Conditions: Atrial Fibrillation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5
Healthy volunteers: no

Brief summary:
This is a prospective randomized comparative evaluation of Edoxaban and Warfarin for safety and efficacy in perioperative use in patients with non-valvular atrial fibrillation (AF) undergoing clinically indicated implantation or replacement of cardiovascular implantable electrical devices.The primary objective is to compare the rates of local and systemic bleeding in subjects randomized to Edoxaban compared to subjects randomized to continuous warfarin in within 30 days of cardiac rhythm device implant with concomitant non-valvular AF.

Detailed description:
This is a prospective randomized comparative evaluation of Edoxaban and Warfarin for safety and efficacy in perioperative use in patients with non-valvular atrial fibrillation undergoing clinically indicated implantation or replacement of cardiovascular implantable electrical devices. This study is a randomized, open label, active-controlled trial with an open-label safety extension, designed to compare local and systemic bleeding within 30 days of cardiac rhythm device implant among subjects randomized to continuous Warfarin or interrupted (\<24 hours) Edoxaban. The study will have three phases, a run in phase to establish stable warfarin therapy, an acute open label 30 day phase when subjects will be randomized in a 1:1 ratio to receive interrupted edoxaban or continuous warfarin followed by an open label follow up phase for an additional 5 months for safety monitoring. Drug transitions will be performed according to approved drug labeling.

Arms:
arm 1: Edoxaban 30 or 60 mg arm 2: Warfarin 1 -1 0 mg

Interventions: intervention 1: Edoxaban intervention 2: Warfarin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
1 
 
ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
CLINICAL STUDY PROTOCOL 
 
 
A PHASE 4, RANDOMIZED, OPEN LABEL, MULTICENTER 
PROSPECTIVE COMPARATIVE STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF  
Edoxaban or Warfarin Therapy In Cardiovascular 
Implantable Electrical Device Procedures in Patients with 
Non-Valvular Atrial Fibrillation  
(“ENTICED-AF Trial”) 
 
Principal Investigator: Sanjeev Saksena MD, FACC, FHRS 
Statistical & Data Management: April Slee MS & Ruth 
McBride Ph. D 
Trial Coordinating Center: 
Electrophysiology Research Foundation 
161 Washington Valley Road, Suite 201, Warren, NJ 07059 
E mail: EPRF@AOL.COM 
Telephone: 732-302-9990 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
www.eprf.org 
Information contained in this document is proprietary to the 
Electrophysiology Research Foundation (EPRF). Its public disclosure 
prior to registration with www.clinicaltrials.gov is not permitted. The 
information is provided to you in confidence to enable you to perform 
the work, which is requested under an agreed upon and signed 
confidentiality statement. 
 
Do not give this document or any copy of it or reveal any proprietary 
information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the 
confidentiality statement) without the prior written permission of an 
authorized representative of EPRF. 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study patients  enrolled under my supervision and providing the 
Electrophysiology Research Foundation with complete and timely information, as outlined in the 
protocol.  It is understood that all information pertaining to the study will be held strictly confidential 
and that this confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of 
the study staff and myself, I agree to maintain the procedures required to carry out the study in 
accordance with accepted GCP principles and to abide by the terms of this protocol. 
 
Protocol Title:  A PHASE 4, RANDOMIZED, OPEN LABEL, MULTICENTER PROSPECTIVE COMPARATIVE 
STUDY TO EVALUATE THE EFFICACY AND SAFETY OF EDOXABAN OR WARFARIN THERAPY IN 
CARDIOVASCULAR IMPLANTABLE ELECTRICAL DEVICE PROCEDURES IN PATIENTS WITH NON-VALVULAR 
ATRIAL FIBRILLATION (“ENTICED-AF TRIAL”). 
Investigator Signature  
 
Date 
 
 
 
Print Name and Title 
Site Name and 
Number 
 
 
Address 
 
 
 
 
 
 
 
Phone number 
 
E mail 
 
 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
Contents 
Protocol Synopsis: ..............................................................................................................................6 
1. 
Background .............................................................................................................................. 11 
2. 
Purpose and Rationale .............................................................................................................. 12 
3. Objectives .................................................................................................................................... 12 
3.1 Primary Objective ................................................................................................................... 12 
3.2 Secondary Objective ............................................................................................................... 12 
3.3 Exploratory Objectives ............................................................................................................ 13 
4. Study Design ................................................................................................................................ 13 
4.1 Overview ................................................................................................................................ 13 
4.2 Justification of key elements of study design ........................................................................... 16 
4.2.1 Primary Endpoint ....................................................................................................................... 16 
4.2.2 Choice of continuous Warfarin as a comparator ....................................................................... 17 
4.2.3 Timing of primary endpoint evaluation ..................................................................................... 17 
4.2.4 Timing of secondary endpoint evaluation ................................................................................. 18 
5. Study Population .......................................................................................................................... 18 
5.1 Device case mix ...................................................................................................................... 18 
5.2 Study Inclusion criteria ........................................................................................................... 18 
5.3 Study Exclusion criteria ........................................................................................................... 19 
6. Study Treatments ......................................................................................................................... 20 
6.1 Investigational and control drugs ............................................................................................ 20 
6.1.1 Run-in Phase ........................................................................................................................ 20 
6.1.2 Acute Open Label Phase ....................................................................................................... 20 
6.1.3 Follow-up Open Label Phase ...................................................................................................... 20 
7.  Study Visits ................................................................................................................................. 21 
8. Assessment of Safety and Monitoring ........................................................................................... 23 
8.1 Adverse events ....................................................................................................................... 24 
8.2 Serious adverse event reporting .............................................................................................. 24 
8.3 Follow-up of Adverse Events and Serious Adverse Events ........................................................ 25 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
9. Quality Control and Data management ......................................................................................... 25 
9.1 Data Collection and Database Management ............................................................................ 25 
9.2 Site training and monitoring ................................................................................................... 25 
10. Assessment of Non-Inferiority Hypothesis and Data Analysis ....................................................... 26 
10.1 Expected event rates............................................................................................................. 26 
10.2 Sample size calculation (Appendix B) ..................................................................................... 26 
10.3 Analysis of the primary objective .......................................................................................... 27 
10.4 Analysis of  secondary objectives .......................................................................................... 27 
10.5 Populations for analysis ........................................................................................................ 27 
10.6 Handling of missing data values/censoring/discontinuations ................................................. 28 
11. Discontinuation of the Study ...................................................................................................... 28 
12. Ethical considerations ................................................................................................................. 28 
12.1 Ethical compliance ................................................................................................................ 28 
12.2 Informed consent procedures ............................................................................................... 28 
12.3 Institutional Review Board/ Independent Ethics Committee / Research Ethics Board .............. 29 
12.4 Responsibilities of the investigator and IRB/IEC/REB.............................................................. 29 
13. Publication strategy .................................................................................................................... 29 
13.1 Publication of results ............................................................................................................ 29 
13. REFERENCES ............................................................................................................................... 30 
Appendix A: Schedule of Visits and Visit Elements ............................................................................ 31 
Appendix B: Details of event rate assumptions ................................................................................. 32 
 
 
 
 
 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
Protocol Synopsis: 
TITLE 
A phase 4, randomized, open label, multicenter prospective 
comparative study to evaluate the efficacy and safety of  
Edoxaban or Warfarin Therapy In Cardiovascular Implantable 
Electrical Device Procedures in Patients with Non-Valvular Atrial 
Fibrillation  
 
SPONSOR 
Electrophysiology Research Foundation 
FUNDING ORGANIZATION 
Daiichi-Sankyo Inc. 
NUMBER OF SITES 
20 
RATIONALE 
Perioperative bleeding is a risk of cardiovascular implantable device 
insertion or replacement procedures. Bleeding complications predispose 
patients to interruption of OAC therapy, use of reversal agents, infection, 
and re-operation and prolong hospital stays. In patients with non valvular 
atrial fibrillation, interrupted Edoxaban therapy may offer safety and 
efficacy that is non inferior to continuous Warfarin therapy during these 
procedures 
STUDY DESIGN 
This is a prospective randomized comparative evaluation of Edoxaban and 
Warfarin for safety and efficacy in perioperative use in patients with non-
valvular atrial fibrillation undergoing clinically indicated implantation or 
replacement of cardiovascular implantable electrical devices. This study is a 
randomized, open label, active-controlled trial with an open-label safety 
extension, designed to compare local and systemic bleeding within 30 days 
of cardiac rhythm device implant among patients randomized to 
continuous Warfarin or interrupted (<24 hours) Edoxaban. The study will 
have three phases; a run in phase to establish stable Warfarin therapy, an 
acute open label 30-day phase when patients will be randomized in a 1:1 
ratio to receive interrupted Edoxaban or continuous Warfarin, which will be 
followed by an open label follow up phase for an additional 5 months for 
safety monitoring.  Drug transitions will be performed according to 
approved drug labeling. 
PRIMARY OBJECTIVE 
The primary objective is to compare the rates of local and systemic 
bleeding in patients randomized to Edoxaban compared to patients 
randomized to continuous Warfarin in within 30 days of cardiac rhythm 
device implant with concomitant non-valvular AF. 
SECONDARY OBJECTIVES 
The secondary objectives are to compare the rates of thrombotic events 
(embolism or stroke) and MACE events through 6 months following the 
procedure in the Edoxaban and Warfarin groups. 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
NUMBER OF PATIENTS  
A maximum of 400 patients will be enrolled 
PATIENT SELECTION 
CRITERIA 
a) Patients with established AF and bradycardia on long term 
(>3 weeks) therapeutic OAC with Warfarin or another OAC 
who are undergoing new pacemaker system implant or 
existing pacemaker system revision. 
b) Patients with newly detected bradycardia –tachycardia 
syndrome and AF who have been recently (less than 3 
weeks) started on Warfarin, have a therapeutic INR and no 
thrombus on trans-esophageal echocardiogram (TEE) who 
are undergoing a new pacemaker system implant or 
revision. 
c) Patients with AF and ventricular tachyarrhythmias (VT or 
VF) or acquired structural heart disease who are candidates 
for ICD therapy and are on long term (>3 weeks) 
therapeutic OAC   with Warfarin or another OAC who are 
undergoing new ICD system implant or existing ICD system 
revision. 
d) Patients with newly detected AF with VT or VF who have 
been recently (less than 3 weeks) started on Warfarin, have 
a therapeutic INR and no thrombus on TEE who are 
undergoing ICD system implant or revision 
 
Exclusion Criteria:  
a. Clinically significant valvular heart disease 
b. Patients requiring CIED lead extraction e.g. for 
device site infection, endocarditis, leads under 
advisory or other conditions warranting lead(s) 
system extraction. 
c. Recent (<1 month) myocardial infarction 
d. Documented LA thrombus on TEE 
e. Contraindications to anticoagulant therapy or 
adverse event with prior Warfarin or Edoxaban 
therapy 
f. 
Creatinine clearance <30ml/min or >95 ml/min 
g. Hepatic disease, advanced 
h. Recent stroke (<3 months) or thromboembolic 
event 
i. 
Recent (<3months) intracranial or other major 
bleeding event 
j. 
Use of concomitant dual antiplatelet therapy or 
other oral, subcutaneous or parenteral 
anticoagulant therapy 
k. Patients on Warfarin without therapeutic INR levels 
before study entry 
l. 
Patients with other clinically significant medical 
condition 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
m. Patients with life expectancy < 1 year 
n. Lead extraction procedures 
 
TEST PRODUCT, DOSE, 
AND ROUTE OF 
ADMINISTRATION 
Edoxaban (30 mg tabs) 
Edoxaban 60 mg orally daily dose for creatinine clearance 50 to 95 ml/min 
and Edoxaban 30 mg orally for creatinine clearance of 30 to 49 ml/min.  
 
 
CONTROL PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Warfarin dose to maintain therapeutic INR, oral administration 
DURATION OF PATIENT 
PARTICIPATION AND 
DURATION OF STUDY 
Screening:  7-26 days 
Treatment:  5 days of randomized therapy prior to procedure (which is a 
single day) 
Follow-up:  180 days 
 
CONCOMMITANT 
MEDICATIONS 
Allowed as per approved FDA guidelines 
 
 
EFFICACY EVALUATIONS 
 
PRIMARY ENDPOINT 
Major local or systemic bleeding as defined in the protocol at 30 days after 
implant procedure 
SECONDARY ENDPOINTS 
The secondary objectives are to compare the rates of thrombotic events 
(embolism or stroke) through 6 months following the procedure in the 
Edoxaban and Warfarin groups and the rates of MACE events through 6 
months following the procedure in the Edoxaban and Warfarin groups 
OTHER EVALUATIONS 
The exploratory objectives are to compare rates of hemoglobin reductions 
from pre-procedure to 24-48 hours post procedure in the Edoxaban and 
Warfarin groups 
 
SAFETY EVALUATIONS 
Safety monitoring during the study will be performed by an independent 
data monitoring committee (DMC), as well as medical and clinical monitors 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
and the coordinating center. Sites will be monitored by a clinical monitor at 
least once during this short trial. Clinical sites will be required to report all 
procedure related complications, deaths and major adverse events to the 
medical monitor within 24 hours of learning of the event. All events will be 
adjudicated by an independent events committee. 
PLANNED INTERIM 
ANALYSES  
When approximately 200 subjects have completed the study through the 
30-day visit, an interim analysis for safety will be conducted by an 
independent data monitoring committee. Serious adverse events will be 
monitored by the committee on an ongoing basis throughout the study. 
Based on the primary outcome in these 200 subjects, the study may 
continue to enroll up to 200 additional subjects, or be terminated.   
STATISTICS 
Primary Analysis Plan 
This study contains an internal pilot, and the primary endpoint will be 
evaluated when 200 patients have reached 30-days post procedure or 
withdrawn. Based on the primary outcome in these 200 patients, the study 
may enroll up to 200 additional subjects, or be terminated. Bleeding rates 
will be compared for non-inferiority using a 1-sided exact test (Primary 
Endpoint).  If non-inferiority of Edoxaban is demonstrated, superiority will 
be assessed using a 2-sided exact test (Secondary Endpoint).   
Rationale for Number of 
Patients  
The study is designed based on a non-inferiority hypothesis, with an overall 
type I error rate of 0.025 (1-sided) with a non-inferiority margin of 1.5%. 
 
 
 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
CIED 
Cardiovascular Implantable Electrical Device 
CRF 
Case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
SAE 
Serious adverse experience 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
1. Background 
Non-valvular (NV) atrial fibrillation (AF) frequently coexists with bradyarrhythmias and 
tachyarrhythmias. (1, 2) NVAF patients frequently have cardiovascular implantable electrical devices 
(CIEDs) implanted for symptomatic bradycardias or tachycardias. In the elderly population, 30-40% of all 
patients with bradyarrhythmias and pacemakers (PM) have concomitant AF. In patients receiving 
implantable cardioverter-defibrillators (ICDs), 15 to 20% can have concomitant AF. Thus, insertion or 
revision of CIEDs is common in NVAF patients and requires management of concomitant anticoagulant 
therapy. Warfarin is the most commonly used oral anticoagulant (OAC) and is either bridged or 
continued for the CIED procedure. Bridging requires hospital admission for intravenous heparin therapy 
in many patients and continuous Warfarin therapy is now being increasingly employed. However, this 
approach is associated with significant peri-procedural bleeding complications during and after CIED 
procedures.   
In the BRUISE control study AF patients with PM or ICD devices were studied using two different 
regimens for peri-procedural anticoagulation. Birnie et al reported “clinically significant” device pocket 
hematomas in 3.5% of on Warfarin and in 16% of patients on heparin bridging therapy. (3) In another 
multi-center study, 9.8% of patients on heparin or Warfarin had significant pocket hematomas after 
pacemaker implantation. (4) This is in contrast to the general CIED population, in whom this complication 
was observed only in 0.2% of implanted individuals in a nationwide experience from Denmark. (5) 
Kutinsky et al reported even higher rates of hematoma formation in the presence of clopidogrel and 
aspirin with continued Warfarin therapy ranging from 9.5 to 24%. (6) Bleeding complications predispose 
patients to interruption of OAC therapy, use of reversal agents, infection, and re-operation and prolong 
hospital stays. Bridging therapy may be associated with increased embolic events due to varying 
anticoagulation status. (3)  
In contrast, in the MOST study performed in patients with only sick sinus syndrome at entry, bleeding 
complications with pacemaker implantation were <0.4%. (7) Dewland et al reported major complication 
rates with ICD implants in the National Cardiovascular Device registry. They noted device related 
complications of approximately 1% exclusive of major bleeding and hematomas with ICD implants. (8) 
 
 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
2. Purpose and Rationale 
The rationale of this study is based on the long half-life of Edoxaban and its potential for reduced 
bleeding risk in comparison to Warfarin in patients with non-valvular AF. Continuous Warfarin therapy 
has been advocated to avoid the need for bridging anticoagulation at the time of elective surgical 
procedures such as CIED insertions or revisions. Bridging can increase bleed rates and prolong hospital 
stay. However, clinical studies show major bleeding complications in 43.5% of such patients in the 
perioperative period. (3) It is proposed that Edoxaban 60 mg when administered up to 18 to 24 hours 
before after the CIED procedure and resumed 12 to 24 hours after the procedure could potentially 
reduce this bleeding risk without loss of efficacy in stroke prevention.  
In patients with non-valvular AF on OAC therapy with concomitant bradyarrhythmias or 
tachyarrhythmias warranting insertion or replacement of a CIED, an interrupted Edoxaban regimen 
without bridging anticoagulation is hypothesized to show comparable safety and efficacy to continuous 
Warfarin therapy for peri-procedural anticoagulation. 
    3. Objectives 
3.1 Primary Objective 
The primary objective is to compare the rates of bleeding (local or systemic) in patients randomized to 
Edoxaban compared to patients randomized to continuous Warfarin in within 30 days of cardiac rhythm 
device implant for non-valvular AF. 
3.2 Secondary Objective 
The secondary objectives are: 
1. To compare the rates of thrombotic events (embolism or stroke) through 6 months following 
the procedure in the Edoxaban and Warfarin groups 
2. To compare the rates of MACE events through 6 months following the procedure in the 
Edoxaban and Warfarin groups 
MACE components include:  
 
Cardiovascular hospitalization 
 
Stroke 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
 
Myocardial infarction 
 
Heart failure 
 
Vascular events  
 
Death 
 
 
3.3 Exploratory Objectives 
The exploratory objectives are: 
1. To compare rates of hemoglobin reductions of ≥2 g/L from pre-procedure to 24-48 hours post 
procedure in the Edoxaban and Warfarin groups 
2. To compare change in hemoglobin from pre-procedure to 24-48 hours post procedure in the 
Edoxaban and Warfarin groups 
3. To compare the rates of other events of interest, including 
 
Hemoglobin decrease of 1.5Gm% or greater after 24 to 48 hrs 
 
Other cardiac procedures 
 
Hematoma requiring no intervention 
 
Device Infection 
 
Device explanation 
 
Major intracranial hemorrhage 
 
Vascular events 
 
Myocardial Infarction (MI) 
 
Cardiovascular Hospitalization  
 
Hospitalization after procedure discharge and prior to study conclusion 
 
Stroke and death composite 
 
4. Study Design 
4.1 Overview 
This study is a randomized, open label, active-controlled trial with a safety extension (follow-up phase). 
It is designed to compare bleeding, local or systemic, within 30 days of cardiac rhythm device implant 
(acute phase) for non-valvular AF among patients randomized to continuous Warfarin or interrupted 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
Edoxaban. Randomization will be stratified by device type and HAS-BLED score (≤ 2 or ≥ 3). Patients will 
be randomized in a 1:1 ratio to receive interrupted Edoxaban or continuous Warfarin. This study 
contains an internal pilot opportunity to adjust the sample size or terminate the study, and there will be 
an interim analysis of the primary endpoint when 200 patients have reached 30-days post procedure or 
withdrawn. Based on the primary outcome in these 200 patients, the study may: 
 
Enroll 200 additional patients (pacemaker capped at 100 patients, ICD capped at 150 patients) 
 
Enroll 100 additional patients  
 
Be terminated 
The study design is outlined in Figure 1. 
Figure 1:  
Study Design Flow Chart 
 
Eligible subjects must be stable on a therapeutic dose of Warfarin (INR 2-3) for three weeks prior to  
randomization.  If potential patients are taking an anticoagulant besides Warfarin, or otherwise not  
meeting this criteria, must be switched to Warfarin and complete 3 weeks of dosing with INRs in the  
therapeutic range (run-in period) at randomization. 
Comment [s1]: Segment into two sentences. 
Insert period 
Comment [s2]: delete 
Comment [s3]: delete 
Comment [s4]: Insert 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
The final INR should be performed on the day of randomization, and the procedure should be scheduled 
a minimum of 5 days and at most 15 days after randomization.  Once eligibility has been confirmed and 
informed consent has been obtained, patients will be randomized via an interactive secure web 
randomization system. Patients will be randomized in a 1:1 ratio to Edoxaban or Warfarin. 
Randomization will be blocked by HAS-BLED score, and based on a randomization list, which will be 
created prior to commencement of the study.  
At randomization, subjects will be provided with a drug kit containing either open-label Edoxaban or 
Warfarin for 30 days at a randomization visit. Patients randomized to Warfarin will take Warfarin on the 
day of procedure and patients randomized to Edoxaban will receive no drug on the day of the 
procedure.  
Routine clinical care will be implemented with patients being scheduled for discharge within 24 hours of 
admission to maintain ambulatory procedural status. Patients requiring longer lengths of stay will have 
documentation of conditions warranting such care.  
The routine standard of care (SOC) is instituted after the procedure, with a pre-discharge visit (4 to 24 
hours after procedure), wound care visit (usually 1 to 2 weeks after the procedure) and standard device 
clinical follow-up procedures. These can include one month, three month or six month visits or remote 
monitoring as clinically employed in the study. 
In the event of an acute procedural bleed, blood products or vitamin K may be administered. In this 
case, the patient will be counted as having met the primary endpoint. The primary outcome of major 
bleed will be assessed at the 30-day visit. The medical monitor will confirm that the primary endpoint 
has been assessed.  
After the 30-day assessment, patients will continue to take the randomized anticoagulant unless it 
becomes medically necessary to change it. The MACE components will be collected at the time of the 6-
month in-clinic visit. 
 
There will be a telephone follow-up at 3 months after the CIED procedure for MACE and hospitalizations 
and vital status. There will be a face to face visit at 6 months which will result in study follow up 
completion and final patient assessment for safety endpoints, hospitalizations and vital status.  


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
 
4.2 Justification of key elements of study design 
4.2.1 Primary Endpoint 
Peri-procedural bleeding and major local bleeding is of clinical concern for patients who require 
anticoagulation. Though catastrophic bleeding is rare, bleeding requiring clinical intervention is more 
frequent and can be studied in a modestly sized trial. Unlike strict use of change in hemoglobin, the 
need for intervention with vitamin K or blood products is recognizable to patients. Reduction in the 
need to administer an intervention for a procedural bleed should also result in lower health care 
resource utilization and costs. 
Major local or systemic bleeding is defined as one of the following events: 
- 
Significant hematoma requiring further surgery, resulting in prolongation of hospitalization, or 
requiring interruption of oral anticoagulation therapy  
- 
Blood transfusion (permitted if hemoglobin is below 8 gm%, or 9 gm% in patients with active 
myocardial ischemia e.g. acute coronary syndrome) 
- 
Surgical or interventional procedure to control bleeding that is symptomatic (shock, severe 
hypotension (90 mm hg systolic) or angina or myocardial infarction which is not amenable to 
conservative measures (pressure dressing, ice packs) or volume expansion with intravenous 
fluids) 
- 
Use of reversal agent injection to control bleeding leading to clinically manifest shock (e.g. 
hypotension requiring pressors, oliguria etc.) or death, severe and symptomatic hypotension (90 
mm hg systolic or lower) or angina or hemoglobin decline to below 8 gm% not amenable to 
conservative measures (pressure dressing, ice packs or volume expansion with intravenous 
fluids)  
- 
Hemorrhage leading to stroke or eventual fatality 
(INR- guidelines for vitamin K injection or blood products will be established- see guideline below).  
(aPTT or anti- factor Xa assay may or may not be available for Edoxaban to guide reversal – clinical and 
Hemoglobin guidelines as established above will be employed to guide use of reversal with blood 
products or transfusion).  
Recommendations for Managing Elevated INRs or Bleeding in Patients Receiving VKAs 
Condition 
Suggested Intervention 
INR less than 4.5 but above 
Hold or reduce Warfarin dose. Resume Warfarin when INR is therapeutic. 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
therapeutic 
INR 4.5 to 10 with no evidence of 
bleeding 
Hold Warfarin. Resume Warfarin when INR is therapeutic. 
Vitamin K not routinely recommended if no evidence of bleeding. 
Vitamin K can be used if urgent surgery needed  
(less than 5 mg, with additional 1 to 2 mg in 24 hrs. if needed) or bleeding risk is high (1 to 2.5 mg). 
INR greater than 10 with no 
evidence of bleeding 
Hold Warfarin therapy and administer vitamin K 2.5 mg to 5 mg orally. 
Monitor INR. 
Resume Warfarin at lower dose when INR therapeutic. 
Serious bleeding at any elevation of 
INR or Life-threatening bleeding 
Consult Hematology. 
Hold Warfarin. 
Administer intravenous vitamin K 5 mg to 10 mg by slow infusion or administer blood products as appropriate. 
*In patients with mild to moderately elevated INRs without major bleeding, give vitamin K or 
blood products as appropriate. Adapted from ACCP Evidence-Based Clinical Practice Guideline 
Chest 2012; 141(Suppl 2): e154S-88s.  
 
4.2.2 Choice of continuous Warfarin as a comparator 
Heparin bridging was standard of care until the BRUISE-CONTROL study showed a reduction of bleeds 
with continuous Warfarin compared to heparin combined with bridging therapy. No robust studies of 
other anticoagulants in procedural settings have been performed to date, so continuous Warfarin is the 
only suitable comparator. 
4.2.3 Timing of primary endpoint evaluation 
Other studies in cardiovascular medicine such as those for interventions during acute myocardial 
infarction or chronic ischemic heart disease consider bleeding events through 30-days post-procedure, 
and so it is a commonly used clinical timeframe. Because this trial is examining a surgical intervention, 
there is potential for bleeds and other acute complications. If this happens, the open label design allows 
investigators to make appropriate treatment decisions as quickly as possible. As always, open-label 
designs have an increased risk of bias. To combat this risk, we have defined a primary endpoint with 
minimal patientivity (see section 4.2.1). We will also have a blinded adjudication committee review each 
potential primary endpoint event to confirm that the study definition has been met.  


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4.2.4 Secondary endpoint evaluation 
The secondary endpoint of superiority for peri-procedural bleeds will be assessed using the same 
methodology as the primary endpoint, except that the test will be for superiority. If the study does not 
meet the non-inferiority endpoint, superiority will not be assessed. The overarching goal is to reduce 
peri-procedural bleeds without causing an increase in stroke. Thrombi may form slowly though clinical 
presentation may occur months later. Considering events through 6 months post procedure helps to 
ensure that the interruption of Edoxaban for the procedure does not result in an increase in late-
occurring thrombi or other safety issues. 
5. Study Population 
5.1 Device case mix 
The case mix in electrophysiology programs currently is approximately 60% ICD procedures and 40% 
permanent pacemaker procedures.  Of these, new implants constitute approximately 50% and device 
replacement procedures constitute 50%. Based on the BRUISE control study data, the bleeding rates 
differ between these groups (de novo implants versus replacement of generator; ICDs versus 
pacemaker). In addition, significant proportions (20%) of patients have additional lead revision, or lead 
insertion for device upgrade procedures that can add to the complexity of the procedure and impact the 
bleed rates. Lead extraction procedures are not permitted in this case mix. The pacemaker component 
will be capped at 100 subjects and ICD patients at 150 subjects in the first phase of the study. Subjects 
for potential enrollment in the study will be identified based on their medical and device history, chart 
review of the outpatient pacemaker clinic or scheduling for device procedures and then undergo 
evaluation for possible study inclusion criteria and subsequent enrollment. 
5.2 Study Inclusion criteria 
1. Subjects must be willing and able to give written informed consent 
2. Outpatients ≥ 18 years of age, male or post- menopausal female patients; premenopausal 
female patients who are on and will maintain continuous birth control therapy during the study. 
3. Subjects must satisfy one of the following four inclusion criteria 
e) Patients with established AF and bradycardia on long term (>3 weeks) therapeutic OAC 
with Warfarin or another OAC who are undergoing new pacemaker system implant or 
existing pacemaker system revision (single chamber, dual chamber or cardiac 
resynchronization device). 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
f) Patients with newly detected bradycardia –tachycardia syndrome and AF who have 
been recently (less than 3 weeks) started on Warfarin, have a therapeutic INR and no 
thrombus on trans-esophageal echocardiogram (TEE) who are undergoing a new 
pacemaker system implant or revision (single chamber, dual chamber or cardiac 
resynchronization device).  
g) Patients with AF and ventricular tachyarrhythmias (VT or VF) or acquired structural 
heart disease who are candidates for ICD therapy and are on long term (>3 weeks) 
therapeutic OAC   with Warfarin or another OAC who are undergoing new ICD system 
implant or existing ICD system revision (single chamber, dual Chamber or cardiac 
resynchronization device).  
h) Patients with newly detected AF with VT or VF who have been recently (less than 3 
weeks) started on Warfarin, have a therapeutic INR and no thrombus on TEE who are 
undergoing ICD system implant or revision (single chamber, dual chamber or cardiac 
resynchronization device).  
4. Subjects must be candidates for long-term OAC therapy based on clinical practice guidelines for 
treatment of NVAF. In subjects on OAC other than Warfarin entering the study, Warfarin 
therapy must be established with therapeutic INR levels before the procedure. 
5. Subjects are candidates for either Warfarin or Edoxaban therapy as per FDA drug approval 
guidelines. Guidelines for GFR as established for Edoxaban will be applicable to all subjects 
regardless of randomized drug choice. 
5.3 Study Exclusion criteria 
1. Clinically significant valvular heart disease (defined as atrial fibrillation in a patient with 
moderate to severe stenosis or regurgitation of one or more cardiac valves and without any 
other associated comorbidity that can contribute to the development of the arrhythmia). 
2. Patients requiring CIED lead extraction e.g. for device site infection, endocarditis, leads under 
advisory or other conditions warranting lead(s) system extraction. 
3. Recent (<1 month) myocardial infarction 
4. Documented LA thrombus on TEE 
5. Contraindications to anticoagulant therapy or adverse event with prior Warfarin or Edoxaban 
therapy 
6. Creatinine clearance <30ml/min or >95ml/min 
7. Advanced hepatic disease 


20 
 
ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
8. Recent stroke (<3 months) or thromboembolic event 
9. Recent (<3months) intracranial or other major bleeding event 
10. Use of concomitant dual antiplatelet therapy or other oral, subcutaneous or parenteral 
anticoagulant therapy 
11. Patients on Warfarin without therapeutic INR levels before study entry 
12. Patients with other clinically significant medical condition 
13. Patients with life expectancy < 1 year 
14. Lead extraction procedures 
15. Premenopausal female patients, who are not on continuous birth control therapy or are 
likely to discontinue it at any time during the entire duration of study enrollment. 
16. Pregnant patients 
6. Study Treatments 
6.1 Investigational and control drugs 
There are only two FDA approved drugs in this study, Edoxaban and Warfarin. No investigational drugs 
are anticipated. 
6.1.1 Run-in Phase 
Warfarin may be taken once per day. The allowable doses are 1- 20 mg per day. Subjects should be 
reminded of dietary and other interactions relevant to Warfarin.   
6.1.2 Acute Open Label Phase 
Subjects eligible for randomization will have maintained INR values in the therapeutic range based on a 
patient-specific dose of Warfarin – or baseline Warfarin therapeutic dose. From randomization to 
assessment of the primary endpoint, the study will be open label in design.  In subjects randomized to 
Edoxaban in accordance with drug labeling, the transition from Warfarin and initiating Edoxaban should 
be performed when the INR has decreased below 2.5 after the discontinuation of Warfarin.  
6.1.3 Follow-up Open Label Phase 
Subjects randomized to continuous Warfarin should have an INR in the first month, and continue 
monthly INRs as per standard practice guideline recommendations. Warfarin dosage should be adjusted 
according to standard practice to keep patients in the therapeutic range. Subjects randomized to 
Edoxaban should take it once daily per package dosing instructions (Edoxaban 60 mg daily dose for 


21 
 
ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
creatinine clearance 50 to 95 ml/min and Edoxaban 30 mg for creatinine clearance of 30 to 49 ml/min). 
Subjects will be followed for an additional five months with a phone follow up at 3 months (+ 1 week) 
and final follow up visit at 6 months (+ 1 week).  After the final follow up visit or after the subject is 
terminated from the study, subjects on Edoxaban transitioning to Warfarin should be maintained on 
Edoxaban until the INR is 2.0 or higher before Edoxaban discontinuation in accordance with drug 
labeling. 
7.  Study Visits 
This study consists of three parts: a run-in or eligibility phase, an acute phase and a follow-up phase. 
Figure 2 for shows a diagram of study activities. Table 2 and Appendix A show visits. 
Figure 2: Study events 
 
Eligibility will be assessed when subjects have completed 3 weeks of Warfarin dosing. The procedure 
should be scheduled 5 to 15 days after randomization so that subjects are adequately anticoagulated 
with Warfarin or Edoxaban. The last dose of Edoxaban will be administered less than 24 hours prior to 
the procedure. Randomization will be obtained via IVRS once eligibility has been confirmed and the 
procedure has been scheduled. 
On the day of the procedure, Warfarin will be continued and Edoxaban will be interrupted. Edoxaban 
dosing will resume a minimum of 16 and a maximum of 24 hours following the procedure. During and 
after the procedure, subjects will be assessed for safety and efficacy endpoints for bleeding and 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
embolism respectively as well as major adverse cardiovascular events (MACE). Edoxaban subjects will in 
general be discharged on the same day as the procedure, whereas Warfarin subjects will have their 
discharge timing determined on an individual basis by the investigator. 
After discharge, subjects must return to the lab that drew the pre-procedure sample for another blood 
sample. This post-procedure blood draw should occur 24 to 48 hours after the procedure. The subjects 
will then resume the standard of care (SOC) follow-up. The SOC includes a pre-discharge visit (4 to 24 
hours after procedure), wound care visit (usually 1 to 2 weeks after the procedure) and standard device 
clinical follow-up procedures. These can include one month, three month or six month visits or remote 
monitoring as clinically employed in the study. 
The primary outcome assessment visit should be 30-days post procedure ± 3 days. Assessments 
including focused H&P, concomitant medications, NYHA class, adverse events and hospitalizations will 
be collected. If a bleeding event has occurred, details including the date, time, required intervention and 
outcome should be recorded. Documentation of intervention may include the hospital order for vitamin 
K or blood products. 
There will be a telephone follow-up at 3 months after the CIED procedure for MACE and hospitalizations 
and vital status. The final safety visit should be scheduled 6 months ± 14-days post procedure or at the 
time of discontinuation if possible. Assessments including focused H&P, concomitant medications, NYHA 
class, adverse events and hospitalizations will be collected. If the investigator suspects that a MACE 
event has occurred, a MACE CRF should be completed. 
 
 
 
 
 
 
 
 
 
 
 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
Table 2: Schedule of study procedures and visits 
Time point 
Pre- 
procedure 
Procedure 
(PM 
or 
ICD) 
Post-procedure 
Blood 
Draw 
SOC 
Post 
Op 
1 
2 
3 
24-48 h 
1-7 d 
1 
m 
3 m* 
6 
m 
Demographics 
  
  
  
  
  
  
  
Medical & AF History 
+ 
  
  
  
  
  
  
Focused H & P 
  
  
  
  
+ 
  
+ 
Con Meds 
+ 
  
  
  
+ 
  
+ 
NYHA Class 
+ 
  
  
  
+ 
  
+ 
Hemoglobin 
+ 
  
+ 
  
  
  
  
Procedure Details 
PM or ICD 
  
  
  
  
  
  
Adverse Events 
+ 
+ 
  
+ 
+ 
+ 
+ 
Hospitalizations 
+ 
  
  
  
+ 
  
+ 
* Phone call 
 
8. Assessment of Safety and Monitoring 
Safety monitoring during the study will be performed by medical and clinical monitors and the 
coordinating center. Sites will be monitored by a clinical monitor at least once during this short trial.  At 
the time of the site visit, the monitors will review implant procedure reports for all cases enrolled.  Any 
issues or problems discovered will be discussed with the investigator; corrective action will be taken as 
necessary. Any findings will be documented in the monitoring reports and follow-up correspondence. 
Clinical sites will be required to report all procedure related complications, deaths and major adverse 
events (AE) to the medical monitor within 24 hours of learning of the event.  The medical monitor will 
review the case within 24 hours of notification and confer with the local physician as appropriate.  The 
study principal investigator will be notified if the complication is serious or if it appears that the 
complication or implant failure may have been due to a deficiency of the operator or support facility and 
personnel.  In this case, or if a clinical site reports implant failure or serious complications in conjunction 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
with two consecutive cases, the clinical site may be suspended from enrolling additional patients until a 
full examination of the complications and their probable cause can be determined and any problems 
have been rectified. All adverse events and procedure related complications will be recorded on CRFs 
and coded using MedDRA and included in tabular reports to the DSMB. 
8.1 Adverse events 
An adverse event (AE) is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after randomization, regardless of the relationship to randomized treatment, 
procedures, underlying disease or comorbidities.  All adverse events that occur or worsen after 
randomization should be reported on the CRF. When possible, the diagnosis or cause of the event 
should be reported instead of reporting symptoms. When multiple symptoms are related to a cause or 
diagnosis, only the cause or diagnosis should be reported. 
Investigators should follow up with adverse events until they have resolved, the subject dies or 
withdraws from the study, or until the study is concluded. 
8.2 Serious adverse event reporting 
Serious adverse events (SAEs) are adverse events where at least one of the following is true: 
 
The event results in death 
 
The event is life-threatening 
 
The event requires or prolongs hospitalization 
 
The event results in permanent disability or incapacity 
 
The event is a congenital abnormality / birth defect 
 
The event is medically important 
In the case of a serious adverse event, the investigator must immediately fax the signed and dated 
Serious Adverse Event case report form, accompanied by copies of all examinations, to the designated 
medical monitor. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the above definition. 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
8.3 Follow-up of Adverse Events and Serious Adverse Events 
The investigator should take all appropriate measures to ensure the safety of the subjects.  The outcome 
of any adverse event (clinical signs, laboratory values, etc.) should be followed up until they return to 
normal or until stabilization of the patient’s condition 
9. Quality Control and Data management 
Data management will be performed by the Data Coordinating Center. Subject identifiers will be 
eliminated and study subject numbers only will be used during data collection in the electronic case 
report forms to ensure compliance with study confidentiality and HIPPAA standards. All study data will 
be maintained in strict confidentiality at the Data Coordinating Center.  Quality control will be 
performed by both Coordinating and Data Management Centers. GCP standards will be followed. 
Monitors will evaluate data collection procedures, and data entry procedures will be defined by the 
Data Coordinating Center. Details on data collection and cleaning are shown in subsequent section. A 
Data Monitoring Committee (DMC) and a charter will be established. Any published data will remove all 
patient identifiers and patients will only be numerically listed in study reports.  
9.1 Data Collection and Database Management 
Data will be collected on standardized Case Report Forms (CRFs) using an online electronic data capture 
system (eCRFs).  Individually assigned user IDs and passwords will be required to gain access to the 
system and access will be controlled based on role in the study.  Extensive online data edits will be 
programmed as part of the electronic data captures system. Other data cleaning procedures will be 
applied as appropriate.   
Adverse events will be coded using the most current version of MedDRA. 
Concomitant medication use will be collected by drug class for commonly prescribed cardiovascular 
medications. 
A separate Data Management Plan will provide details of the data collection, coding, cleaning and 
archival processes.   
9.2 Site training and monitoring  
Prior to study initiation, all investigators and research coordinators will be trained in the study protocol 
at a central investigators meeting.  Each clinical site will be visited by trained clinical monitors at least 
once during the study to make sure that study protocol procedures are being followed, consent is being 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
obtained per regulation and data are being collected contemporaneously and accurately.  Clinical 
monitoring visits will be scheduled as needed thereafter.  Any serious complications of the implant 
procedure will be reviewed by the DMC and a summary of the failures and complications will be 
presented to the DMC at each meeting. 
10. Assessment of Non-Inferiority Hypothesis and Data Analysis 
This study was designed based on a non-inferiority hypothesis, with an overall type I error rate of 0.025 
(1-sided). The non-inferiority margin is 1.5%. 
10.1 Expected event rates 
See section 5.1 for case mix assumptions. For Warfarin, the 30-day primary event rate is estimated to be 
3.51 % based on the continuous Warfarin arm of the BRUISE control study (3). For Edoxaban, we estimate 
the primary endpoint rate to be 0.5%. In the Danish study by Kirkfeldt (4), major perioperative 
hematomas requiring re-intervention was 0.2% for new implants and 0.1% for generator changes. In this 
study, 26.6% of implants were ICDs and 73.4% were pacemakers. In the report by Dewland from the 
NCDR registry, ICD hematoma rates were estimated at 0.8% for new implants. Using the case mix 
assumptions in section 5.1, 30% new ICDs, 20% new pacemaker implants, 30% generator changes only, 
and 20% pulse generator changes and lead revisions, the estimate is more conservative (lower). 
Details of this calculation and comparison to other studies can be found in Appendix A  
10.2 Sample size calculation (Appendix B) 
It is possible, due to the low event rate in the Edoxaban arm and small sample size, that we could see no 
events in this arm. Thus, these sample size calculations are based on absolute risk differences rather 
than relative risk differences. Assuming event rates for Warfarin and Edoxaban of 3.51% and 0.5%, 
respectively, 300 total patients provides approximately 80% power to detect non-inferiority (margin 
1.5%).  
This study is a randomized, open label, active-controlled trial with an open-label safety extension, 
designed to compare local or systemic bleeding within 30 days of cardiac rhythm device implant for non-
valvular AF among patients randomized to continuous Warfarin or interrupted Edoxaban. The DMC will 
review a formal interim analysis of the first 200 patients. Based on this analysis the DMC will make a 
recommendation about whether the study should be stopped or continued as planned. They may 
recommend that the study: 


27 
 
ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
1. Be terminated for futility  
2. Enroll an additional 100 patients in part II 
3. Enroll an additional 200 patients in part II 
Details about the criteria for this decision will be included in an interim statistical analysis plan and/or 
the DMC charter prior to the first data safety review. Because there is no opportunity to stop for efficacy 
after the first 200 patients, no type I error adjustment for the final analysis is necessary. 
10.3 Analysis of the primary objective  
The primary comparison of rates will be based on the Exact test. If appropriate given the event 
distribution, the Cochran–Mantel–Haenszel test will be performed as a supportive analysis, including the 
stratification factors. 
10.4 Analysis of secondary objectives 
The assessment of superiority of Edoxaban will be assessed if the primary endpoint analysis shows non-
inferiority. In this case, the test will use the same methodology but will test the hypothesis that the 
difference in bleed rates (Warfarin – Edoxaban) is significantly different from zero rather than 
significantly greater than -1.5%.  
With the exception of continuous change in hemoglobin, all remaining secondary endpoints are binary. 
They will be summarized with the number and percent in each group, and as rates based on the total 
patient-years of follow-up. The treatments will be compared as for the primary endpoint. If there are 
sufficient numbers of events, survival analysis techniques will also be used. 
Continuous change in hemoglobin will be compared using ANCOVA, adjusted for baseline and trial 
stratification factors. 
A statistical analysis plan (SAP) containing more information about end of study statistical analyses will 
be finalized prior to database lock. 
10.5 Populations for analysis 
The main populations for analysis will be as follows: 
 
The intention-to-treat population will include all randomized subjects, grouped by randomized 
treatment assignment. Since randomization occurs on the day of the procedure, all randomized 
subjects are expected to undergo device implant. 


28 
 
ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
The primary and secondary endpoints will be evaluated in the intention-to-treat population. Adverse 
events and other safety information will be reported for all subjects where the implant procedure was 
started. 
10.6 Handling of missing data values/censoring/discontinuations 
Sensitivity analyses will be performed using multiple imputation and other techniques to determine the 
impact of missing data. The algorithms used for data imputation will be described in the SAP and 
finalized prior to database lock. 
11. Discontinuation of the Study  
This study is a randomized, open label, active-controlled trial with an open-label safety extension, 
designed to compare local or systemic bleeding within 30 days of cardiac rhythm device implant for non-
valvular AF among patients randomized to continuous Warfarin or interrupted Edoxaban. The study may 
be terminated for futility. It may also be terminated for safety if a statistically higher than expected 
adverse event or local and systemic bleeding rate is encountered in either arm. These safety boundaries 
will be defined prospectively by the DMC. 
12. Ethical considerations 
12.1 Ethical compliance 
The study and all its processes and procedures must comply with the Declaration of Helsinki, ICH-GCP 
and conformity with other international standards. If these guidelines are in conflict, the guideline that 
affords the most protection to the individual patient should be followed. 
 
For studies conducted in the USA, the investigator will additionally ensure adherence to the basic 
principles of “Good Clinical Practice” as outlined in 21 CFR, subchapter D, part 312, “Responsibilities of 
Sponsors and Investigators”, part 50, “Protection of Human Patients”, and part 56, “Institutional Review 
Boards”. 
12.2 Informed consent procedures 
The investigator or a person designated by the investigator should fully inform the subject of all 
pertinent aspects of the clinical trial including the written information approved by the local 
IRB/IEC/REC.  Prior to assessment of eligibility, subjects may only be included in the study after providing 
written, IRB/IEC/REB-approved informed consent. The informed consent must be consistent with local 


29 
 
ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
legal and site requirements, and must be signed and dated by the patient prior to any study-specific 
procedures occur.  
12.3 Institutional Review Board/ Independent Ethics Committee / Research Ethics Board 
The investigator must submit this protocol to the appropriate IRB/ REB. He or she is required to forward 
to the Data Coordinating Center a copy of the written and dated approval opinion by the Chair of the 
IRB/IEC/REB composition.  Where allowed, a central IRB (Western IRB) will be used and the Data 
Coordinating Center will facilitate the application. 
The study (protocol number, protocol title and version number), the documents reviewed (protocol, 
Informed Consent Form, etc.) and the date of the review should be clearly stated on the written 
IRB/IEC/REB approval opinion. During the clinical trial, any amendment or modification to the protocol 
should be sent to the IRB/IEC/REB.  It should also be informed of any event likely to affect the safety of 
patients or the continued conduct of the study, in particular any change in safety. 
12.4 Responsibilities of the investigator and IRB/IEC/REB 
The investigators undertake full responsibility to perform the study in accordance with this protocol, 
Good Clinical Practice and the applicable regulatory requirements. 
The investigator is required to ensure adherence with the visit schedule and procedures as required by 
the protocol.  The investigator agrees to provide all information requested in the Case Report from in an 
accurate manner. 
13. Publication strategy 
13.1 Publication of results 
The design of this study will be posted in a publicly accessible database such as www.clinicaltrials.gov. In 
addition, upon study completion, database lock and unblinding, the results of this trial will be submitted 
for publication in a peer-reviewed journal and the Late Breaking Clinical Trials at a major national 
meeting. All study data will remain at the DCC, and all analyses will be conducted and validated at the 
DCC.  
 
 


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13. REFERENCES 
1. 
Delfaut P, Saksena S et al: Long-term outcome of patients with drug-refractory atrial flutter and 
fibrillation after single-and dual-site atrial pacing for arrhythmia prevention.  JACC 32:7, 1900-8. 
2. 
Kannel WB, Aboot RD et al: Epidemiologic features of chronic atrial fibrillation: The Framingham 
study. New England J of Med 306:1018-22 
3. 
Birnie DH, Healey JS, Well G et al: Pacemaker or Defibrillator surgery without interruption of 
anticoagulation. New England J of Medicine 368:22,  
4. 
Milic DJ, Salinger SS: Prevention of pocket related complications with fibrin sealant in patients 
undergoing pacemaker implantation who are receiving anticoagulant treatment. Europace 7, 374-379, 
2005 
5. 
Kirkfeldt RE, Nielsen JC: Complications after cardiac implantable electronic device implantations: 
an analysis of a complete, nationwide cohort in Denmark. European Heart Journal 35, 1186-1194, 2014 
Circulation Arrhythmia and Electrophysiology. 3:312-318, 2010. 
6. 
Kutinsky I, Jarandella R, Jewett M, Haines, DE: Risk of Hematoma Complications after Device 
Implant in the Clopidogrel Era Clinical Perspective. Circ Arrhythm Electrophysiol.  3(4):312-318.  2010 
7. 
Lamas G, Lee K, Sweeney M et al: Ventricular pacing or dual chamber pacing for sinus node 
dysfunction. New Eng. J. Med 2002: 346:1854-62 
8. 
Dewland T, Pellegrini C, Wang Y et al: Dual chamber implantable-cardioverter defibrillator 
selection is associated with increased complications and mortality in patients enrolled in the NCDR 
implantable-cardioverter defibrillator registry. JACC 2011:58:1007-1013 
 
 


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ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
Appendix A: Schedule of Visits and Visit Elements 
Time point 
Pre- 
procedure 
Procedure 
(PM 
or 
ICD) 
Post-procedure 
Blood 
Draw 
SOC 
Post 
Op 
1 
2 
3 
24-48 h 
1-7 d 
1 
m 
3 m* 
6 
m 
Demographics 
  
  
  
  
  
  
  
Medical & AF History 
+ 
  
  
  
  
  
  
Focused H & P 
  
  
  
  
+ 
  
+ 
Con Meds 
+ 
  
  
  
+ 
  
+ 
NYHA Class 
+ 
  
  
  
+ 
  
+ 
Hemoglobin 
+ 
  
+ 
  
  
  
  
Procedure Details 
PM or ICD 
  
  
  
  
  
  
Adverse Events 
+ 
+ 
  
+ 
+ 
+ 
+ 
Hospitalizations 
+ 
  
  
  
+ 
  
+ 
* Phone call 
Abbreviations: Con – concomitant; NYHA – New York Heart Association; PM – pacemaker; ICD – 
implantable cardioverter-defibrillator 
 


32 
 
ENTICED-AF Trial Version 3.0 (12-24-2015) 
 
Appendix B: Details of event rate assumptions 
 
 
Calculation of Major Bleed Rate Assumption
BRUISE-CONTROL Continuous Warfarin
Patients
% mITT
% ITT
Bleeds
% of Row
N - ITT
343
12
3.50%
Did not have procedure
8
0
0.00%
Had procedure (mITT)
335
100.00%
97.67%
12
3.58%
Weight 
Comp.
New Implant
156
46.57%
45.48%
5
3.21%
50%
ICD
98
29.25%
28.57%
4
4.08%
30%
1.22%
PM
58
17.31%
16.91%
1
1.72%
20%
0.34%
Replacement / Revision
179
53.43%
52.19%
7
3.91%
50%
Pulse generator change only
106
31.64%
30.90%
2
1.89%
30%
0.57%
Pulse generator change - plus*
73
21.79%
21.28%
5
6.85%
20%
1.37%
Weighted Average Total
3.51%
RE-LY
# surgeries # bleed
# surgeries
# bleed
# surgeries # bleed % bleed
Urgent surgery
107
19
141
25
111
24
21.62%
Major surgery
473
29
511
33
498
39
7.83%
Elective surgery
1380
38
1405
53
1447
48
3.32%
Minor surgery
424
8
435
14
436
8
1.83%
Total
2384
2492
2492
Major + Minor + Elective
2381
95
3.99%
Other trial overall major bleed rates
Bleed Rate
N
% Total Pts Wt. Comp.
RE-LY
4.6%
1558
19.0%
0.0088
Yokoshiki
5.1%
59
0.7%
0.0004
Denmark - haematoma
2.3%
5918
72.3%
0.0169
Kutinsky (no drug)
8.7%
630
7.7%
0.0067
Milic
4.8%
20
0.2%
0.0001
Total (Weighted Average %)
8185
3.28%
D110
D150
Warfarin
Assumed 
Distribution
*Additional procedure including repositioning or adding a lead, device pocket revision, upgrade from PM to ICD