The Effect of Intravenous Cangrelor and Oral Ticagrelor on Platelets, the Microcirculation and Myocardial Damage in Patients Admitted With STEMI Treated by Primary Percutaneous Coronary Intervention: A Randomized Controlled Pilot Trial
Phase: PHASE4
Conditions: Acute Coronary Syndrome (ACS), High On-treatment Platelet Reactivity (HTPR), Microvascular Obstruction (MVO), ST-segment Elevation Myocardial Infarction (STEMI), Thrombolysis in Myocardial Infarction (TIMI), Unstable Angina (UA)
Sponsor: The Royal Wolverhampton Hospitals NHS Trust

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The Effect of Intravenous Cangrelor and Oral 
Ticagrelor on Platelets, the Microcirculation 
and Myocardial Damage in Patients admitted 
with STEMI Treated by Primary Percutaneous 
Coronary Intervention  
A randomized controlled pilot trial 
Version 3 14/03/2016 
 
 
 
SPONSOR: The Royal Wolverhampton NHS Trust 
FUNDERS: Tripartite Charitable Research Funds 
 
 
NHS REC reference: 16/EM/0094 
 
 
Study Management Group 
 
Chief Investigator:  
 
Prof J Cotton 
 
Co-investigators:  
 
Dr S Ubaid  
Ms N Khan 
Dr E McAlindon 
Dr B Wrigley 
Dr A Armesilla 
Dr J Vickers 
 
Statistician:   
 
Prof A Nevill 
 
Study Management:   
Dr S Ubaid, Mr Andrew Smallwood 
 

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Glossary of Abbreviations and Technical Terms 
 
 
 
 
4 
Keywords 
 
 
 
 
 
 
 
 
 
4 
1 
Lay Summary  
 
 
 
 
 
 
 
5 
2 
Introduction 
 
 
 
 
 
 
 
 
6 
 
2.1 
Background 
 
 
 
 
 
 
 
6-7 
 
2.2 
Rationale for Current Study  
 
 
 
 
8 
3 
Study Objectives 
 
 
 
 
 
 
 
8 
4 
Study Design  
 
 
 
 
 
 
 
9 
 
4.1 
Study Outcome Measures 
 
 
 
 
 
9 
 
4.2 
In patient Safety Endpoints 
 
 
 
 
 
9 
 
5 
Participant Entry 
 
 
 
 
 
 
 
9 
 
5.1 
Consent 
 
 
 
 
 
 
 
9-10 
 
5.2 
Eligibility Criteria 
 
 
 
 
 
 
10 
 
5.3 
Randomisation 
 
 
 
 
 
 
10 
5.4 
Inclusion Criteria 
 
 
 
 
 
 
10-11 
 
5.5 
Exclusion Criteria 
 
 
 
 
 
 
11 
 
5.6 
Withdrawal Criteria  
 
 
 
 
 
11 
6 
Assessment and Follow-up 
 
 
 
 
 
 
12 
 
6.1 
Subjects 
 
 
 
 
 
 
 
12 
 
6.2 
Sampling and Dosing  
 
 
 
 
 
12 
 
6.3 
Pharmacodynamic Analysis  
 
 
 
 
13 
 
6.3.1 Verify Now for P2Y12 Analysis 
 
 
 
 
13 
 
6.3.2 VASP Flow Cytometry 
 
 
 
 
 
13 
 
6.4 
TIMI Flow Grade                                                                               14  
 
6.5 
Enzyme Estimation of Myocardial Infarct Size                                 14 
 
6.6 
IMR Estimation  
 
 
 
 
 
 
15 
6.7 
ST Segment Resolution post Acute Myocardial Infarction                15 

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6.8 
CMR Assessment of Myocardial Infarct Size 
 
 
16 
7 
Statistics and Data Analysis   
 
 
 
 
 
16 
8 
End of Study  
 
 
 
 
 
 
 
16 
9 
Adverse Events 
 
 
 
 
 
 
 
17 
 
9.1 
Definitions 
 
 
 
 
 
 
 
17 
 
 
9.1.1 Adverse Events 
 
 
 
 
 
17 
 
 
9.1.2 Serious Adverse Events 
 
 
 
 
17 
 
9.2 
Reporting Procedures  
 
 
 
 
 
17 
 
 
9.2.1 Non-serious Adverse Events  
 
 
 
18 
 
 
9.2.2 Serious Adverse Events 
 
 
 
 
18 
10 
Ethical Considerations 
 
 
 
 
 
 
18 
 
10.1 
Review by an NHS Research Ethics Committee  
 
 
18 
 
10.2 
Potential Risks and Benefits of Participation  
 
 
18 
11 
Regulatory Issues 
 
 
 
 
 
 
 
19 
 
11.1 
Confidentiality 
 
 
 
 
 
 
19 
11.2  Safety and Data Monitoring  
 
 
 
 
19 
 
11.3 
Indemnity 
 
 
 
 
 
 
 
19 
 
11.4 
Sponsor 
 
 
 
 
 
 
 
19 
 
11.5 
Funding 
 
 
 
 
 
 
 
19 
 
11.6 
Audits and Inspections 
 
 
 
 
 
19 
12 
Study Management 
 
 
 
 
 
 
 
19 
13 
Publication Policy 
 
 
 
 
 
 
 
19 
14 
References 
 
 
 
 
 
 
 
 
20-24 
15 
Appendices 
 
 
 
 
 
 
 
 
25 
 
15.1 
Appendix 1 
 
 
 
 
 
 
 
25-26 
16 
Study Summary Tables 
 
 
 
 
 
 
27-30 
17 
Study Costs 
 
 
 
 
 
 
 
 
30 

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GLOSSARY OF ABBREVIATIONS AND TECHNICAL TERMS 
ACS 
Acute coronary syndrome 
ADP 
Adenosine diphosphate 
AE 
Adverse event 
CABG 
Coronary artery bypass graft 
CMR 
Cardiovascular magnetic resonance 
ECG 
Electrocardiogram 
IMR 
Index of microvascular resistance 
HTPR 
High on-treatment platelet reactivity 
MVO 
Microvascular obstruction 
PW 
Pressure Wire 
PPCI 
Primary percutaneous coronary intervention 
SAE 
Serious adverse event 
STEMI 
ST-segment elevation myocardial infarction 
TIMI 
Thrombolysis in myocardial infarction 
UA 
Unstable angina 
VASP 
Vasodilator stimulated phosphoprotein phosphorylation 
 
 
KEYWORDS 
 
Pharmacodynamic 
Antiplatelet 
Myocardial Infarction 
Cangrelor 
Ticagrelor 
STEMI 
IMR 
CMR 
 
 
 

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1. 
LAY SUMMARY 
 
Major heart attacks are caused by a number of factors, the two major of which are furring up 
of a coronary artery with atheroma and then sudden clot formation on this area leading to a 
blockage and interruption of blood flow. The clots that lead to heart attacks are largely made 
of clotting blood cells (platelets) that in health repair blood vessels and inhibit spontaneous 
bleeding. One of the main treatment strategies for heart attacks is to make these cells less 
“sticky”. Aspirin is a main stay of anti-platelet treatment in the UK and in addition one of 
three other oral antiplatelet agents acting on the same platelet activation pathway (P2Y12 
receptor) is licensed for use. When a patient is admitted with a major heart attack, they are 
treated with emergency primary percutaneous coronary intervention (PPCI) a technique 
where a wire and balloon are used to reopen the coronary artery and then usually a stent (a 
slotted metal tube) is placed to keep the artery open. Aspirin and one of the P2Y12 inhibitor 
agents are given to prevent further clots and all have been shown to reduce negative events 
following heart attacks and angioplasty with stent insertion. There are increasing data, 
including from our own institution, showing that in the setting of heart attacks, the oral 
P2Y12 inhibitors are poorly absorbed and have little effect at the time of most need, i.e. soon 
after dosing while the primary PCI is being performed.  
All three current P2Y12 inhibitor agents are taken in tablet form immediately before the 
emergency PPCI procedure. It appears that in healthy stable patients these agents take at least 
30 min to 2 hours to have an adequate effect. In heart attack patients the angioplasty 
procedure is usually performed well within this timescale. Furthermore, patients who are 
having a heart attack do not have normal drug absorption with blood being diverted away 
from the stomach and gut activity being suppressed by other drugs such as morphine. 
 
In this current study, patients with major heart attacks will be given our standard oral agent, 
Ticagrelor, or the newer intravenous agent Cangrelor prior to PPCI. Blood samples will be 
taken to assess the effect of the anti-platelet agents when the balloon opens the artery and 4 
hours after taking the drugs. A final sample will be taken at 24-36 hours to assess effect of 
the anti-platelet agents and also to assess myocardial damage. 
 
We will assess the two drug therapies by looking at 
i) 
The effect of the drugs on blood platelet “stickiness” 
ii) 
The effect on patency of the treated artery (TIMI Flow Grade) 
iii) 
The effect on the ECG markers of success 
iv) 
The effect on the extent of heart muscle damage using Cardiac MRI scanning 
v) 
The effect on the flow in the capillary blood vessels in the heart muscle (Index of 
Microcirculatory Resistance, IMR) using an intracoronary pressure wire. 
 
In total the patients in the study will require up to 3 extra blood tests, each using around 10-
15 ml of blood (approximately 3 teaspoons of blood). This will not cause any ill effects but 
may involve up to 2 extra needle pricks (as the first sample will be taken from the radial or 
femoral sheaths and does not involve a needle prick). The angioplasty procedure itself will be 
prolonged slightly (after the “life-saving” part of the procedure when flow in the artery has 
been restored) by the introduction of a further coronary wire (pressure wire) to measure 
coronary pressure flow and the index of microcirculatory resistance (IMR). 
Three months after the index admission, patients will undergo a Cardiac Magnetic Resonance 
Scan to assess the amount of heart muscle damaged. 
 

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2. 
INTRODUCTION  
 
2.1 
BACKGROUND 
The success of modern treatment for ST-segment elevation myocardial infarction (STEMI) is 
dependent, in part, on the adequate suppression of platelet activity. Primary percutaneous 
coronary intervention (PPCI) for STEMI management has led to marked reductions in 
morbidity and mortality (1, 2). Aspirin is the mainstay anti-platelet agent. It is rapidly 
absorbed in the upper gastrointestinal (GI) tract and results in a measurable inhibition of 
platelet function within 60 minutes (3, 4). The advent of the platelet P2Y12 inhibitors has led 
to further improvement in outcomes in patients with acute coronary syndromes (ACS) 
undergoing PCI with reduced ischaemic complications (5) albeit at an increase in rate of 
bleeding complications. These agents have a synergistic effect on platelet function with the 
addition of Clopidogrel to Aspirin leading to approximately 20% reduction in negative 
cardiovascular events (6). 
Activation of platelets leads to a conformational change in the surface glycoprotein IIb/IIIa 
receptor that allows cross bridging with fibrinogen and rapid aggregation (platelet thrombus 
formation) (7, 8) 
During PPCI, thrombus formation and dispersion can have a major impact on outcome. 
Intravenous platelet IIb/IIIa receptor antagonists such as Abciximab were initially shown to 
have a positive impact on primary angioplasty outcomes leading to a class IIa indication 
within the European Society of Cardiology (ESC) guidelines for use in the treatment of 
STEMI with angioplasty (9). 
 
As oral antiplatelet inhibition has improved (specifically with the addition of Clopidogrel, 
Prasugrel or Ticagrelor) there has been a concomitant reduction in the use of intravenous 
IIb/IIIa agents during PCI for patients with ACS. This has been partly informed by later 
studies suggesting that the additive value of these agents to dual anti-platelet therapy is 
questionable (10).  
In addition, the extra bleeding complications are seen by some to be excessive (11).  
 
Current NICE recommendations for the treatment of STEMI include Aspirin plus one of the 
P2Y12 agents Clopidogrel, Prasugrel or Ticagrelor. 
Ticagrelor, a reversible p2Y12 agent (cyclopentyltriazolopyrimidine CPTP) has been shown 
to be superior to Clopidogrel in ACS patients in the PLATO trial (12).  
In this multicenter, randomized, double-blind trial, 18,624 patients were recruited. 7544 
patients with STEMI were allocated to either Ticagrelor 180mg loading dose followed by 90 
mg twice daily or Clopidogrel 300mg loading dose followed by 75 mg daily for 6 to 12 
months. At 12 months, the primary end point — a composite of death from vascular causes, 
myocardial infarction, or stroke — had occurred in 9.8% of patients receiving Ticagrelor as 
compared with 11.7% of those receiving Clopidogrel (hazard ratio, 0.84; 95% confidence 
interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points 
showed significant differences in the rates of other composite end points, as well as 
myocardial infarction alone (5.8% in the Ticagrelor group vs. 6.9% in the Clopidogrel group, 
P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone 
(1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with Ticagrelor 
(4.5%, vs. 5.9% with Clopidogrel; P<0.001) (12) 

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We currently use Ticagrelor in patients admitted with STEMI prior to PPCI. Recently 
published data suggests however that even with this rapidly effective oral agent, it is not fully 
functional at the time of PPCI given the short timelines involved (13, 14) 
 
Ticagrelor differs from the thienopyridine class of antiplatelet agents (Clopidogrel, Prasugrel, 
and Ticlopidine) as it does not exist as a prodrug and thus does not require biotransformation 
by hepatic enzymes before becoming active. Also Ticagrelor binds reversibly to P2Y12 
receptors leading to a faster onset and offset than Clopidogrel (15).   
Moreover, in the RESPOND study, Ticagrelor therapy was associated with uniform and 
superior platelet inhibition in both previously identified Clopidogrel responders and non-
responders, and that inhibition, in turn, was associated with an extremely low prevalence of 
high on-treatment platelet reactivity (16).  
 
Ticagrelor has recently received recommendation in the ESC guideline as a front-line 
treatment option for STEMI and NSTEMI (17, 18) 
 
Ideally a full antiplatelet effect would be evident at the start of the PPCI, whereas in practice 
dosing of Clopidogrel, Prasugrel or Ticagrelor typically occurs on admission to hospital 
(possible only 10-20 minutes prior to PPCI).  
Cangrelor is an adenosine diphosphate analogue that reversibly binds to and inhibits the 
P2Y12 ADP receptor. It has a half-life of 3 to 6 minutes and, when given as a bolus plus 
infusion, quickly and consistently inhibits platelets to a high degree, with normalisation of 
platelet function within 60 minutes after discontinuation (19). 
Cangrelor [Kengrexal (EU), Kengreal (USA)] has been licensed for use in Europe, USA and 
the UK since March 2015, June 2015 and July 2015 respectively. Co-administered with 
Aspirin, is indicated for the reduction of thrombotic cardiovascular events in adult patients 
with coronary artery disease undergoing percutaneous coronary intervention (PCI) who have 
not received an oral P2Y12 inhibitor prior to the PCI procedure and in whom oral therapy 
with P2Y12 inhibitors is not feasible or desirable.  
The use of Cangrelor in patients undergoing PCI has been studied in three phase 3 trials, the 
Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition 
(CHAMPION) PCI study, the CHAMPION PLATFORM study and the CHAMPION 
PHOENIX study (19)(20)(21).  In the CHAMPION PCI and the CHAMPION PLATFORM 
studies, Cangrelor, compared to oral Clopidogrel was not associated with a significant 
reduction in the primary efficacy end point (All cause death, MI or ischaemia driven 
revascularization at 48 hours) but was associated with reductions in secondary end points, 
including the rate of stent thrombosis, with no excess in severe bleeding. In the CHAMPION 
PLATFORM study there was also a reduction of the pre-specified secondary endpoint of 
death in the Cangrelor arm. The CHAMPION PHOENIX trial enrolled 11,145 patients 
undergoing PCI for SA, NSTEMI/UA or STEMI. Patients were randomized to either IV 
Cangrelor followed by Clopidogrel or oral Clopidogrel (300 or 600 mg) before during or 
immediately after PCI. In this study patients treated with the intravenous agent were 
significantly less likely to experience one of the primary endpoints (all cause death, MI or 
ischaemia driven revascularization at 48 hours), with no significant increase in bleeding. The 
study included 1992 patients with STEMI, who appeared to have a similar benefit to the SA 
and NSTEMI patients. Currently there are no data comparing the relative efficacy of 
Cangrelor with the more potent and rapidly acting Ticagrelor in patients undergoing PPCI for 
acute STEMI of less than 12 hours duration. 

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2.2 
RATIONALE FOR CURRENT STUDY 
Gastrointestinal absorption during a STEMI is not equivalent to that of a resting patient (22). 
Hypotension and/or diversion of splanchnic blood flow are likely to slow drug absorption and 
the intrinsic increase in platelet activity seen during STEMI (23) (24) may also inhibit the 
antiplatelet effect of drugs. A previous pharmacokinetic study has shown reduced drug 
absorption during STEMI (25). Administration of Morphine to ease STEMI pain appears to 
attenuate the antiplatelet effects of newer P2Y12 inhibitors in the hours after primary PCI 
(26). 
In the current study we aim to demonstrate whether intravenous Cangrelor has a better 
antiplatelet effect than Ticagrelor during the primary angioplasty (STEMI patients), and 
investigate the pharmacodynamics properties of these agents in the setting of STEMI by 
assessing the impact of these agents on a variety of STEMI related outcome variables. 
A number of methods have been developed to assess the effect of P2Y12 receptor inhibition. 
Their effect is probably best measured using techniques that specifically measure P2Y12 ADP 
receptor activation, such as vasodilator stimulated phosphoprotein phosphorylation (VASP) 
utilising flow cytometry, and the VerifyNow P2Y12 near patient system (Accumetrics, San 
Diego, CA). 
 
We will utilise both of these methods in this study. 
 
3. 
STUDY OBJECTIVES 
 
1) To determine the degree and time-course of platelet inhibition in patients admitted 
with STEMI treated with IV Cangrelor vs oral Ticagrelor. 
2) To assess the impact of Cangrelor vs Ticagrelor on the index of myocardial 
microcirculatory resistance using IMR. 
3) To investigate the impact of Cangrelor vs Ticagrelor on markers of PPCI success 
(TIMI flow grade assessment to evaluate coronary blood flow after PPCI). 
4) To assess ST segment resolution post PPCI. 
5) To investigate the impact of Cangrelor vs Ticagrelor on initial myocardial infarct size 
based on Peak Troponin.  
6) To investigate the impact of Cangrelor vs Ticagrelor on final myocardial infarct size 
by CMR at three months post PPCI. 
 
 
 
 
 
 
 
 
 

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4. 
STUDY DESIGN 
This is an open label randomised controlled pilot trial. We will enrol 100 patients (50 in each 
arm). We anticipate the conclusion of subject recruitment in 12 months from the study start 
date, with a further 6 months for data analysis and manuscript preparation. Patients in the 
intravenous Cangrelor arm will receive Cangrelor as an initial bolus dose given as per body 
weight followed by an intravenous infusion for no longer than three hours (The total dose of 
IV Kengrexal to be administered based on average body weight of 80 Kg is 510 
micrograms/kg given over two hours), they will then switch to oral Ticagrelor given at 
maintenance dose of 90mg twice daily for 12 months. Patients in the oral Ticagrelor arm will 
receive Ticagrelor at a loading dose of 180mg followed by maintenance dose of 90mg twice 
daily for 12 months.  All the 100 participants will undergo a CMR scan three months post 
PPCI.  
 
 
 
4.1 
STUDY OUTCOME MEASURES 
 
a) Degree of platelet inhibition measured with VerifyNow TM rapid platelet function analyser 
and also VASP flow cytometry at infarct vessel open time (also known as balloon time), 4 
and 24-36 hours post dosing. 
b) Index of Microvascular Resistance (IMR) measurement using pressure wire studies 
immediately following the PPCI procedure.  
c) Measurement of thrombolysis in myocardial infarction (TIMI) flow grade using TIMI 
Frame Count. 
d) ST Segment Resolution by ECG at 90-120 minutes post PPCI.  
e) Infarct size by Peak Troponin at 24-36 hours post PPCI. 
f) Final infarct size by CMR at three months in both patient groups (total of 100 subjects). 
 
This study is not powered for clinical outcomes; however clinical and safety data will be 
recorded. 
 
4.2 IN PATIENT SAFETY ENDPOINTS  
 
• BARC definition for bleeding (see appendix 1) 
• Target Vessel Failure 
• Vital Status at Discharge  
 
5 
PARTICIPANT ENTRY  
 
5.1 
CONSENT 
Consent will be a two-stage process for patients undergoing PPCI for STEMI. Verbal assent 
will be brief prior to the PPCI and first blood sample, so as not to lead to a reduction in the 
quality of patient care (MI outcomes are related to the door to balloon time with PPCI). A 

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shortened patient information sheet will be read to the patient and if verbal assent is gained it 
will be recorded in the clinical notes and the site file. This is in line with NRES guidelines 
that suggest that patients admitted with STEMI are considered as unconscious patients 
initially.  
Following emergency PCI and IMR measurement, when the patient is pain free and has been 
able to rest, a full patient information sheet will be proffered and written consent sought. If 
the patient does not want to be part of the trial, he or she will be withdrawn from the study 
and future tests will not be performed. Treatment will continue in accordance with clinical 
guidelines. The patients’ participation in the trial will last for 3 months. At the end of three 
months a Cardiac MRI scan will be performed unless there are specific contraindications. 
Vital status will be determined on discharge and at three months when patients turn up to 
have their cardiac MRI scan. If a patient fails to attend Cardiac MRI scan appointment in 
three months’ time, a telephone call will be made to the relevant GP to determine the vital 
status of the patients.   
 
 
5.2 
ELIGIBILITY CRITERIA  
All research subjects will be identified from STEMI patients admitted for PPCI at the Heart 
and Lung Centre in Wolverhampton. 
 
 
5.3 
RANDOMISATION 
 
Potential patients will be reviewed by a member of the research team before randomisation to 
confirm eligibility. Once the eligibility of the patient is confirmed by the trial coordinators 
and the verbal assent is gained, randomisation will be carried out prior to patient’s transfer to 
the cardiac catheter suite. Randomisation will be performed via a secure online web-based 
service. There will be a single password which will give access for randomisation for the trial 
on fully encrypted password-protected computers at the heart and lung centre, New Cross 
Hospital. The system is accessed via a secure connection (SSL) over the internet. This 
connection encrypts data between the user’s internet browser and the server. Online 
randomisation is achieved by the trial coordinator entering a patient identifier (text field – 
will be unique), own email address and the randomisation system password. Randomisation 
is by random permuted blocks to oral Ticagrelor or IV Cangrelor in 1:1 ratio. 
An email notification is generated displaying the chosen treatment group or code and sent to 
the email address given by the user randomising and the administrator email address. The 
administrator email address is the one provided when the system is set up (usually a trial 
coordinator or central trial email address).There is only one password and only members of 
the research team can perform a randomisation.  
 
 
5.4 
INCLUSION CRITERIA 
1) Patients presenting with STEMI eligible for PPCI  
2) Able to give verbal assent pre procedure and written consent following the procedure. 
3) Age ≥18 years  
4) No contraindication to Cangrelor or Ticagrelor 

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5) Thienopyridine naïve 
 
 
 
Women of childbearing potential would be advised to use appropriate contraceptive 
measures to avoid pregnancy during treatment with the IMPS following the acute event.  
 
If a patient gives verbal assent but is unable to provide a written consent at a later stage 
due to continued incapacitation, presumed consent will be continued. The reasons why a 
patient becomes incapacitated and becomes unable to provide a written consent will be 
recorded during data collection. As soon as the patient is able to provide written consent, 
written consent will be sort for continued participation or withdrawal as the patient 
wishes.  
 
5.5 
EXCLUSION CRITERIA 
1) Be unable to provide verbal assent and written consent 
2) Allergic to Aspirin or any of the P2Y12 antagonists in the trial 
3) Have pre-existing cardiogenic shock 
4) Previous myocardial infarction 
5) Have a concurrent septic or inflammatory disease e.g. rheumatoid arthritis, lupus, and 
pneumonia. 
6) Already taking a P2Y12 inhibitor 
7) Known bleeding diathesis 
8) Significant active bleeding 
9) History of intracranial hemorrhage  
10) Patients who are being treated with formal anticoagulation (Vitamin K antagonist, 
Factor II or Xa inhibitors) or have an indication for anticoagulation during the first 
four hours of the study period. Example is patients known to have atrial fibrillation, 
pulmonary embolism or deep vein thrombosis.  
11) Known severe renal dysfunction requiring renal replacement therapy. 
 
 
 
 
 
 
5.6 
WITHDRAWAL CRITERIA 
Patients are able to withdraw from the trial if they wish without the need to provide reasons 
and without their care being affected or compromised. Patients who decide to withdraw their 
consent to participate in the study will have all samples collected up to the time of withdrawal 
disposed of in appropriate manner. All information collected on the patient for the purpose of 
the study will be erased. The withdrawal shall be recorded in the study patient identification 
log. The treatment of the patient will continue in accordance with clinical guidelines should 
the participant choose to withdraw or not. If a patient dies after obtaining verbal assent but 
before gaining a written consent, they will still be included in the study and data collected up 
to the time of death will still be used. Patients who will need administration of glycoprotein 
IIb/IIIa inhibitors during or post PPCI procedure and patients who fail to have Cangrelor or 

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Ticagrelor for unexpected circumstances will be withdrawn from the study and their data will 
not be collected. 
 
 
 
 Safety stopping criteria: 
A participant would be withdrawn from the trial if the Clinician feels that continued 
participation would be unsafe for the participant.  
This could include, but not restricted to: 
• An anaphylactic shock 
• An SAE occurring 
 
6. ASSESSMENT AND FOLLOW-UP  
 
6.1 Subjects: A total of 100 subjects will be included in the study. Patient’s demographic 
data will be collected. 
6.2 Sampling and Dosing 
6.2.1  Study subjects will have a P2Y12 inhibitor administered (Ticagrelor or Cangrelor) 
after recorded verbal assent following randomisation. The time of loading dose will be 
recorded and the patient transferred to the cardiac catheterization suite. After the insertion of 
the radial or femoral sheath, 10 ml of whole blood will be drawn from this sheath at the first 
intracoronary balloon inflation time. A further 10 ml will be taken 4 hours post dosing (or as 
close as is practicable). Further sampling (15 ml) on the ward will take place 24-36 hours 
post dosing from an anticubital vein using a 21-gauge needle (see study summary tables). 
Samples taken will be analysed to assess P2Y12 activity using VerifyNow ™ (Accumetrics, 
San Diego, California, USA) and VASP Flow Cytometry tests. Peak Troponin levels will be 
assessed as well using the same blood samples. 
6.2.2 Dosing: Patients will be divided into two arms; Oral Ticagrelor (50 patients) and 
Intravenous Cangrelor (50 patients) arms.  
Ticagrelor arm: Patients will receive Ticagrelor 180mg loading dose on the cardiology ward 
prior to transfer to the catheter lab. Thereafter, a maintenance dose of 90mg twice daily will 
be given and continued for 12 months duration.  
Cangrelor arm: Patients will receive Cangrelor administered at a rate of 30 micrograms/kg 
intravenous bolus followed immediately by 4 micrograms/kg/min intravenous infusion. The 
bolus and infusion will be initiated in the cardiac catheter lab prior to the PCI procedure and 
continued for at least two hours or for the duration of the procedure (to increase up to three 
hours), whichever is longer. 30 minutes prior to stopping Cangrelor infusion, Ticagrelor 180 
mg will be given followed by 90mg twice daily maintenance dose continued for duration of 
12 months. Cangrelor will be obtained directly from The Medicines Company, retained at the 

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pharmacy department at New Cross Hospital and issued by the pharmacy department for our 
clinical trial purposes only. Ticagrelor will be received by the pharmacy department and 
designated for our clinical trial purposes only. 
Cangrelor vials and Ticagrelor tablets will be stored at controlled room temperatures (20°C to 
25°C) in special cupboards on the cardiology ward. Only members of the research team will 
have access to the drug. Each vial contains Cangelor tetrasodium corresponding to 50 mg 
Cangrelor. After reconstitution 1 mL of concentrate contains 10 mg Cangrelor. After dilution 
1 mL of solution contains 200 micrograms Cangrelor. Weight conversion charts in the 
catheter lab will be used to calculate the required dose of Cangrelor to be administered.  
 
6.3 PHARMACODYNAMIC ANALYSIS 
6.3.1 VerifyNow for P2Y12 Activity Analysis 
VerifyNow ™ (Accumetrics, San Diego, California, USA) is a near patient test comprising a 
turbidimetric based optical detection system that measures platelet aggregation as an increase 
in light transmittance.  
We are already using this system for clinical research in our department and it has regulatory 
approval for the assessment of P2Y12 activity. VerifyNow has also been used in the 
assessment of Ticagrelor activity in a number of studies (16, 27, 28). 2 ml of whole blood is 
transferred into a Greiner Bio-One Vacuette containing 3.2% sodium citrate (Accumetrics, 
San Diego, California, USA) and inverted carefully, after which the tube is left at room 
temperature for a minimum of 15 and 30 minutes for P2Y12 activity assay. The tube is then 
loaded into a specific assay device and analysed (within 4 hours from blood sampling) as per 
the manufacturers’ instructions (Accumetrics). The system is calibrated daily electronically 
and full quality control is performed with each batch of assay devices. This system uses a 
similar principle to formal platelet aggregometry. 
Results are shown as P2Y12 reaction units (PRU) for P2Y12 assay  
6.3.2 VASP Flow Cytometry 
VASP, an intracellular actin regulatory protein, is a substrate of both cyclic adenosine 
monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP)-dependent protein 
kinases (29) .  
Dephosphorylation of VASP follows P2Y12 stimulation. Conversely, inhibition of the P2Y12 
receptor by Clopidogrel and stimulation of prostaglandin E1-activated adenylyl cyclase 
induce phosphorylation of VASP by cAMP-dependent protein kinases. Thus levels of VASP 
phosphorylation/dephosphorylation reflect P2Y12 inhibition/activation. Despite using a 
commercially available assay (Biocytex, Asnieres, France), VASP flow cytometry is 
primarily a research-based assessment owing to the complexity of the procedure and the 
requirement for significant technical expertise. It is seen by some as a gold standard test for 
P2Y12 inhibition. Whole blood transferred to tubes containing 3.2% sodium citrate is 

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incubated with PGE1 or PGE1 and ADP for 10 minutes then fixed with paraformaldehyde, 
then platelets are permeabilized with non – ionic detergent. The cells are than labelled with a 
monoclonal antibody against 239-phosphorylated VASP and then a secondary fluoroscein 
isothicyanate-conjurgated polyclonal antibody. Analysis will be performed on a Becton 
Dickinson (Plymouth, UK) FACS Calibur flow cytometer, and 10,000 platelets will be gated 
per assessment as per the manufacturer’s instructions. Results are expressed as percentage 
platelet reactivity index (% PRI). Samples will be taken to clinical chemistry department at 
New Cross Hospital and stored in freezers at minus 80 degrees. Samples will then be 
transferred in sealed protective containers to Wolverhampton University where flow 
cytometric analysis is performed under the supervision of Dr James Vickers. 
VASP Flow cytometric analysis measures activity at the P2Y12 receptor very effectively and 
thereby indirectly the activity of P2Y12 inhibitor and has been shown to be of value in a 
number of clinical trials including one carried out by our own research group (30) (31). 
6.4 
TIMI Flow Grade  
 
In acute ST elevation myocardial infarction early reperfusion of the occluded coronary artery, 
limits the size of infarction, reduces the degree of left ventricular dysfunction, and improves 
survival (32). Assessment of the degree of reperfusion was achieved using the Thrombolysis 
in Myocardial Infarction (TIMI) flow grading system developed in the TIMI 1 trial (Grade 
0—No perfusion; Grade 1—Penetration without perfusion; Grade 2—Partial perfusion; 
Grade 3—Complete perfusion) (33). A larger improved survival was observed in patients 
who achieved TIMI grade 3 flow (34, 35). There is a nearly linear correlation between higher 
rates of early TIMI grade 3 flow and improved survival (35). 
In our study, we will assess the index of blood flow through the culprit coronary artery using 
TIMI Frame Count (TFC). The TFC is a simple, reproducible, objective, and quantitative 
index of coronary flow that allows standardization of TIMI flow grades and facilitates 
comparisons of angiographic end points between trials (36).  
The number of cine-frames required for contrast to first reach standardized distal coronary 
landmarks in the infarct-related artery (the TIMI frame count) will be measured with a frame 
counter on the GE cine-viewer. The first frame to be used for TIMI frame counting will be 
the first frame in which dye fully enters the artery. The last frame is defined as the frame 
when dye first enters the distal landmark branch.  
6.5 
Enzyme Estimation of Myocardial Infarct Size 
 
After an acute myocardial infarction, infarct size quantification is clinically important 
because it correlates with mortality and morbidity (37). 
The gold standard for infarct size quantification is cardiac magnetic resonance imaging 
(CMR). We will use CMR in all subjects in this trial. In addition, biochemical markers 
remain a realistic and simple method for infarct size estimation. Troponin is a protein 
complex consisting of three subunits (I, C and T) that modulate the calcium-mediated 
interaction between actin and myosin in skeletal and cardiac muscle tissue (38). 

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Circulating levels of highly sensitive troponin not only correlate with infarct size and ejection 
fraction but also predict clinical outcomes after a ST-segment elevation myocardial infarction 
(STEMI) (39).  
The first articles detailing the relationship between cTnT and infarct size were published in 
1993 (40). (41). 
All studies have found a consistent and positive correlation between cardiac troponin and 
infarct size determined by both CMR and SPECT. Therefore, cardiac troponin T (cTnT) can 
be used as a surrogate measure for this purpose. The 24 hours value of troponin after the 
onset of symptoms had the nearest associations with all outcomes (42).  
In our study, cardiac troponin will be employed as a surrogate endpoint for infarct size. 
A blood sample will be taken 24-36 hours post PPCI to determine peak high sensitivity 
troponin I levels. This blood test is performed routinely in our centre in patients presenting 
with STEMI and analysis is performed in clinical chemistry department at New Cross 
Hospital. 
 
 
6.6 Index of Microvascular Resistance (IMR) Estimation 
At the end of the clinical procedure a coronary pressure-/ temperature-sensitive guidewire 
(Radi Medical Systems, Uppsala, Sweden) will be utilised. The guidewire will be calibrated 
outside the body then equalized within the guide catheter, with the pressure sensor positioned 
at the ostium of the guide catheter. The guidewire microsensor will be advanced into the 
distal third of the culprit artery. The apparent IMR is calculated by multiplying the distal 
coronary pressure by the mean transit time of a 3 ml bolus of saline at room temperature 
during coronary hyperaemia induced by intravenous adenosine (43) 
Adenosine 140 mcg/kg/min will be used to induce maximal hyperaemia via a large peripheral 
vein. The mean aortic and distal coronary pressures will be recorded during maximal 
hyperaemia. 
IMR is calculated as the distal coronary pressure multiplied by the mean transit time of the 3-
ml saline bolus at maximal hyperaemia, measured simultaneously (automated on the St Jude 
Medical RadiAnalyzer TM Xpress). This assessment is expected to add no more than thirty 
seconds to screening time during a coronary angioplasty procedure. Having to screen for 
duration of thirty seconds long will increase radiation exposure by approximately 3% 
6.7 ST Segment Resolution post-acute Myocardial Infarction 
Percutaneous coronary intervention is the preferred treatment strategy in patients with acute 
ST-Elevation myocardial infarction (STEMI). It promotes an early and sustained restoration 
of epicardial blood flow in the target vessel (17). (45). 
Successful reperfusion of the epicardial vessel is essential, but it is the microvascular flow 
that most strongly correlates with outcome. ST-segment changes reflect myocardial rather 
than epicardial flow and hence provide prognostic information beyond that provided by 
coronary angiogram alone (46-49). 
The resolution of the ST-segment after the institution of reperfusion therapy is an important 

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predictor of patency of the artery related to the event and of effective microcirculatory 
perfusion (50). 
Various studies have shown a remarkably consistent relationship between the degree of ST 
resolution and subsequent mortality (51). ECG is useful, simple, noninvasive, broadly 
accessible, easily repeatable/applied, and affordable tool (52).  
The persistence of ST-segment elevation on the ECG, despite the restoration of a normal 
epicardial flow, reflects a poor prognosis and correlates with larger infarct size and higher 
combined rate of severe cardiovascular adverse events (53). In our study, an ECG will be 
recorded 90-120 minutes post PPCI to assess the degree of ST segment resolution. 
 
 
6.8 CMR Assessment of Myocardial Infarct Size  
CMR has become the gold standard for surrogate endpoints in clinical trials. CMR of 
myocardial infarction has been correlated with histology (54). It can accurately measure 
infarct size (55), LV volumes (56), myocardial salvage (57), microvascular obstruction 
(MVO) (58) and myocardial oedema (area at risk). Myocardial infarct size, myocardial 
salvage and MVO have all been shown to be associated with worse outcomes.  
CMR assessment of final infarct size will be performed at three months post STEMI. Infarct 
size will be quantified by planimetering the region of hyperintensity in the myocardium 10 
minutes following gadolinium contrast administration. We will notify patients and their 
responsible general practitioners about the CMR examination result in writing. 
 
 
7. 
STATISTICS AND DATA ANALYSIS 
All statistical analysis will be performed in collaboration with Professor Nevill, Professor of 
biomedical statistics at University of Wolverhampton on fully encrypted password-protected 
computers at New Cross Hospital. 
Continuous variables will be compared using parametric and non-parametric tests as 
appropriate. Dichotomous variables will be compared by Fishers exact test. Logistic 
regression analysis will be used to predict the significant independent predictors of poor 
outcome post angiography.  
 
7.1 Sample Size Calculation  
A previous open label, multicentre study assessed the pharmacodynamics of Cangrelor in a 
number of patients with acute coronary syndrome (39 patients) (66). Our study is an open 
label single centre pilot trial planning to enrol 100 patients. Our study will provide the basis 
for power calculation for future similar studies. This study is a pilot study and not designed to 
test or determines clinical outcomes such as mortality, but rather we will be looking at the 
clinical efficacy of Cangrelor versus Ticagrelor in the context of platelet inhibition and effect 
on myocardial necrosis. Therefore, no formal sample size calculation has been conducted.  
 
8. 
END OF STUDY 

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End of the study will be marked by the last patient’s last visit samples when they have been 
analysed. The data will then be scrutinised, and finally an article summarising the study 
written and submitted to a peer-reviewed journal for consideration of publication. Positive 
trial results might lead to implementation of the use of intravenous Cangrelor in clinical 
practice. 
 
Study termination 
The safety monitoring committee/Steering Committee will meet on a regular basis. The trial will be 
terminated early if there is evidence of unexpected excess bleeding with cangrelor or severe or 
unexpected complications from the IMR procedure.   
 
 
9. 
ADVERSE EVENTS 
 
9.1 
DEFINITIONS   
 
 
9.1.1 Adverse Event (AE): any untoward medical occurrence in a patient or clinical study 
subject. Adverse events will stop being recorded after 36 hours from the index admission. 
 
 
9.1.2 Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or 
effect that: 
• 
Results in death 
• 
Is life-threatening – refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe 
• 
Requires hospitalisation, or prolongation of existing inpatients’ 
hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
 
 
 
Common expected post-procedural adverse events listed below are the conditions not going 
to be classed as SAEs: 
 
• Acute renal failure requiring haemodialysis, peritoneal dialysis or haemofiltration 
• Ventricular arrhythmia requiring direct-current (DC) cardioversion 
• Atrial arrhythmia requiring intervention 
• Significant heart block requiring temporary or permanent pacing  
• Cardiac tamponade requiring urgent surgical intervention 
• Cardiogenic shock requiring intra-aortic balloon pump or other assist device 
• Emergency coronary artery bypass graft operation 

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• Arterial complications 
• Blood or platelet transfusion 
 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations.  Important AEs that are not immediately life-threatening or do not result in death 
or hospitalisation but may jeopardise the subject or may require intervention to prevent one of 
the other outcomes listed in the definition above, should also be considered serious. 
 
 
 
 
9.2 
REPORTING PROCEDURES 
 
All serious adverse events will be reported.  Depending on the nature of the event the 
reporting procedures below will be followed. Any questions concerning serious adverse 
events reporting will be directed to the Chief Investigator in the first instance.w3433; 
 
 
9.2.1 Non serious AEs 
All such events, whether expected or not, will be recorded. 
 
9.2.2 Serious AEs 
 
An SAE form will be completed and faxed to the Chief Investigator within 24 hours.  However 
hospitalisations for elective treatment of a pre-existing condition do not need reporting as SAEs. 
Information about all serious adverse events will be collected and recorded on the Serious Adverse 
Event Report Form and faxed to the R&D Directorate at New Cross Hospital within 24 hours of 
learning of its occurrence. 
All serious adverse events will be reported to the appropriate regulatory and ethical authorities. 
Contact details for reporting SAEs 
Fax: 01902 695646, attention Prof James Cotton 
Please send SAE forms to: Prof James Cotton Tel: 01902 694200 (Mon to Fri 09.00 – 17.00) 
 
10 
ETHICAL CONSIDERATIONS 
 
10.1 
Review by an NHS Research Ethics Committee  
Ethics review of the protocol for the trial and other trial related essential documents (e.g. patient 
information sheet, consent form…) will be carried out by a UK Research Ethics Committee (REC). 
Any amendments to these documents, after a favourable opinion from the REC has been given, will 
be submitted to the REC for approval prior to implementation. 
10.2 
Potential Risks and Benefits of Participation  
Potential Benefits to Participants: CMR clinical report will be generated and available to clinical 
care team with assessment of LV function and infarct characteristics that may guide future 
management. 
Potential Harms to Participants: The magnetic fields and radio waves used in cardiac MRI have no 
side effects. This method of taking pictures of organs and tissues doesn't carry a risk of causing cancer 

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or birth defects. There is a small risk of side effects due to contrast administration during CMR. 
Gadolinium contrast medium is generally very safe. Side effects or reactions are uncommon but may 
occur. The most common adverse reactions are brief headache, nausea (feeling sick) and dizziness for 
a brief time following the injection. This occurs in 1% to 5% of contrast injections. Infrequently, a 
feeling of coldness may occur at the injection site. There is a negligible incremental risk of IMR 
measurement above those for PPCI. IMR measurement is expected to add no more than thirty seconds 
to screening time during a coronary angioplasty procedure. Having to screen for duration of thirty 
seconds long will increase radiation exposure by approximately 5% of the total PPCI radiation dose. 
Blood Sampling from arm: may cause bruising and discomfort. 
Benefits to Society: this study will allow better understanding of antiplatelet function in 
patients with STEMI with potential benefits to future patients. 
 
 
11. REGULATORY ISSUES 
 
11.1  CONFIDENTIALITY 
Blood samples will be anonymised with members of the research team at New Cross Hospital 
having access to the patient’s details. All data collected on the patient will be stored in an 
anonymised fashion on fully encrypted password-protected computers at New Cross 
Hospital. The study will be archived for 5 years after the study has ended and then destroyed 
in line with the Research and Development Department policy. 
 
 
11.2  SAFETY AND DATA MONITORING 
Due to the nature of the study, data monitoring committee will not be required.  
 
11.3  INDEMNITY 
 
Standard NHS Indemnity is in place for this study. 
 
11.4 
SPONSOR 
 
The Royal Wolverhampton NHS Trust will act as Sponsor for this Study.  
 
11.5 
FUNDING 
 
Part funding is being successful. Further funding is being applied for. 
 
11.6 
AUDITS AND INSPECTIONS  
 
The study will be audited and monitored by the sponsor’s monitoring team. 
 
11.7 
TRAINING 
 

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The required training to undertake this project will be provided to members of the research 
team and the cardiac catheter lab nurses. An example is the administration of intravenous 
Cangrelor. 
 
12. 
STUDY MANAGEMENT 
 
The day-to-day management of the study will be co-ordinated by Dr Salahaddin Ubaid 
 
Trial Management Committee: J Cotton, S Ubaid, A Smallwood and E McAlindon. Study 
management committee will meet up on a 1-2 monthly basis.  
 
13. 
PUBLICATION POLICY 
 
We intend to submit an article detailing the results of the study to a peer review journal for 
consideration of publication. 
 
14. 
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2005;7:447-57. 
57. 
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microvascular obstruction on high resolution first-pass perfusion, early and late gadolinium 

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de Waha S, Desch S, Eitel I, Fuernau G, Zachrau J, Leuschner A, et al. Impact of early vs. late 
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15 
APPENDICES: 
 
 
15.1 Appendix 1 – The Bleeding Academic Research Consortium (BARC) proposes 5 bleeding types (67) 
• 
Type 0: no bleeding 
• 
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or 
treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without 
consulting a healthcare professional  
• 
Type 2: any overt, actionable sign of haemorrhage (eg, more bleeding than would be expected for a clinical circumstance, including 
bleeding found by imaging alone) that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) 
requiring nonsurgical, medical intervention by a healthcare professional, (2) leading to hospitalization or increased level of care, or (3) 
prompting evaluation  
• 
Type 3  
o Type 3a  
▪ 
Overt bleeding plus haemoglobin drop of 3 to <5 g/dL* (provided haemoglobin drop is related to bleed)  
▪ 
Any transfusion with overt bleeding 
o Type 3b  
▪ 
Overt bleeding plus haemoglobin drop ≥5 g/dL* (provided haemoglobin drop is related to bleed)  
▪ 
Cardiac tamponade 
▪ 
Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/haemorrhoid) 
▪ 
Bleeding requiring intravenous vasoactive agents 

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o Type 3c  
▪ 
Intracranial haemorrhage (does not include microbleeds or haemorrhagic transformation, does include intraspinal) 
▪ 
Subcategories confirmed by autopsy or imaging or lumbar puncture 
▪ 
Intraocular bleed compromising vision 
• 
Type 4: CABG-related bleeding  
o Perioperative intracranial bleeding within 48 h 
o Reoperation after closure of sternotomy for the purpose of controlling bleeding 
o Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period† 
o Chest tube output ≥2L within a 24-h period 
• 
Type 5: fatal bleeding  
o Type 5a  
▪ 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious 
o Type 5b  
• 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
 
 
 
 

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Appendix 2: Study Summary Tables 
 
1 
2 
3 
4 
5 
6 
7 
8 
Timepoint 
reference 
Prior to 
PPCI  
First IC 
balloon 
inflation 
End of PPCI 
(following the 
life-saving 
part) 
90-120 
minutes 
post PPCI 
4 hours 
post 
dosing 
24-36 hours post dosing 
(15 ml blood for VASP/VerifyNow 
and peak Troponin) 
Discharge 
Three months 
post PPCI 
Eligibility 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Verbal Assent 
X 
 
 
 
 
 
 
 
Randomisation 
X 
 
 
 
 
 
 
 
Dispensation of 
treatment 
X 
 
 
 
 
 
 
 
Initiation of 
either oral 
Ticagrelor or IV 
Cangrelor 
therapy 
X 
 
 
 
 
 
 
 
Written 
Informed 
consent 
 
 
X 
 
 
 
 
 
Demographic 
data collection  
X 
 
 
 
 
 
 
 
10ml blood 
collection for 
VASP/ 
VerifyNow   
 
X 
 
 
X 
X 
 
 
IMR 
 
 
X 
 
 
 
 
 
ECG 
 
 
 
X 
 
 
 
 

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10ml blood 
collection for 
Peak Troponin 
Level (routine) 
 
 
 
 
 
 
X 
 
 
TIMI Flow 
Grade 
 
 
X 
 
 
 
 
 
Vital Status 
assessment 
 
 
 
 
 
 
 
X 
X 
BARC definition 
for bleeding  
 
 
 
X 
 
 
 
 
 
Target Vessel 
Failure 
 
 
 
X 
 
 
 
 
 
CMR 
 
 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
review 
X 
X 
X 
X 
X 
X  to stop at 36 hours 
 
 
 
 
 
 
 

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Study Steps 
 
Time  
1-Quick initial assessment of patients suitable for 
enrollment in the trial 
Upon arrival at the Heart and Lung centre, 
New Cross Hospital 
2-Verbal assent  
After the initial assessment  
3-Randomisation to either one of the two trial 
treatment groups 
After obtaining verbal assent  
4-Initiation of either oral Ticagrelor or IV Cangrelor 
therapy  
Based on randomisation result 
5-Primary PCI procedure 
Once the second antiplatelet therapy is 
initiated (Ticagrelor or Cangrelor) 
6-Blood sampling for P2Y12 inhibition estimation 
(using VASP phosphorylation and VerifyNow tests) 
 
A- At the time of first intracoronary balloon 
inflation (10 ml of blood from the femoral or 
radial sheath)  
B- 4 hours post dosing (10 ml of blood from 
an anticubital vein)  
C- 24-36 hours post dosing (15 ml in total. 10 
ml for VASP/VerifyNow and 5 ml for peak 
Troponin level. One needle prick) 
7-IMR measurement  
Immediately following PPCI (same procedure 
setting) 
8-Patient information sheet will be provided and 
written consent sought 
After successful completion of PPCI 
9-ECG recording to assess the degree of ST-segment 
resolution. 
90-120 minutes post PPCI 
 

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10-Peak Troponin level assessment 
24-36 hours post PPCI.  
11-TIMI flow grade assessment 
Post PPCI 
12-Vital Status assessment 
 
On discharge and at three months post PPCI 
13-CMR estimation of final myocardial infarct size 
At three months post PPCI 
 
STUDY COSTS 
 
 
CMR   
 
100 scans @ reduced research rate £100  = £10,000 
 
 
 
IMR estimation 
100 pressure wires @ £300 Unit  
 
= £30,000 
 
 
Blood Tests  
300 Verify now @ £38.78 per sample 
= £11,634 
 
  
 
100 Troponin @ £9  
 
 
= £900 
 
  
 
300 VASP @ £16 per sample 
 
= £4,800 
Drug Costs 
 
50 doses Cangrelor   
 
 
= £7500 
 
Sponsor Monitoring Costs  
 
 
 
 
= £2,000 
Travel/Presentation costs 
 
 
 
 
 
= £2,000 
 
Total Cost 
 
 
 
 
 
 
 
= £68,834