and Reporting  
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuing dosing. If applicable, SAEs must be collected that relate to 
any later protocol-specific procedure (such as follow-up skin biopsy). 
The investigator should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness.  
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy, or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
SAEs, whether related or unrelated to the study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on the SAE Report Form; Pregnancies on a Pregnancy 
Surveillance Form. 
SAE Email Address: dlakkireddy@gmail.com 
SAE Fax Number: 913-575-2157 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.)  
All SAEs should be followed to resolution or stabilization. 
SAE Reconciliation 
The investigator will reconcile the clinical database SAE cases transmitted to the study team. The 
DSMB and study steering committee will adjudicate the adverse events in the event of 
disagreement. 


 
 
 
28 
 
Non-Serious Events 
A non-serious adverse event is an AE not classified as serious. 
Non-Serious Adverse Events (NSAEs) Collecting and Reporting 
The collection of non-serious adverse event (NSAE) information should begin at initiation of 
study drug. Non-serious adverse event information should also be collected from the start of a 
placebo lead-in period or other observational period intended to establish a baseline status for the 
subjects.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug, or those that are present at the end of study treatment as 
appropriate.  
Laboratory Test Abnormalities 
The following laboratory abnormalities should be captured and reported as appropriate: 
• 
Any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted 
• 
Any laboratory test result abnormality that required the subject to receive specific 
corrective therapy.  
It is expected that wherever possible, the clinical rather than the laboratory term will be used by 
the reporting investigator (eg, use the term anemia rather than low hemoglobin value).  
Laboratory test abnormalities are provided to BMS via annual safety reports (if applicable), and 
interim or final study reports. 
 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives after product administration, the investigational product will 


 
 
 
29 
 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety).  
The investigator must immediately notify WorldwideSafety@BMS.com of this event via the 
Pregnancy Surveillance Form within 24 hours and in accordance with SAE reporting procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on a Pregnancy 
Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy may also be collected on the Pregnancy Surveillance Form. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs. 
Potential Drug-Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs. 
Potential drug induced liver injury is defined as  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase), 
AND 


 
 
 
30 
 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious 
adverse event, as appropriate, and reported accordingly. 
DATA MONITORING COMMITTEE  
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 physicians 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 50 patients and then at the completion of 
the study.  
If the major bleeding events in the  DOAC group occur at >15% but <30% (absolute event rate) 
of those in the ASA group during any of the assessments, a recommendation will be made to 
consider modifying the study by the members of the DSMB. First consideration to modify is to 
decrease the dose of the drug to 2.5mg PO twice daily. If the major bleeding events in the  
DOAC group occur at >30% (absolute event rate) of those in the ASA group during any of the 
assessments, a recommendation will be made to stop the study by the members of the DSMB. 
STATISTICAL CONSIDERATIONS 
Study Management and Sample Size Justification 
This is a pilot study and 52 total patients will be enrolled in the study.  We expect to analyze a 
total of 50 patients and each arm will consist of 25 patients. The additional 2 allows for attrition. 
Since this is a pilot study, the number needed to treat to achieve a pre-specified statistical 
significance cannot be calculated accurately. Exact sample size could not be given due to lack of 
pre-existing data on this subject. We hypothesize a 30% difference in outcomes can be seen with 
a total sample size of 50 patients.  
Data Collection Center 


 
 
 
31 
 
The Kansas City Heart Rhythm Research Foundation will be the coordinating site for the study. 
A project manager (PM) with the help of the PI will create the study worksheets and create the 
CRFs. The sites will complete the paper CRF and submit via secure email to the project 
manager. The PM will assist the Database Manager (DM) with updating the access database and 
providing computer support for outside centers. All data will be submitted via secure email 
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; the linking list will be destroyed at the completion of the project.  
Statistical analysis: Patients will be randomized in a stratified manner to control arm versus 
treatment arm. We will analyze the differences in secondary endpoints between the two groups 
for major, minor bleeding and cardiovascular mortality up to 30 days post ablation. Categorical 
variables will be reported as counts and percentages and continuous variables will be expressed 
as mean ± SD. Continuous variables will be compared using t-test for normally distributed data 
or Mann Whitney U test for non-normally distributed data as deemed appropriate. Categorical 
events will be compared using chi-square test for parametric data. 
Univariate and multi-variate analysis will be performed to identify the predictors of systemic 
thromboembolic events and mortality. This is a pilot study to study the feasibility and safety of 
the study.  A larger study will be done in the future if there is a positive signal.  
Compliance with the Protocol 
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by the study team.  


 
 
 
32 
 
GLOSSARY OF TERMS 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by either the 
investigator or the sponsor to be related to the 
investigational product. 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures.  
Hemostasis 
Defined by no further ooze from groin puncture sites after 
pressure hold is released. Typically, 3-4 hours post 
procedure. 
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction as 
termed by the European Clinical Trial Directive 
(2001/20/EC).  
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, 
Investigator Brochure for an unapproved investigational 
product). 
Peri-Procedural Bleeding 
Occurring prior to the procedure within 48 hours and up 
to 48 hours post procedure. 
Recent MI 
Recent is defined as within 30 days of the planned 
procedure.   


 
 
 
33 
 
LIST OF ABBREVIATIONS 
ACE 
Asymptomatic Cerebrovascular Event 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
ASA 
Aspirin 
DOAC 
Direct Oral Anticoagulant 
CIED 
Cardiac Implantable Electrical Devices 
CTCAE Common Terminology Criteria for Adverse Events 
CVA 
Cerebrovascular Accident 
CVE 
Cerebrovascular Events 
EP 
Electrophysiology 
ESR 
Expedited Safety Report 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
HCG 
Human Chorionic Gonadotropin 
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICD 
Implantable Cardioverter Defibrillator 


 
 
 
34 
 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
ISR 
Investigator-Sponsored Research 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NIHSS 
National Institute of Health Stroke Score 
NSAE 
Non-Serious Adverse Event 
RFA 
Radiofrequency Ablation 
SAE 
Serious Adverse Event 
SUSAR Suspected Unexpected Serious Adverse Reaction 
TIA 
Transient Ischemic Attack 
TIMI 
Thrombolysis In Myocardial Infarction 
VT 
Ventricular Tachycardia 
VKA 
Vitamin K Antagonist 
WOCBP Women of Child-Bearing Potential 
 
 
 


 
 
 
35 
 
Attachment A 
Algorithm for subjects who have Cardiac implantable devices and who are undergoing 
brain MRI examination (as adopted from [2]) 
General: 
1. MRI scans will be performed in a 1.5 T scanner. 
2. Subjects will undergo interrogation of the device (CIED) before and after the scan by 
experienced heart rhythm management personnel, outside the MRI room. 
3. Patient height and weight will be recorded to determine the specific absorption rate (SAR) 
levels not to exceed the manufacturer’s pre-specified limits, if in case, the parameters, 
repetition times, number of slices and angle will be changed accordingly. 
4. A crash cart and ACLS trained health care professional will be available during the entire 
procedure. 
5. Blood pressure, pulse oximetry and cardiac rhythm will be monitored. If any signs of 
hemodynamic instability (BP<90/60, HR<40) or ventricular fibrillation the procedure will be 
stopped and patient will be managed as per the ACLS protocol. 
Device (CIED) interrogation and monitoring: 
1. Device interrogation will include measurements of battery voltage, P- and R-wave 
amplitudes (if present), and lead impedance and pacing threshold for all leads. 
2. Pacing threshold measurements will be performed at 10 beats/min above the programmed 
pacing rate (if pacemaker dependent) or, 10 beats/min above the patient's intrinsic rate. The 
pacing rate for testing can be increased by increments of 10 beats/min, if there is insufficient 
suppression of the patient's underlying rhythm. 
3. The pacing rate will gradually be decreased to 40 beats/min, if the patient has an intrinsic 
rhythm of greater than 40 beats/min, the device will be programmed to pacing and sensing 
functions disabled (ODO) [Chamber paced-none; Chamber sensed--atria and ventricle; Mode 
of response –none] or OVO [Chamber paced-none; Chamber sensed-ventricle; Mode of 
response-none]). The patient will then be observed for 5 minutes before the scan. If 
symptoms are noted, the pacing function will be reprogrammed to an asynchronous pacing 
mode (DOO) [asynchronous pacing mode using both atrial and ventricular leads] or (VOO) 
[asynchronous pacing mode using only the ventricular lead]. If the patient has a device that 
does not allow permanent reprogramming to an ODO or OVO mode, the patient will be 


 
 
 
36 
 
reprogrammed to an asynchronous mode (DOO or VOO), and the pacing output for all active 
leads and pulse width will be set to a minimum value. If there is no intrinsic rhythm when the 
device is reprogrammed to 40 beats/min, the patient will be considered pacemaker 
dependent, and the device will be programmed to an asynchronous pacing mode (DOO or 
VOO). The patient will be observed for 5 minutes before the scan to ensure that the 
asynchronous pacing is well tolerated. If not, the original pacing parameters will be restored 
and the scan will not be performed. 
4. Immediately after the scan, initial device parameters will be restored. Post scan device 
parameter interrogation will be performed using the pre-scan interrogation protocol. If there 
is a significant increase in pacing threshold (≥0.5 V at 0.4 ms or any increase at a wider pulse 
width) after the scan compared with before the scan, the pacing output will be increased to 
maintain a 2- to 2.5-times amplitude safety margin at the physician's discretion. If there is a 
significant decrease in the P- and R-wave amplitudes, the sensitivities will be adjusted to 
maintain adequate atrial and ventricular electrocardiogram detection. 
Implantable cardioverter-defibrillator interrogation and programming: 
1. The pacing rate will gradually be decreased to, 40 beats/min. If the patient has an intrinsic 
rhythm and is asymptomatic, the device will be programmed to no pacing (ODO or OVO). 
All tachycardia therapy and detection functions will be disabled. The patient will be observed 
for 5 minutes before the scan. If the patient does not have a stable intrinsic heart rate or 
symptoms are noted, the patient will be considered pacemaker dependent. Subjects with 
ICDs who are pacemaker dependent are excluded from the study. 
2. Immediately after the scan, all tachycardia therapy and detection functions will be 
restored. Post scan interrogation will be performed as described earlier for pacemaker 
Subjects. 
3. Subjects with 1 or more parameter changes will be asked to return for 3 follow-up 
interrogations over a six-month period, which will be scheduled less than 7 days after the 
procedure, again at 3 months (±30 days) after the MRI procedure, and at 6 months (±30 days) 
after the MRI procedure. If no parameter changes requiring multiple follow-up visits occur, 
the patient will require a single-device interrogation between 3 and 6 months (±30 days) after 
the MRI procedure. 


 
 
 
37 
 
REFERENCES 
1. Cabral KP, Ansell JE. The role of factor Xa inhibitors in venous thromboembolism 
treatment. Vasc Health Risk Manag. 2015 Jan 30;11:117-23. doi: 
10.2147/VHRM.S39726. eCollection 2015. Review.   PubMed ID: 25673997. 
 
2. Ghanbari H, Başer K, Jongnarangsin K, Chugh A, Nallamothu BK, Gillespie BW, Başer 
HD, Suwanagool A, Crawford T, Latchamsetty R, Good E, Pelosi F Jr, Bogun F, Morady 
F, Oral H. Mortality and cerebrovascular events after radiofrequency catheter ablation of 
atrial fibrillation. Heart Rhythm. 2014 Sep;11(9):1503-11. doi: 
10.1016/j.hrthm.2014.05.003. Epub 2014 May 6. Erratum in: Heart Rhythm. 2015 
Jan;12(1):253. Swangasool, Arisara [corrected to Suwanagool, Arisara].   PubMed 
ID: 24813379.