Clinical trial NCT01522417
Conditions: Myocardial Infarction Acute Coronary Syndromes Unstable Angina
Sponsor: Medicure
Start date: 2012-04-01; Completion date: 2019-03-01
Enrollment: 535 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose this study is to assess whether a tirofiban regimen of a high-dose bolus plus a shortened infusion duration compared to label-dosing eptifibatide in patients undergoing percutaneous coronary intervention (PCI) is associated with a non-inferior composite rate of death, PCI-related myocardial infarction, urgent target vessel revascularization or in-hospital major bleeding within 48 hours following PCI or hospital discharge, whichever comes first.

Detailed description:

Arms: arm 1: Tirofiban (Aggrastat) will be dosed as a 25 mcg/kg i.v. bolus followed by a 0.15 mcg/kg/min i.v. infusion during a PCI plus 1 to 2 hours post-PCI.

Patients will receive tirofiban (Aggrastat) on a background of dual oral anti-platelet agents and unfractionated heparin (50 U/kg and repeat dosing per protocol guidelines). arm 2: Eptifibatide (Integrilin) will be dosed as a 180 mcg/kg bolus followed by a 2.0 mcg/kg/min infusion for 12 to 18 hours, with a second 180 mcg/kg bolus 10 min after the first.

Patients will receive eptifibatide (Integrilin) on a background of dual oral anti-platelet agents and unfractionated heparin (50 U/kg and repeat dosing per protocol guidelines). arm 3: Tirofiban (Aggrastat) will be dosed as a 25 mcg/kg i.v. bolus followed by a 0.15 mcg/kg/min i.v. infusion for 12 to 18 hours post PCI.

Patients will receive tirofiban (Aggrastat) on a background of dual oral anti-platelet agents and unfractionated heparin (50 U/kg and repeat dosing per protocol guidelines).
Interventions: intervention 1: Short Tirofiban intervention 2: Eptifibatide intervention 3: Long Tirofiban
Intervention descriptions: intervention 1: 25 mcg/kg i.v. bolus followed by a 0.15 mcg/kg/min i.v. infusion during a PCI plus 1 to 2 hours post-PCI. intervention 2: 180 mcg/kg bolus followed by a 2.0 mcg/kg/min infusion for 12 to 18 hours, with a second 180 mcg/kg bolus 10 min after the first. intervention 3: 25 mcg/kg i.v. bolus followed by a 0.15 mcg/kg/min i.v. infusion for 12 to 18 hours post-PCI.

Protocol documents:
Prot_000.pdf: 
SAVI-PCI 
Shortened Aggrastat Versus Integrilin in 
Percutaneous Coronary Intervention 
A Randomized, Multicenter, Open-Label Study to 
Evaluate the Efficacy of Tirofiban Using a High-
Dose Bolus Plus a Shortened Infusion Duration 
Versus Label-Dosing Eptifibatide in Patients 
Undergoing Percutaneous Coronary Intervention  
NCT01522417
Date: February 1, 2018 
Study Protocol 
Version 3.0 


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SAVI-PCI 
Shortened Aggrastat Versus Integrilin in 
Percutaneous Coronary Intervention 
A Randomized, Multicenter, Open-Label Study to Evaluate the Efficacy of 
Tirofiban Using a High-Dose Bolus Plus a Shortened Infusion Duration 
Versus Label-Dosing Eptifibatide in Patients Undergoing Percutaneous 
Coronary Intervention  
Protocol No. 11002 
IND No. 38,899 
Date: February 1, 2018 
Version 3.0 
SPONSOR 
Medicure International Inc. 
c/o CanAm Bioresearch Inc. 
9-1250 Waverley Street
Winnipeg, MB  R3T 6C6
Phone: 204-928-7908 
Fax: 204-488-9823 
Medical Monitor 
Ahmad Khalil, MD, PhD 
________________________________________________________________ 
The information in this document is considered privileged and is a confidential 
communication of Medicure International Inc. Acceptance of this document 
constitutes agreement that this protocol and related information may not be copied, 
published, or disclosed to others except to the extent necessary to obtain Ethics 
Committee approval, informed consent, or as required by Law. 


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STUDY TITLE 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................. 7 
CONTACT INFORMATION ........................................................................................... 11 
1.0 
BACKGROUND AND RATIONALE ................................................................. 13 
1.1 
Percutaneous Coronary Intervention and Coronary Stents .......................... 13 
1.2 
Antiplatelet Therapy ..................................................................................... 13 
1.3 
Challenges with the GPIIb/IIIa Inhibitor Therapy Class of Drugs .................. 14 
1.4 
Tirofiban ....................................................................................................... 15 
1.4.1 Rationale for Tirofiban High-Dose Bolus Regimen ..................................... 16 
1.4.2 Clinical Studies Conducted with Tirofiban High-Dose Bolus Regimen ........ 18 
1.4.3 Rationale for a GPIIb/IIIa Shortened Infusion Duration ............................... 20 
1.4.4 Tirofiban Dosing in Patients with Renal Insufficiency .................................. 21 
1.5 
Summary ..................................................................................................... 21 
2.0 
OBJECTIVES ................................................................................................. 23 
2.1 
Primary Objective ........................................................................................ 23 
2.2 
Secondary Objective .................................................................................... 23 
3.0 
PRIMARY HYPOTHESIS ............................................................................... 23 
4.0 
POPULATION................................................................................................. 23 
4.1 
Inclusion Criteria .......................................................................................... 23 
4.2 
Exclusion Criteria ......................................................................................... 24 
5.0 
STUDY DESIGN ............................................................................................. 25 
5.1 
Summary of Study Design ........................................................................... 25 
5.2 
Sequence of Procedures ............................................................................. 26 
5.2.1 Baseline/Pretreatment Period .................................................................... 26 
5.2.2 Randomization ........................................................................................... 27 
5.2.3 Timing of Oral Antiplatelet Therapy, PCI & Study Drug Administration ....... 28 
5.2.4 In The Event of Thrombotic Complications ................................................. 29 
5.2.5 Following the Procedure ............................................................................ 30 
5.2.5.1 Antithrombin Use ....................................................................................... 30 
5.2.5.2 Sheath Removal ........................................................................................ 31 
5.2.5.3 Blood Sampling .......................................................................................... 31 
5.2.6 Safety Evaluation, Discharge and Follow-Up ................................................ 31 
5.2.7 Evaluation of Endpoints ................................................................................ 32 
5.2.8 Criteria for Discontinuation of Study Drug ..................................................... 32 
5.2.9 Concomitant Medication(s)/Treatment(s) ...................................................... 32 
5.2.9.1 Permitted ................................................................................................... 32 
5.2.9.2 Prohibited .................................................................................................. 33 
5.2.10 Patient Withdrawal ...................................................................................... 34 
6.0 
PRIMARY EFFICACY MEASUREMENTS ...................................................... 34 


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6.1 
Death ........................................................................................................... 34 
6.2 
Periprocedural Myonecrosis ......................................................................... 34 
6.3 
Urgent Target Vessel Revascularization ...................................................... 35 
7.0 
SAFETY MEASUREMENTS ........................................................................... 35 
7.1 
Bleeding ....................................................................................................... 35 
7.1.1  Bleeding Site .............................................................................................. 36 
7.1.2 Primary Safety Measurement Non-CABG REPLACE-2 Major Bleeding 
Definition .................................................................................................... 36 
7.1.3 Other Bleeding Definitions .......................................................................... 36 
7.1.3.1  TIMI Major Bleeding Definition .................................................................. 37 
7.1.3.2  TIMI Minor Bleeding Definition .................................................................. 37 
7.1.3.3 REPLACE-2 Minor Bleeding Definition ....................................................... 37 
7.1.3.4 REPLACE-2 Plus Major Bleeding Definition ............................................... 38 
7.1.3.5 TIMI Plus Major Bleeding Definition ........................................................... 38 
7.2 
Thrombocytopenia ....................................................................................... 38 
7.2.1 Moderate Thrombocytopenia ..................................................................... 39 
7.2.2 Severe Thrombocytopenia ......................................................................... 39 
8.0 
ADVERSE EVENTS ....................................................................................... 39 
8.1 
Definitions .................................................................................................... 39 
8.2 
Study Drug Causality ................................................................................... 40 
8.3 
Severity ...................................................................................................... 40 
8.4 
Collection of Adverse Events ....................................................................... 40 
8.4.1 Collection and Reporting of Nonserious Adverse Events............................ 40 
8.4.2 Collection and Reporting of Serious Adverse Events ................................. 40 
8.4.3 Collection and Reporting of Endpoints ....................................................... 41 
8.5 
Submission of Follow-up Data ..................................................................... 41 
8.6 
Ethics Committee SAE Reporting ................................................................ 41 
9.0 
STATISTICAL CONSIDERATIONS ................................................................ 42 
9.1 
Study Design ............................................................................................... 42 
9.2 
Statistical Alternative Hypothesis (Ha) ......................................................... 43 
9.3 
Study Endpoints, Covariates, and Subgroups .............................................. 43 
9.3.1 Primary Endpoint and Associated Tests ..................................................... 43 
9.3.2 Secondary Endpoints and Associated Tests .............................................. 43 
9.3.3 Safety Endpoints ........................................................................................ 44 
9.3.4 Potential Covariates and/or Subgroups ...................................................... 44 
9.4 
Analysis Population...................................................................................... 45 
9.5 
Sample Size Calculations ............................................................................ 45 
9.6 
Planned Methods of Analysis ....................................................................... 46 
9.7 
Timing of Final Analyses .............................................................................. 47 
10.0 
STUDY DRUG MANAGEMENT ...................................................................... 47 


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10.1 
Packaging and Labeling ............................................................................... 47 
10.1.1 Tirofiban ..................................................................................................... 47 
10.1.2 Eptifibatide ................................................................................................. 47 
10.2 
 Storage ....................................................................................................... 47 
10.3 
 Accountability .............................................................................................. 47 
11 
STUDY DOCUMENTATION ........................................................................... 47 
12 
RECORDS RETENTION ................................................................................ 48 
13 
QUALITY CONTROL AND QUALITY ASSURANCE....................................... 49 
14 
MONITORING ................................................................................................ 49 
15 
AUDITING ...................................................................................................... 49 
16 
ETHICS AND RESPONSIBILITY .................................................................... 49 
17 
INFORMED CONSENT .................................................................................. 49 
18 
AUTHORIZATION FOR USE AND DISCLOSURE OF PROTECTED HEALTH 
INFORMATION (HIPAA) ............................................................................................... 50 
19 
INSTITUTIONAL REVIEW BOARD (IRB) ....................................................... 51 
20.0 
CONFIDENTIALITY ........................................................................................ 51 
20.1 
 Confidentiality of Data ................................................................................. 51 
20.2 
 Confidentiality of Patient Records ............................................................... 52 
20.3 
 Confidentiality of Investigator Information ................................................... 52 
21 
DEBARMENT ................................................................................................. 52 
22 
COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS ............. 52 
23 
PUBLICATIONS ............................................................................................. 52 
PROTOCOL SIGNATURE PAGE .................................................................................. 54 
REFERENCES .............................................................................................................. 55 
LIST OF APPENDICES ................................................................................................. 61 
APPENDIX 1 ................................................................................................................. 62 
Schedule of Evaluations and Procedure .................................................................... 62 
APPENDIX 2 ................................................................................................................. 64 
Laboratory Evaluations .............................................................................................. 64 
APPENDIX 3 ................................................................................................................. 65 
Study Drug Dosing Tables......................................................................................... 65 
APPENDIX 4 ................................................................................................................. 68 
ACT Measurements and Unfractionated Heparin Dosing Algorithm .......................... 68 
APPENDIX 5 ................................................................................................................. 70 
Guidelines for Management of Urgent Target Vessel Revascularization ................... 70 
APPENDIX 6 ................................................................................................................. 71 
Guidelines for Management of Serious Bleeding ....................................................... 71 
Transfusion Guidelines .............................................................................................. 72 
APPENDIX 7 ................................................................................................................. 73 
Guidelines for Management of Thrombocytopenia .................................................... 73 


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LIST OF ABBREVIATIONS 
 
ACC    American College of Cardiology 
ACT    Activated clotting time 
ADP    Adenosine diphosphate 
AHA    American Heart Association 
AE     Adverse event 
aPTT    Activated partial thromboplastin time 
CABG   Coronary artery bypass graft 
CBC    Complete blood count 
CDS    Clinical development solutions 
CK     Creatine kinase 
CK-MB   Creatine kinase-myocardial band 
CNS    Central nervous system 
CRA    Clinical research associate 
CRF    Case report form 
CVA    Cerebrovascular accident 
Da     Dalton 
DSMB   Drug Safety Monitoring Board 
ECG    Electrocardiogram 
ESC    European Society of Cardiology 
ESPRIT 
 Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin 
Therapy 
ESRD   End stage renal disease 
ENT    Ears, nose, throat 
FDA    Food and Drug Administration 
GCP    Good clinical practice 
GI     Gastrointestinal 
GPIIb/IIIa  Glycoprotein IIb/IIIa receptor antagonist 
GU     Genitourinary 
Hct     Hematocrit 
Hgb    Hemoglobin 
HIPAA   Health Insurance Portability and Accountability Act 
HDB    High-dose bolus (25 g/kg tirofiban) 
h      Hour(s) 
Hg     Mercury 
ICF     Informed consent form 
IND    Investigational new drug 
INR    International normalized ratio 
IRB     Institutional review board 
ITT     Intent to treat 
I.V.     Intravenous 
kg     kilogram 
LTA    Light transmission aggregometry 
mg     milligram 


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MI  
Myocardial infarction 
min   
minute 
mL  
milliliter 
mm   
millimeter 
MITT  
Modified intent to treat 
NS  
Non-significant 
NSTEMI 
Non-ST elevation myocardial infarction 
NSTE  
Non-ST elevation 
PCI   
Percutaneous coronary intervention 
PK  
Pharmacokinetic 
PPACK   D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone
PPM  
Periprocedural myonecrosis 
PRISM 
The Platelet Receptor Inhibition In Ischemic Syndrome Management 
PRISM PLUS The Platelet Receptor Inhibition In Ischemic Syndrome Management 
In Patients Limited By Unstable Signs and Symptoms 
PT 
Prothrombin time 
PTCA 
Percutaneous transluminal coronary angioplasty 
REPLACE-2 Randomized Evaluation of PCI Linking Angiomax to Reduced 
Clinical Events 
RESTORE Randomized Efficacy Study of Tirofiban for Outcomes and 
Restenosis 
RPFA 
Rapid platelet function assay 
SAE(s) 
Serious adverse event(s) 
SAP 
Statistical analysis plan 
SCRI 
Sarah Cannon Research Institute 
sec 
second 
SOP 
Standard operating procedure 
TARGET 
Do Tirofiban and ReoPro Give Similar Efficacy Trial 
TRAP 
Thrombin receptor agonist peptide 
STEMI 
ST elevation myocardial infarction 
TIMI 
Thrombolysis in myocardial infarction 
uTVR  
Urgent target vessel revascularization 
U 
Units 
ULN 
Upper limit of normal 
UFH 
Unfractionated heparin 
uTVR  
Urgent target vessel revascularization 
vs. 
versus 
WHF 
World Heart Federation 
μg 
microgram 
μL 
microliter 


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PROTOCOL SYNOPSIS 
 
PROTOCOL ACRONYM (WORKING TITLE): SAVI-PCI (Shortened Aggrastat 
Versus Integrilin in Percutaneous Coronary Intervention) 
________________________________________________________________ 
 
FULL PROTOCOL TITLE: A Randomized, Multicenter, Open-Label Study to 
Evaluate the Efficacy of Tirofiban Using a High-Dose Bolus Plus a Shortened 
Infusion Duration Versus Label-Dosing Eptifibatide in Patients Undergoing 
Percutaneous Coronary Intervention  
________________________________________________________________ 
 
CLINICAL PHASE: II 
________________________________________________________________ 
 
PRIMARY OBJECTIVE: The first primary objective of this study is to assess 
whether a tirofiban regimen of a high-dose bolus plus a shortened infusion duration 
compared to label-dosing eptifibatide in patients undergoing percutaneous 
coronary intervention (PCI) is associated with a non-inferior composite rate of 
death, periprocedural myonecrosis (PPM), urgent target vessel revascularization 
(uTVR) or in-hospital major bleeding within 48 hours following PCI or hospital 
discharge, whichever comes first. 
 
The co-primary objectives of this study are to assess whether: (i) a short tirofiban 
regimen of a high-dose bolus plus a 1-2 hour infusion post procedure compared to 
a long tirofiban regimen of a high-dose bolus plus a 12-18 hour infusion, and (ii) a 
long tirofiban regimen of a high-dose bolus plus a 12-18 hour infusion compared 
to label-dosing eptifibatide, are associated with non-inferior composite rates of 
death, PPM, uTVR, or in-hospital major bleeding within 48 hours following PCI or 
hospital discharge, whichever comes first. 
_____________________________________________________________ 
 
SECONDARY OBJECTIVE: The first secondary objective of this study is to assess 
whether a tirofiban regimen of a high-dose bolus plus a shortened infusion duration 
is safe compared to label-dosing eptifibatide among patients undergoing PCI, as 
assessed by the incidence of major bleeding within 48 hours following PCI or 
hospital discharge, whichever comes first. 
 
The co-secondary objectives of this study are to assess whether: (i) a short 
tirofiban regimen of a high-dose bolus plus a 1-2 hour infusion post procedure is 
safe compared to a long tirofiban regimen of a high-dose bolus plus a 12-18 hour 
infusion, and (ii) a long tirofiban regimen of a high-dose bolus plus a 12-18 hour 
infusion is safe compared to label-dosing eptifibatide, among patients undergoing 
PCI as assessed by the incidence of major bleeding within 48 hours following PCI 
or hospital discharge, whichever comes first. 
_____________________________________________________________ 


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PRIMARY HYPOTHESIS: The first primary hypothesis is a tirofiban regimen of a 
high-dose bolus plus a shortened infusion duration is non-inferior to label-dosing 
eptifibatide among patients undergoing PCI with respect to death, PPM, uTVR or 
major bleeding within 48 hours following PCI or hospital discharge, whichever 
comes first. 
 
The co-primary hypotheses include: (i) a short tirofiban regimen of a high-dose 
bolus plus a 1-2 hour infusion duration post procedure is non-inferior to a long 
tirofiban regimen of a high-dose bolus plus a 12-18 hour infusion, and (ii) a long 
tirofiban regimen of a high-dose bolus plus a 12-18 hour infusion is non-inferior to 
label-dosing eptifibatide, among patients undergoing PCI with respect to death, 
PPM, uTVR or major bleeding within 48 hours following PCI or hospital discharge, 
whichever comes first. 
________________________________________________________________ 
 
STUDY DESIGN AND DURATION: A randomized, multicenter, open-label study 
comparing tirofiban I.V. bolus injection followed by a maintenance infusion for the 
duration of the PCI procedure plus a minimum of one hour and up to a maximum 
of two hours post-PCI versus label-dosing eptifibatide. Patients were initially 
randomized to tirofiban or eptifibatide using a 1:1 allocation ratio. At 159 
randomized patients, a 1:1:1 randomization was initiated, randomizing patients to 
short tirofiban, eptifibatide or long tirofiban. Enrolment in the long tirofiban arm has 
been completed.  Patients are mandated to stay a minimum of 18 hours following 
PCI. 
 
Physician-directed standard background therapies will include dual oral 
antiplatelet therapy with aspirin and an approved oral P2Y12 antagonist as well as 
antithrombotic therapy with unfractionated heparin. Physician-directed P2Y12 
antagonist therapy and choice of femoral or radial access site must be pre-
specified prior to randomization.  
 
The first 159 patients were randomized to the following two treatment arms on a 
1:1 basis: 
 
1. Tirofiban (25 μg/kg bolus followed by a 0.15 μg/kg/min infusion for the duration 
of the PCI procedure plus a minimum of one hour and up to a maximum of two 
hours post-PCI).  
 
2. Eptifibatide (180 g/kg bolus followed by a 2.0 g/kg/min infusion for 18 hours 
post-PCI [minimum 12 hours mandated], with a second 180 g/kg bolus 10 min 
after the first). 
 
The three treatment arms for enrollment after the 159th patient were: 
 


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1. Short Tirofiban (25 μg/kg bolus followed by a 0.15 μg/kg/min infusion for the 
duration of the PCI procedure plus a minimum of one hour and up to a maximum 
of two hours post-PCI).  
 
2. Eptifibatide (180 g/kg bolus followed by a 2.0 g/kg/min infusion for 18 hours 
post-PCI [minimum 12 hours mandated], with a second 180 g/kg bolus 10 min 
after the first). 
 
3. Long Tirofiban (25 µg/kg bolus followed by a 0.15 µg/kg/min infusion for 18 hours 
post-PCI) [minimum 12 hours mandated].  
 
Enrolment in the Long Tirofiban arm has been completed.  Enrolment continues in 
the Short Tirofiban and Eptifibatide arms as outlined above. 
________________________________________________________________ 
 
SAMPLE SIZE: Approximately 550 patients will be enrolled in the trial. The rate of 
the primary composite endpoint is assumed to be 51% in both the eptifibatide and 
tirofiban treatment groups. The absolute margin for the difference between the 
eptifibatide and the short tirofiban group is set at 19.1%. A sample size of 
approximately 500 for the comparison between the short tirofiban and the 
eptifibatide group was obtained by setting a power at 99% and a 1-sided alpha at 
0.025. For the second test, a sample size of approximately 350 for the comparison 
between the short tirofiban and the long tirofiban group was obtained by setting 
power at 94.5% and a 1-sided alpha at 0.025. For the third test, a sample size of 
approximately 350 for the comparison between the long tirofiban and the 
eptifibatide group was obtained by setting power at 94.5% and a 1-sided alpha at 
0.025.  
________________________________________________________________ 
 
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN 
 
Aspirin:           As per local practice and physician discretion 
P2Y12 Receptor Antagonist:  
As per local practice and physician discretion 
Unfractionated Heparin: 
50 U/kg bolus and repeat dosing guided per 
guidelines in Appendix 4  
Short Tirofiban: 
25 μg/kg bolus followed by a 0.15 μg/kg/min infusion 
for the duration of the PCI procedure plus a minimum 
of one hour and up to a maximum of two hours post-
PCI 
Eptifibatide:  
180 g/kg bolus followed by a 2.0 g/kg/min infusion 
for 18 hours post-PCI (minimum 12 hours mandated), 
with a second 180 g/kg bolus 10 min after the first 
Long Tirofiban: 
25 µg/kg bolus followed by a 0.15 µg/kg/min infusion 
for 18 hours post-PCI (minimum 12 hours mandated) 
 
Tirofiban in premixed bags/vials (5 mg per 100 mL) to be supplied by sponsor.  


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Eptifibatide and all other medications to be supplied by hospital pharmacy. 
________________________________________________________________ 
 
EFFICACY MEASUREMENTS: The primary endpoint is a composite of events 
defined as any of the following within 48 hours following PCI or hospital discharge, 
whichever comes first: death, PPM (defined as 3 times the upper limit of normal 
troponin and at least 20% or greater than the baseline troponin value), uTVR or 
non-CABG-related major bleeding within 48 hours following PCI or hospital 
discharge, whichever comes first, quantified according to REPLACE-2 criteria. 
________________________________________________________________ 
 
SAFETY MEASUREMENTS: The primary safety endpoint will be non-CABG-
related major bleeding within 48 hours following PCI or hospital discharge, 
whichever comes first, quantified according to REPLACE-2 criteria. 
________________________________________________________________ 
 
DATA ANALYSIS: All efficacy analyses will be performed on the modified intent-
to-treat (MITT) population, i.e. all randomized patients who underwent PCI and 
received study drug. Safety analyses will be performed on the safety population, 
i.e. patients who received any study drug. 
________________________________________________________________ 


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CONTACT INFORMATION 
 
REPORTING OF SERIOUS ADVERSE EVENTS 
ANY 
SERIOUS 
ADVERSE 
EVENT, 
WHICH 
REQUIRES 
EXPEDITED 
REPORTING, MUST BE REPORTED WITHIN 24 HOURS TO THE SPONSOR’S 
SAFETY SURVEILLANCE. See Protocol Section 8 (Adverse Events) for 
definitions (8.1), collection and reporting (8.4.2) of serious adverse events. 
 
SAFETY SURVEILLANCE 
Phone: 204-928-7906 
Fax: 204-489-0175 
 
MEDICAL MONITOR 
Ahmad Khalil, MD, PhD 
Phone: 204-807-2777 
 
Lead Clinical Research Organization 
GVI Clinical Development Solutions Inc (GVI-CDS) 
4-1250 Waverley Street 
Winnipeg, Manitoba  R3T 6C6 
Contact Name: Nancy Stewart, PhD 
Tel: 204-478-5607 
Fax: 204-453-1370 
 
Academic Research Organization 
Sarah Cannon Research Institute 
3322 West End Avenue, Suite 900 
Nashville, Tennessee 37203 
Tel: 615-329-7274 
Fax: 615-329-7539 
 
Principal Investigator 
Steven V. Manoukian, MD 
Director of Cardiovascular Research, Sarah Cannon Research Institute  
Sarah Cannon Research Institute 
3322 West End Avenue, Suite 900 
Nashville, Tennessee 37203 
Tel: (615) 344-1107  
Fax: (866) 707-8988  
   
Sponsor Contact 
Medicure International Inc. 
c/o CanAm Bioresearch Inc. 
9-1250 Waverley Street 
Winnipeg, MB  R3T 6C6 
Contact Name: Michael Janzen, PhD 


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Tel: 204-928-7908 
Fax: 204-488-9823 
 
 


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1.0 BACKGROUND AND RATIONALE 
1.1 Percutaneous Coronary Intervention and Coronary Stents 
An estimated 596,000 patients underwent percutaneous coronary intervention (PCI) 
procedures in the United States in 2009, and the majority of these patients received a 
coronary stent as part of their treatment. The number of percutaneous revascularization 
procedures performed has dramatically increased in the last decade, and PCI is the most 
common procedure performed on hospitalized adult Americans [1].  
 
PCI carries an inherent risk of thrombotic complications. Patients therefore receive 
periprocedural pharmacotherapies targeted at inhibiting anticoagulation, including platelet 
aggregation. The same mechanisms that confer the benefits of these agents, however, 
also increase the risk of bleeding which has been correlated with adverse outcomes [2,3]. 
Selecting the appropriate pharmacotherapies requires close attention to the delicate 
balance between reducing the risk of ischemic events and minimizing bleeding risk. 
 
A broad range of antiplatelet agents is available, including aspirin, thienopyridines, and 
glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, all of which have shown considerable efficacy 
and satisfactory safety in the population of patients undergoing PCI. Direct and indirect 
thrombin inhibitors (e.g. bivalirudin and unfractionated heparin), while not providing 
substantial antiplatelet inhibition, are used in conjunction with, and sometimes in place of, 
GPIIb/IIIa inhibitors.  
1.2  Antiplatelet Therapy 
Antiplatelet therapy is relevant during PCI since disruption of the arterial wall results in 
platelet activation, adhesion and aggregation, which leads to thrombus formation. Aspirin 
reduces the incidence of acute thrombotic complications during PCI and is considered 
standard therapy. However, aspirin is a relatively weak platelet inhibitor, inhibiting the 
cyclooxygenase pathway, which is only one of the many pathways to platelet aggregation. 
More potent antiplatelet agents have been proven superior to aspirin, and when 
administered together are synergistic [4]. When combined with aspirin, oral 
thienopyridines such as ticlopidine, clopidogrel, prasugrel and ticagrelor provide additional 
platelet inhibition, thereby reducing the rate of ischemic events, particularly among 
patients receiving a coronary stent.  
 
Three GPIIb/IIIa inhibitors are approved for use in the United States: abciximab (Eli Lilly 
& Company, Indianapolis, Indiana), eptifibatide (Merck & Co., Whitehouse Station, New 
Jersey), and tirofiban HCl (Medicure Pharma Inc., Somerset, New Jersey) [5]. These 
agents block the GPIIb/IIIa receptor on platelets, blocking what has frequently been 
termed the final common pathway of aggregation, i.e., fibrinogen-mediated cross-linkage 
[6]. Their efficacy in preventing PCI-related complications [7-14] and in treatment of non-
ST-segment-elevation (NSTE) acute coronary syndrome (ACS) [15-19] has been 
demonstrated in multiple large-scale trials, with overall risk reductions in adverse 
thrombotic events in PCI populations of 35% and in NSTE ACS of 44% [5].  
 
Some important differences exist between the three GPIIb/IIIa inhibitors. For example, 
abciximab is a large molecule (47,600Da) that binds the GPIIb/IIIa receptor with very high 
affinity while very little unbound abciximab remains in the circulating bloodstream [20]. In 
contrast, eptifibatide and tirofiban are both small molecules and their administration results 
in as many as 200 molecules of circulating drug for every molecule that binds to a receptor 


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[20]. Tirofiban is a slightly smaller molecule than eptifibatide (495Da vs. 832Da), is more 
potent (143 nM vs. 810 nM for concentration required to achieve 50% platelet inhibition) 
and has a slightly shorter half-life (2h vs. 2.5h). It is generally considered that eptifibatide 
and tirofiban are more alike than either is to abciximab.  
1.3 Challenges with the GPIIb/IIIa Inhibitor Therapy Class of Drugs 
There have been at least three challenges in the GPIIb/IIIa class. First, suboptimal dosing 
was a serious challenge for the small-molecule GPIIb/IIIa inhibitors in their early clinical 
development. Eptifibatide was initially administered using a single bolus dose, 135 μg/kg, 
followed by a 0.5 or 0.75 μg/kg/min maintenance infusion, which was found to be too low 
to provide adequate levels of platelet inhibition [21]. The dosing was subsequently 
increased to a double bolus dose of 180 μg/kg administered 10 min apart, which is then 
followed by a 2.0 μg/kg/min maintenance infusion for 18 to 24 hours [22]. This dose leads 
to very high levels of receptor occupancy throughout the infusion. The current double 
bolus dose of eptifibatide was studied in Enhanced Suppression of the Platelet IIb/IIIa 
Receptor with INTEGRILIN Therapy (ESPRIT) which compared eptifibatide to placebo in 
reducing ischemic complications in coronary artery disease patients undergoing elective 
coronary stent implantation. The trial showed a significant 37% reduction (p=0.0015) in 
the combined primary endpoint of death, myocardial infarction (MI), urgent target vessel 
revascularization (uTVR) or "thrombotic bail-out" at 48 hours, with eptifibatide treatment 
compared to placebo [22]. Eptifibatide is now the most commonly used GPIIb/IIIa inhibitor 
in the United States. Suboptimal dosing was also a challenge for tirofiban in its clinical 
development [23]. In recent years, new data have demonstrated that a higher tirofiban 
dose (25 g/kg bolus followed by a 0.15 g/kg/min maintenance infusion) than is currently 
included in the product’s labeling (0.4 g/kg/min for 30 min followed by a 0.1 g/kg/min 
maintenance infusion) is appropriate in the setting of PCI. While both tirofiban dosing 
regimens achieve similar levels of platelet inhibition (~90-95%), the high-dose bolus 
achieves maximal inhibition more rapidly (within minutes) compared to the approved 
dosing regimen (30 minutes) [24,25]. No new safety concerns have been identified with 
the high-dose bolus [26]. 
 
A second challenge with GPIIb/IIIa inhibitor therapy is their extended infusion duration 
after the initial bolus. The long duration of infusion has several disadvantages such as an 
increase in bleeding tendencies, increased cost of therapy and the need for overnight 
hospitalization. Bleeding is an increasing concern for interventional cardiologists since it 
is associated with worse short- and long-term outcomes, including higher rates of 
mortality, compared with those who do not experience bleeding complications [27]. One 
possible solution to lower the bleeding risk associated with GPIIb/IIIa inhibitor therapy is 
to use a shortened infusion duration. This strategy is particularly attractive given today’s 
PCI practice patterns for several reasons. First, patients today have superior oral anti-
platelet medication with the combination of aspirin and clopidogrel, prasugrel or ticagrelor 
compared to aspirin only protection used in the early GPIIb/IIIa inhibitor clinical studies. 
With today’s more potent oral antiplatelet therapies, patients undergoing PCI reach and 
sustain a greater degree of platelet inhibition in the immediate post-procedural period. A 
GPIIb/IIIa inhibitor infusion may therefore be needed for a shorter period following PCI. 
Second, PCI has evolved over the past 15 years to the point where it is a more common 
and routine procedure conducted over a shorter period of time. Shorter GPIIb/IIIa infusion 
durations are becoming increasingly popular and there is increasing demand for 
optimizing the duration of infusion. Fung and colleagues assessed the safety and efficacy 
of a bolus plus up to 2h eptifibatide infusion in nonemergent and uncomplicated PCI 


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versus a bolus plus up to 18h eptifibatide infusion [28]. Rates of REPLACE-2 major 
bleeding were found to be less frequent in the <2h group (1.0% vs. 4.2%; p=0.02) and the 
incidence of periprocedural myonecrosis (defined as troponin-I 3x ULN) was non-inferior 
between the two groups (30.1% in the <2h group vs. 28.3% in the 18h group; p<0.012 for 
noninferiority). The authors concluded following uncomplicated PCI, eptifibatide infusion 
can be abbreviated safely to <2h [28].  
 
A third challenge with the GPIIb/IIIa inhibitor therapies is that the endpoint definitions, 
background medical therapies, and procedural approaches used to establish their label 
dosing are no longer considered contemporary. For example, CK-MB was the enzyme 
biomarker used to measure MI rates in GPIIb/IIIa inhibitor registration studies. The 
contemporary definition of MI (according to a recent Task Force involving the AHA, ACC, 
ESC, and WHF) in the setting of PCI is, however, based on the enzyme biomarker troponin 
[29a]. In the SAVI-PCI study, the term MI was originally used to describe ≥3x ULN troponin 
elevation but was changed to the term periprocedural myonecrosis in light of the recently 
updated Task Force publication [29b] and considerably higher than expected event rates 
in the first 159 patients. With respect to medical therapy, high-dose clopidogrel, prasugrel 
and bivalirudin are all routinely used today in the setting of PCI but were not studied in the 
early GPIIb/IIIa inhibitor registration trials. The efficacy and safety of a GPIIb/IIIa inhibitor 
on top of contemporary agents is therefore not fully understood. Measuring the clinical 
effectiveness of GPIIb/IIIa inhibitor therapies using modern endpoint definitions and 
pharmacotherapies is therefore of clear medical and scientific interest.  
1.4 Tirofiban 
Tirofiban is a highly selective non-peptide antagonist of the GPIIb/IIIa receptor whose 
structure mimics the RGD peptide sequence in fibrinogen. Tirofiban is similar to 
eptifibatide but is a smaller molecule (495Da vs. 832Da), is more potent (143 nM vs. 810 
nM for concentration required to achieve 50% platelet inhibition), with a slightly shorter 
half-life (2h vs. 2.5h). Compared to abciximab, tirofiban is reversible, is not known to be 
immunogenic, and, in combination with heparin, has been shown to be effective in 
reducing ischemic events among patients with acute coronary syndrome. Data from 6 
large clinical trials using tirofiban at the currently approved label dose [10,16,17,23,30,31] 
demonstrated its efficacy and safety in reducing acute ischemic events in a broad range 
of patients (cumulative N >12,000) with ACS, moderate to high-risk coronary lesion 
anatomy, or both. Despite evidence for efficacy of the approved dosing in ACS, further 
investigations established the tirofiban label-dosing to be suboptimal for settings such as 
PCI and stent setting where rapid (<30 minute) attainment of therapeutic platelet inhibition 
is required and that a higher dose bolus (HDB) regimen of tirofiban (25 g/kg followed by 
a 0.15 g/kg/min maintenance infusion) is necessary. Data for the HDB tirofiban regimen 
from 15 clinical studies and 50 peer-reviewed publications since 2003 have clearly 
demonstrated its efficacy and safety profile [26, 33-56]. The tirofiban high-dose bolus 
regimen is approved for use in the setting of PCI in Europe, but not in the United States. 
 
Three large-scale clinical trials, RESTORE [10], PRISM [17], and PRISM-PLUS [16], 
supported the current label-dosing of tirofiban in the management of patients with ACS 
undergoing percutaneous transluminal coronary angioplasty or atherectomy. 
 
TARGET, the only head-to-head comparison of GP IIb/IIIa inhibitors sponsored by a 
pharmaceutical company, was designed to test whether tirofiban, using a bolus dose of 
10 g/kg followed by a 0.15 g/kg/min maintenance infusion for 18 to 24 hours, was non-


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inferior to abciximab among PCI patients receiving a coronary stent [23]. At 30 days the 
primary efficacy endpoint of death, MI, and urgent TVR occurred more frequently in the 
tirofiban group (7.6%) than in the abciximab group (6.0%; p=0.038). The rate of major 
bleeding was similar between the 2 study groups, although minor bleeding and 
thrombocytopenia occurred less frequently among tirofiban-treated patients. The reason 
for the higher event rate in the tirofiban group was primarily due to procedure-related 
myocardial infarctions occurring immediately after the PCI procedure, suggesting the 
potency of the tirofiban bolus injection at the time of intervention was suboptimal. 
1.4.1 Rationale for Tirofiban High-Dose Bolus Regimen  
Several studies performed following the completion of TARGET strongly suggested that 
the 10 μg/kg bolus dose of tirofiban was inadequate. The TARGET dosing regimen of 
tirofiban inhibited 20 M ADP-mediated platelet aggregation only by 60-66% from 15-60 
minutes after onset of treatment when tested with PPACK as a sample anticoagulant, and 
as a result of rapid tissue redistribution yielded a tirofiban plasma level of 35-40 ng/mL 
[24]. Abciximab, as it was dosed in the TARGET trial, produced a 90-95% inhibition of 
platelet aggregation in this same time period. This difference in extent of platelet 
aggregation inhibition was proposed as the reason why more procedure-related ischemic 
events occurred more frequently among patients receiving tirofiban in the TARGET trial. 
 
Schneider and co-workers evaluated bolus doses of tirofiban that were higher than the 
bolus dose used in the TARGET trial, comparing the results with the extent of inhibition 
provided by abciximab [24, 25]. They tested tirofiban bolus doses of 20 μg/kg and 25 μg/kg 
in 30 patients undergoing PCI primarily for an acute coronary syndrome. The tirofiban 
infusion dose was 0.15 μg/kg/min. The authors found that the 20 μg/kg bolus inhibited 
platelet aggregation by 84-89% (Figure 1) and produced a 67-82 ng/mL plasma level 
(Figure 2) of tirofiban [24, 25]. The 25 μg/kg dose consistently provided a level of inhibition, 
similar to that provided by abciximab. Importantly, during the first hour of treatment, the 
lower limit of the 95% confidence interval for platelet inhibition with this tirofiban dosing 
regimen was >85% during the first hour of treatment. At 15 to 60 minutes following the 25 
μg/kg bolus dose of tirofiban, the inhibition of platelet aggregation was 92-95%, and the 
plasma level of tirofiban ranged 80-99 ng/mL [24, 25] (Figure 2).  
 
 


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Figure 1. Inhibition of turbidometric platelet aggregation (LTA) in response to 20 μM ADP 
(left) and in response to thrombin receptor agonist peptide (TRAP) and measured by 
rapid platelet function assay (RPFA) (right). Patients were treated with either 20 μg/kg or 
25 μg/kg bolus of tirofiban followed by an infusion of 0.15 μg/kg/min. Values are the 
means and the lower bounds of the 95% confidence interval. [25] 
 
 
Figure 2. The concentration of tirofiban in blood from patients treated with a 10, 20, or 25 
μg/kg bolus of tirofiban followed by a 0.15μg/kg/min infusion. The concentration of 
tirofiban, evaluated by radioimmunoassay, was found to be consistently >80 ng/mL with 
the 25 μg/kg bolus. [24] 
 
Schneider and co-workers collected blood from patients with acute coronary syndrome 
undergoing PCI and was spiked (ex vivo) with tirofiban, resulting in concentrations of 0, 
50, 100, or 150 ng/mL of drug. Inhibition of platelet aggregation to 20 μM ADP was found 
to plateau (on average) at greater than 95% once reaching a plasma concentration beyond 
80 ng/mL [24] (Figure 3). When pursuing yet higher plasma concentrations, the residual 
ability of platelets to bind fibrinogen was not significantly different (18% to 16%) between 
the 100 ng/mL and 150 ng/mL samples. 


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Figure 3. The association between the concentration of tirofiban and the turbidometric 
platelet aggregation induced by 20 μM ADP. Each point depicts results during the first 2 
hours of therapy from patients treated with a 10, 20, or 25 μg/kg bolus of tirofiban followed 
by a 0.15μg/kg/min infusion. The sigmoidal dose-response relationship shows limited 
additional aggregation inhibition provided by concentrations of tirofiban >90 ng/mL. [24] 
 
The above-referenced studies demonstrated that a single 25 μg/kg bolus followed by a 
0.15 μg/kg/min infusion of tirofiban consistently and effectively inhibits platelet function to 
a high degree and that this dosing regimen provided the peak inhibitory effects most 
similar to those produced by the abciximab-labeled dosing regimen. 
1.4.2 Clinical Studies Conducted with Tirofiban High-Dose Bolus Regimen 
Based on the published findings demonstrating that a higher bolus dose of tirofiban 
provided platelet inhibition on par with abciximab during the PCI peri-procedural period, 
the TENACITY trial was initiated by Guilford Pharmaceuticals. Unfortunately, due to 
financial constraints, TENACITY was halted in June 2005, after enrolling 383 patients out 
of a planned 8000. 
 
TENACITY was a double-blind, randomized active-comparator study comparing the high-
dose bolus regimen of tirofiban to abciximab in intermediate to high-risk ACS patients. A 
second randomization assigned patients to receive either unfractionated heparin or 
bivalirudin as their direct thrombin inhibitor. All patients received clopidogrel and aspirin 
prior to randomization. 
 
The results of the TENACITY study were analyzed with the 383 patients enrolled in the 
study and recently published [62]. At 30-days there was a non-significant difference 
between high-dose bolus tirofiban and abciximab, and the percent of patients with death, 
non fatal MI or urgent target vessel revascularization was 6.9% in the high-dose bolus 
tirofiban group versus 8.8% in the abciximab group (P=NS). This difference was driven 
primarily by an almost 2% absolute difference in rates of non-fatal myocardial infarction 
between high-dose bolus tirofiban and abciximab (5.9% vs. 7.7%; P=NS). There were no 
differences in bleeding between the two groups. When analyzed for combined death, MI, 
urgent TVR and major bleeding at 30-days, the combination of high-dose bolus tirofiban 


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and bivalirudin (5.6%) was non-significantly lower than abciximab and UFH (9.1%), 
abciximab and bivalirudin (10.5%), and high-dose bolus tirofiban and UFH (10.1%). 
 
The ADVANCE trial evaluated the efficacy and safety of HDB tirofiban compared with 
placebo in treating high-risk patients [35]. The study enrolled 202 patients with either a 
single coronary artery occlusion or diabetes, diagnosed NSTEMI, or multivessel coronary 
artery disease. This trial demonstrated a statistically significant decrease in 6-month 
MACE or bailout GPIIb/IIIa inhibitor use for patients treated with HDB tirofiban versus 
placebo (19.8% vs. 34.7%; P=0.01). HDB tirofiban was shown to significantly reduce the 
increase in cardiac markers (both troponin I and CK-MB) associated with ischemic events. 
Subgroup analysis showed a statistically significant decrease in the primary endpoint for 
diabetic and ACS patients treated with HDB tirofiban. Finally, there was no major bleeding, 
no need for red blood cell transfusion, or severe thrombocytopenia, and there was no 
significant difference in even minor bleeding rates between HDB tirofiban-treated patients 
and those treated with placebo (4% vs. 1%; P = 0.19). 
 
The 3T/2R trial evaluated the effect of tirofiban in patients with aspirin and/or clopidogrel 
resistance [52]. 263 patients who were non-responders to either aspirin or clopidogrel or 
both underwent double-blind randomization to receive HDB tirofiban (25 μg/kg in three 
minutes, followed by 12-24 hour infusion at 0.15 μg/kg/min) or placebo on top of standard 
aspirin and clopidogrel therapy. The primary end point was the rate of periprocedural 
myocardial infarction defined as an elevation of troponin I or T at least three times the 
upper limit of normal within 48 hours after the procedure. The primary endpoint was 
observed in 20.4 percent of patients in the tirofiban group, compared to 35.1 percent of 
patients in the placebo group (P=0.009; RRR=0.42). The benefit seen in the tirofiban 
group was maintained at 30 days, with a 21.2 percent incidence of major adverse 
cardiovascular events, compared to 36.6 percent in the placebo group (P=0.0065). The 
incidence of bleeding was low and did not differ significantly between the two groups [52]. 
 
The On-TIME 2 trial evaluated whether patients undergoing primary coronary angioplasty 
(PCI) would benefit from early administration of high-dose tirofiban [48]. The study enrolled 
984 patients with ST-elevation myocardial infarction (STEMI) who were indicated for 
primary PCI. Once enrolled, patients were randomly assigned to receive tirofiban (25 
μg/kg bolus dose followed by a 0.15 μg/kg/min infusion for 18 hours) or placebo. 
 
The primary endpoint, residual ST deviation one hour after PCI, favored tirofiban (3.6 mm) 
over placebo (4.8 mm); P=0.003). Major bleeding rates were similar between the two 
groups (4% vs. 3%; P=0.36). The authors concluded that early administration of high-dose 
tirofiban improved ST-segment resolution and clinical outcomes after PCI. 
 
Schiariti and co-workers published a clinical study investigating the efficacy and safety 
profile of HDB tirofiban (N=1,578) [54]. The study compared, as a primary endpoint, the 
combination of bleeding and access site complications of patients undergoing PCI under 
double anti-aggregating drugs (i.e. any two of ASA, clopidogrel, or ticlopidine) in the 
absence or presence of intravenous high-dose tirofiban given just before PCI followed by 
an 18 hour infusion. Based on the rates of blood transfusions (2.2% tirofiban vs. 2.1%; 
P=NS) and in-hospital complications (5.3% tirofiban vs. 5.9%; P=NS) the authors 
concluded the that high-dose tirofiban did not increase the complication risk for patients 
undergoing elective, primary or rescue PCI. 
 


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Schiariti and co-workers also compared the use of tirofiban HDB and eptifibatide in 
patients (N=666) undergoing PCI when added to standard antiaggregating drugs (aspirin 
and clopidogrel or ticlopidine) to prevent ischemic events within 1 year [56]. Adjusted 
hazard ratios showed that eptifibatide use, as compared to tirofiban (hazard ratio 1.85, 
95% CI 1.04–3.29, P=0.04), was a significant risk factor and it seems these effects are 
due to a lower efficacy of eptifibatide on CK-MB levels. Additional risk factors identified 
were age, chronic renal failure, pre-PCI values of CK-MB, and intra-aortic balloon pump.  
 
A meta-analysis of 31 studies involving 20,006 patients was published by Valgimigli and 
co-workers in 2010. The analysis showed tirofiban to be an efficacious treatment option in 
reducing ischemic events in patients with acute coronary syndromes and/or those 
undergoing PCI [26]. When employed as a high-dose bolus just prior to PCI, the authors 
concluded tirofiban provides similar efficacy but with an improved safety profile when 
compared to abciximab. In the 4,076 patients enrolled in studies employing the tirofiban 
high-dose bolus regimen, 1,863 were controlled with placebo and 2,213 were controlled 
with abciximab. For the HDB tirofiban versus placebo comparison, a reduction in short-
term (30 days) mortality (P = 0.07) and mortality or MI (P = 0.006) were observed. For the 
HDB tirofiban versus abciximab comparison, mortality (P = 0.38), the composite of death 
or MI (P = 0.54) or long-term death or MI rate (P = 0.35), or MACE rate (P = 0.51) were 
similar [26]. 
 
These trials represent a significant clinical experience demonstrating the safety and 
efficacy of the HDB tirofiban administered at the time of PCI. The HDB tirofiban regimen 
is approved in Europe, however, has not been approved in the United States.  
1.4.3 Rationale for a GPIIb/IIIa Shortened Infusion Duration 
Several studies involving GPIIb/IIIa inhibitor therapies have investigated the clinical 
effectiveness and safety of using a bolus plus a shortened infusion duration or a bolus-
only dosing regimen in the PCI setting. These reduced regimens are seen as attractive to 
interventional cardiologists since it has potential to reduce bleeding tendencies, lower the 
cost of therapy, and reduce the need for overnight hospitalization without compromising 
efficacy. 
 
Bertrand and co-workers [58] showed a high-dose bolus only of abciximab to be not 
clinically inferior to the standard bolus plus 12 hour infusion of abciximab after 
uncomplicated PCI in their study patient population. Fung and co-workers [28] showed 
that a <2 hour infusion of eptifibatide is non-inferior to the standard 18 hour eptifibatide 
infusion in preventing ischemic outcomes and is superior in reducing major bleeding after 
successful coronary intervention. Marmur and co-workers [59] showed that a high-dose of 
tirofiban (25 μg/kg) during PCI is safe and, in a sub-population of ACS patients, compares 
favorably to the post-PCI MI incidence of REPLACE-2 [60]. These studies suggest a bolus 
plus a shortened infusion of GPIIb/IIIa inhibitor therapy can be safe and effective in the 
setting of PCI.  
 
In order to further investigate this hypothesis, the SAVI-PCI study will provide a 
comparison of tirofiban using a shortened infusion duration versus eptifibatide using a 12-
18 hour infusion duration. In addition, to further isolate and distinguish the specific effects 
of the duration of dosing, a comparison of shortened infusion tirofiban versus regular (12-
18 hr) infusion tirofiban will be conducted in the study. Lastly, to further isolate and 
compare the clinical differences between the two small molecule agents, tirofiban and 


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eptifibatide will be compared using the same duration of infusion (12-18 hour infusion 
duration for both treatment arms). 
1.4.4 Tirofiban Dosing in Patients with Renal Insufficiency 
A pharmacokinetic modeling study, based on the available tirofiban pharmacokinetic 
literature, was conducted to determine the optimal tirofiban dosing regimen for patients 
with renal insufficiency (i.e., creatinine clearance <30 mL/min) [63a]. The study concluded 
that patients with renal insufficiency would have a tirofiban exposure profile (i.e., plasma 
concentration time profile) similar to that observed in patients with normal renal function 
when tirofiban is administered as a 25 μg/kg bolus plus a reduced infusion rate of 0.10 
μg/kg/min infusion instead of the usually recommended 0.15 μg/kg/min rate. The modeling 
results also indicate that the estimated low and high tirofiban plasma concentration ranges 
for this dosing regimen would be similar (or slightly greater) compared to the low and high 
ranges of patients with normal renal function. Thus, patients with renal impairment would 
most likely not reach elevated tirofiban plasma concentrations (after either the IV bolus or 
IV infusion doses of tirofiban) that could result in any adverse event that has not already 
been observed in patients with normal renal function. In addition, the PK modeling of low 
and high dose ranges indicates that tirofiban plasma concentrations in patients with renal 
impairment are sufficient to produce and maintain the desired pharmacological activity. 
 
During the course of SAVI-PCI, the FDA requested Medicure conduct a Phase 1 study in 
healthy volunteers with varying degrees of renal insufficiency to evaluate the impact of 
renal function on the PK profile of tirofiban administered using a single high-dose bolus 
(25 µg/kg). The study showed that patients with renal insufficiency (i.e. creatinine 
clearance <60 mL/min) should receive the 25 µg/kg bolus followed by a reduced infusion 
rate of 0.10 µg/kg/min infusion, instead of the recommended 0.15 µg/kg/min rate. This 
change in dosing for patients with renal insufficiency was implemented after 159 patients 
were enrolled [63b].  
 
On October 11, 2013 the FDA approved the 25 µg/kg bolus followed by a reduced infusion 
rate of 0.075 µg/kg/min for patients with creatinine clearance ≤60 mL/min [69]. For patients 
with creatinine clearance >60 mL/min, the approved Aggrastat dosing regimen is a 25 
µg/kg bolus followed by an infusion rate of 0.15 µg/kg/min [69]. 
 
A shortened infusion duration of tirofiban should further reduce safety concerns for 
patients with renal insufficiency. If an average PCI procedure takes 45 minutes [60], then 
according to the SAVI-PCI protocol, tirofiban will be infused for a total of 165 minutes. This 
is a substantial reduction in tirofiban dosing compared to recent clinical studies ON-TIME 
2 [48], MULTISTRATEGY [46] and 3T/2R [52]. For example, the total amount of tirofiban 
drug used in a HDB tirofiban followed by a 165 minute infusion regimen is 4478 μg (for a 
90kg patient). In comparison, for the same 90kg patient, the total amount of tirofiban drug 
administered in 3T/2R was between 13590 μg (for a 14h infusion) and 21690 μg (for a 
24h infusion) representing a relative reduction in tirofiban dosing of 67% and 79%, 
respectively. A substantial reduction in tirofiban dosing should reduce tirofiban dosing 
safety concerns for patients with renal insufficiency. 
1.5 Summary 
Anti-platelet therapy is established as improving outcomes in the setting of PCI of which 
GPIIb/IIIa inhibitors are the most potent and efficacious. Both eptifibatide and tirofiban 
experienced serious challenges in establishing an optimal dosing regimen during their 


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clinical development. After refinement of dosing, treatment guidelines now recommend 
their use to improve outcomes [65,66]. Over time, and with the continued evolution of 
therapy, concerns linked to safety and inconvenience of the relatively long infusion have 
complicated and limited the use of these agents despite their demonstrated efficacy. There 
is, therefore, a clear medical and scientific interest to re-evaluate and to further optimize 
the GPIIb/IIIa inhibitor therapy dosing regimen. 
 
This clinical protocol was designed to evaluate the efficacy and safety of a 25 μg/kg bolus 
dose of tirofiban followed by an infusion 0.15 µg/kg/min for the duration of PCI procedure 
plus a minimum of one hour and up to a maximum of two hours post-PCI among patients 
undergoing PCI with a planned placement of a coronary stent and to compare the efficacy 
and safety of this regimen of tirofiban to label-dosing eptifibatide. In addition, a comparison 
of tirofiban using a shortened infusion duration versus tirofiban using a longer infusion 
duration will also be evaluated to isolate any clinical differences using different infusion 
durations of the same drug. The third comparison of tirofiban versus eptifibatide (using a 
12-18 hour infusion duration for both treatment arms) will be evaluated to isolate any 
clinical differences between the two drugs using the same infusion duration. 
Approximately 550 patients will be enrolled into the study. 
 


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2.0 OBJECTIVES 
2.1  Primary Objective 
The first primary objective of this study is to assess whether a tirofiban regimen of a high-
dose bolus plus a shortened infusion duration compared to label-dosing eptifibatide in 
patients undergoing PCI is associated with a non-inferior composite rate of death, PPM, 
uTVR or in-hospital major bleeding within 48 hours following PCI or hospital discharge, 
whichever comes first.  
 
The co-primary objectives of this study are to assess whether: (i) a short tirofiban regimen 
of a high-dose bolus plus a 1-2 hour infusion post procedure compared to a long tirofiban 
regimen of a high-dose bolus plus a 12-18 hour infusion, and (ii) a long tirofiban regimen 
of a high-dose bolus plus a 12-18 hour infusion compared to label-dosing eptifibatide, are 
associated with non-inferior composite rates of death, PPM, uTVR, or in-hospital major 
bleeding within 48 hours following PCI or hospital discharge, whichever comes first. 
2.2 Secondary Objective 
The first secondary objective of this study is to assess whether a tirofiban regimen of a 
high-dose bolus plus a shortened infusion duration is safe compared to label-dosing 
eptifibatide among patients undergoing PCI, as assessed by the incidence of major 
bleeding within 48 hours following PCI or hospital discharge, whichever comes first.  
 
The co-secondary objectives of this study are to assess whether: (i) a short tirofiban 
regimen of a high-dose bolus plus a 1-2 hour infusion post procedure is safe compared to 
a long tirofiban regimen of a high-dose bolus plus a 12-18 hour infusion, and (ii) a long 
tirofiban regimen of a high-dose bolus plus a 12-18 hour infusion is safe compared to 
label-dosing eptifibatide, among patients undergoing PCI as assessed by the incidence of 
major bleeding within 48 hours following PCI or hospital discharge, whichever comes first. 
 
3.0 PRIMARY HYPOTHESIS 
The first primary hypothesis is a tirofiban regimen of a high-dose bolus plus a shortened 
infusion duration is non-inferior to label-dosing eptifibatide among patients undergoing PCI 
with respect to death, PPM, uTVR or major bleeding within 48 hours following PCI or 
hospital discharge, whichever comes first. 
 
The co-primary hypotheses include: (i) a short tirofiban regimen of a high-dose bolus plus 
a 1-2 hour infusion duration post procedure is non-inferior to a long tirofiban regimen of a 
high-dose bolus plus a 12-18 hour infusion, and (ii) a long tirofiban regimen of a high-dose 
bolus plus a 12-18 hour infusion is non-inferior to label-dosing eptifibatide, among patients 
undergoing PCI with respect to death, PPM, uTVR or major bleeding within 48 hours 
following PCI or hospital discharge, whichever comes first. 
 
4.0 POPULATION 
Patients who meet all of the inclusion criteria and none of the exclusion criteria at the time 
of randomization will be eligible for the study. 
4.1 Inclusion Criteria 
a. 
Age 18 years of age  


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b. 
Scheduled to undergo PCI with an FDA approved or cleared device (stent or 
procedures such as balloon angioplasty, rotoblation, AngioSculpt, laser 
atherectomy, etc.) in one or more native coronary target lesions  
c. 
Written informed consent. 
 
4.2 Exclusion Criteria 
a. 
Primary PCI for STEMI as index procedure 
b. 
Prior STEMI within 48 hours before randomization 
c. 
Prior PCI within 30 days before randomization 
d. 
Planned staged PCI within the subsequent 48 hours after index PCI 
e. 
Planned PCI of vein graft lesions only  
f. 
Use of abciximab within 7 days before randomization 
g. 
Use of tirofiban or eptifibatide within 12 hours before randomization 
h. 
Use of low-molecular weight heparin within 12 hours before randomization 
i. 
Use of bivalirudin within 12 hours before randomization 
j. 
Use of warfarin within 7 days before randomization unless INR ≤1.3  
k. 
Use of dabigatran or rivaroxaban within 3 days prior to randomization 
l. 
Use of thrombolytic agents administered within 24 hours before randomization 
m. 
Pregnant 
n. 
Active pericarditis 
o. 
Presumed or documented history of vasculitis 
p. 
Uncontrolled hypertension (blood pressure >180/110 mm Hg) 
q. 
Dependency on renal dialysis 
r. 
Active internal bleeding or bleeding diathesis, surgery, trauma or 
gastrointestinal/genitourinary tract bleeding within 6 weeks prior to randomization  
s. 
Prior intracranial hemorrhage, hemorrhagic stroke, cerebrovascular accident 
(CVA) within 2 years or CVA with significant residual neurological deficit, 
intracranial neoplasm, arteriovenous malformation, aneurysm, or structural 
abnormality 
t. 
Thrombocytopenia (platelet count <100 x 10³µL) or history of thrombocytopenia 
following heparin, tirofiban or eptifibatide 
u. 
Planned participation in any other clinical trial of an investigational drug or device, 
or a clinical trial of an approved drug or device for a non-approved use, up to 48 
hours following PCI 
v. 
Participation in another clinical trial 30 days prior to participation in the current 
study 
w. 
Any other condition that in the opinion of the investigator may compromise the 
safety or compliance of the patient or would preclude patient successfully 
completing the trial  
x. 
Known inability to comply with the protocol for the duration of the study. 


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5.0 STUDY DESIGN 
5.1 Summary of Study Design 
A randomized, multicenter, open-label study comparing tirofiban I.V. bolus injection 
followed by a maintenance infusion for the duration of the PCI procedure plus a minimum 
of one hour and up to a maximum of two hours post-PCI versus label-dosing eptifibatide. 
Patients were randomized to tirofiban or eptifibatide using a 1:1 allocation ratio. At 159 
randomized patients, a 1:1:1 randomization was initiated, randomizing patients to short 
tirofiban, eptifibatide or long tirofiban. Enrolment in the long tirofiban arm has been 
completed. Patients are mandated to stay a minimum of 18 hours following PCI. 
 
Physician-directed standard background therapies will include dual oral antiplatelet 
therapy with aspirin and an approved oral P2Y12 antagonist as well as antithrombotic 
therapy with unfractionated heparin. Physician-directed P2Y12 antagonist therapy and 
choice of femoral or radial access site must be pre-specified prior to randomization.  
 
The first 159 patients were randomized to the following two treatment arms on a 1:1 basis: 
 
1. Tirofiban (25 μg/kg bolus followed by a 0.15 μg/kg/min infusion for the duration of the 
PCI procedure plus a minimum of one hour and up to a maximum of two hours post-PCI).  
 
2. Eptifibatide (180 g/kg bolus followed by a 2.0 g/kg/min infusion for 18 hours post-PCI 
[minimum 12 hours mandated], with a second 180 g/kg bolus 10 min after the first). 
 
The three treatment arms for enrollment after the 159th patient were: 
 
1. Short Tirofiban (25 μg/kg bolus followed by a 0.15 μg/kg/min infusion for the duration of 
the PCI procedure plus a minimum of one hour and up to a maximum of two hours post-
PCI).  
 
2. Eptifibatide (180 g/kg bolus followed by a 2.0 g/kg/min infusion for 18 hours post-PCI 
[minimum 12 hours mandated], with a second 180 g/kg bolus 10 min after the first). 
 
3. Long Tirofiban (25 µg/kg bolus followed by a 0.15 µg/kg/min infusion for 18 hours post-
PCI) [minimum 12 hours mandated]. 
 
Subject enrolment in the Long Tirofiban arm has been completed.  Enrolment continues 
in the Short Tirofiban and Eptifibatide arms as outlined above. 
 
The short tirofiban versus eptifibatide comparison involves approximately 500 patients; 
the short tirofiban versus long tirofiban comparison involves approximately 350 patients; 
and the long tirofiban versus eptifibatide comparison involves approximately 350 patients. 
Approximately 550 patients will be enrolled into the study. 
 
Patients will sign an informed consent form and a HIPAA authorization form prior to 
initiation of study procedures. Patients will be assessed by the Investigator according to 
the selection criteria for the study. A patient who signs the consent and authorization 
forms, meets the inclusion criteria, and does not meet any of the exclusion criteria is 
eligible for inclusion into the study.  


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Study drug administration will begin prior to initiation of the PCI procedure as described in 
Section 5.2.5.  
 
At the end of the PCI procedure, all patients experiencing an intraprocedural thrombotic 
complication will be recorded. If a patient randomized to short tirofiban is experiencing an 
intraprocedural thrombotic complication, then the infusion is to be continued for a minimum 
of 12 hours. If a patient is randomized to eptifibatide and is experiencing an intraprocedural 
thrombotic complication, then no change is to be made to the infusion duration (i.e. the 
infusion continues for 18 hours post-PCI [minimum 12 hours mandated]). 
 
Initiation of the PCI procedure is defined as advancement of the guidewire out of the 
guiding catheter. Completion of the PCI procedure is defined as final removal of the 
guiding catheter.  
 
If femoral access is used, the sheath should be removed when the ACT is 180 seconds 
(or aPTT 50 seconds if ACT unavailable). If radial access is used, the sheath should be 
removed based on the discretion of the treating physician. 
 
Troponin (either troponin I or troponin T) will be sampled immediately prior to PCI, 
preferably from the PCI access sheath or guiding catheter, at 9±3 hours after PCI, and at 
21±3 hours after PCI. If the patient remains in the hospital longer than 36 hours after PCI, 
a third post-PCI troponin will be sampled at 42±6 hours after PCI. All troponin samples will 
be analyzed by the local laboratory. It is mandated that patients be observed for a 
minimum of 18 hours following PCI to allow for at least two post-PCI troponin samples.  
 
Hemoglobin, hematocrit and platelet count will be sampled at the same time as the 
troponin draws, i.e., immediately prior to PCI, preferably from the PCI access sheath or 
guiding catheter, at 9±3 hours following PCI, and at 21±3 hours. If the patient remains in 
the hospital longer than 36 hours after PCI, a third hemoglobin, hematocrit and platelet 
count post-PCI draw will be sampled at 42±6 hours after PCI. All hemoglobin, hematocrit 
and platelet count samples will be analyzed by the local laboratory. 
 
Patients will be assessed for serious adverse experiences (including serious bleeding 
events) that occur within 48 hours following PCI or hospital discharge, whichever comes 
first. Patients will be assessed for non-serious adverse experiences that occur within 48 
hours following PCI or hospital discharge, whichever comes first. 
 
5.2 Sequence of Procedures 
A Schedule of Evaluations and Procedures is shown in Appendix 1.  
5.2.1 Baseline/Pretreatment Period 
The Investigator has the ultimate responsibility for obtaining written informed consent and 
HIPAA authorization. This process will be completed for a patient before performing any 
protocol-specific procedure. No sedation shall be administered to the patient within 
reasonable proximity, consistent with local IRB rules, to exert a meaningful pharmacologic 
effect before written informed consent and HIPAA authorization is obtained. Consent will 
include HIPAA authorization. 
 


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The following procedures must be performed prior to randomization (maximum timing prior 
to randomization in parenthesis): 
a. brief medical history (within 7 days) 
b. brief physical examination (within 7 days) 
c. vital signs (height, weight, body temperature, heart rate, systolic and diastolic 
blood pressure) (within 7 days) 
d. serum or urine pregnancy if of child bearing potential (within 7 days) 
e. serum creatinine (within 24 hours) 
f. PT-INR for patients receiving oral anticoagulation (warfarin derivatives) within 7 
days prior to randomization (assessment must be done subsequent to last dose); 
if the last value prior to PCI (within 24 hours prior to randomization) is >1.3 times 
the control, patient is not eligible for enrollment (within 24 hours) 
g. hematology: hemoglobin, hematocrit and platelet count (within 24 hours) 
 
The following baseline sampling will be performed immediately prior to PCI: 
a. Baseline blood sample for troponin 
b. Baseline blood sample for hemoglobin, hematocrit and platelet count 
c. ACT (see Appendix 4) 
 
Whenever institutional policies allow, blood sampling can be obtained from sheaths, 
catheters, or central lines (including arterial lines) if available. Otherwise, an additional 
peripheral in-dwelling catheter may be inserted for venous blood sampling (e.g. heparin 
lock). 
 
Blood pressure will be assessed per institutional policy. 
5.2.2 Randomization 
Once all baseline examinations and tests are completed, the site will once again carefully 
review the inclusion and exclusion criteria described in the protocol to ensure that the 
patient is eligible to enter the study. 
 
Naming of oral P2Y12 antagonist agent (clopidogrel, prasugrel, or ticagrelor) to be used 
post-randomization must be pre-specified prior to randomization.   
 
Selection of either the femoral or radial access site must be pre-specified prior to 
randomization. 
 
Randomization may occur only if all of the following criteria are satisfied: 
a. Consented patient is confirmed to be eligible for the study, AND 
b. name of intended oral P2Y12 antagonist agent used post-randomization is pre-
specified, AND  
c. access site for PCI is pre-specified, AND 
d. decision to proceed to PCI is finalized, AND 
e. timing between randomization and initiation of the PCI procedure is less than 2 
hours. 
 
Once the above criteria are satisfied, the patient may be randomized. The timing for 
randomization in this study is critical. The reason for timing the study drug administration 
so close to time of PCI is to minimize inappropriate patient enrollment. Situations where 


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this might occur include the procedure where PCI is aborted or otherwise not performed 
or when a decision is made not to administer study medication for whatever reason. 
 
At randomization, the patient will be assigned a study number that will allow identification 
of the patient throughout the study, and the appropriate staff will prepare the 
corresponding study drug.  
 
Patients will be randomized via a centralized randomization system to receive either 
tirofiban or eptifibatide.  
 
The randomization will stratify patients according to femoral or radial access. 
5.2.3  Timing of Oral Antiplatelet Therapy, PCI & Study Drug Administration 
PCI will be performed according to institutional guidelines and standards. The index PCI 
procedure will be completed as clinically appropriate. Any PCI device approved by the 
FDA may be used (investigational stents may not be used in this study). 
 
All clinical events from the time of study drug administration will be recorded. The number 
and position of coronary stents placed as well as the outcome of the procedure will be 
recorded.  
 
All patients must receive aspirin (81 - 325 mg daily is recommended) and oral P2Y12 
antagonist therapy throughout the course of the study.  
 
Patients who are on a P2Y12 antagonist at time of randomization should remain on that 
same P2Y12 agent post-randomization. 
 
Patients who have not received any oral P2Y12 antagonist therapy within 24 hours prior to 
randomization must receive a loading dose between randomization and 15 minutes after 
completion of the PCI (defined as final removal of the guiding catheter), preferably as 
close to time of randomization as possible. 
 
Recommended loading doses for the oral P2Y12 antagonist therapies are the following: 
clopidogrel 600 mg; prasugrel 60 mg; and ticagrelor 180 mg. 
 
Patients will be administered unfractionated heparin as an initial I.V. bolus of 50 U/kg prior 
to PCI. Additional heparin boluses will be administered according to the suggested 
guidelines in Appendix 4.  
 
Study drug will be prepared and labeled accordingly for each patient as described in the 
pharmacy manual. Tirofiban will be provided by Sponsor and packaged in 100 mL 
bags/vials containing 5.0 mg of tirofiban. Eptifibatide will be provided by the Institution and 
packaged in 10 mL bolus vials containing 20 mg eptifibatide and 100 mL infusion vials 
containing 75 mg of eptifibatide. See Pharmacy Manual for details of study drug 
preparation.  
 
Patients assigned to short tirofiban will receive a 25 μg/kg bolus administered by I.V. push 
followed by a 0.15 μg/kg/min infusion for the duration of the PCI procedure plus a minimum 
of one hour and up to a maximum of two hours post-PCI. Sites have the option of 
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bolus push with syringe. Sponsor will supply T-ports (Trudell Medical Marketing) to use 
for filling syringe for bolus administration.  
 
Patients assigned to short tirofiban with renal insufficiency (creatinine clearance ≤60 
mL/min) will receive a 25 μg/kg bolus followed by a 0.075 μg/kg/min maintenance infusion 
for the duration of the PCI procedure plus a minimum of one hour and up to a maximum 
of two hours post-PCI. 
 
Patients assigned to eptifibatide will receive a 180 μg/kg bolus followed by a 2.0 g/kg/min 
infusion for 18 hours post-PCI (minimum 12 hours mandated), with a second 180 μg/kg 
bolus 10 min after the first.  
 
Patients assigned to eptifibatide with renal insufficiency (creatinine clearance <50 mL/min) 
will receive a 180 μg/kg bolus followed by a 1.0 μg/kg/min infusion for 18 hours post-PCI 
(minimum 12 hours mandated), with a second 180 μg/kg bolus 10 min after the first.  
 
Patients assigned to long tirofiban received a 25 µg/kg bolus administered by I.V. push 
followed by a 0.15 µg/kg/min infusion for 12-18 hours post-PCI.  
Patients assigned to long tirofiban with renal insufficiency (creatinine clearance ≤60 
mL/min) received a 25 µg/kg bolus followed by a 0.075 µg/kg/min maintenance infusion 
for 12-18 hours post-PCI. 
 
The study drug boluses of tirofiban or eptifibatide will be administered intravenously by 
volume according to patient weight (see Appendix 3 for dosing tables). The bolus volume 
and infusion rate increases with increasing patient weight, but is capped at the patient 
weight of 153 kg and 121 kg for tirofiban and eptifibatide, respectively. Therefore, any 
patient randomized to tirofiban weighing over 153 kg will receive the same bolus volume 
and infusion rate as a patient randomized to tirofiban weighting 153 kg. Similarly, any 
patient randomized to eptifibatide weighing over 121 kg will receive the same bolus 
volume and infusion rate as a patient randomized to eptifibatide weighting 121 kg. 
Administration of the bolus will begin prior to the initiation of the PCI procedure. Initiation 
of the PCI procedure is defined as advancement of the guidewire out of the guiding 
catheter. 
 
In patients with known coronary anatomy (i.e., a baseline angiogram was previously 
performed), the bolus will be administered after arterial access is achieved, prior to 
advancement of the guidewire out of the guiding catheter. In patients without a baseline 
angiogram, the bolus will be administered after completion of the initial angiography, once 
the decision has been made to proceed with PCI, prior to advancement of the guidewire 
out of the guiding catheter. The study drug infusion will be started immediately after 
completion of the bolus (first bolus in the case of eptifibatide). Upon completion of the 
study drug bolus administration and initiation of study drug infusion, advancement of the 
guidewire out of the guiding catheter and PCI may proceed. 
5.2.4 In The Event of Thrombotic Complications 
At the end of the PCI procedure all patients will be assessed to determine if a thrombotic 
complication persists according to the following criteria: 
 
1. abrupt or threatened closure, with reduced flow, and/or 
2. no reflow or slow flow, due to distal embolization, and/or 


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3. visible thrombus. 
 
Determination of whether one or more of these criteria has been satisfied will be at the 
determination of the investigator. 
 
Patients administered short tirofiban experiencing a thrombotic complication will continue 
to receive an infusion of tirofiban at a dose of 0.15 μg/kg/min (or 0.075 μg/kg/min for 
patients with renal insufficiency (creatinine clearance ≤60 mL/min)) for a minimum of 12 
hours following PCI. See Appendix 3 for dosing tables. 
 
Patients administered eptifibatide experiencing a thrombotic complication will continue to 
receive an infusion of eptifibatide at a dose of 2.0 μg/kg/min (or 1.0 μg/kg/min for patients 
with renal insufficiency (creatinine clearance <50 mL/min)) for 18 hours following PCI 
(minimum 12 hours mandated, no maximum infusion duration). See Appendix 3 for dosing 
tables. 
 
Patients administered long tirofiban experiencing a thrombotic complication continued to 
receive an infusion of tirofiban at a dose of 0.15 μg/kg/min (or 0.075 μg/kg/min for patients 
with renal insufficiency (creatinine clearance ≤60 mL/min)) for 18 hours following PCI 
(minimum 12 hours mandated, no maximum infusion duration). See Appendix 3 for dosing 
tables. 
 
5.2.5 Following the Procedure 
Short tirofiban will be infused for the duration of the procedure plus a minimum of one hour 
and up to a maximum of two hours post-PCI. For example, if the procedure takes 25 
minutes (i.e. 25 minutes from the time of advancement of the guidewire out of the guiding 
catheter to final removal of the guiding catheter) then tirofiban will be infused for a total of 
25 minutes plus a minimum of one hour (for a total infusion time of 85 minutes) and up to 
a maximum of two hours (for a total infusion time of 145 minutes). For another example, 
if the PCI procedure takes 55 minutes, then tirofiban will be infused for a total of 55 minutes 
plus a minimum of one hour (for a total infusion time of 115 minutes) and up to a maximum 
of two hours (for a total infusion time of 175 minutes).  
 
Eptifibatide will be infused for a total of 18 hours following PCI (minimum 12 hours 
mandated). 
 
Long tirofiban was infused for a total of 18 hours following PCI (minimum 12 hours 
mandated). 
 
During study drug administration and following discontinuation of study drug, the patient 
will be observed for signs of bleeding. Blood pressure and heart rate will be monitored 
according to the institution’s standard procedures. 
 
For the definition of procedure duration, final removal of the guiding catheter will define 
procedure completion. 
5.2.5.1 Antithrombin Use 
Routine use of unfractionated heparin post-procedure is not recommended.  


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5.2.5.2 Sheath Removal 
If femoral access is used, the sheath should be removed when the ACT is 180 seconds 
(or aPTT 50 seconds if ACT unavailable). If radial access is used, the sheath should be 
removed based on the discretion of the treating physician. 
 
If a closure device is utilized, it will not be necessary to wait until the ACT or aPTT reaches 
the prescribed levels. Institutional guidelines for ambulating following sheath removal 
should be followed. Patients may be ambulated while study drug infusions continue if 
institutional guidelines permit it. 
5.2.5.3 Blood Sampling 
Whenever institutional policies allow, blood sampling can be obtained from sheaths, 
catheters, or central lines (including arterial lines) if available. Otherwise, an additional 
peripheral in-dwelling catheter may be inserted for venous blood sampling (eg, heparin 
lock).  
 
The following evaluations will be performed at the times indicated (see Schedule of 
Evaluations and Procedures, Appendix 1; all evaluations and laboratory measurements 
should be performed within the time specified, unless otherwise specified): 
 
a. Hemoglobin, hematocrit and platelet count will be sampled at the same time as 
the troponin draws (see below), i.e., immediately prior to PCI, preferably from the 
PCI access sheath or guiding catheter, at 9±3 hours following PCI, and at 21±3 
hours. If the patient remains in the hospital longer than 36 hours after PCI, a third 
hemoglobin, hematocrit and platelet count post-PCI draw will be sampled at 42±6 
hours after PCI. All hemoglobin, hematocrit and platelet count samples will be 
analyzed by the local laboratory. 
 
b. If a platelet count falls below 100,000 cells/µL and decreases at least 25% from 
the baseline value in any sample compared to any previous sample, additional 
repeat platelet counts and/or further laboratory analyses (i.e., microscopic) per local 
institution guidelines must be performed to exclude laboratory error (clumping, etc.). 
The repeat platelet counts should be performed according to the specific practice 
at each institution. See Appendix 7 for guidelines for management of 
thrombocytopenia. 
 
c. Troponin (troponin I or troponin T) will be sampled immediately prior to PCI, 
preferably from the PCI access sheath or guiding catheter, at 9±3 hours following 
PCI, and at 21±3 hours. If the patient remains in the hospital longer than 36 hours 
after PCI, a third post-PCI troponin will be sampled at 42±6 hours after PCI. All 
troponin samples will be analyzed by the local laboratory. It is mandated that 
patients be observed for a minimum of 18 hours following PCI to allow for at least 
two post-PCI troponin samples.  
 
See Appendix 2 for a complete listing of local laboratory evaluations. 
5.2.6 Safety Evaluation, Discharge and Follow-Up 
Patients will be assessed for serious adverse events (including serious bleeding events) 
and non-serious adverse events of interest that occur from the time of study drug initiation 


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through 48 hours following PCI or hospital discharge, whichever comes first. These events 
will be documented on the CRF. Some serious adverse events will require expedited 
reporting (see Adverse Events Section 8.0). 
 
Patients are mandated to stay a minimum of 18 hours following PCI to allow for at least 
two post-PCI troponin samples to be obtained at time-points 93 hours and 213 hours 
following PCI. If the patient remains in the hospital longer than 36 hours after PCI, a third 
post-PCI troponin will be sampled at 42±6 hours after PCI. 
5.2.7 Evaluation of Endpoints 
Evaluation of death, PPM uTVR and REPLACE-2 Major bleeding and other endpoints will 
not be adjudicated.  
5.2.8 Criteria for Discontinuation of Study Drug 
If at any time during the study the Investigator responsible for the clinical care of the patient 
decides that continued use of the study drug is contraindicated, administration of the study 
drug should be stopped. Study drug should be discontinued if any of the following develop: 
 
a. Unusual or excessive bleeding; 
Signs or symptoms of abnormal, pathological bleeding from any source that 
cannot be controlled without discontinuation of the study drug. Hematoma 
at the site of the vascular sheath insertion is expected and should not serve 
as a reason to discontinue study drug, unless the bleeding cannot be 
controlled with normal measures. 
b. Development of a new, neurologic deficit or significant alteration in mental 
status. 
c. Development of a platelet count <50,000/mm3.  
d. Any serious adverse event possibly related to or exacerbated by study drug 
administration. 
e. Need for urgent CABG. Appropriate measures should be taken to minimize 
surgical risk (see Appendix 5 Guidelines for Management of Urgent Target Vessel 
Revascularization). 
f. Any need for a surgical procedure with the exception of those procedures 
performed under local anesthesia. 
 
If the study drug is discontinued prematurely, the Sponsor will be notified as soon as 
possible. A patient for whom study drug is discontinued will continue to be monitored 
according to the protocol tests and procedures after study drug has been discontinued. 
5.2.9 Concomitant Medication(s)/Treatment(s) 
Only FDA-approved drugs may be administered in this study. Concomitant oral P2Y12 
antagonist medications must be pre-specified prior to randomization. 
5.2.9.1 Permitted 
Antiplatelet/Anticoagulant agents 
The following concomitant antiplatelet/anticoagulant agents are permitted in the study: 
 
aspirin 
 
clopidogrel 
 
prasugrel 


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 
ticagrelor 
 
unfractionated heparin  
 
The name, timing and dosing of the above antiplatelet/anticoagulant agents should all be 
recorded on the CRF. 
 
Clopidogrel is contraindicated with prasugrel and ticagrelor; prasugrel is contraindicated 
with clopidogrel and ticagrelor; and ticagrelor is contraindicated with clopidogrel and 
prasugrel. 
 
Oral, sublingual, topical, or I.V. nitrates 
Any of these medications may be given if necessary based on the discretion of the treating 
physician. These medications received during the procedure and for 48 hours following 
PCI or until hospital discharge, whichever comes first will be recorded on CRFs, according 
to drug class (recording of name, dosage and timing is not required). 
 
Ace-inhibitors, calcium channel blockers, beta-blockers, lipid-lowering therapy, 
angiotensin receptor blockers, diuretics, digoxin and diabetes medications. 
Any of these medications may be given if necessary based on the discretion of the treating 
physician. These medications received during the procedure and for 48 hours following 
PCI or until hospital discharge, whichever comes first will be recorded on CRFs, according 
to drug class (recording of name, dosage and timing is not required).  
 
Nonsteroidal anti-inflammatory agents 
Any of these medications may be given if necessary based on the discretion of the treating 
physician. These medications received during the procedure and for 48 hours following 
PCI or until hospital discharge, whichever comes first will be recorded on CRFs, according 
to drug class (recording of name, dosage and timing is not required). 
5.2.9.2 Prohibited 
Oral anticoagulation 
Oral anticoagulation medications (warfarin derivatives) should not be administered until at 
least 12 hours after completion of the study drug infusions unless INR ≤1.3. 
 
Antiplatelet/Anticoagulant agents 
No other antiplatelet agents (except aspirin, clopidogrel, prasugrel or ticagrelor) or 
anticoagulant  agents (except unfractionated heparin) should be administered until 
completion of the study drug infusion. Low-molecular-weight heparin should not be 
administered during infusion of study drug. Dextran may not be used during or prior to 
study drug infusion.  
 
Thrombolytic agents 
Thrombolytic agents must be discontinued for at least 24 hours prior to randomization and 
may not be used until at least 12 hours after completion of the study drug infusion.  
 
Bivalirudin 
Bivalirudin must be discontinued for at least 12 hours prior to randomization and may not 
be used until at least 12 hours after completion of the study drug infusion. 
 
Ticlopidine 


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Ticlopidine should not be administered in this study. 
 
Unapproved agents 
Therapeutic agents not approved by the FDA at the time of the protocol finalization should 
be discontinued at least 48 hours prior to randomization and may not be used until after 
24 hours following PCI.  
5.2.10 Patient Withdrawal 
Patients may withdraw at any time during the study without prejudice, or be discontinued 
from the study at the discretion of the Investigator if medically necessary or if any untoward 
effects occur. In addition, a patient may be withdrawn by the Investigator or the Sponsor 
if the patient violates the study plan or for administrative and or other safety reasons. The 
Investigator or study coordinator must notify the Sponsor immediately (via telephone or 
fax) when a patient has been discontinued or withdrawn because of an adverse 
experience. When a patient discontinues or withdraws prior to study completion, all 
applicable activities scheduled for the end of study should be performed at the time of 
discontinuation. Any adverse experiences that are present at the time of 
discontinuation/withdrawal should be reported and followed-up in accordance with the 
safety requirements outlined in the Adverse Events Section 8.0. 
 
Unless the patient has explicitly withdrawn consent for further data collection, it is 
important that complete data are obtained for all patients whether or not they receive their 
assigned treatment or have discontinued study drug. Every attempt should be made to 
collect information. All procedures and laboratory specimens or tests requested for 
evaluation following administration of the study drug should be carried out when possible 
whether or not a patient continues to receive treatment according to the protocol. 
Discontinued patients will not be replaced. 
  
6.0  PRIMARY EFFICACY MEASUREMENTS 
The primary endpoint will be the composite of death, PPM, uTVR or major bleeding (where 
major bleeding is defined in Section 7.1 and discussed further in Section 9) within 48 hours 
following PCI or hospital discharge, whichever comes first.  
 
All clinical events from the time of study drug administration will be recorded. The number, 
type and length of coronary stents placed as well as the outcome of the procedure will be 
recorded on the CRF.  
 
After study drug administration, the development of any of the following events will be 
recorded on the appropriate CRF. 
6.1  Death 
Death due to any cause will be assessed through to 48 hours following PCI or hospital 
discharge, whichever comes first.  
 
Death will not be adjudicated. 
6.2 Periprocedural Myonecrosis  
The definition of periprocedural myonecrosis is the following: 
 


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Periprocedural myonecrosis will have occurred if there is at least one troponin 
(troponin I or troponin T) value of 3 times the upper limit of normal AND at least 
20% or greater than the baseline troponin value, per the troponin Local Laboratory, 
within 48 hours following PCI or hospital discharge, whichever comes first.  
 
Periprocedural myonecrosis will not be adjudicated. 
 
To be included in the primary composite endpoint analysis and in the secondary PPM 
endpoint analysis, a patient MUST have the pre-PCI troponin Local Laboratory 
measurement AND at least one troponin Local Laboratory measurement within 48 hours 
following PCI or hospital discharge, whichever comes first. 
 
Patients without a pre-PCI troponin Local Laboratory measurement will NOT be included 
in the PPM endpoint analysis, but will still be included in the intention to treat analysis and 
be analyzed for death and uTVR. 
 
Patients without any troponin Local Laboratory measurements within 48 hours following 
PCI or hospital discharge, whichever comes first will NOT be included in the PPM endpoint 
analysis, but will still be included in the intention to treat analysis and be analyzed for 
death, uTVR and major bleeding. 
6.3 Urgent Target Vessel Revascularization 
Urgent Target Vessel Revascularization (uTVR) is either a PCI following the index PCI or 
any CABG procedure performed after the index PCI on a non-selective basis in the target 
vessel because of recurrent myocardial ischemia. A revascularization procedure in the 
target vessel is considered urgent if it is due to one or more episodes of chest pain, 
presumed to be ischemic in origin and lasting at least 5 minutes, and results in either 
urgent repeat PCI or urgent coronary artery bypass surgery involving the target vessel. In 
the absence of pain, new ischemic ST-segment or T-wave changes, acute pulmonary 
edema, ventricular arrhythmias presumed to be ischemic in origin will constitute sufficient 
evidence of ischemia. The episode of ischemia leading to urgent repeat PCI must occur 
following completion of the index PCI and guidewire removal.  
 
For uTVR to count towards the primary composite endpoint, uTVR will have to be initiated 
during the course of the study (i.e., 48 hours following PCI or hospital discharge, whichever 
comes first).   
 
uTVR will not be adjudicated. 
 
7.0 SAFETY MEASUREMENTS 
The following adverse events will be monitored closely from study drug administration 
through 48 hours following PCI or hospital discharge, whichever comes first.  
7.1 Bleeding 
Bleeding complications will be closely monitored clinically and by serial determinations of 
hemoglobin and hematocrit. All bleeding events from study drug administration through 
48 hours following PCI or hospital discharge, whichever comes first, will be collected and 
categorized by site and quantified according to REPLACE-2 Major bleeding criteria. While 
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used in the primary safety analysis and in the bleeding component of the primary 
composite endpoint.  
 
Hemoglobin, hematocrit and platelet count will be sampled at the same times as the 
troponin draws. i.e., immediately prior to PCI, preferably from the PCI access sheath or 
guiding catheter, and at 9±3 hours following PCI, and at 21±3 hours. If the patient remains 
in the hospital longer than 36 hours after PCI, a third hemoglobin, hematocrit and platelet 
count post-PCI draw will be sampled at 42±6 hours after PCI. 
 
Bleeding events will not be adjudicated. 
7.1.1  Bleeding Site 
Each site will be recorded on the CRF and evaluated separately. Bleeding sites include 
intracranial, retroperitoneal, sheath puncture site, other puncture site, ENT bleed, GI 
bleed, GU bleed, cardio/pulmonary bleed, other, and unknown. Microscopic hematuria 
and positive fecal occult blood will be recorded as laboratory adverse events only and will 
not be captured as bleeding events. Information on whether the bleeding event was a 
result of CABG will be collected on the CRF. 
7.1.2 Primary Safety Measurement Non-CABG REPLACE-2 Major Bleeding 
Definition 
Major bleeding is defined using the criteria from the REPLACE-2 trial. Major bleeding is 
defined as follows [57]: 
 
a. transfusion of 2 units whole blood or packed red blood cells, or 
b. intracranial hemorrhage, or 
c. retroperitoneal hemorrhage, or 
d. a fall in Hgb < 4 g/dL (or 12% of Hct) with no bleeding site identified despite 
attempts to determine, or 
e. spontaneous or non-spontaneous blood loss associated with a Hgb drop >3 
g/dL (or 10% of Hct) with an overt site of hemorrhage. 
 
The REPLACE-2 Major bleeding definition takes into account blood transfusions, so that 
hemoglobin and hematocrit values are adjusted by 1 g/dl or 3%, respectively, for each 
unit of blood transfused. 
 
Therefore, the true change in hemoglobin or hematocrit if there has been an intervening 
transfusion between two blood measurements is calculated as follows [68]: 
 
Hemoglobin = [baseline Hgb - post-transfusion Hgb] + [number of transfused units]; 
 
Hematocrit = [baseline Hct - post-transfusion Hct] + [number of transfused units x 3]. 
 
7.1.3 Other Bleeding Definitions 
While not part of the primary safety analysis and composite endpoint, bleeding will be 
evaluated using alternate definitions as described below. 


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7.1.3.1  TIMI Major Bleeding Definition 
Major bleeding is defined using the criteria from the trials of Thrombolysis in Myocardial 
Infarction (TIMI criteria). Major bleeding is defined as follows [64]: 
 
a.  if there was a reduction of hemoglobin of 5 g/dl or more (or >15% in 
hematocrit); or 
b.  any intracranial bleeding. 
 
The TIMI Major bleeding definition takes into account blood transfusions, so that 
hemoglobin and hematocrit values are adjusted by 1 g/dl or 3%, respectively, for each 
unit of blood transfused. 
 
Therefore, the true change in hemoglobin or hematocrit if there has been an intervening 
transfusion between two blood measurements is calculated as follows [68]: 
 
Hemoglobin = [baseline Hgb - post-transfusion Hgb] + [number of transfused units]; 
 
Hematocrit = [baseline Hct - post-transfusion Hct] + [number of transfused units x 3]. 
7.1.3.2  TIMI Minor Bleeding Definition 
Minor bleeding is defined using the criteria from the trials of Thrombolysis in Myocardial 
Infarction (TIMI criteria). Minor bleeding is defined as follows [64]: 
 
a.  If there is an observed blood loss and a drop in hemoglobin of 3 to 5 g/dl (or 
in hematocrit from 10% to 15%) from study entry to the time of the lowest 
hemoglobin (hematocrit); or 
 
b.  if there was spontaneous gross hematuria or hematemesis (>120 mL), even if 
the hemoglobin or hematocrit drop was less than 3 g or less than 10%, 
respectively; or 
 
c.  if there was an unobserved blood loss 4 g/dl or more in hemoglobin or 12% or 
more in hematocrit. 
 
The TIMI Minor bleeding definition takes into account blood transfusions, so that 
hemoglobin and hematocrit values are adjusted by 1 g/dl or 3%, respectively, for each unit 
of blood transfused. 
 
Therefore, the true change in hemoglobin or hematocrit if there has been an intervening 
transfusion between two blood measurements is calculated as follows [68]: 
 
Hemoglobin = [baseline Hgb - post-transfusion Hgb] + [number of transfused units]; 
 
Hematocrit = [baseline Hct - post-transfusion Hct] + [number of transfused units x 3]. 
7.1.3.3 REPLACE-2 Minor Bleeding Definition 
Minor bleeding is defined as any observed bleeding event that does not meet the criteria 
for a major hemorrhage. 


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7.1.3.4 REPLACE-2 Plus Major Bleeding Definition 
REPLACE-2 Plus Major bleeding is defined using criteria from the REPLACE-2 trial, with 
the exception of transfusion. REPLACE-2 Plus Major bleeding is defined as follows: 
 
a. any transfusion of whole blood or packed red blood cells, or 
b. intracranial hemorrhage, or 
c. retroperitoneal hemorrhage, or 
d. a fall in Hgb < 4 g/dL (or 12% of Hct) with no bleeding site identified despite 
attempts to determine, or 
e. spontaneous or non-spontaneous blood loss associated with a Hgb drop >3 
g/dL (or 10% of Hct) with an overt site of hemorrhage. 
 
The REPLACE-2 Plus Major bleeding definition takes into account blood transfusions, so 
that hemoglobin and hematocrit values are adjusted by 1 g/dl or 3%, respectively, for 
each unit of blood transfused. 
 
Therefore, the true change in hemoglobin or hematocrit if there has been an intervening 
transfusion between two blood measurements is calculated as follows [68]: 

Hemoglobin = [baseline Hgb - post-transfusion Hgb] + [number of transfused units]; 

Hematocrit = [baseline Hct - post-transfusion Hct] + [number of transfused units x 3]. 
 
7.1.3.5 TIMI Plus Major Bleeding Definition 
 
TIMI Plus Major bleeding is defined using the criteria from the trials of Thrombolysis in 
Myocardial Infarction (TIMI criteria) with the exception of transfusion [64]: 
 
a.  any transfusion of whole blood or packed red blood cells, or 
b.  if there was a reduction of hemoglobin of 5 g/dl or more (or >15% in 
hematocrit); or 
c.  any intracranial bleeding. 
   
The TIMI Plus Major bleeding definition takes into account blood transfusions, so that 
hemoglobin and hematocrit values are adjusted by 1 g/dl or 3%, respectively, for each 
unit of blood transfused. 
 
Therefore, the true change in hemoglobin or hematocrit if there has been an intervening 
transfusion between two blood measurements is calculated as follows [68]: 

Hemoglobin = [baseline Hgb - post-transfusion Hgb] + [number of transfused units]; 

Hematocrit = [baseline Hct - post-transfusion Hct] + [number of transfused units x 3]. 
 
7.2 Thrombocytopenia 
If a platelet count falls below 100,000 cells/µL and decreases at least 25% from the 
baseline value in any sample compared to any previous sample, additional repeat platelet 


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counts and/or further laboratory analyses (i.e., microscopic) per local institution guidelines 
must be performed to exclude laboratory error (clumping, etc.). The repeat platelet counts 
should be performed according to the specific practice at each institution. See Appendix 
7 for guidelines for management of thrombocytopenia. 
7.2.1 Moderate Thrombocytopenia 
Moderate thrombocytopenia is defined as a platelet count <50,000 cells/L. 
7.2.2 Severe Thrombocytopenia 
Severe thrombocytopenia is defined as a platelet count <20,000 cells/L. 
 
8.0 ADVERSE EVENTS 
8.1  Definitions 
An adverse event (AE) is any untoward new medical problem or exacerbation of an 
existing problem, experienced by a patient while enrolled in the study, whether or not it is 
considered drug-related by the Investigator.  
 
Expected complications of percutaneous procedures as well as study endpoints that are 
not felt to be related to study drug are not to be considered adverse events, although any 
bleeding endpoint will still be recorded.  
 
In addition, planned hospital admissions and/or surgical operations for an illness or 
disease which existed before the drug was given or the patient was randomized in a 
clinical study are not to be considered adverse events. 
 
A serious adverse event (SAE) is any adverse event occurring within 48 hours that: 
 
 Results in death; or 
 
 Is life threatening (places the patient, in the opinion of the Investigator, at immediate risk 
of death from the experience as it occurred. [This does not include an adverse event 
that, had it occurred in a more severe form, might have caused death.]); or 
 
 Results in a persistent or significant disability/incapacity (substantial disruption of one’s 
ability to conduct normal life functions); or 
 
 Results in or prolongs an existing in-patient hospitalization (hospitalization is defined as 
an in-patient admission, regardless of length of stay, even if the hospitalization is a 
precautionary measure for continued observation); or 
 
 Is a congenital anomaly/birth defect (in offspring of patient taking the product regardless 
of time to diagnosis); or 
 
 Is medically significant: requires medical or surgical interventions to prevent one or more 
of the outcomes above. 


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8.2 Study Drug Causality 
The relationship of an AE to treatment will be assessed by the Investigator as one of the 
following: 
 
 Probably related: There is a reasonable causal relationship between the study drug 
and the AE. The event responds to de-challenge. 
 
 Possibly related: There is a reasonable causal relationship between the study drug 
and the AE. 
 
 Unlikely related: There is not a temporal or causal relationship to the study drug 
administration. 
8.3 Severity 
The intensity of adverse events will be graded by the Investigator on a 3-point scale as 
indicated on the CRF. The intensity of an adverse event is defined as follows: 
 
 Mild: Discomfort noticed, but no disruption to daily activity 
 
 Moderate: Discomfort sufficient to reduce or affect normal daily activity 
 
 Severe: Inability to work or perform normal daily activity 
8.4 Collection of Adverse Events 
The Investigator will periodically assess patients for the occurrence of adverse events. To 
avoid bias in eliciting adverse events, patients should be asked the following non-leading 
question: “How are you feeling?” All adverse events (serious and non-serious) reported 
by the patient will be followed until the event has resolved or has stabilized. 
8.4.1 Collection and Reporting of Nonserious Adverse Events 
Nonserious adverse events will be collected from study drug initiation through to 48 hours 
following PCI or hospital discharge, whichever comes first on the CRF but will not require 
urgent expedited reporting.  
8.4.2 Collection and Reporting of Serious Adverse Events 
Serious adverse events (including serious bleeding events) will be collected on the CRF. 
The Investigator is responsible for following all SAEs until the event has resolved or has 
stabilized. 
 
In the event of an SAE, or in the event of death due to any cause, immediately (within 24 
hours) the SAE form is to be completed and submitted to:   
 
Name: Monique Vonk 
Title: Clinical Safety Officer 
Fax: 204-489-0175 
Email: safety@gvicds.com 
Phone: 204-928-7208 
 


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If details of the event are not known submit the SAE form within 24 hours and update the 
information as it becomes available. 
8.4.3 Collection and Reporting of Endpoints 
Endpoints will be collected on the case report form from study drug administration through 
48 hours following PCI or hospital discharge, whichever comes first. Any coronary 
ischemic or anginal event will be collected on the CRF but will not require urgent/expedited 
reporting. Endpoints will not be reported as SAEs. 
8.5 Submission of Follow-up Data 
The Investigator is responsible for following all SAEs until the event has resolved or has 
stabilized. The Sponsor’s Safety Surveillance Contact will follow all SAEs with outcomes 
pending until the last patient enrolled has completed the study.  
8.6 Ethics Committee SAE Reporting 
The Investigator will be responsible for reporting adverse events to the Independent 
Review Board (IRB) and their local regulatory authorities in accordance with their local 
guidelines. 


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9.0 STATISTICAL CONSIDERATIONS 
This section summarizes the statistical aspects of the protocol. A final statistical analysis 
plan (SAP), which will provide detailed descriptions of the statistical methodology and 
mock tables, listings and figures (TLFs), will be completed prior to any blinded sample size 
reassessment or final analysis. 
9.1 Study Design 
A randomized, multicenter, open-label study comparing tirofiban I.V. bolus injection 
followed by a maintenance infusion for the duration of the PCI procedure plus a minimum 
of one hour and up to a maximum of two hours post-PCI versus label-dosing eptifibatide. 
Patients were randomized to tirofiban or eptifibatide using a 1:1 allocation ratio. After 159 
patients were randomized, a 1:1:1 randomization was initiated, randomizing patients to 
short tirofiban, eptifibatide or long tirofiban.  Randomization in the long tirofiban arm is 
completed, changing the allocation ratio back to 1:1. Patients are mandated to stay a 
minimum of 18 hours following PCI. 
 
Physician-directed standard background therapies will include dual oral antiplatelet 
therapy with aspirin and an approved oral P2Y12 antagonist as well as antithrombotic 
therapy with unfractionated heparin. Physician-directed P2Y12 antagonist therapy and 
choice of femoral or radial access site must be pre-specified prior to randomization.  
 
The first 159 patients were randomized to the following two treatment arms on a 1:1 basis: 
 
1. Tirofiban (25 μg/kg bolus followed by a 0.15 μg/kg/min infusion for the duration of the 
PCI procedure plus a minimum of one hour and up to a maximum of two hours post-PCI).  
 
2. Eptifibatide (180 g/kg bolus followed by a 2.0 g/kg/min infusion for 18 hours post-PCI 
[minimum 12 hours mandated], with a second 180 g/kg bolus 10 min after the first). 
 
The three treatment arms for enrollment after the 159th patient were: 
 
1. Short Tirofiban (25 μg/kg bolus followed by a 0.15 μg/kg/min infusion for the duration of 
the PCI procedure plus a minimum of one hour and up to a maximum of two hours post-
PCI).  
 
2. Eptifibatide (180 g/kg bolus followed by a 2.0 g/kg/min infusion for 18 hours post-PCI 
[minimum 12 hours mandated], with a second 180 g/kg bolus 10 min after the first). 
 
3. Long Tirofiban (25 µg/kg bolus followed by a 0.15 µg/kg/min infusion for 18 hours post-
PCI) [minimum 12 hours mandated]. 
 
Enrolment in the Long Tirofiban arm is completed.  Enrolment continues in the Short 
Tirofiban and Eptifibatide arms as outlined above. 
 
Approximately 550 patients will be enrolled into the study.  
 


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9.2 Statistical Alternative Hypothesis (Ha) 
The first primary test is that short tirofiban is non-inferior to eptifibatide for death, PPM, 
uTVR or REPLACE-2 Major bleeding within 48 hours following PCI or hospital discharge, 
whichever comes first. The original non-inferiority margin was 12.4% (with an expected 
pooled rate of 32.5%), but based on the higher observed pooled event rate of 51% after 
159 randomized patients, the non-inferiority margin was revised to be 19.1% in order to 
maintain the same relative margin (i.e. 12.4% / 32.5% = 19.1% / 51% = 0.38) For the co-
primary tests, the same non-inferiority margin (19.1%) will be used. 
 
9.3 Study Endpoints, Covariates, and Subgroups 
9.3.1 Primary Endpoint and Associated Tests 
First primary test: A short tirofiban regimen of a high-dose bolus plus a shortened 
infusion duration is non-inferior to label-dosing eptifibatide among patients undergoing 
PCI with respect to death, PPM, uTVR or major bleeding within 48 hours following PCI 
or hospital discharge, whichever comes first. Co-primary tests: (i) a short tirofiban 
regimen of a high-dose bolus plus a 1-2 hour infusion post procedure is non-inferior to 
a long tirofiban regimen of a high-dose bolus plus a 12-18 hour infusion with respect 
to death, PPM, uTVR or major bleeding within 48 hours following PCI or hospital 
discharge, whichever comes first, and (ii) a long tirofiban regimen of a high-dose bolus 
plus a 12-18 hour infusion is non-inferior to label-dosing eptifibatide with respect to 
death, PPM, uTVR or major bleeding within 48 hours following PCI or hospital 
discharge, whichever comes first. No adjustments for multiple testing will be made. 
9.3.2 Secondary Endpoint and Associated Tests 
First secondary test: A short tirofiban regimen of a high-dose bolus plus a shortened 
infusion duration is non-inferior to label-dosing eptifibatide among patients undergoing 
PCI with respect to the following list:  
 
 death, PPM or uTVR within 48 hours following PCI or hospital discharge, whichever 
comes first 
 PPM within 48 hours following PCI or hospital discharge, whichever comes first 
 uTVR within 48 hours following PCI or hospital discharge, whichever comes first 
 death within 48 hours following PCI or hospital discharge, whichever comes first 
 death, PPM, uTVR or major bleeding within 48 hours following PCI or hospital 
discharge, whichever comes first, where PPM is defined as at least one troponin 
elevation of ≥10 times the upper limit of normal AND at least 20% of greater than the 
baseline troponin value, per the troponin Local Laboratory within 48 hours following 
PCI or hospital discharge, whichever comes first (a non-inferiority margin of 12.4% will 
be used for the short tirofiban versus eptifibatide comparison) 
 at least one troponin elevation of ≥10 times the upper limit of normal AND at least 
20% of greater than the baseline troponin value, per the troponin Local Laboratory, 
within 48 hours following PCI or hospital discharge, whichever comes first (a non-
inferiority margin of 12.4% will be used for the short tirofiban versus eptifibatide 
comparison) 
 at least one troponin elevation of ≥20 times the upper limit of normal AND at least 
20% of greater than the baseline troponin value, per the troponin Local Laboratory, 
within 48 hours following PCI or hospital discharge, whichever comes first 


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 at least one troponin elevation of ≥50 times the upper limit of normal AND at least 
20% of greater than the baseline troponin value, per the troponin Local Laboratory, 
within 48 hours following PCI or hospital discharge, whichever comes first. 
Co-secondary tests: (i) a short tirofiban regimen of a high-dose bolus plus a 1-2 hour 
infusion duration post procedure is non-inferior to a long tirofiban regimen of a high-
dose bolus plus a 12-18 hour infusion, and (ii) a long tirofiban regimen of a high-dose 
bolus plus a 12-18 hour infusion is non-inferior to label-dosing eptifibatide with respect 
to the same secondary tests in the list above. 
 
9.3.3 Safety Endpoints 
 Nature, severity, and study drug relationship of all bleeding events  
Specifically, 
Bleeding events according to REPLACE-2 Major bleeding definition 
Bleeding events according to TIMI Major bleeding definition 
Bleeding events according to REPLACE-2 Minor bleeding definition 
Bleeding events according to TIMI Minor bleeding definition 
Bleeding events according to REPLACE-2 Plus Major bleeding definition 
Bleeding events according to TIMI Plus Major bleeding definition 
Sum of REPLACE-2 Major and Minor bleeding 
Sum of REPLACE-2 Plus Major and Minor bleeding 
Sum of TIMI Major and Minor bleeding 
Sum of TIMI Plus Major and Minor bleeding 
 
 Non-bleeding adverse events 
 
 Change in lab parameters 
Specifically, 
Thrombocytopenia (<100,000 cells/L) 
Severe Thrombocytopenia (<50,000 cells/L) 
Profound Thrombocytopenia (<20,000 cells/L) 
 
 Length of hospital stay 
9.3.4 Potential Covariates and/or Subgroups 
 Patient with acute coronary syndromes 
 STEMI >48 hours 
 Stable angina 
 Troponin baseline negative 
 Troponin baseline positive 
 Femoral access PCI 
 Radial access PCI 
 Total stent length 
 Use of a closure device 
 Number of stents implanted 
 Single vessel 
 Multivessel 
 Number of vessels treated 
 Total infusion time 


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 Patients receiving P2Y12 antagonist therapy between 24 and 6 hours prior to  
randomization 
 Patients receiving P2Y12 antagonist therapy between 6 and 1 hours prior to 
randomization 
 Patients receiving P2Y12 antagonist therapy between 1 hour prior to 
randomization and 15 minutes after completion of the PCI procedure 
 Type 1 diabetes mellitus 
 Type 2 diabetes mellitus 
 Prior use of GPIIb/IIIa inhibitor therapy  
 Indication for PCI 
 Age < 65 years, 65 years and 75 years 
 Sex 
 Race 
 Clopidogrel 
 Prasugrel 
 Ticagrelor 
 Elective PCI 
 Urgent PCI 
9.4 Analysis Population 
All efficacy analyses will be performed on the modified intent-to-treat population (MITT) 
(i.e. randomized patients who underwent PCI and received study drug) and on the per-
protocol population (i.e. patients who completed the full course of the study without major 
protocol violations). Safety analyses will be performed on the safety population (i.e. 
patients who received any study treatment). 
9.5 Sample Size Calculations 
The primary outcome variable for this trial is the composite of death, PPM, uTVR or 
REPLACE-2 Major bleeding. 
 
Sample size calculations ensure that the one-sided non-inferiority hypothesis of the first 
primary outcome can be tested with a type-I error rate of 2.5% and 99% power. An event 
rate of 32.5% will be assumed for the active control and test group which was then later 
assumed to be 51% based on pooled analysis after 159 randomized patients. A sample 
size re-estimation was conducted after 159 randomized patients.  
 
For the two co-primary tests, a sample size of approximately 350 was obtained by setting 
the non-inferiority margin at 19.1%, power at 94.5% and a 1-sided alpha at 0.025 
assuming an event rate of 51%. 
 
For the secondary endpoints involving ≥10 times troponin and comparing short tirofiban 
to eptifibatide, a sample size of approximately 500 was obtained by setting the non-
inferiority margin at 12.4%, power at 85% and a 1-sided alpha at 0.025 assuming an event 
rate of 32% (based on ≥10 times troponin elevation data from the 159 randomized 
patients). 
 
SAS version 9.2 (SAS Institute, Cary, NC) was used for the sample-size calculations. 
 


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The trial may be terminated for futility at an interim point in time. Details of the methodology 
and stopping boundaries will be provided in the Statistical Analysis Plan.  
9.6 Planned Methods of Analysis 
General Principles 
For continuous variables, descriptive statistics (mean, SD, median, and quartiles) will be 
tabulated by treatment group. For categorical variables, the number and proportion of 
patients in each category will be tabulated. 
 
The primary and secondary endpoints will be analyzed using the MITT population. Safety 
endpoints will be analyzed using the safety population. Demographics, baseline 
characteristics, and other study assessments will be analyzed using the MITT and intent-
to-treat (ITT) population.  
 
Confidence intervals will be used to assess hypotheses of non-inferiority and superiority. 
Details of the statistical methods will be developed in the Statistical Analysis Plan (SAP). 
 
Demography and Baseline Characteristics 
All appropriate background data will be summarized for each treatment group. If there are 
heterogeneities between two groups in any of the patient characteristics that are of clinical 
importance or could affect the study outcome, the impact of the imbalances will be 
investigated. If necessary, adjustments may be made in the efficacy and safety analysis 
and will be documented in the study report. 
 
Primary Endpoint 
The first primary and co-primary endpoints will be analyzed by the use of a one-sided 
97.5% confidence interval 
 
Subgroup/Covariate Analyses 
Formal subgroup analyses will be performed by including the appropriate interaction terms 
in multivariable logistic regression models. The effects of potential covariates (see Section 
9.3.4) will be assessed using multi-variable logistic regression.  
 
Secondary Endpoints 
The analysis of the secondary endpoints will be conducted in the same way as for the 
primary endpoint. 
 
Safety Endpoints 
The analysis of these safety endpoints will compare the incidence in the short tirofiban 
treatment group to the incidence in the eptifibatide group, the incidence in the short 
tirofiban treatment group to the incidence in the long tirofiban treatment group and the 
incidence in the long tirofiban treatment group to the incidence in the eptifibatide group, 
using the Fisher’s mid-p (Berry and Armitage, 1995). Serious adverse events will also be 
tabulated overall and by severity for each treatment group.  
 
Multiplicity (Multiple Endpoints) 
The clinical decision rule is that tirofiban can only claim to have demonstrated an effect if 
it shows a clinical benefit based on the primary endpoint (death, PPM, uTVR or REPLACE-
2 Major bleeding) within 48 hours following PCI or hospital discharge, whichever comes 
first), irrespective of the outcome of the secondary endpoints. 


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Missing Data 
Imputation methods will not be used for missing data. 
9.7 Timing of Final Analyses 
The final analysis will be conducted when all patients have completed their assessment 
(within 48 hours following PCI or hospital discharge whichever comes first) This database 
will include all patients’ data up to this timepoint from the date of study drug administration. 
The database will be cleaned, locked, and unblinded before the commencement of the 
statistical analysis.  
 
10.0 STUDY DRUG MANAGEMENT 
See the Pharmacy Manual for complete details and requirements for Study Drug 
packaging, labeling, storage, preparation, administration and accountability. 
10.1 Packaging and Labeling 
10.1.1 Tirofiban 
Supply of open-label tirofiban will be the responsibility of the Sponsor. 
10.1.2 Eptifibatide 
Supply of open-label eptifibatide will be the responsibility of the hospital pharmacy. 
10.2 Storage 
Store tirofiban at 25°C (77°F) with excursions permitted between 15°-30°C (59°F-86°F). 
Do not freeze. Protect from exposure to light until used. 
10.3 Accountability 
Investigational clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
research pharmacist, Investigator and/or designated assistants have access. Clinical 
supplies are to be dispensed only in accordance with the protocol. The research 
pharmacist and/or Investigator and/or designate is responsible for keeping accurate 
records of the clinical supplies received from the Sponsor, the amount dispensed and 
returned, and the amount remaining at the conclusion of the study. The above 
accountability is not required for eptifibatide (which is supplied by the hospital pharmacy). 
 
11 STUDY DOCUMENTATION 
Study documentation includes all electronic and paper case report forms, data correction 
forms, source documents, monitoring logs and appointment schedules, Sponsor-
Investigator correspondence and regulatory documents (e.g., signed protocol and 
amendments, Ethics or Institutional Review Committee correspondence and approval, 
approved and signed patient consent forms, Statement of Investigator form, and clinical 
supplies receipts and distribution records). 
 
This study will use web-based electronic CRFs (e-CRFs) developed through a validated, 
ERES-compliant platform (21 CFR Part 11). Prior to initiation of the trial, each site will be 
contacted as to computer availability, hardware specifications, internet connectivity, to 
evaluate their capacity to use this type of data collection system. The Investigator's site 


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staff who will be entering data into this system will receive training on the system, after 
which each person will be issued a unique user identification and password. 
 
For security reasons, and in compliance with regulatory guidelines, it is imperative that 
only the person who owns the user identification and password access the system using 
their own unique access codes. Access codes are non-transferable. Site personnel who 
have not undergone training may not use the system and will not be issued user 
identification and password until appropriate training is completed. 
 
During monitoring visits the site will make their computer and/or high speed Internet 
access available to the CRA so that he/she may verify the data entries with the source 
documentation. At the conclusion of the study, each enrolling site will be provided with a 
compact disc (CD), or equivalent electronic storage device, containing PDF files of both 
the data for each individual patient enrolled at the site and the audit trail (changes made 
to the database). This will be maintained at the site according to the requirements for 
records retention. 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. Accordingly, source documents include, but are not limited to, laboratory 
reports, ECG tracings, X rays, radiologist reports, patient diaries, biopsy reports, 
ultrasound photographs, patient progress notes, hospital charts or pharmacy records and 
any other similar reports or records of any procedure performed in accordance with the 
protocol. 
 
Whenever possible, the original recording of an observation should be retained as the 
source document; however, a photocopy is acceptable provided that it is a clear, legible, 
and exact duplication of the original document. 
 
The Investigator shall prepare and maintain complete and accurate study documentation 
in compliance with Good Clinical Practice standards and applicable federal, state, and 
local laws, rules and regulations; and, for each patient participating in the study, promptly 
complete all original case report forms and such other reports as required by this protocol 
following completion or termination of the clinical study or as otherwise required pursuant 
to any agreement with the Sponsor. 
 
Study documentation will be promptly and fully disclosed to the Sponsor by the 
Investigator upon request and also shall be made available at the Investigator’s site upon 
request for inspection, copying, review and audit at reasonable times by representatives 
of the Sponsor or any regulatory agencies. The Investigator agrees to promptly take any 
reasonable steps that are requested by the Sponsor as a result of an audit to cure 
deficiencies in the study documentation and case report forms. 
 
12 RECORDS RETENTION 
As this study is being conducted under a US Investigational New Drug application, FDA 
regulations require all Investigators participating in clinical drug trials to maintain detailed 
clinical data for one of the following periods: 
 
 A period of at least 2 years following the date on which a New Drug Application is 
approved by the FDA (for this dose/concomitant use); 


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 A period of 2 years after the Sponsor notifies the Investigator that no further 
application is to be filed with the FDA. 
 
The Investigator will not dispose of any records relevant to this study without either (1) 
written permission from the Sponsor or (2) providing an opportunity for the Sponsor to 
collect such records. The Investigator shall take responsibility for maintaining adequate 
and accurate hard copy source documents of all observations and data generated during 
this study. Such documentation is patient to inspection by the Sponsor and its agents as 
well as the FDA and other regulatory agencies. 
 
13 QUALITY CONTROL AND QUALITY ASSURANCE 
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems with written SOPs to ensure 
that trials are conducted and data are generated, documented, and reported in compliance 
with the protocol, accepted standards of Good Clinical Practice, and all applicable federal, 
state, and local laws, rules and regulations relating to the conduct of the clinical study. 
 
14 MONITORING 
The Sponsor has ethical, legal and scientific obligations to follow this study in a detailed 
and orderly manner in accordance with established research principles and applicable 
regulations. As part of a concerted effort to fulfill these obligations (maintain current 
personal knowledge of the progress of the study), the Sponsor or its designee will visit the 
center(s) during the study in addition to maintaining frequent telephone and written 
communication. 
 
15 AUDITING 
The Sponsor may conduct audits at the study center(s). Audits will include, but not be 
limited to the following: audit trail of data handling and processes, SOPs, drug supply, 
presence of required documents, the informed consent process, and comparison of case 
report forms/database with source documents. The Investigator agrees to accommodate 
and participate in audits conducted at a reasonable time in a reasonable manner, as 
needed. 
 
Regulatory authorities worldwide may also audit the Investigator during or after the study. 
The Investigator should contact the Sponsor immediately if this occurs, and must fully 
cooperate with governmental (e.g. FDA) audits conducted at a reasonable time in a 
reasonable manner. 
 
16 ETHICS AND RESPONSIBILITY 
By signing this protocol, the Investigator agrees to conduct the study in compliance with 
the protocol, the Sponsor’s standard operating procedures and/or guidelines, the United 
States Food and Drug Administration (FDA) regulations, the International Conference on 
Harmonisation (ICH) GCP guidelines, the Declaration of Helsinki, and all applicable 
federal, state, and local laws, rules and regulations relating to the conduct of the clinical 
study. 
 
17 INFORMED CONSENT 
Written informed consent will be obtained from all patients (or their legal representative) 
before any study-related procedures (including any pre-treatment procedures, such as 
pre-procedure sedation) are performed or given. The Investigator(s) has both ethical and 


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legal responsibility to ensure that each patient being considered for inclusion in this study 
is given a full explanation of the study. This shall be documented on a written informed 
consent form, which shall be approved by the same Ethics Committee responsible for 
approval of this protocol. Each informed consent form shall include the elements required 
by FDA regulations in 21 CFR Part 50 and ICH GCPs. The investigator agrees to obtain 
approval from the Sponsor of any written informed consent form used in the study, prior 
to submission to the IRB. 
 
Once the appropriate essential information has been provided to the patient and fully 
explained by the Investigators (or a qualified designee) and it is felt that the patient 
understands the implications of participating, the patient and the Investigator (or designee) 
shall sign and date the Ethics Committee approved written informed consent form. The 
patient shall be given a copy of the signed informed consent form, and the original shall 
be kept in the site’s regulatory file. A second copy may be filed in the patient's medical 
record, if allowed by the institution. 
 
If the patient is illiterate, an impartial witness should be present during the entire informed 
consent reading and discussion. Afterward, the patient should sign and date the informed 
consent, if capable. The impartial witness should also sign and date the informed consent 
along with the individual who read and discussed the informed consent (i.e., study staff 
personnel). 
 
The initial informed consent form, any subsequent revised written informed consent form, 
and any written information given to the patient must receive the Ethics Committee 
approval/favorable opinion in advance of use. The patient or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes 
available that may be relevant to the patient’s willingness to continue participation in the 
trial. The communication of this information should be documented. 
 
18 
AUTHORIZATION FOR USE AND DISCLOSURE OF PROTECTED 
HEALTH INFORMATION (HIPAA) 
An authorization for use and disclosure of protected health information under the HIPAA 
Privacy Rule [45 CFR § 164.102 et seq] will be obtained from every trial patient prior to, 
or at the time of, enrollment. It will be presented to, and signed by, the trial patient at the 
same time as the Informed Consent Form (ICF). The Investigator is responsible for 
obtaining trial patients’ (or their legal representatives’) authorizations and signatures, and 
for explaining the elements of the HIPAA Authorization form if necessary.  
 
HIPAA Authorization may either be a separate form or included in the study ICF, 
dependent upon local requirements. If a separate HIPAA document is signed, the 
Investigator will append one signed original of each executed HIPAA Authorization to the 
trial patient’s signed ICF, and file it in the site’s regulatory file. If a second copy of the 
signed ICF is filed in the patient’s medical records, an additional copy of the signed HIPAA 
Authorization form will be appended. Trial patients will be given the other signed duplicate 
for their personal records. 
 
The HIPAA Authorization form will contain all elements required under the HIPAA Privacy 
Rule. By law, site Ethics Committee approval of the Sponsor-provided Authorization form 
for use in this study is not required, and no such approval will be sought or requested. 
However, the Sponsor, upon request, will provide advance copies of its HIPAA 


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Authorization form to the Investigator or the site’s privacy board or privacy official, and will 
work with the site to eliminate any concerns. 
 
The Investigator or the site will promptly inform the Sponsor of any restrictions on the use 
or disclosure of Protected Health Information of any trial patient to which the site or the 
investigator have agreed under the Privacy Rule. The investigator or the site will also 
promptly inform the Sponsor of any written revocation of any trial patient’s HIPAA 
Authorization. 
 
19 INSTITUTIONAL REVIEW BOARD (IRB) 
The Investigator is responsible for obtaining initial and continuing review of the study by 
an IRB. Written approval from the IRB must be forwarded to the Sponsor before clinical 
supplies will be shipped. This protocol and the written informed consent form shall be 
submitted to the IRB identified with this responsibility at the Institution. Notification in 
writing of approval must come from the IRB chairman or secretary to the investigator, 
either as a letter or as a copy of the appropriate section of the IRB meeting minutes where 
this protocol and associated informed consent form were discussed. The Investigator will 
not participate in the decision to approve the protocol. If the Investigator is an IRB member, 
the written approval must indicate such non-participation. The Investigator will submit 
status reports to the IRB at least annually (when applicable). The IRB must be notified by 
the Investigator in writing of the interruption and/or completion of the study; the 
Investigator must promptly report to the IRB all changes in research (protocol 
amendments) and will not make such changes without IRB approval except where 
necessary to eliminate apparent immediate hazards to human patients. In these cases, 
the IRB must be notified within five days of the change. The Investigator will promptly 
report to the IRB all unanticipated problems involving risk to patients or others. The 
Investigator is required to maintain an accurate and complete record of all written 
correspondence to and received from the IRB and must agree to share all such documents 
and reports with the Sponsor. 
 
The IRB will comply with all federal, state, and local laws. Particular attention is drawn to 
the Food and Drug Administration Regulations for Institutional Review Boards (21 CFR, 
Part 56), and the International Conference on Harmonisation (ICH) Guidelines for Good 
Clinical Practices for IRB Committees. 
 
The Sponsor will promptly be advised of any regulatory inspection (relating to this study), 
of either the institution or the IRB. The Investigator will promptly provide the Sponsor with 
a copy of any inspection report. 
 
20.0 CONFIDENTIALITY 
20.1 Confidentiality of Data 
Particular attention is drawn to the regulations promulgated by the Food and Drug 
Administration under the Freedom of Information Act providing, in part, that information 
furnished to clinical Investigators and Institutional Review Boards will be kept confidential 
by the Food and Drug Administration only if maintained in confidence by the clinical 
Investigator and Institutional Review Board. 
 
By signing this protocol, the Investigator affirms to the Sponsor that information furnished 
to the Investigator by the Sponsor will be maintained in confidence and such information 


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will be divulged to the Institutional Review Board, Ethics Review Committee, or similar or 
expert committee; affiliated institution; and employees only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees. Data generated by this study will be considered confidential by the 
Investigator, except to the extent that it is included in a publication. 
20.2 Confidentiality of Patient Records 
By signing this protocol, the Investigator agrees that the Sponsor (or Sponsor 
representative), Institutional Review Board (IRB) or Regulatory Agency representatives 
may consult and/or copy study documents in order to verify case report form data. By 
signing the consent form, the patient agrees to this process. If study documents will be 
photocopied during the process of verifying case report form information, the patient will 
be identified by unique code only; full names/initials will be masked. Notwithstanding the 
foregoing, to the extent that Protected Health Information is used and/or disclosed in the 
course of this study, all applicable provisions of the HIPAA Privacy Rule [45 CFR § 
164.102 et seq] will be complied with. 
20.3 Confidentiality of Investigator Information 
By signing this protocol, the Investigator recognizes that certain personal identifying 
information (e.g., name, hospital or clinic address, curriculum vitae) may be made part of 
a regulatory submission and may be transmitted (either in hardcopy or electronically) to 
all Medicure International affiliates/agents worldwide for internal study management 
purposes or as required by individual regulatory agencies. Additionally, the Investigator’s 
name, hospital/clinic address/phone number may be included when reporting certain 
serious adverse events to regulatory agencies or to other Investigators. 
 
21 DEBARMENT 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
agency will not be allowed to conduct or work on this Sponsor's studies. The Investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred, or if any proceeding for debarment is pending or, to the 
best of the Investigator’s knowledge, threatened. 
 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that site’s IRB. 
 
22 COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS 
By signing this protocol, the Investigator agrees to provide to the Sponsor accurate 
financial information to allow the Sponsor to submit complete and accurate certification 
and disclosure statements as required by U.S. Food and Drug Administration regulations 
(21 CFR Part 54). This requirement also extends to sub-investigators. 
 
23 PUBLICATIONS 
Members of the Steering Committee will be primarily responsible for the creation, review 
and submission of publications and presentations relating to the major aspects of the study 
(design, baseline data, mortality and safety data) and approved sub-study, ancillary 
analyses within a timely fashion after completion of the study. 
 


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The Investigator agrees that all data regarding the study will be the property of the 
Sponsors. The Investigator agrees to consider the results as information patient to 
confidentiality and use restrictions until the results are presented in the public domain. 
 
The underlying principles by which clinical study publication of safety and efficacy data will 
be managed are as follows: 
 
 Manuscripts for publication will be submitted to the Steering Committee with 
representation from the Sponsor. 
 
 Members of the Steering Committee will determine the focus of the manuscript and 
will also select the appropriate journal(s) in which to publish, and will determine the 
appropriate tables and figures for inclusion. 
 
 


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PROTOCOL SIGNATURE PAGE 
 
IND# 38,899; Protocol #11002; Version 3.0 A Randomized, Multicenter, Open-
Label Study to Evaluate the Efficacy of Tirofiban Using a High-Dose Bolus Plus a 
Shortened Infusion Duration Versus Label-Dosing Eptifibatide in Patients 
Undergoing Percutaneous Coronary Intervention 
 
 
SITE PRINCIPAL INVESTIGATOR 
 
I agree to conduct this clinical study in accordance with the design and specific 
provisions of this protocol; deviations from the protocol are acceptable only with a 
mutually agreed upon protocol amendment. I also agree to report all information 
or data in accordance with the protocol and, in particular, I agree to report any 
serious adverse experiences as defined in Adverse Events Section of this protocol. 
I also agree to handle all clinical supplies provided by the SPONSOR and collect 
and handle all clinical specimens in accordance with the protocol. 
 
 
 
 
 
__________________________________ 
Site Principal Investigator (Printed Name) 
 
 
 
 
 
_________________________________ 
Site Principal Investigator (Signature) 
 
 
 
 
 
_________________________________ 
Date 
 
 


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Blockers in Patients Undergoing a High-Risk Percutaneous Coronary Intervention. Am 
J Cardiol 2006;97:489-93. 
 
41. Gunasekara AP, Walters DL, Aroney CN. Comparison of abciximab with ‘‘high-dose’’ 
tirofiban in patients undergoing percutaneous coronary intervention. Int J Cardiol 
2006;109:16-20. 
 
42. Mardikar HM, Hiremath MS, Moliterno DJ, et al. Optimal platelet inhibition in patients 
undergoing PCI: Data from the Multicenter Registry of High-Risk Percutaneous 
Coronary Intervention and Adequate Platelet Inhibition (MR PCI) study. Am Heart J 
2007;154:344.e1-344.e5. 
 
43. Serebruany V, Malinin A, Pokov A, et al. Effects of escalating doses of tirofiban on 
platelet aggregation and major receptor expression in diabetic patients: Hitting the 
TARGET in the TENACITY trial? Thromb Res 2007;119:175-81. 
 
44. Mukherjee D, Roffi M. Current strategies with high-dose tirofiban. Expert Opin Drug 
Metab Toxicol 2007;3:275-80. 
 
45.  van Werkum JW, Gerritsen WBM, Kelder JC, et al. Inhibition of platelet function by 
abciximab or high-dose tirofiban in patients with STEMI undergoing primary PCI: a 
randomised trial. Neth Heart J 2007;15:375-82. 
 
46. Valgimigli M, Campo G, Percoco G, et al. Comparison of Angioplasty With Infusion of 
Tirofiban or Abciximab and With Implantation of Sirolimus-Eluting or Uncoated Stents 
for Acute Myocardial Infarction The MULTISTRATEGY Randomized Trial. JAMA 
2008;299:1788-99. 
 
47. Marmur JD, Poludasu S, Agarwal A, et al. High-Dose Tirofiban Administered as Bolus-
Only during Percutaneous Coronary Intervention. J Invasive Cardiol 2008;20:53-58. 


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48. van‘t Hof AWJ, ten Berg J, Heestermans T, et al. Prehospital initiation of tirofiban in 
patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-
TIME 2): a multicentre, double-blind, randomised controlled trial. Lancet 
2008;372:537-46. 
 
49. Marzocchi A, Manari A, Piovaccari G, et al. Randomized comparison between tirofiban 
and abciximab to promote complete ST-resolution in primary angioplasty: results of 
the facilitated angioplasty with tirofiban or abciximab (FATA) in ST-elevation 
myocardial infarction trial. Eur Heart J 2008;29:2972-80. 
 
50. van’t Hof AWJ, Valgimigli M. Defining the Role of Platelet Glycoprotein Receptor 
Inhibitors in STEMI: Focus on Tirofiban. Drugs 2009;69:85-100. 
 
51. Marmur JD, Poludasu S, Lazar J, et al. Long-Term Mortality After Bolus-Only 
Administration of Abciximab, Eptifibatide, or Tirofiban During Percutaneous Coronary 
Intervention. Catheter Cardiovasc Interv 2009;73:214-21. 
 
52. Valgimigli M, Campo G. de Cesare N, et al. Intensifying Platelet Inhibition With 
Tirofiban in Poor Responders to Aspirin, Clopidogrel, or Both Agents Undergoing 
Elective Coronary Intervention. Circulation 2009;119:3215-22. 
 
53. Valgimigli M, Biondi-Zoccai G, Tebaldi M, et al. Tirofiban as adjunctive therapy for 
acute coronary syndromes and percutaneous coronary intervention: a meta-analysis 
of randomized trials. Eur Heart J 2010;31:35-49. 
 
54. Schiariti M, Saladini A, Missiroli B, et al. Safety of downstream high-dose tirofiban 
bolus among 1578 patients undergoing percutaneous coronary intervention: the 
Sant'ANna TIrofiban Safety study. J Cardiovasc Med 2010;11:250-9. 
 
55. ten Berg JM, van 't Hof AW, Dill T, et al. Effect of early, pre-hospital initiation of high 
bolus dose tirofiban in patients with ST-segment elevation myocardial infarction on 
short- and long-term clinical outcome. J Am Coll Cardiol 2010;55:2446-55. 
 
56. Schiariti M, Saladini, A,, Cuturello D, Missiroli B et al. Long-term efficacy of high-dose 
tirofiban versus double-bolus eptifibatide in patients undergoing percutaneous 
coronary intervention. J Cardiovasc Med 2011;12:29-36. 
 
57. Lincoff AM, Bittl JA, Harrington RA, Feit F et al. Bivalirudin and provisional glycoprotein 
IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade 
during percutaneous coronary intervention. J Am Med Assoc 2003;289:853-63. 
 
58. Bertrand OF, De Larochelliere R, Rodes-Cabau J., Proulx G et al. A randomized study 
comparing same-day home discharge and abciximab bolus only to overnight 
hospitalization and abciximab bolus and infusion after transradial coronary stent 
implantation. Circulation 2006;114:2636-43. 
 
59. Marmur JD, Poludasu S, Agarwal A, Manjappa N, Cavusoglu E. High-dose tirofiban 
administered as bolus-only during percutaneous coronary intervention. J Invasive 
Cardiol 2008;20:53-8. 


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60. Lincoff AM, Bittl JA, Harrington RA, Feit F et al. Bivalirudin and provisional glycoprotein 
Iib/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade 
during percutaneous coronary intervention. J Am Med Assoc 2003;289:853-63.  
 
61. Conde ID, Kleiman NS. Patient-specific antiplatelet therapy. J Thromb Thrombolysis 
2004;17:63-77. 
 
62. Moliterno DJ. A randomized two-by-two comparison of high-dose bolus versus 
abciximab and unfractionated heparin versus bivalirudin during percutaneous 
coronary revascularization and stent placement: the tirofiban evaluation of novel 
dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study 
trial. Cathet Cardiovasc Interv 2011;77:1001-9. 
 
63. a) Medicure Study Report 11001. Dosing regimen model for tirofiban administration to 
patients with severe renal impairment. b) Medicure Study Report 12001. A 
pharmacokinetic, pharmacodynamic, and safety evaluation of tirofiban using a single 
high-dose bolus in subjects with normal renal function and subjects with moderate-to-
severe renal impairment. 
 
64. Chesebro JH, Knatterud G, Roberts R, Borer J et al. Thrombolysis in Myocardial 
Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen 
activator and intravenous streptokinase. Clinical findings through hospital discharge. 
Circulation 1987;76:142-154. 
 
65. Wright RS, Anderson JL, Adams CD et al. 2011 ACCF/AHA Focused update of the 
guidelines for the management of patients with unstable angina/non–ST-Elevation 
myocardial infarction (updating the 2007 guideline). J Am Coll Cardiol 2011;57:1-40. 
 
66. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for 
percutaneous coronary intervention. J Am Coll Cardiol 2011;58:1-79. 
 
67. Integrilin Prescribing Information. http://www.spfiles.com/piintegrilin.pdf 
 
68. Rao SV, Eikelboom JA, Granger CB, Harrington RA et al. Bleeding and blood 
transfusion issues in patients with non-ST-segment elevation acute coronary 
syndromes. Eur Heart J 2007;28:1193-1204. 
 
69. Aggrastat Prescribing Information.  
 


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LIST OF APPENDICES 
 
 
Appendix 1: Schedule of Evaluations and Procedures 
Appendix 2: Laboratory Evaluations 
Appendix 3: Study Drug Dosing Tables 
Appendix 4: ACT Measurements and Unfractionated Heparin Dosing Algorithm 
Appendix 5: Guidelines for Management of Urgent Target Vessel Revascularization 
Appendix 6: Guidelines for Management of Serious Bleeding 
Appendix 7: Guidelines for Management of Thrombocytopenia 


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APPENDIX 1 
Schedule of Evaluations and Procedure  
 
EVALUATION/ 
PROCEDURE 
Timing  
Within 
7 days of 
randomization 
Within 24 h of 
randomization 
Just 
Prior 
to PCI 
Just 
After 
PCI 
93 h 
following 
PCI 
213 h 
following 
PCI 
426 h 
following 
PCI 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Review 
X 
 
 
 
 
 
 
Physical Exam  
X 
 
 
 
 
 
 
Brief Medical History 
X 
 
 
 
 
 
 
Serum/Urine pregnancy 
if of child bearing 
potential 
X 
 
 
 
 
 
 
Serum Creatinine 
 
X 
 
 
 
 
 
PT-INR 
X3 
 
 
 
 
 
 
Hemoglobin/Hematocrit/ 
Platelet Count 
  
X 
X5 
 
X5 
X5 
X1 
Vital Signs 
X4 
 
 
 
X6 
 
 
Activated Clotting Time 
 
 
X 
X7 
 
 
 
Troponin I/T (Local Lab) 
 
 
X5 
 
X5 
X5 
X1 
Randomization  
 
 
X 
 
 
 
 
Unfractionated Heparin 
 
 
X 
 
 
 
 
Bolus (study drug) 
 
 
X 
 
 
 
 
Infusion Initiated (study 
drug) 
 
 
X 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
 
X 
X 
X2 
Adverse Events 
 
 
X 
 
X 
X 
X2 
1 426 h sample is required if patient stays in the hospital longer than 36 h following PCI. 
2 426 h assessment is required if patient stays in the hospital longer than 36 h following 
PCI. 
3 PT-INR for patients receiving oral anticoagulation (warfarin derivatives) within 7 days 
prior to randomization (assessment must be done subsequent to last dose); if the last 
value prior to PCI (within 24 hours prior to randomization) is >1.3 times the control, patient 
is not eligible for enrollment (within 24 hours) 


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4 Vital signs within 7 days prior to randomization include height and weight, body 
temperature, heart rate and systolic and diastolic blood pressure. 
5 Sampling is mandated. 
6 Vital signs at 93 hours following PCI include heart rate and systolic and diastolic blood 
pressure only. 
7 ACT measurement at start of study drug. 
 


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APPENDIX 2 
Laboratory Evaluations 
 
Local Laboratory 
The following laboratory evaluations will be performed by a local laboratory according to 
local practice standards: 
 
 Serum or Urine Pregnancy 
If per institutional policy (within 7 days prior to randomization). 
 
 Serum Creatinine 
Baseline assessment (within 24 hours prior to randomization). 
 
 PT-INR 
PT-INR for patients receiving oral anticoagulation (warfarin derivatives) within 7 
days prior to randomization (assessment must be done subsequent to last dose); 
if the last value prior to PCI (within 24 hours prior to randomization) is >1.3 times 
the control, patient is not eligible for enrollment (within 24 hours). 
 
 Troponin 
Troponin (either troponin I or troponin T) will be sampled immediately prior to PCI, 
preferably from the PCI access sheath or guiding catheter, and at 9±3 hours after 
PCI, and at 21±3 hours after PCI. If the patient remains in the hospital longer than 
36 hours after PCI, a third post-PCI troponin will be sampled at 42±6 hours after 
PCI. All troponin samples will be analyzed by the local laboratory. It is mandated 
that patients be observed for a minimum of 18 hours following PCI to allow for at 
least two post-PCI troponin samples.  
 Hemoglobin, Hematocrit and Platelet Count 
Hemoglobin, hematocrit and platelet count will be sampled at the same time as the 
troponin draws (see above), i.e., immediately prior to PCI, preferably from the PCI 
access sheath or guiding catheter, and at 9±3 hours following PCI, and at 21±3 
hours. If the patient remains in the hospital longer than 36 hours after PCI, a third 
hemoglobin, hematocrit and platelet count post-PCI draw will be sampled at 42±6 
hours after PCI. All hemoglobin, hematocrit and platelet count samples will be 
analyzed by the local laboratory. It is mandated that patients be observed for a 
minimum of 18 hours following PCI to allow for at least two post-PCI hemoglobin, 
hematocrit and platelet count samples. 
 
 PT/aPTT 
If/as indicated for bleeding or sheath removal. 
 
Note no central laboratory work is required for this study. 


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APPENDIX 3 
Study Drug Dosing Tables 
 
Refer to Pharmacy Manual for detailed dosing and drug preparation description. 
 
Short Tirofiban will be administered as a 25 μg/kg bolus followed by a 0.15 μg/kg/min 
infusion for the duration of the PCI procedure plus a minimum of one hour and up to a 
maximum of two hours post-PCI.  
 
Eptifibatide will be administered as a 180 g/kg bolus followed by a 2.0 g/kg/min infusion 
for 18 hours post-PCI (minimum 12 hours mandated), with a second 180 g/kg bolus 10 
min after the first. 
 
Long Tirofiban was administered as a 25 µg/kg bolus followed by a 0.15 µg/kg/min infusion 
for 18 hours post-PCI (minimum 12 hours mandated). 
 
The study drug boluses of tirofiban or eptifibatide will be administered intravenously by 
volume according to patient weight (see Appendix 3 for dosing tables). The bolus volume 
and infusion rate increases with increasing patient weight, but is capped at the patient 
weight of 153 and 121 kg for tirofiban and eptifibatide, respectively. Therefore, any patient 
randomized to short or long tirofiban weighing over 153 kg will receive the same bolus 
volume and infusion rate as a patient randomized to tirofiban weighting 153 kg. Similarly, 
any patient randomized to eptifibatide weighing over 121 kg will receive the same bolus 
volume and infusion rate as a patient randomized to eptifibatide weighting 121 kg. See 
Tables 1 and 2 for study-drug dosing information. 
 
In The Event of Thrombotic Complications 
 
The following six paragraphs refer ONLY to patients assessed a thrombotic complication 
(according to the criteria defined in section 5.2.4) persisting at the end of the PCI 
procedure:  
 
Patients administered short tirofiban with normal renal function shall receive a 
continuing infusion of 0.15 μg/kg/min maintenance infusion of tirofiban for a minimum 
of 12 hours following PCI. See Table 1 for study-drug dosing table. After 159 patients 
were randomized, a 1:1:1 randomization was initiated, randomizing patients to short 
tirofiban, eptifibatide or long tirofiban. 
 
Patients administered short tirofiban with renal insufficiency (creatinine clearance ≤60 
mL/min) shall receive a continuing infusion of 0.075 μg/kg/min maintenance infusion 
(i.e. 1/2 the usual rate) of tirofiban for a minimum of 12 hours following PCI. See Table 
1 for study-drug dosing table. The change in dosing for patients with renal 
insufficiency (<30 mL/min to <60 mL/min creatinine clearance) randomized to either 
short or long tirofiban was implemented after 159 patients were enrolled. The second 
change in dosing for patients with creatinine clearance ≤60 mL/min (0.10 to 0.075 
μg/kg/min was implemented after 167 patients were enrolled. 
 
Patients administered eptifibatide with normal renal function shall continue to receive 
a 2.0 μg/kg/min maintenance infusion of eptifibatide for 18 hours following PCI 


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(minimum 12 hours mandated, no maximum infusion duration). See Table 2 for study-
drug dosing table. 
 
Patients administered eptifibatide with renal insufficiency (creatinine clearance <50 
mL/min) shall continue to receive a 1.0 μg/kg/min maintenance infusion (i.e. 1/2 the 
usual rate) of eptifibatide for 18 hours following PCI (minimum 12 hours mandated, 
no maximum infusion duration). See Table 2 for study-drug dosing table. 
 
Patients administered long tirofiban with normal renal function received a continuing 
infusion of 0.15 μg/kg/min maintenance infusion of tirofiban for 18 hours following PCI 
(minimum 12 hours mandated, no maximum infusion duration). See Table 1 for study-
drug dosing table. 
 
Patients administered long tirofiban with renal insufficiency (creatinine clearance ≤60 
mL/min) received a continuing infusion of 0.075 μg/kg/min maintenance infusion (i.e. 
1/2 the usual rate) of tirofiban for 18 hours following PCI (minimum 12 hours 
mandated, no maximum infusion duration). See Table 1 for study-drug dosing table. 
 


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Table 1. Tirofiban dosing table using 100 mL injection premixed bags. 
Patient Weight 
(kg) 
Bolus Volume 
(mL) 
0.15 g/kg/min 
Infusion Rate 
(mL/hr) 
0.075 g/kg/min 
Infusion Rate 
(mL/hr) 
30-37 
17 
6 
3 
38-45 
21 
7.5 
3.75 
46-54 
25 
9 
4.5 
55-62 
29 
10.5 
5.25 
63-70 
33 
12 
6 
71-79 
37.5 
13.5 
6.75 
80-87 
42 
15 
7.5 
88-95 
46 
16.5 
8.25 
96-104 
50 
18 
9 
105-112 
54 
19.5 
9.75 
113-120 
58 
21 
10.5 
121-128 
62 
22.5 
11.25 
129-137 
66.5 
24 
12 
138-145 
71 
25.5 
12.75 
146-153 
75 
27 
13.5 
 
Table 2. Eptifibatide dosing table [67]. 
 
 


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APPENDIX 4 
ACT Measurements and Unfractionated Heparin Dosing Algorithm 
 
For Patients Administered Background Unfractionated Heparin Therapy 
 
In this study, the recommended target for the ACT is 200-300 seconds for patients 
administered background unfractionated heparin and randomized to either short or long 
tirofiban or eptifibatide. The following sequence of events is recommended for all patients 
administered background unfractionated heparin and randomized to either tirofiban or 
eptifibatide in this study: 
 
If unfractionated heparin therapy was used pre-procedure, the infusion must be turned off 
before the start of the index procedure. 
 
The following sequence of events is recommended for all patients administered 
background unfractionated heparin and randomized to either tirofiban or eptifibatide in this 
study: 
 
 Establish vascular access. 
 
 If the patient is not receiving intravenous unfractionated heparin, administer 50 U/kg 
of heparin and then proceed to the next step. If the patient has received an 
intravenous unfractionated heparin infusion within the previous 6 hours, proceed 
directly to the next step. 
 
 Obtain ACT, perform guide shot angiograms. 
 
 If ACT is  200 seconds, the intervention may begin. 
 
 If ACT is  200 seconds, administer additional heparin per the following dosing 
guidelines. 
 
Baseline ACT  
(seconds) 
Unfractionated Heparin dose  
(U/kg) 
<150 
40 
150-174 
25 
175-199 
10 
 
 The initial bolus dose should not exceed 6,000 units. 
 
 An ACT should be checked a minimum of 2 minutes after the initial unfractionated 
heparin bolus. If the ACT is  200 seconds, the intervention may begin. 
 
 If the ACT is <200 seconds, an additional bolus should be administered as in the 
table above. An ACT should then be checked a minimum of 2 minutes after this 
additional bolus. 


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 Additional boluses of unfractionated heparin may be given as in the table above 
until an ACT of  200 seconds is achieved. 
 
These recommendations are to serve as guidelines. Additional boluses of unfractionated 
heparin may also be administered according to the discretion of the operator to achieve 
and maintain the ACT in the target range of 200-300 seconds. 
 
During the procedure: 
 
 After an initial ACT of 200-300 seconds is obtained, the ACT should be re- 
checked 30 minutes later, and every 30 minutes thereafter for the duration of the 
procedure. 
 
 If the ACT is  200 seconds, no additional unfractionated heparin should be given. 
 
 If the ACT is <200 seconds, an additional bolus may be administered as in the  
table above. An ACT should then be checked a minimum of 2 minutes after this 
additional bolus. 
 
These recommendations are to serve as guidelines. Additional boluses of unfractionated 
heparin may also be administered according to the discretion of the operator to maintain 
the ACT in the target range of 200-300 seconds. 
 


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APPENDIX 5 
Guidelines for Management of Urgent Target Vessel Revascularization 
 
If the PCI procedure is unsuccessful and the patient requires urgent CABG (within 24 
hours post-procedure), study drug should be discontinued and appropriate measures be 
taken to minimize the surgical risk. Both short and long tirofiban and eptifibatide treated 
patients will generally recover platelet function within 4 to 8 hours, although platelet and/or 
fresh frozen plasma transfusions might be considered for bleeding. There is limited 
experience with the efficacy of either of these interventions, though cryoprecipitate or FFP 
has been suggested for urgent reversal of tirofiban’s effect. 
 
Delayed Elective CABG 
If the patient is scheduled for delayed elective CABG, study drug infusions should continue 
if clinically appropriate. Optimally, elective CABG should be deferred for 3-5 days to allow 
for normalization of platelet function among patients who have received study drug and 
clopidogrel.  


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APPENDIX 6 
Guidelines for Management of Serious Bleeding 
 
Should a major bleeding complication occur during study drug infusion, the first step in 
treatment should be to immediately discontinue the study drug. Packed red blood cells 
should be transfused as clinically indicated (see Transfusion Guidelines appended in this 
Appendix). Transfusion of platelets may also be considered, especially in the presence of 
severe thrombocytopenia (see Appendix 7). 
 
Any patient experiencing clinically significant bleeding which does not warrant immediate 
discontinuation of study drug must have a complete blood count (CBC) including platelet 
count and a PT/PTT repeated within four (4) hours of the observed blood loss or the last 
CBC. Based upon the results of this CBC and platelet count and subsequent clinical 
events either: 
 
a. In the opinion of the Investigator the patient is clinically stable; then study drug 
infusions may continue and another repeat CBC/platelet and PT/PTT must be 
obtained 4 hours later to confirm patient stability, OR 
 
b. In the opinion of the Investigator the patient is considered unstable as 
determined by clinical symptoms or assessment of labs, then the study drugs 
should be discontinued. 
 
Consideration should be given to transfusion of fresh frozen plasma in the event of serious 
bleeding. Platelet function should return to near baseline in approximately 90% of patients 
in 4 to 8 hours.  
 
A decision to administer platelets should be based on clinical judgment, taking into 
account the site and severity of bleeding and time of discontinuation of study drug. In the 
case of documented or suspected central nervous system (CNS) hemorrhage, platelet 
transfusions are strongly recommended regardless of treatment assignment. If a decision 
is made to administer platelets, it is recommended that 10 units of platelets be given 
initially. If platelet function does not return to normal or cannot be measured, repeat 
platelet transfusions should be considered within 1 to 2 hours if there is evidence of 
progressive CNS hemorrhage or uncontrollable gastrointestinal, genitourinary, or 
retroperitoneal hemorrhage. If serious bleeding occurs in the setting of thrombocytopenia, 
platelet transfusions should be administered. 
 


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Transfusion Guidelines 
 
Guidelines for Transfusion in Asymptomatic Patients: 
a) Assess the patient’s intravascular volume status. All asymptomatic patients 
should be normovolemic. Normovolemic anemia (hemoglobin 7 –10 g/dl) can be 
well tolerated in asymptomatic patients. 
 
b) If hypovolemic, intravascular volume of patients should be adequately restored 
with crystalloids. 
 
c) In asymptomatic, normovolemic patients transfusion is not indicated unless the 
hgb is 7 g/dl or a deterioration in vital signs is seen or unless the patient develops 
signs and symptoms, as described below. 
 
Guidelines for Transfusion in Symptomatic Patients: 
If the following signs and symptoms occur, syncope, dyspnea, postural hypotension, 
tachycardia, angina, transient ischemic attack: 
 
a) Use crystalloids to replace intravascular volume. 
 
b) If symptoms persist after volume repletion, the patient should receive 
transfusion(s) with autologous blood (if available). 
 
c) If autologous blood is not available, the patient should receive transfusion(s) 
with homologous blood on a unit-by-unit basis to relieve symptoms. Remember: 
One unit may be sufficient. 
 
 
 
 
 
 
 
 


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APPENDIX 7 
Guidelines for Management of Thrombocytopenia 
 
< 100,000 cells/L and a decrease of at least 25% from the baseline 
If a platelet count falls below 100,000 cells/µL and decreases at least 25% from the 
baseline value in any sample compared to any previous sample, additional repeat platelet 
counts and/or further laboratory analyses (i.e., microscopic) per local institution guidelines 
must be performed to exclude laboratory error (clumping, etc.). The repeat platelet counts 
should be performed according to the specific practice at each institution.  
 
If thrombocytopenia is verified and determined not to be an artifact caused by the 
interaction with anticoagulants (pseudothrombocytopenia), a daily platelet count is to be 
obtained until the platelet count steadily and adequately increases or returns to within 
normal range. 
 
< 50,000 cells/μL 
In addition to the above, if a patient’s platelet count drops to less than 50,000 cells/μL, 
aspirin and the study drug infusions should be discontinued. 
 
< 20,000 cells/μL 
In addition to the above, if a patient’s platelet count drops below 20,000 cells/μL, 
transfusion should be considered to maintain a platelet count greater than 50,000 cells/μL. 
 
 
 

SAP_001.pdf: 
SAVI-PCI 
Shortened Aggrastat Versus Integrilin in 
Percutaneous Coronary Intervention 
A Randomized, Multicenter, Open-Label Study to 
Evaluate the Efficacy of Tirofiban Using a High-
Dose Bolus Plus a Shortened Infusion Duration 
Versus Label-Dosing Eptifibatide in Patients 
Undergoing Percutaneous Coronary Intervention  
NCT01522417
Date: February 20, 2019 
Statistical Analysis Plan 
Version 2.0 


 
CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and Medicure International Inc. 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
Study Title: 
A Randomized, Multicenter, Open-Label Study to Evaluate the Efficacy of Tirofiban Using a 
High-Dose Bolus Plus a Shortened Infusion Duration Versus Label-Dosing Eptifibatide in 
Patients Undergoing Percutaneous Coronary Intervention  
(SAVI-PCI) 
 
Study Protocol #: 11002 
 
 
Medicure International Inc. 
c/o CanAm Bioresearch Inc. 
9-1250 Waverley Street 
Winnipeg, MB R3T 6C6 
Phone: 204-928-7908 
Fax: 204-488-9823 
 
 
Prepared by JSS Medical Research 
Version FINAL 2.0 
20 February, 2019


Study Name: SAVI-PCI (MIDCAN040318) 
Version FINAL 2.0 | 20FEB2019  
Page 2 of 79 
 
 
CONFIDENTIAL INFORMATION | No Distribution or Publication without written                                                       
authorization from JSS Medical Research Inc. and Medicure International Inc. 
 
 
Statistical Analysis Plan Approval 
Prepared by: 
 
 
Viet Ahn Tran 
Biostatistician 
JSS Medical Research Inc. 
9400 Henri Bourassa Blvd. West 
Montreal (St Laurent), QC, H4S 1N8 
 
 
Date: 
Signature: 
Dr. John S. Sampalis 
Chief Executive and Scientific Officer 
JSS Medical Research Inc. 
9400 Henri Bourassa Blvd. West 
Montreal (St Laurent), QC, H4S 1N8 
 
 
Date: 
Signature: 
Reviewed & Approved at Medicure by: 
Deborah Douglas PhD 
VP Operations, Manufacturing 
Medicure Inc.  
Cell: 204-333-2085 Office: 204-594-3624 
Email: ddouglas@medicure.com   
 
 
Date: 
Signature: 
 
 
Neil Owens, PhD 
Director, Scientific Affairs 
Medicure Inc.  
Cell: 204-298-5520 
Email: nowens@medicure.com   
 
 
Date: 
Signature: 
 
 


SAVI-PCI 
Statistical Analysis Plan 
Version FINAL 
20 February, 2019 
Page 3 of 79 
 
 
 
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TABLE OF CONTENTS 
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SAVI-PCI 
Statistical Analysis Plan 
Version FINAL 
20 February, 2019 
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CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and Medicure International Inc. 
 
LIST OF ABBREVIATIONS 
ACC 
American College of Cardiology  
ACT 
Activated clotting time  
ADP 
Adenosine diphosphate  
AHA 
American Heart Association  
AE 
Adverse event 
aPTT 
Activated partial thromboplastin time  
CABG 
Coronary artery bypass graft  
CBC 
Complete blood count  
CDS 
Clinical development solutions  
CK 
Creatine kinase 
CK-MB 
Creatine kinase-myocardial band  
CNS 
Central nervous system  
CRA 
Clinical research associate  
CRF 
Case report form  
CVA 
Cerebrovascular accident  
Da 
Dalton 
DSMB 
Drug Safety Monitoring Board 
ECG 
Electrocardiogram 
ESC 
European Society of Cardiology 
ESPRIT 
Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin 
Therapy 
ESRD 
End stage renal disease 
ENT 
Ears, nose, throat 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
GPIIb/IIIa 
Glycoprotein IIb/IIIa receptor antagonist 
GU 
Genitourinary 
Hct 
Hematocrit 
Hgb 
Hemoglobin 


SAVI-PCI 
Statistical Analysis Plan 
Version FINAL 
20 February, 2019 
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CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and Medicure International Inc. 
 
HIPAA 
Health Insurance Portability and Accountability Act  
HDB 
High-dose bolus (25 µg/kg tirofiban) 
h 
Hour(s) 
Hg 
Mercury 
ICF 
Informed consent form  
IND 
Investigational new drug  
INR 
International normalized ratio  
IRB 
Institutional review board  
ITT 
Intent to treat  
I.V. 
Intravenous  
kg 
kilogram 
LTA 
Light transmission aggregometry  
mg 
milligram 
MI 
Myocardial infarction 
min 
minute 
mL 
milliliter 
mm 
millimeter 
MITT 
Modified intent to treat 
NS 
Non-significant 
NSTEMI 
Non-ST elevation myocardial infarction 
NSTE 
Non-ST elevation 
PCI 
Percutaneous coronary intervention 
PK 
Pharmacokinetic 
PPACK 
D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone  
PPM 
Periprocedural myonecrosis 
PRISM  
The Platelet Receptor Inhibition in Ischemic Syndrome Management  
PRISM PLUS 
The Platelet Receptor Inhibition in Ischemic Syndrome Management in 
Patients Limited By Unstable Signs and Symptoms PT 
PTCA 
Prothrombin time 
PTCA 
Percutaneous transluminal coronary angioplasty 


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REPLACE-2 
Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical 
Events 
RESTORE  
Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis 
RPFA 
Rapid platelet function assay 
SAE(s) 
Serious adverse event(s) 
SAP 
Statistical analysis plan 
SCRI 
Sarah Cannon Research Institute second 
sec 
Seconds 
SOP 
Standard operating procedure 
TARGET 
Do Tirofiban and ReoPro Give Similar Efficacy Trial 
TRAP 
Thrombin receptor agonist peptide 
STEMI 
ST elevation myocardial infarction 
TIMI 
Thrombolysis in myocardial infarction 
uTVR 
Urgent target vessel revascularization 
u 
Units 
ULN 
Upper limit of normal 
uFH 
Unfractionated heparin 
uTVR 
Urgent target vessel revascularization  
vs. 
versus 
WHF 
World Heart Federation 
µg 
microgram 
µL 
microliter 


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Statistical Analysis Plan 
Version FINAL 
20 February, 2019 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide a detailed description of the 
statistical analyses that will be performed according to the study protocol. 
 
The SAP presents a summary of the study protocol and describes the populations that will be 
analyzed. Relevant subject characteristics and parameters to be evaluated are described along with 
the specific statistical methods assessing the study endpoints. 
 
2 
PROTOCOL SUMMARY  
2.1 
Background 
An estimated 596,000 patients underwent percutaneous coronary intervention (PCI) procedures in 
the United States in 2009, and the majority of these patients received a coronary stent as part of 
their treatment. The number of percutaneous revascularization procedures performed has 
dramatically increased in the last decade, and PCI is the most common procedure performed on 
hospitalized adult Americans [1]. 
 
PCI carries an inherent risk of thrombotic complications. Patients therefore receive periprocedural 
pharmacotherapies targeted at inhibiting anticoagulation, including platelet aggregation. The same 
mechanisms that confer the benefits of these agents, however, also increase the risk of bleeding 
which has been correlated with adverse outcomes [2, 3]. Selecting the appropriate 
pharmacotherapies requires close attention to the delicate balance between reducing the risk of 
ischemic events and minimizing bleeding risk. 
 
A broad range of antiplatelet agents are available, including aspirin, thienopyridines, and 
glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, all of which have shown considerable efficacy and 
satisfactory safety in the population of patients undergoing PCI. Antiplatelet therapy is relevant 
during PCI since disruption of the arterial wall results in platelet activation, adhesion and 


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Statistical Analysis Plan 
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aggregation, which leads to thrombus formation. Aspirin reduces the incidence of acute thrombotic 
complications during PCI and is considered standard therapy. However, aspirin is a relatively weak 
platelet inhibitor, inhibiting the cyclooxygenase pathway, which is only one of the many pathways 
to platelet aggregation. More potent antiplatelet agents have been proven superior to aspirin, and 
when administered together are synergistic [4]. When combined with aspirin, oral thienopyridines 
such as ticlopidine, clopidogrel, prasugrel and ticagrelor provide additional platelet inhibition, 
thereby reducing the rate of ischemic events, particularly among patients receiving a coronary 
stent. Direct and indirect thrombin inhibitors (e.g. bivalirudin and unfractionated heparin), while 
not providing substantial antiplatelet inhibition, are used in conjunction with, and sometimes in 
place of, GPIIb/IIIa inhibitors. 
 
Three GPIIb/IIIa inhibitors are approved for use in the United States: abciximab (Eli Lilly & 
Company, Indianapolis, Indiana), eptifibatide (Merck & Co., Whitehouse Station, New Jersey), 
and tirofiban HCl (Medicure Pharma Inc., Princeton, New Jersey) [5]. These agents block the 
GPIIb/IIIa receptor on platelets, blocking what has frequently been termed the final common 
pathway of aggregation, i.e., fibrinogen-mediated cross-linkage [6]. Their efficacy in preventing 
PCI-related complications [7-14] and in treatment of non- ST-segment-elevation (NSTE) acute 
coronary syndrome (ACS) [15-19] has been demonstrated in multiple large-scale trials, with 
overall risk reductions in adverse thrombotic events in PCI populations of 35% and in NSTE ACS 
of 44% [5]. 
 
Tirofiban, more specifically, is a highly selective non-peptide antagonist of the GPIIb/IIIa receptor 
whose structure mimics the RGD peptide sequence in fibrinogen. Tirofiban is similar to 
eptifibatide but is a smaller molecule (495Da vs. 832Da), is more potent (143 nM vs. 810 nM for 
concentration required to achieve 50% platelet inhibition), with a slightly shorter half-life (2h vs. 
2.5h). Compared to abciximab, tirofiban is reversible, is not known to be immunogenic, and, in 
combination with heparin, has been shown to be effective in reducing ischemic events among 
patients with acute coronary syndrome. Data from 6 large clinical trials using tirofiban at the 
currently approved label dose [14, 15, 17, 20-22] demonstrated its efficacy and safety in reducing 


SAVI-PCI 
Statistical Analysis Plan 
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acute ischemic events in a broad range of patients (cumulative N >12,000) with ACS, moderate to 
high-risk coronary lesion anatomy, or both. Despite evidence for efficacy of the approved dosing 
in ACS, further investigations established the tirofiban label-dosing to be suboptimal for settings 
such as PCI and stent setting where rapid (<30 minute) attainment of therapeutic platelet inhibition 
is required and that a higher dose bolus (HDB) regimen of tirofiban (25 µg/kg followed by a 0.15 
µg/kg/min maintenance infusion) is necessary. Data for the HDB tirofiban regimen from 15 
clinical studies and 50 peer-reviewed publications since 2003 have clearly demonstrated its 
efficacy and safety profile [23-46]. The tirofiban high-dose bolus regimen is approved for use in 
the setting of PCI in Europe and the United States. 
 
In addition, several studies involving GPIIb/IIIa inhibitor therapies have investigated the clinical 
effectiveness and safety of using a bolus plus a shortened infusion duration or a bolus- only dosing 
regimen in the PCI setting. These reduced regimens are seen as attractive to interventional 
cardiologists since it has potential to reduce bleeding tendencies, lower the cost of therapy, and 
reduce the need for overnight hospitalization without compromising efficacy. 
 
Bertrand and co-workers [47] showed a high-dose bolus only of abciximab to be not clinically 
inferior to the standard bolus plus 12 hour infusion of abciximab after uncomplicated PCI in their 
study patient population. Fung and co-workers [48] showed that a <2 hour infusion of eptifibatide 
is non-inferior to the standard 18 hour eptifibatide infusion in preventing ischemic outcomes and 
is superior in reducing major bleeding after successful coronary intervention. Marmur and co-
workers [31] showed that a high-dose of tirofiban (25 µg/kg) during PCI is safe and, in a sub-
population of ACS patients, compares favorably to the post-PCI MI incidence of REPLACE-2 
[49]. These studies suggest a bolus plus a shortened infusion of GPIIb/IIIa inhibitor therapy can 
be safe and effective in the setting of PCI. 
 
2.2 
Rationale 
Anti-platelet therapy is established as improving outcomes in the setting of PCI of which 
GPIIb/IIIa inhibitors are the most potent and efficacious. Both eptifibatide and tirofiban 


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experienced serious challenges in establishing an optimal dosing regimen during their clinical 
development. After refinement of dosing, treatment guidelines now recommend their use to 
improve outcomes [50, 51]. Over time, and with the continued evolution of therapy, concerns 
linked to safety and inconvenience of the relatively long infusion have complicated and limited 
the use of these agents despite their demonstrated efficacy. There is, therefore, a clear medical and 
scientific interest to re-evaluate and to further optimize the GPIIb/IIIa inhibitor therapy dosing 
regimen. 
 
This clinical protocol was designed to evaluate the efficacy and safety of a 25 µg/kg bolus dose of 
tirofiban followed by an infusion 0.15 µg/kg/min for the duration of PCI procedure plus a 
minimum of one hour and up to a maximum of two hours post-PCI among patients undergoing 
PCI with a planned placement of a coronary stent and to compare the efficacy and safety of this 
regimen of tirofiban to label-dosing eptifibatide. In addition, a comparison of tirofiban using a 
shortened infusion duration versus tirofiban using a longer infusion duration will also be evaluated 
to isolate any clinical differences using different infusion durations of the same drug. The third 
comparison of tirofiban versus eptifibatide (using a 12-18 hour infusion duration for both treatment 
arms) will be evaluated to isolate any clinical differences between the two drugs using the same 
infusion duration.  
 
2.3 
Study Objectives 
2.3.1 Primary Objective: 
The first primary objective of this study is to assess whether a tirofiban regimen of a high dose 
bolus plus a shortened infusion duration compared to label-dosing of eptifibatide in patients 
undergoing PCI is associated with a non-inferior composite rate of death, PPM, uTVR or in-
hospital major bleeding within 48 hours following PCI or hospital discharge, whichever comes 
first. 
 
The co-primary objectives of this study are to assess whether:  


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(i) a short tirofiban regimen of a high-dose bolus plus a 1-2 hour infusion post procedure compared 
to a long tirofiban regimen of a high-dose bolus plus a 12-18 hour infusion, and (ii) a long tirofiban 
regimen of a high-dose bolus plus a 12-18 hour infusion compared to label-dosing eptifibatide, are 
associated with non-inferior composite rates of death, PPM, uTVR, or in-hospital major bleeding 
within 48 hours following PCI or hospital discharge, whichever comes first. 
 
2.3.2 Secondary Objective(s): 
The first secondary objective of this study is to assess whether a tirofiban regimen of a high-dose 
bolus plus a shortened infusion duration is safe compared to label-dosing eptifibatide among 
patients undergoing PCI, as assessed by the incidence of major bleeding within 48 hours following 
PCI or hospital discharge, whichever comes first. 
 
The co-secondary objectives of this study are to assess whether: (i) a short tirofiban regimen of a 
high-dose bolus plus a 1-2 hour infusion post procedure is safe compared to a long tirofiban 
regimen of a high-dose bolus plus a 12-18 hour infusion, and (ii) a long tirofiban regimen of a 
high-dose bolus plus a 12-18 hour infusion is safe compared to label-dosing eptifibatide, among 
patients undergoing PCI as assessed by the incidence of major bleeding within 48 hours following 
PCI or hospital discharge, whichever comes first. 
 
2.4 
Study Design  
This is a randomized, multicenter, open-label study comparing tirofiban I.V. bolus injection 
followed by a maintenance infusion for the duration of the PCI procedure plus a minimum of one 
hour and up to a maximum of two hours post-PCI versus label-dosing eptifibatide. Patients were 
randomized to tirofiban or eptifibatide using a 1:1 allocation ratio. At 159 randomized patients, a 
1:1:1 randomization was initiated, randomizing patients to short tirofiban, eptifibatide or long 
tirofiban. Enrolment in the long tirofiban arm has been completed. Patients are mandated to stay a 
minimum of 18 hours following PCI. 
 


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Physician-directed standard background therapies will include dual oral antiplatelet therapy with 
aspirin and an approved oral P2Y12 antagonist as well as antithrombotic therapy with 
unfractionated heparin. Physician-directed P2Y12 antagonist therapy and choice of femoral or 
radial access site must be pre-specified prior to randomization. 
 
The first 159 patients were randomized to the following two treatment arms on a 1:1 basis: 
1. Tirofiban (25 g/kg bolus followed by a 0.15 g/kg/min infusion for the duration of the 
PCI procedure plus a minimum of one hour and up to a maximum of two hours post-PCI). 
2. Eptifibatide (180 g/kg bolus followed by a 2.0 g/kg/min infusion for 18 hours post-PCI 
[minimum 12 hours mandated], with a second 180 g/kg bolus 10 min after the first). 
 
The three treatment arms for enrollment after the 159th patient were: 
1. Short Tirofiban (25 g/kg bolus followed by a 0.15 g/kg/min infusion for the duration of 
the PCI procedure plus a minimum of one hour and up to a maximum of two hours post-
PCI). 
2. Eptifibatide (180 g/kg bolus followed by a 2.0 g/kg/min infusion for 18 hours post-PCI 
[minimum 12 hours mandated], with a second 180 g/kg bolus 10 min after the first). 
3. Long Tirofiban (25 µg/kg bolus followed by a 0.15 µg/kg/min infusion for 18 hours post-
PCI) [minimum 12 hours mandated]. 
 
The short tirofiban versus eptifibatide comparison involves approximately 500 patients; the short 
tirofiban versus long tirofiban comparison involves approximately 350 patients; and the long 
tirofiban versus eptifibatide comparison involves approximately 350 patients. Approximately 550 
patients will be enrolled into the study. 
The study procedures to take place during the course of the study are summarized in the following 
Schedule of Evaluations and Procedures (Table 1).  
 


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Table 1. Schedule of Evaluations and Procedures 
 
Timing 
EVALUATION/ 
PROCEDURE 
Within
7 days of 
randomization
Within 24 h 
of 
randomization
Just
Prior 
to PCI
Just
After
PCI 
9±3 h
following 
PCI 
21 ±3 h
following 
PCI 
42±6 h
following 
PCI 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Review
X 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
Brief Medical History 
X 
 
 
 
 
 
 
Serum/Urine pregnancy if 
of child bearing potential
X 
 
 
 
 
 
 
Serum Creatinine 
 
X 
 
 
 
 
 
PT-INR 
X3 
 
 
 
 
 
 
Hemoglobin/Hematocrit/ 
Platelet Count 
 
X 
X5 
 
X5 
X5 
X1 
Vital Signs 
X4 
 
 
 
X6 
 
 
Activated Clotting Time 
 
 
X 
X7 
 
 
 
Troponin I/T (Local Lab) 
 
 
X5 
 
X5 
X5 
X1 
Randomization 
 
 
X 
 
 
 
 
Unfractionated Heparin 
 
 
X 
 
 
 
 
Bolus (study drug) 
 
 
X 
 
 
 
 
Infusion Initiated (study 
drug)
 
 
X
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
 
X 
X 
X2 
Adverse Events 
 
 
X 
 
X 
X 
X2 
1 42±6 h sample is required if patient stays in the hospital longer than 36 h following PCI. 
2 42±6 h assessment is required if patient stays in the hospital longer than 36 h following PCI. 
3 PT-INR for patients receiving oral anticoagulation (warfarin derivatives) within 7 days prior to randomization (assessment 
must be done subsequent to last dose); if the last value prior to PCI (within 24 hours prior to randomization) is >1.3 times the 
control, patient 
is not eligible for enrollment (within 24 hours) 
4 Vital signs within 7 days prior to randomization include height and weight, body temperature, heart rate and systolic and 
diastolic blood pressure. 


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5 Sampling is mandated. 
6 Vital signs at 9±3 hours following PCI include heart rate and systolic and diastolic blood pressure only. 
7 ACT measurement at start of study drug. 
 
2.5 
Study Duration 
Subject enrolment in the Long Tirofiban arm has been completed. Enrolment continues in the 
Short Tirofiban and Eptifibatide arms as outlined in Section 2.4 above. 
 
2.6 
Sample Size 
The primary outcome variable for this trial is the composite of death, PPM, uTVR or REPLACE-
2 major bleeding. 
 
Sample size calculations ensure that the one-sided non-inferiority hypothesis of the first primary 
outcome can be tested with a type-I error rate of 2.5% and 99% power. An event rate of 32.5% 
was assumed for the active control and test group, which was then later adjusted to be 51% based 
on pooled analysis after 159 randomized patients. A sample size re-estimation was conducted after 
159 randomized patients. 
 
For the two co-primary tests, a sample size of approximately 350 was obtained by setting the non-
inferiority margin at 19.1%, power at 94.5% and a 1-sided alpha at 0.025 assuming an event rate 
of 51%. 
 
For the secondary endpoints involving  10 times troponin and comparing short tirofiban to 
eptifibatide, a sample size of approximately 500 was obtained by setting the noninferiority margin 
at 12.4%, power at 85% and a 1-sided alpha at 0.025 assuming an event rate of 32% (based on 10 
times troponin elevation data from the 159 randomized patients). 
 
SAS version 9.2 (SAS Institute, Cary, NC) was used for the sample-size calculations. 
 


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2.7 
Subject Selection  
Patients who meet all of the inclusion criteria and none of the exclusion criteria at the time of 
randomization will be eligible for the study. 
 
2.7.1 Inclusion Criteria  
a. Age  18 years of age 
b. Scheduled to undergo PCI with an FDA approved or cleared device (stent or procedures 
such as balloon angioplasty, rotoblation, AngioSculpt, laser atherectomy, etc.) in one or 
more native coronary target lesions 
c. Written informed consent. 
 
2.7.2 Exclusion Criteria 
a. Primary PCI for STEMI as index procedure 
b. Prior STEMI within 48 hours before randomization 
c. Prior PCI within 30 days before randomization 
d. Planned staged PCI within the subsequent 48 hours after index PCI 
e. Planned PCI of vein graft lesions only 
f. Use of abciximab within 7 days before randomization 
g. Use of tirofiban or eptifibatide within 12 hours before randomization 
h. Use of low-molecular weight heparin within 12 hours before randomization 
i. Use of bivalirudin within 12 hours before randomization 
j. Use of warfarin within 7 days before randomization unless INR  1.3 
k. Use of dabigatran or rivaroxaban within 3 days prior to randomization 
l. Use of thrombolytic agents administered within 24 hours before randomization 
m. Pregnant 
n. Active pericarditis 
o. Presumed or documented history of vasculitis 
p. Uncontrolled hypertension (blood pressure > 180/110 mm Hg) 
q. Dependency on renal dialysis 


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r. Active internal bleeding or bleeding diathesis, surgery, trauma or gastrointestinal / 
genitourinary tract bleeding within 6 weeks prior to randomization 
s. Prior intracranial hemorrhage, hemorrhagic stroke, cerebrovascular accident (CVA) within 
2 years or CVA with significant residual neurological deficit, intracranial neoplasm, 
arteriovenous malformation, aneurysm, or structural abnormality 
t. Thrombocytopenia (platelet count <100 x 10³µL) or history of thrombocytopenia following 
heparin, tirofiban or eptifibatide 
u. Planned participation in any other clinical trial of an investigational drug or device, or a 
clinical trial of an approved drug or device for a non-approved use, up to 48 hours following 
PCI 
v. Participation in another clinical trial 30 days prior to participation in the current study 
w. Any other condition that in the opinion of the investigator may compromise the safety or 
compliance of the patient or would preclude patient successfully completing the trial 
x. Known inability to comply with the protocol for the duration of the study. 
 
2.8 
Randomization 
Once all baseline examinations and tests are completed, the site will once again carefully review 
the inclusion and exclusion criteria described in the protocol to ensure that the patient is eligible 
to enter the study. 
 
Naming of oral P2Y12 antagonist agent (clopidogrel, prasugrel, or ticagrelor) to be used post-
randomization must be pre-specified prior to randomization. 
 
Selection of either the femoral or radial access site must be pre-specified prior to randomization. 
Randomization may occur only if all of the following criteria are satisfied: 
a. Consented patient is confirmed to be eligible for the study, AND 
b. name of intended oral P2Y12 antagonist agent used post-randomization is prespecified, 
AND 
c. access site for PCI is pre-specified, AND 


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d. decision to proceed to PCI is finalized, AND 
e. timing between randomization and initiation of the PCI procedure is less than 2 hours. 
 
Once the above criteria are satisfied, the patient may be randomized. The timing for randomization 
in this study is critical. The reason for timing the study drug administration so close to time of PCI 
is to minimize inappropriate patient enrollment. Situations where this might occur include the 
procedure where PCI is aborted or otherwise not performed or when a decision is made not to 
administer study medication for whatever reason. 
 
At randomization, the patient will be assigned a study number that will allow identification of the 
patient throughout the study, and the appropriate staff will prepare the corresponding study drug. 
Patients will be randomized via a centralized randomization system to receive either tirofiban or 
eptifibatide. 
 
The randomization will stratify patients according to femoral or radial access.  
 
2.9 
Study Endpoints 
The following sections describe the study endpoints used to address the study objectives. 
 
2.9.1 Efficacy Measures 
2.9.1.1 Primary Endpoint 
The primary objective will be assessed with the composite of death, PPM, uTVR or major bleeding 
within 48 hours following PCI or hospital discharge, whichever comes first. 
− First primary test: A short tirofiban regimen of a high-dose bolus plus a shortened infusion 
duration is non-inferior to label-dosing eptifibatide among patients undergoing PCI with 
respect to death, PPM, uTVR or major bleeding within 48 hours following PCI or hospital 
discharge, whichever comes first.  
− Co-primary tests:  


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• (i) a short tirofiban regimen of a high-dose bolus plus a 1-2 hour infusion post 
procedure is non-inferior to a long tirofiban regimen of a high-dose bolus plus a 12-
18 hour infusion with respect to death, PPM, uTVR or major bleeding within 48 
hours following PCI or hospital discharge, whichever comes first, and  
• (ii) a long tirofiban regimen of a high-dose bolus plus a 12-18 hour infusion is non-
inferior to label-dosing eptifibatide with respect to death, PPM, uTVR or major 
bleeding within 48 hours following PCI or hospital discharge, whichever comes 
first. No adjustments for multiple testing will be made. 
 
2.9.1.2 Secondary Endpoints 
Secondary endpoints will be: 
− First secondary test: A short tirofiban regimen of a high-dose bolus plus a shortened 
infusion duration is non-inferior to label-dosing eptifibatide among patients undergoing 
PCI with respect to the following list: 
• death, PPM or uTVR within 48 hours following PCI or hospital discharge, 
whichever comes first 
• PPM within 48 hours following PCI or hospital discharge, whichever comes first 
• uTVR within 48 hours following PCI or hospital discharge, whichever comes first 
• death within 48 hours following PCI or hospital discharge, whichever comes first 
• death, PPM, uTVR or major bleeding within 48 hours following PCI or hospital 
discharge, whichever comes first, where PPM is defined as at least one troponin 
elevation of  10 times the upper limit of normal and at least 20% of greater than 
the baseline troponin value, per the troponin Local Laboratory within 48 hours 
following PCI or hospital discharge, whichever comes first (a non-inferiority 
margin of 12.4% will be used for the short tirofiban versus eptifibatide comparison) 
• at least one troponin elevation of  10 times the upper limit of normal and at least 
20% of greater than the baseline troponin value, per the troponin Local Laboratory, 
within 48 hours following PCI or hospital discharge, whichever comes first (a 


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noninferiority margin of 12.4% will be used for the short tirofiban versus 
eptifibatide comparison) 
• at least one troponin elevation of  20 times the upper limit of normal and at least 
20% of greater than the baseline troponin value, per the troponin Local Laboratory, 
within 48 hours following PCI or hospital discharge, whichever comes first  
• at least one troponin elevation of  50 times the upper limit of normal and at least 
20% of greater than the baseline troponin value, per the troponin Local Laboratory, 
within 48 hours following PCI or hospital discharge, whichever comes first. 
− Co-secondary tests:  
• (i) a short tirofiban regimen of a high-dose bolus plus a 1-2 hour infusion duration 
post procedure is non-inferior to a long tirofiban regimen of a high-dose bolus plus 
a 12-18 hour infusion, and  
• (ii) a long tirofiban regimen of a high-dose bolus plus a 12-18 hour infusion is non-
inferior to label-dosing eptifibatide with respect to the same secondary tests in the 
list above.  
 
2.9.1.3 Definition of Composite Endpoint 
− Death due to any cause will be assessed through to 48 hours following PCI or hospital 
discharge, whichever comes first. 
− Periprocedural myonecrosis will have occurred if there is at least one troponin (troponin I 
or troponin T) value of  3 times the upper limit of normal and at least 20% or greater than 
the baseline troponin value, per the troponin Local Laboratory, within 48 hours following 
PCI or hospital discharge, whichever comes first. 
• To be included in the primary composite endpoint analysis and in the secondary 
PPM endpoint analysis, a patient must have the pre-PCI troponin Local Laboratory 
measurement and at least one troponin Local Laboratory measurement within 48 
hours following PCI or hospital discharge, whichever comes first. 


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• Patients without a pre-PCI troponin Local Laboratory measurement will not be 
included in the PPM endpoint analysis but will still be included in the intention to 
treat analysis and be analyzed for death and uTVR. 
• Patients without any troponin Local Laboratory measurements within 48 hours 
following PCI or hospital discharge, whichever comes first will not be included in 
the PPM endpoint analysis but will still be included in the intention to treat analysis 
and be analyzed for death, uTVR and major bleeding. 
− Urgent Target Vessel Revascularization (uTVR) is either a PCI following the index PCI, 
or any CABG procedure performed after the index PCI on a non-selective basis in the target 
vessel because of recurrent myocardial ischemia. A revascularization procedure in the 
target vessel is considered urgent if it is due to one or more episodes of chest pain, 
presumed to be ischemic in origin and lasting at least 5 minutes, and results in either urgent 
repeat PCI or urgent coronary artery bypass surgery involving the target vessel. In the 
absence of pain, new ischemic ST-segment or T-wave changes, acute pulmonary edema, 
ventricular arrhythmias presumed to be ischemic in origin will constitute sufficient 
evidence of ischemia. The episode of ischemia leading to urgent repeat PCI must occur 
following completion of the index PCI and guidewire removal. For uTVR to count towards 
the primary composite endpoint, uTVR will have to be initiated during the course of the 
study (i.e., 48 hours following PCI or hospital discharge, whichever comes first). 
− Major bleeding is defined using the criteria from the REPLACE-2 trial. Major bleeding is 
defined as follows: 
a. transfusion of  2 units whole blood or packed red blood cells, or 
b. intracranial hemorrhage, or 
c. retroperitoneal hemorrhage, or 
d. decrease in  Hgb more than 4 g/dL (or 12% of Hct) with no bleeding site identified 
despite attempts to determine, or 
e. spontaneous or non-spontaneous blood loss associated with a Hgb drop > 3 g/dL 
(or 10% of Hct) with an overt site of hemorrhage. 
 


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The REPLACE-2 Major bleeding definition takes into account blood transfusions, so that 
hemoglobin and hematocrit values are adjusted by 1 g/dl or 3%, respectively, for each unit of blood 
transfused. 
 
Therefore, the true change in hemoglobin or hematocrit if there has been an intervening transfusion 
between two blood measurements is calculated as follows: 
•  Hemoglobin = [baseline Hgb - post-transfusion Hgb] + [number of transfused units]; 
•  Hematocrit = [baseline Hct - post-transfusion Hct] + [number of transfused units x 3]. 
 
2.9.2 Safety  
Safety will be assessed with: 
− Nature, severity, and study drug relationship of all bleeding events, specifically, 
• Bleeding events according to REPLACE-2 Major bleeding definition 
• Bleeding events according to TIMI Major bleeding definition 
• Bleeding events according to REPLACE-2 Minor bleeding definition 
• Bleeding events according to TIMI Minor bleeding definition 
• Bleeding events according to REPLACE-2 Plus Major bleeding definition 
• Bleeding events according to TIMI Plus Major bleeding definition 
• Sum of REPLACE-2 Major and Minor bleeding 
• Sum of REPLACE-2 Plus Major and Minor bleeding 
• Sum of TIMI Major and Minor bleeding 
• Sum of TIMI Plus Major and Minor bleeding 
− Non-bleeding adverse events 
− Change in lab parameters, specifically, 
• Thrombocytopenia (< 100,000 cells/µL) 
• Severe Thrombocytopenia (< 50,000 cells/µL) 
• Profound Thrombocytopenia (< 20,000 cells/µL) 
− Length of hospital stay. 


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3 
STATISTICAL METHODS 
3.1 
Statistical Handling Policy 
 
3.1.1 Analysis Conventions 
This section details general guidelines to be used for the statistical analyses. Deviations from these 
general policies may be given in the specific detailed sections of this statistical analysis plan. When 
this situation occurs, the rules set forth in the specific section take precedence over the general 
conventions. The following policies will be applied to all data presentations and analyses: 
• Two-tailed tests will be performed for analyses that use statistical testing with a 
significance level of α = 0.05. One-tailed tests will be performed for analyses with a 
significance level of α = 0.025, if applicable. 
• Summary descriptive statistics will consist of the number and percentage of responses in 
each category for discrete variables, and the mean, median, standard deviation (SD), 
minimum, maximum, and 95% confidence interval for continuous variables. 
• All mean and median values will be formatted to one decimal place. Standard deviation 
values will be formatted to two decimal places.  
• All percentages will be rounded to one decimal place. Where appropriate, the number and 
percentage of responses will be presented in the form XX (XX.X %), where the percentage 
is in the parentheses. 
• For any analysis output, estimates and their corresponding standard deviations and/or 
standard errors will be reported up to the 3rd or 4th decimal place, per the default output of 
SAS. 
• All p-values will be rounded to 4 decimal places (SAS format p-value). All p-values that 
round to 0.000 will be presented as ‘<0.001’ and p-values that round to 1.000 will be 
presented as ‘>0.999’. Any p-value ≤ 0.05 will be considered statistically significant.  
• All listings will be sorted for presentation in order of treatment group, site number, subject 
number, and date of procedure or event, when applicable. 


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• When necessary for analysis purposes, partial dates will be imputed (i.e., turned into 
complete dates) using the most conservative approach.  
• Where appropriate, all analyses and summary tables will have the population sample size 
for each treatment group in the column heading. 
• Tables will include titles with the corresponding analysis population and footnotes 
describing the analyses involved, and listings of covariates included in the analyses, where 
relevant. 
• Version 20.0 (or higher) of MedDRA will be used for adverse event and pre-treatment 
conditions coding. 
• Version 2015 (or later) of the World Health Organization (WHO) Drug Classifications will 
be used for the coding of medications. 
• Version 9.4 (or later) of SAS will be the statistical software package used to produce all 
summaries, listings, statistical analyses, and graphs. 
 
3.2 
Analysis Population 
The Modified Intent-to-treat (mITT) Population is defined as all randomized patients who 
underwent PCI and received study drug.  
 
The Per Protocol (PP) Population will consist of all randomized patients who completed the full 
course of the study without major protocol violations.  
 
The Safety Population is defined as all randomized subjects who received any study treatment.  
All efficacy analyses will be performed on the modified intent-to-treat population (mITT) and on 
the per-protocol population (PP). Safety analyses will be performed on the safety population. 
 
3.3 
Subject Disposition and Discontinuations 
Patient disposition will be summarized for the total enrolled population and by treatment group. 
The following data will be presented: 
• The number of patients who were screened, enrolled and randomized 


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• The number and proportion of patients in each analysis population 
• The number and percentage of patients who completed the study 
• The number and percentage of patients who discontinued prematurely from the study and 
the associated reasons. 
 
3.4 
Treatment Exposure and Dosing 
Treatment exposure will be calculated in terms of number of hours exposed to treatment using 
SAS function ‘INTCK’ in the following formula, and presented by the descriptive statistics 
including mean, median, SD, minimum, maximum and 95% CI of the mean: 
 
Exposure (hours) = INTCK (“Hour”, Start of Dosing, End of Dosing) 
 
In addition, the cumulative dosing medication used will be calculated for each patient by 
computing the sum of study drug of tirofiban or eptifibatide administered pre and post-PCI. 
 
3.5 
Subject Demographics and Baseline Characteristics 
Descriptive statistics will be presented for all patient demographic and characteristics data 
including age, gender, ethnicity and race. Age will be calculated as follows: Age = Largest Integer 
 [(Visit 1 Date – Date of Birth + 1)/365.25; or as per the SAS function Age=YRDIF (date of birth, 
baseline date, ‘ACTUAL’).  
 
3.6 
Medical History 
Medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and the number and percentage of subjects with medical history will be reported by 
System Organ Class (SOC) and Preferred Term (PT). 
 
3.7 
Vital Signs/Physical Examination 
The vital signs at each visit will be assessed by treatment group using descriptive statistics. 
 


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3.8 
Clinical Laboratory Assessments 
The hematology and urine analysis tests will be described with the number and percentage of 
subjects reporting normal and abnormal (NCS and CS) results. In addition the actual results for all 
hematology tests will be summarized by treatment group using descriptive statistics.  
 
3.9 
Concomitant Medications 
All concomitant medications recorded on the CRF will be coded and summarized according to the 
generic drug names using the WHO Drug Classifications. Summary will give the number and 
percentage of patients in the safety population who took medications that were coded to each 
generic drug name, as well as the number and percentage of patients that took any medication at 
all.  
 
3.10 Analysis of the Study Endpoints 
3.10.1 Analysis of the Primary Endpoint 
To evaluate the effectiveness of tirofiban versus eptifibatide, we look at the proportion of patients 
with at least one of the following endpoint measurements: death, PPM, uTVR or REPLACE-2 
Major bleeding within 48 hours following PCI or hospital discharge, whichever comes first. For 
each pairwise comparison: 
• The short tirofiban group is non-inferior to the eptifibatide group; 
• The short tirofiban group is non-inferior to the long tirofiban group; 
• The long tirofiban group is non-inferior to the eptifibatide group; 
 
The following hypothesis will be tested: 
H0: C – T  -0.191 
H1: C – T > -0.191 
 
To test this hypothesis, the difference (C – T) and its associated one-sided 97.5% confidence 
interval will be calculated. If the lower bound of the interval is greater than -0.191, the non-
inferiority will be claimed. In order to compute the risk (proportion) difference for data with binary 


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response (“Yes” vs. “No”), a bivariate logistic regression will be performed for each pairwise 
comparison with the following specifications: 
• The dependent variable will be “composite endpoint” and the  independent factor will be 
“treatment group”; 
• The risk (proportion) difference between two methods as well as its confidence interval 
will be estimated; 
• The non-inferiority margin is 19.1% 
 
3.10.2 Analysis of the Secondary Endpoints 
The analysis of the secondary endpoints will be conducted in the same way as for the primary 
endpoint.  
 
3.10.3 Analysis of Safety Endpoints 
 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and the 
following information will be summarized: 
• Overall AEs will also be described according to seriousness, severity, action taken with 
study drug, relationship to study drug and outcome of AE. 
• The total number of AEs, the total number and proportion of patients experiencing at least 
one AE during the treatment period will be summarized by system organ class (SOC) and 
preferred term (PT). To count the number of patients who experience each AE, patients 
experiencing the same AE multiple times will only be counted once for the corresponding 
PT. AEs will be tabulated presenting the SOCs alphabetically.  
• AEs will also be summarized as described above for serious adverse events (SAEs).  
 
Furthermore, the analysis of these safety endpoints will compare the incidence in the short tirofiban 
treatment group to the incidence in the eptifibatide group, the incidence in the short tirofiban 
treatment group to the incidence in the long tirofiban treatment group and the incidence in the long 
tirofiban treatment group to the incidence in the eptifibatide group, by using the Fisher’s mid-p 
test (Berry and Armitage, 1995) and Student t-test for binary and quantitative safety outcomes, 


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respectively. Serious adverse events will also be tabulated overall and by severity for each 
treatment group. 
 
3.10.4 Potential Covariates and/or Subgroups 
As an exploratory analysis, appropriate univariate statistics will be used to identify potential 
confounders for inclusion in multivariable regression models for assessment of the primary 
endpoint. The following covariates will be considered: 
• Patient with acute coronary syndromes (defined as any previous diagnosis of unstable 
angina, NSTEMI or STEMI) 
• STEMI > 48 hours 
• Stable angina 
• Baseline troponin  (positive vs. negative) 
• Planned PCI access (femoral vs. radial) 
• Number of stents implanted  
• Number of vessels treated (multivessel vs. single vessel) 
• Total infusion time 
• Patients receiving P2Y12 antagonist therapy between 24 and 6 hours prior to 
randomization 
• Patients receiving P2Y12 antagonist therapy between 6 and 1 hours prior to randomization 
• Patients receiving P2Y12 antagonist therapy between 1 hour prior to randomization and 15 
minutes after completion of the PCI procedure 
• Type 2 diabetes mellitus 
• Age < 65 years,  65-74 years and  75 years 
• Sex 
• Clopidogrel 
• Prasugrel 
• Ticagrelor 
• Indication for PCI (Urgent vs. Elective) 


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3.11 Multiplicity 
The clinical decision rule is that tirofiban can only claim to have demonstrated an effect if it shows 
a clinical benefit based on the primary endpoint (death, PPM, uTVR or REPLACE-2 Major 
bleeding) within 48 hours following PCI or hospital discharge, whichever comes first), irrespective 
of the outcome of the secondary endpoints. No adjustments for multiple testing will be made. 
 
3.12 Interim Analysis 
 
No interim analyses will be conducted. 
 
3.13 Accounting for Missing, Unused, and Spurious Data 
Imputation methods will not be used for missing data. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 
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authorization from JSS Medical Research Inc. and Medicure International Inc. 
 
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CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and Medicure International Inc. 
 
19. 
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Bolognese L, Falsini G, Liistro F, et al. Randomized Comparison of Upstream Tirofiban 
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After Administration of Optimal Dose of Glycoprotein IIb/IIIa Receptor Blockers in Patients 
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Danzi GB, Sesana M, Capuano C, et al. Comparison in Patients Having Primary Coronary 
Angioplasty of Abciximab Versus Tirofiban on Recovery of Left Ventricular Function. Am J 
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Danzi GB, Sesana M, Capuano C, et al. Downstream administration of a high-dose 
tirofiban bolus in high-risk patients with unstable angina undergoing early percutaneous coronary 
intervention. Int J Cardiol 2006;107:241-6. 


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CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and Medicure International Inc. 
 
29. 
Gunasekara AP, Walters DL, Aroney CN. Comparison of abciximab with ‘‘high-dose’’ 
tirofiban in patients undergoing percutaneous coronary intervention. Int J Cardiol 2006;109:16-
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Mardikar HM, Hiremath MS, Moliterno DJ, et al. Optimal platelet inhibition in patients 
undergoing PCI: Data from the Multicenter Registry of High-Risk Percutaneous Coronary 
Intervention and Adequate Platelet Inhibition (MR PCI) study. Am Heart J 2007;154:344.e1-
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Only during Percutaneous Coronary Intervention. J Invasive Cardiol 2008;20:53-58. 
32. 
Marmur JD, Poludasu S, Lazar J, et al. Long-Term Mortality After Bolus-Only 
Administration of Abciximab, Eptifibatide, or Tirofiban During Percutaneous Coronary 
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33. 
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34. 
Mukherjee D, Roffi M. Current strategies with high-dose tirofiban. Expert Opin Drug 
Metab Toxicol 2007;3:275-80. 
35. 
Schiariti M, Saladini A, Missiroli B, et al. Safety of downstream high-dose tirofiban bolus 
among 1578 patients undergoing percutaneous coronary intervention: the Sant'ANna TIrofiban 
Safety study. J Cardiovasc Med 2010;11:250-9. 
36. 
Schiariti M, Saladini, A,, Cuturello D, Missiroli B et al. Long-term efficacy of high-dose 
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intervention. J Cardiovasc Med 2011;12:29-36. 
37. 
Serebruany V, Malinin A, Pokov A, et al. Effects of escalating doses of tirofiban on platelet 
aggregation and major receptor expression in diabetic patients: Hitting the TARGET in the 
TENACITY trial? Thromb Res 2007;119:175-81. 


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CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and Medicure International Inc. 
 
38. 
ten Berg JM, van 't Hof AW, Dill T, et al. Effect of early, pre-hospital initiation of high 
bolus dose tirofiban in patients with ST-segment elevation myocardial infarction on short- and 
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39. 
Valgimigli M, Biondi-Zoccai G, Tebaldi M, et al. Tirofiban as adjunctive therapy for acute 
coronary syndromes and percutaneous coronary intervention: a meta-analysis of randomized trials. 
Eur Heart J 2010;31:35-49. 
40. 
Valgimigli M, Campo G, Percoco G, et al. Comparison of Angioplasty With Infusion of 
Tirofiban or Abciximab and With Implantation of Sirolimus-Eluting or Uncoated Stents for Acute 
Myocardial Infarction The MULTISTRATEGY Randomized Trial. JAMA 2008;299:1788-99. 
41. 
Valgimigli M, Campo G. de Cesare N, et al. Intensifying Platelet Inhibition With Tirofiban 
in Poor Responders to Aspirin, Clopidogrel, or Both Agents Undergoing Elective Coronary 
Intervention. Circulation 2009;119:3215-22. 
42. 
Valgimigli M, Percoco G, Barbieri D, et al. The Additive Value of Tirofiban Administered 
With the High-Dose Bolus in the Prevention of Ischemic Complications During High- Risk 
Coronary Angioplasty. J Am Coll Cardiol 2004;44:14-9. 
43. 
Valgimigli M, Percoco G, Malagutti P, et al. Tirofiban and Sirolimus-Eluting Stent vs 
Abciximab and Bare-Metal Stent for Acute Myocardial Infarction. JAMA 2005;293:2109-17. 
44. 
van Werkum JW, Gerritsen WBM, Kelder JC, et al. Inhibition of platelet function by 
abciximab or high-dose tirofiban in patients with STEMI undergoing primary PCI: a randomised 
trial. Neth Heart J 2007;15:375-82. 
45. 
van‘t Hof AWJ, ten Berg J, Heestermans T, et al. Prehospital initiation of tirofiban in 
patients with ST-elevation myocardial infarction undergoing primary angioplasty (On- TIME 2): 
a multicentre, double-blind, randomised controlled trial. Lancet 2008;372:537-46. 
46. 
van’t Hof AWJ, Valgimigli M. Defining the Role of Platelet Glycoprotein Receptor 
Inhibitors in STEMI: Focus on Tirofiban. Drugs 2009;69:85-100. 
47. 
Bertrand OF, De Larochelliere R, Rodes-Cabau J., Proulx G et al. A randomized study 
comparing same-day home discharge and abciximab bolus only to overnight hospitalization and 
abciximab bolus and infusion after transradial coronary stent implantation. Circulation 
2006;114:2636-43. 


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CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and Medicure International Inc. 
 
48. 
Fung AY, Saw J, Starovoytov A, Densem C et al. Abbreviated infusion of eptifibatide after 
successful coronary intervention. J Am Coll Cardiol 2009;53:837-45. 
49. 
Lincoff AM, Bittl JA, Harrington RA, Feit F et al. Bivalirudin and provisional glycoprotein 
lib/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during 
percutaneous coronary intervention. J Am Med Assoc 2003;289:853-63. 
50. 
Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for 
percutaneous coronary intervention. J Am Coll Cardiol 2011;58:1-79. 
51. 
Wright RS, Anderson JL, Adams CD et al. 2011 ACCF/AHA Focused update of the 
guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial 
infarction (updating the 2007 guideline). J Am Coll Cardiol 2011;57:1-40. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5 
HISTORICAL CHANGE 
 
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authorization from JSS Medical Research Inc. and the [Sponsor’s Name]. 
 
6 
MOCK TABLES & FIGURES 
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SAVI-PCI 
Statistical Analysis Plan 
Version FINAL 
20 February, 2019 
Page 39 of 79 
 
                                       
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Table 1. Patient Disposition 
 
Treatment Group 
Total 
 
Disposition 
Short Tirofiban 
Eptifibatide 
Long Tirofiban 
Eligible, n 
 
 
 
 
Randomized, n 
 
 
 
 
Modified Intent-to-Treat Population (mITT) 1, n (%) * 
 
 
 
 
Per-Protocol Population (PP) 2, n (%) * 
 
 
 
 
Safety Population I 3, n (%) 
 
 
 
 
 Completed the study, n (%) * 
 
Yes 
 
 
 
 
 
No 
 
 
 
 
 If no, reason for non-completion of the study, n (%) † 
 
Non-compliance with study protocol 
 
 
 
 
 
Adverse event 
 
 
 
 
 
Death 
 
 
 
 
 
Withdrawal of consent 
 
 
 
 
 
Treating physician decision to withdraw subject 
 
 
 
 
 
Other reason 
 
 
 
 
 
1 Defined as all randomized patients who underwent PCI and received study drug. 
2 Defined as all randomized patients who completed the full course of the study without major protocol violations. 
3 Defined as all randomized patients who received any study treatment. 
* Percentages based on the total number of mITT patients in each treatment group. 
† Percentages based on the total number of mITT patients who had a premature study discontinuation. 


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Table 2a. Treatment Exposure and Dosing by Treatment Group – mITT Population without renal insufficiency1 
 
Treatment Group 
 
Parameter 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
Number of hours exposed to treatment drug  
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Cumulative treatment drug received (g) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
1 Creatinine clearance >60 mL/min 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 
 
 


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Table 2b. Treatment Exposure and Dosing by Treatment Group – mITT Population with renal insufficiency1 
 
Treatment Group 
 
Parameter 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
Number of hours exposed to treatment drug  
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Cumulative treatment drug received (g) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 1 Creatinine clearance 60 mL/min 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 
 


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Table 3. Patient Demographics and Baseline Characteristics by Treatment Group – mITT Population 
 
Treatment Group 
 
Parameter 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Age (years) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Gender, n (%) 
 
Female 
 
 
 
 
Male 
 
 
 
Ethnicity, n (%) 
 
Latino 
 
 
 
 
Non-Latino 
 
 
 
Race, n (%) 
 
White 
 
 
 
 
Black or African American 
 
 
 
 
Asian 
 
 
 
 
Native Hawaiian or other Pacific Islander 
 
 
 
 
American Indian or Alaska Native 
 
 
 
 
Other 
 
 
 
 
Note: This table will also be repeated for Per-Protocol Population. 
 


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Table 4.  Concomitant Medications by Treatment Group– mITT Population 
 
Treatment Group 
 Medication 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Aspirin, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Oral P2Y12 antagonist -Clopidogrel, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Oral P2Y12 antagonist - Prasugrel n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Oral P2Y12 antagonist- Ticagrelor, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
I.V. Heparin, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Oral, sublingual, topical, or I.V. nitrates, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Calcium channel blockers n (%) 
 
Yes 
 
 
 
 
No 
 
 
 


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Statistical Analysis Plan 
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Treatment Group 
 Medication 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Lipid-lowering therapy n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Ace-inhibitors n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Beta-blocker n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Nonsteroidal anti-inflammatory agents n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Other cardioactive medications n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Angiotensin Receptor Blockers n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Diuretics n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Insulin n (%) 


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Treatment Group 
 Medication 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
 
Yes 
 
 
 
 
No 
 
 
 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 5. Concomitant Antiplatelet/Anticoagulant Dose by Treatment Group – mITT Population 
 
Treatment Group 
 
Parameter 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
Aspirin (mg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Oral P2Y12 antagonist loading dose- Clopidogrel (mg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Oral P2Y12 antagonist maintenance dose- Clopidogrel  (mg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Oral P2Y12 antagonist loading dose- Prasugrel (mg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 


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Treatment Group 
 
Parameter 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Oral P2Y12 antagonist maintenance dose- Prasugrel (mg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Oral P2Y12 antagonist loading dose- Ticagrelor (mg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Oral P2Y12 antagonist maintenance dose- Ticagrelor (mg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
IV Heparin (IU) 


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Statistical Analysis Plan 
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Treatment Group 
 
Parameter 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6. Medical History by Treatment Group – mITT Population 
 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
System Organ Class (SOC) 
Preferred Term (PT) 
Event 
Subject (%) 
Event 
Subject (%)
Event 
Subject (%)
TOTAL (ALL SOC/PT) 
 
 
 
 
 
 
SOC 1 
    PT 1.1 
    PT 1.2     
 
 
 
 
 
 
 
 
 
 
 
 
SOC 2 
    PT 2.1 
    PT 2.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Medical history were coded by MedDRA version x. A patient may have reported more than one medical history. Percentages based on the total number of mITT patients in 
treatment group. 
NA= Not Applicable 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 7(a). Vital Signs Prior to Randomization by Treatment Group – mITT Population 
 
Treatment Group 
 Vital Signs 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 Height (cm) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 Weight (kg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 Body temperature (°C) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 Heart rate (beats/minute) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 


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Treatment Group 
 Vital Signs 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 Systolic blood pressure (mmHg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 Diastolic blood pressure (mmHg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 


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Table 7(b). Vital Signs at 9±3 Hours following PCI by Treatment Group – mITT Population 
 
Treatment Group 
 Vital Signs 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 Heart rate (beats/minute) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 Systolic blood pressure (mmHg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 Diastolic blood pressure (mmHg) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 


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Table 8. Physical Examination Prior to Randomization by Treatment Group – mITT Population 
 
Treatment Group 
 Body System 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 Cardiovascular, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Dermatological, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Endocrine, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Gastrointestinal, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Genitourinary, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 H/E/N/T, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Hematological, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 


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Treatment Group 
 Body System 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 Hepatobiliary, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Immunological, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Lymphatic, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Musculoskeletal, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Nervous, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Renal, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Reproductive, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Respiratory, n (%) 


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Statistical Analysis Plan 
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Treatment Group 
 Body System 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 Other, n (%) 
 
Normal 
 
 
 
 
Abnormal  
 
 
 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 
 
 
 
 
 


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Table 9. Serum Creatinine Results Prior to Randomization by Treatment Group – mITT Population 
 
Treatment Group 
 Tests 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 Serum creatinine (mg/dL) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Creatine clearance (ml/min)1 
 
 
 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 Serum creatinine, n (%) 
 
Clinically significant 
 
 
 
 
Non-clinically significant 
 
 
 
1 Cockcroft and Gault formula  
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 


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Table 10. Hematology Lab Results at Each Visit by Treatment Group – mITT Population 
 
Treatment Group 
 Tests 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 Hemoglobin (g/dL) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Hemoglobin, n (%) 
 
Clinically significant 
 
 
 
 
Non-clinically significant 
 
 
 
 Hematocrit (%) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Hematocrit, n (%) 
 
Clinically significant 
 
 
 
 
Non-clinically significant 
 
 
 
 Platelet count, 109/L 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 


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Treatment Group 
 Tests 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max 
 
 
 
Platelets, n (%) 
 
Clinically significant 
 
 
 
 
Non-clinically significant 
 
 
 
 
Note: This table will also be repeated for the Per-Protocol Population and for each of the following timepoints: 
− 
Prior to Randomization 
− 
Prior to PCI 
− 
9± 3 h following PCI 
− 
21± 3 h following PCI 
− 
42± 6 h following PCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 11. Troponin Results at Each Visit by Treatment Group – mITT Population 
 
Treatment Group 
 Tests 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 Troponin (µg/L) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 Troponin, n (%) 
 
Clinically significant 
 
 
 
 
Non-clinically significant 
 
 
 
 
Note: This table will be repeated for the Per-Protocol Population and for each of the following timepoints: 
− 
Prior to PCI 
− 
9± 3 h following PCI 
− 
21± 3 h following PCI 
− 
42± 6 h following PCI 
 
 
 
 
 
 
 
 
 
 


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Table 12. Descriptive Statistics of Bleeding Sites and Treatment of Bleed by Treatment Group – mITT Population 
 
Treatment Group 
 Parameter 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Bleeding Site, n (%) 
 
Intracranial 
 
 
 
 
Retroperitoneal 
 
 
 
 
Sheath puncture site 
 
 
 
 
Other puncture site 
 
 
 
 
ENT bleed 
 
 
 
 
GI bleed 
 
 
 
 
GU bleed 
 
 
 
 
Cardio/pulmonary bleed 
 
 
 
 
Other 
 
 
 
Treatment of Bleed, n (%) 
 
Transfusion 
 
 
 
 
Pressure Dressing 
 
 
 
 
No treatment  
 
 
 
If transfusion, type of transfusion, n (%) 
 
Heparinized pump blood replacement 
 
 
 
 
Whole blood 
 
 
 
 
PRBCs 
 
 
 
 
FFP 
 
 
 
 
Platelets 
 
 
 
 
Cryoprecipitate 
 
 
 


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Treatment Group 
 Parameter 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
 
Cell-saver 
 
 
 
 
Albumin 
 
 
 
 
Other  
 
 
 
Note: This table will also be repeated for Per-Protocol Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 13. Descriptive Statistics of Potential Covariates Not Summarized Elsewhere by Treatment Group – mITT Population 
 
Treatment Group 
 Parameter 
Short 
Tirofiban (N=)
Eptifibatide (N=) 
Long Tirofiban 
(N=) 
Age category, years, n (%) 
 
< 65 
 
 
 
 
 65- 74 
 
 
 
 
 75 
 
 
 
 Patient with acute coronary syndromes 1, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 STEMI > 48 hours, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Stable angina, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Troponin baseline, n (%) 
 
Negative  
 
 
 
 
Positive 
 
 
 
Planned PCI access, n (%) 
 
Femoral 
 
 
 
 
Radial 
 
 
 
 Number of stents implanted 


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Treatment Group 
 Parameter 
Short 
Tirofiban (N=)
Eptifibatide (N=) 
Long Tirofiban 
(N=) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
Vessel involvement, n (%)2 
 
Single Vessel 
 
 
 
 
Mulitvessel 
 
 
 
 Patients receiving P2Y12 antagonist therapy between 24 and 6 hours prior to randomization, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Patients receiving P2Y12 antagonist therapy between 6 and 1 hours prior to randomization, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Patients receiving P2Y12 antagonist therapy between 1 hour prior to randomization and 15 minutes after completion of the PCI procedure, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Type 2 diabetes mellitus, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
Indication for  PCI, n (%) 


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Treatment Group 
 Parameter 
Short 
Tirofiban (N=)
Eptifibatide (N=) 
Long Tirofiban 
(N=) 
 
Elective 
 
 
 
 
Urgent 
 
 
 
1 Defined as any previous diagnosis of unstable angina, NSTEMI or STEMI 
2Ascertained by ‘Number if stents implanted’ indicated on the Procedure Report Form; 1 implanted stent = multivessel 
 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 14. Descriptive Statistics of Primary Outcome by Treatment Group – mITT Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The primary outcome is the composite of death, PPM, uTVR or REPLACE-2 major bleeding within 48 hours following PCI or hospital discharge, whichever comes first. 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 
Treatment Group 
 Parameter 
Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 Primary outcome, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Death, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Periprocedural myonecrosis (PPM), n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Urgent target vessel revascularization (uTVR), n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 REPLACE-2 major bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 


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Table 15. Bivariate Logistic Regression Model for Primary Outcome – mITT Population 
Parameter 
Level 
Estimate 
Standard 
Error (SE) 
Odds Ratio 
(OR) 
95% CI for 
OR 
Risk 
(Proportion 
Difference) 
Standard 
Error (SE) 
of Risk 
Difference 
95% CI for 
Risk 
Difference 
p-value * 
Primary 
composite 
outcome
Short Tirofiban vs. 
Eptifibatide 
 
 
 
 
 
 
 
 
Primary 
composite 
outcome
Short Tirofiban vs. 
Long Tirofiban 
 
 
 
 
 
 
 
 
Primary 
composite 
outcome
Long Tirofiban vs. 
Eptifibatide 
 
 
 
 
 
 
 
 
 
*  p-value is the overall p-value from the logistic regression model. 
 
Note: The primary outcome is the composite of death, PPM, uTVR or REPLACE-2 major bleeding within 48 hours following PCI or hospital discharge, whichever comes first. 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 
 
 
 
 
 


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Table 15 (a) Multivariate Logistic Regression Models for Primary Outcome – mITT Population 
Parameter 
Level 
Estimate 
Standard 
Error (SE) 
Odds Ratio 
(OR) 
95% CI for 
OR 
Risk 
(Proportion 
Difference) 
Standard 
Error (SE) 
of Risk 
Difference 
95% CI for 
Risk 
Difference 
p-value * 
Primary 
composite 
outcome
Short Tirofiban vs. 
Eptifibatide 
 
 
 
 
 
 
 
 
Primary 
composite 
outcome
Short Tirofiban vs. 
Long Tirofiban 
 
 
 
 
 
 
 
 
Primary 
composite 
outcome
Long Tirofiban vs. 
Eptifibatide 
 
 
 
 
 
 
 
 
* p-value is the overall p-value from the logistic regression model. 
Note: The following potential covariates, as well as all significant 2-way interaction terms, will be assessed using appropriate univariate statistics for consideration in the multivariate 
regression models: 
- 
Patient with acute coronary syndrome 
- 
STEMI > 48 hours 
- 
Stable angina 
- 
Baseline troponin (positive vs. negative) 
- 
Planned PCI access (femoral vs. radial) 
- 
Number of stents implanted  
- 
Number of vessels treated (multivessel vs. single vessel) 
- 
Total infusion time 
- 
Patients receiving P2Y12 antagonist therapy between 24 and 6 hours prior to randomization 
- 
Patients receiving P2Y12 antagonist therapy between 6 and 1 hours prior to randomization 
- 
Patients receiving P2Y12 antagonist therapy between 1 hour prior to randomization and 15 minutes after completion of the PCI procedure 
- 
Type 2 diabetes mellitus 
- 
Age < 65 years,  65- 74 years and  75 years 


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- 
Sex 
- 
Clopidogrel 
- 
Prasugrel 
- 
Ticagrelor 
- 
Indication for PCI (Urgent vs. Elective) 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 16. Descriptive Statistics of Secondary Outcomes by Treatment Group – mITT Population 
 
Treatment Group 
 Parameter 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
 Secondary outcome 1, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Secondary outcome 2, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Secondary outcome 3, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Secondary outcome 4, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Secondary outcome 5, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Secondary outcome 6, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Secondary outcome 7, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 


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Treatment Group 
 Parameter 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
 Secondary outcome 8, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 
Note: The definitions of secondary outcomes are: 
− 
Secondary outcome 1: death, PPM or uTVR within 48 hours following PCI or hospital discharge, whichever comes first 
− 
Secondary outcome 2: PPM within 48 hours following PCI or hospital discharge, whichever comes first 
− 
Secondary outcome 3: uTVR within 48 hours following PCI or hospital discharge, whichever comes first 
− 
Secondary outcome 4: death within 48 hours following PCI or hospital discharge, whichever comes first 
− 
Secondary outcome 5: death, PPM, uTVR or major bleeding within 48 hours following PCI or hospital discharge, whichever comes first, where PPM is defined as at least 
one troponin elevation of  10 times the upper limit of normal and at least 20% of greater than the baseline troponin value, per the troponin Local Laboratory within 48 
hours following PCI or hospital discharge, whichever comes first (a non-inferiority margin of 12.4% will be used for the short tirofiban versus eptifibatide comparison) 
− 
Secondary outcome 6: at least one troponin elevation of  10 times the upper limit of normal and at least 20% of greater than the baseline troponin value, per the troponin 
Local Laboratory, within 48 hours following PCI or hospital discharge, whichever comes first (a noninferiority margin of 12.4% will be used for the short tirofiban versus 
eptifibatide comparison) 
− 
Secondary outcome 7: at least one troponin elevation of  20 times the upper limit of normal and at least 20% of greater than the baseline troponin value, per the troponin 
Local Laboratory, within 48 hours following PCI or hospital discharge, whichever comes first  
− 
Secondary outcome 8: at least one troponin elevation of  50 times the upper limit of normal and at least 20% of greater than the baseline troponin value, per the troponin 
Local Laboratory, within 48 hours following PCI or hospital discharge, whichever comes first 
 
Note: This table will also be repeated for Per-Protocol Population. 
 
 
 


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Table 17. Bivariate Logistic Regression Model for Secondary Outcomes – mITT Population 
Parameter 
Level 
Estimate 
Standard 
Error (SE) 
Odds Ratio 
(OR) 
95% CI for 
OR 
Risk 
(Proportion 
Difference) 
Standard 
Error (SE) 
of Risk 
Difference 
95% CI for 
Risk 
Difference 
p-value * 
Secondary 
outcome
Short Tirofiban vs. 
Eptifibatide
 
 
 
 
 
 
 
 
Secondary 
outcome
Short Tirofiban vs. 
Long Tirofiban
 
 
 
 
 
 
 
 
Secondary 
outcome
Long Tirofiban vs. 
Eptifibatide
 
 
 
 
 
 
 
 
 
*  p-value is the overall p-value from the logistic regression model. 
 
Note: The definitions of secondary outcomes are: 
− 
Secondary outcome 1: death, PPM or uTVR within 48 hours following PCI or hospital discharge, whichever comes first 
− 
Secondary outcome 2: PPM within 48 hours following PCI or hospital discharge, whichever comes first 
− 
Secondary outcome 3: uTVR within 48 hours following PCI or hospital discharge, whichever comes first 
− 
Secondary outcome 4: death within 48 hours following PCI or hospital discharge, whichever comes first 
− 
Secondary outcome 5: death, PPM, uTVR or major bleeding within 48 hours following PCI or hospital discharge, whichever comes first, where PPM is defined as at least 
one troponin elevation of  10 times the upper limit of normal and at least 20% of greater than the baseline troponin value, per the troponin Local Laboratory within 48 
hours following PCI or hospital discharge, whichever comes first (a non-inferiority margin of 12.4% will be used for the short tirofiban versus eptifibatide comparison) 
− 
Secondary outcome 6: at least one troponin elevation of  10 times the upper limit of normal and at least 20% of greater than the baseline troponin value, per the troponin 
Local Laboratory, within 48 hours following PCI or hospital discharge, whichever comes first (a noninferiority margin of 12.4% will be used for the short tirofiban versus 
eptifibatide comparison) 
− 
Secondary outcome 7: at least one troponin elevation of  20 times the upper limit of normal and at least 20% of greater than the baseline troponin value, per the troponin 
Local Laboratory, within 48 hours following PCI or hospital discharge, whichever comes first  
− 
Secondary outcome 8: at least one troponin elevation of  50 times the upper limit of normal and at least 20% of greater than the baseline troponin value, per the troponin 
Local Laboratory, within 48 hours following PCI or hospital discharge, whichever comes first 
 
Note: This table will also be repeated for Per-Protocol Population. 
 


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Table 18. Summary of Incidence of Adverse Events by Treatment Group – Safety Population 
 
 Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 Parameter 
N  
of Events 
N of 
Subjects 
% of 
Subjects 
N 
of Events 
N of 
Subjects 
% of 
Patients 
N  
of Events
N of 
Subjects 
% of 
Subjects 
 Is it a Serious Adverse Event? 
 
Yes 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 If yes, serious indicator 
 
Death 
 
 
 
 
 
 
 
 
 
 
Life-threatening 
 
 
 
 
 
 
 
 
 
 
Required/prolonged hospitalization 
 
 
 
 
 
 
 
 
 
 
Significant/permanent disability 
 
 
 
 
 
 
 
 
 
 
Medically significant 
 
 
 
 
 
 
 
 
 
 Is this event ongoing? 
 
Yes 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 Severity of adverse event 
 
Mild 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 Relationship to study drug 
 
Probably related 
 
 
 
 
 
 
 
 
 
 
Possibly related 
 
 
 
 
 
 
 
 
 
 
Unlikely related 
 
 
 
 
 
 
 
 
 


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 Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
 Parameter 
N  
of Events 
N of 
Subjects 
% of 
Subjects 
N 
of Events 
N of 
Subjects 
% of 
Patients 
N  
of Events
N of 
Subjects 
% of 
Subjects 
 Action taken to the study drug 
 
None 
 
 
 
 
 
 
 
 
 
 
Discontinued 
 
 
 
 
 
 
 
 
 
 Outcome 
 
Recovered 
 
 
 
 
 
 
 
 
 
 
Recovered with sequelae 
 
 
 
 
 
 
 
 
 
 
Unresolved 
 
 
 
 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
The percentage is based on the number of serious adverse events. 
Note: A patient may have reported more than one adverse event. Percentages based on the total number of safety population patients in each treatment group. 
 
Note: This table will also be repeated for Serious Adverse Events. 
 
 
 
 
 
 
 
 
 
 
 


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Table 19. Incidence of Adverse Events by System Organ Class (SOC) and Preferred Term (PT) by Treatment Group – Safety Population 
 
 Short Tirofiban (N=) 
Eptifibatide (N=) 
Long Tirofiban (N=) 
System Organ Class (SOC) 
Preferred Term (PT) 
Event 
Subject 
(%) 
Event 
Subject (%)
Event 
Subject 
(%) 
TOTAL (ALL SOC/PT) 
 
 
 
 
 
 
SOC 1 
    PT 1.1 
    PT 1.2     
 
 
 
 
 
 
 
 
 
 
 
 
SOC 2 
    PT 2.1 
    PT 2.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Adverse Events will be coded by MedDRA version x. A patient may have reported more than one adverse event. Percentages based on the total number of safety population patients in each
treatment group. 
 
Note: This table will also be repeated for Serious Adverse Events. 
 
 
 
 
 
 
 
 
 
 


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Table 20. Descriptive Statistics of Safety Outcomes by Treatment Group – Safety Population 
 
Treatment Group 
 Parameter 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
REPLACE-2 major bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 TIMI major bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 REPLACE-2 minor bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 TIMI minor bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 REPLACE-2 plus major bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 TIMI plus major bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Sum of REPLACE-2 major and minor bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 


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Treatment Group 
 Parameter 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
 Sum of REPLACE-2 plus major and minor bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Sum of TIMI major and minor bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Sum of TIMI plus major and minor bleeding, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Non-bleeding adverse event, n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Thrombocytopenia (< 100,000 cells/µL), n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Severe thrombocytopenia (< 50,000 cells/µL), n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Profound thrombocytopenia (< 20,000 cells/µL), n (%) 
 
Yes 
 
 
 
 
No 
 
 
 
 Length of hospital stay (hours) 


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Treatment Group 
 Parameter 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
Short Tirofiban (N=) 
 
Available n 
 
 
 
 
Mean ± SD 
 
 
 
 
95% CI for Mean 
 
 
 
 
Median (IQR) 
 
 
 
 
Min - Max  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 21. Fisher’s Exact Test for Binary Safety Outcomes – Safety Population 
Statistic 
Level 
DF 
Value 
p-value 
Fisher’ exact test 
Short Tirofiban vs. Eptifibatide 
 
 
 
Fisher’ exact test 
Short Tirofiban vs. Long Tirofiban
 
 
 
Fisher’ exact test 
Long Tirofiban vs. Eptifibatide 
 
 
 
 
Note: p-value is based on the Fisher’s mid-p test.  
Note: The Binary Safety Outcomes are the following: 
− 
Bleeding events according to REPLACE-2 Major bleeding definition 
− 
Bleeding events according to TIMI Major bleeding definition 
− 
Bleeding events according to REPLACE-2 Minor bleeding definition 
− 
Bleeding events according to TIMI Minor bleeding definition 
− 
Bleeding events according to REPLACE-2 Plus Major bleeding definition 
− 
Bleeding events according to TIMI Plus Major bleeding definition 
− 
Sum of REPLACE-2 Major and Minor bleeding 
− 
Sum of REPLACE-2 Plus Major and Minor bleeding 
− 
Sum of TIMI Major and Minor bleeding 
− 
Sum of TIMI Plus Major and Minor bleeding 
− 
Non-bleeding adverse events 
− 
Thrombocytopenia (< 100,000 cells/µL) 
− 
Severe Thrombocytopenia (< 50,000 cells/µL) 
− 
Profound Thrombocytopenia (< 20,000 cells/µL) 


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Table 22. Student t-Test for Quantitative Safety Outcome – Safety Population 
Statistic 
Level 
DF 
t Value 
p-value 
t-test 
Short Tirofiban vs. Eptifibatide 
 
 
 
t-test 
Short Tirofiban vs. Long Tirofiban
 
 
 
t-test 
Long Tirofiban vs. Eptifibatide 
 
 
 
 
Note: p-value is based on the Student t-test.  
Note: The Quantitative Safety Outcome is the length of hospital stay.