Conditions: ST Segment Elevation Myocardial Infarction Percutaneous Coronary Intervention
Keywords: ticagrelor cangrelor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: no

Brief summary:
In STEMI patients undergoing PPCI there is a delayed onset of action of oral P2Y12 receptor inhibitors, including prasugrel and ticagrelor. Crushing prasugrel and ticagrelor improves their PK and PD profiles as it favors drug absorption and onset of antiplatelet effects and because of this, it is commonly used in STEMI patients undergoing PPCI. However, despite the use of crushed tablets, up to one-third of patients may still have high on-treatment platelet reactivity (HPR) within the first 2 hours after loading dose (LD) administration of these oral agents. Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events compared with clopidogrel in P2Y12 receptor naïve patients undergoing PCI. To date most studies have explored cangrelor in the setting of PCI subjects treated with clopidogrel. The PD effects of cangrelor in STEMI patients undergoing PPCI treated with a newer generation P2Y12 receptor inhibitor and how this compares with a crushed formulation of the oral drug is unexplored. The aim of this prospective randomized study is to investigate the PD effects of cangrelor in STEMI patients undergoing PPCI treated with crushed ticagrelor.

Detailed description:
In STEMI patients undergoing PPCI there is a delayed onset of action of oral P2Y12 receptor inhibitors, including prasugrel and ticagrelor, which require more than 2 hours to exert their full antiplatelet effects, and thus exposing these high-risk patients to an increased risk of early thrombotic complications. The mechanism of this delayed onset of antiplatelet effect is likely multifactorial due to the presence in the setting of STEMI of specific conditions that translate into delayed drug absorption which in turn affect the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of oral P2Y12 receptor inhibitors. Crushing prasugrel and ticagrelor improves their PK and PD profiles as it favors drug absorption and onset of antiplatelet effects and because of this, it is commonly used in STEMI patients undergoing PPCI. However, despite the use of crushed tablets, up to one-third of patients may still have high on-treatment platelet reactivity (HPR) within the first 2 hours after loading dose (LD) administration of these oral agents. Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events compared with clopidogrel in P2Y12 receptor naïve patients undergoing PCI. To date most studies have explored cangrelor in the setting of PCI subjects treated with clopidogrel and the clinical profile of cangrelor among patients treated with prasugrel or ticagrelor is currently unknown. This is noteworthy because ACS patients, in particular STEMI undergoing PPCI, are commonly treated with either prasugrel or ticagrelor. PD investigations conducted in vitro or ex vivo in stable patients have shown cangrelor to be associated with enhanced platelet inhibition compared with that induced by prasugrel and ticagrelor. However, the PD effects of cangrelor in STEMI patients undergoing PPCI treated with a newer generation P2Y12 receptor inhibitor and how this compares with a crushed formulation of the oral drug is unexplored. The aim of this prospective randomized study is to investigate the PD effects of cangrelor in STEMI patients undergoing PPCI treated with crushed ticagrelor.

Arms:
arm 1: Cangrelor will be administered as 30 μg/kg bolus followed by 4 μg/kg/min infusion for 2 hours arm 2: Normal saline bolus and infusion for 2 hours

Interventions: intervention 1: Cangrelor intervention 2: Placebo
Intervention descriptions: intervention 1: Patients will be randomly assigned 1:1 to receive either cangrelor or matching placebo. The bolus will be administered at the same time of a 180 mg crushed ticagrelor loading dose and infusion will be continued for 2 h. intervention 2: Patients will be randomly assigned 1:1 to receive either cangrelor or matching placebo. The bolus will be administered at the same time of a 180 mg crushed ticagrelor loading dose and infusion will be continued for 2 h.

Protocol document:
Prot_SAP_000.pdf: 
 
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Platelet Inhibition with CANgrelor and Crushed TICagrelor in STEMI Patients 
Undergoing Primary Percutaneous Coronary Intervention:  
The CANTIC Study 
 
NCT03247738 
Protocol version 2, approved 07/20/2018 
 
 
 
 
 
 
Dominick J Angiolillo, MD, PhD, FACC, FESC, FSCAI 
Director of Cardiovascular Research 
Professor of Medicine 
Division of Cardiology 
University of Florida College of Medicine - Jacksonville 
655 West 8th Street 
Jacksonville, FL – 32209 
Tel: 904-2443933, Fax: 904-2443102 
dominick.angiolillo@jax.ufl.edu 


 
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Background and Significance: 
Dual antiplatelet therapy consisting of aspirin and an ADP P2Y12 receptor antagonist is 
the cornerstone of treatment for the prevention of thrombotic events in patients with acute 
coronary syndrome (ACS), including patients with ST-segment elevation myocardial infarction 
(STEMI) undergoing primary percutaneous coronary intervention (PPCI) [1-3]. The new-
generation P2Y12 receptor inhibitors prasugrel and ticagrelor are associated with more prompt 
and potent platelet inhibition, and better clinical outcomes than clopidogrel in ACS patients [4]. 
Therefore, prasugrel and ticagrelor are considered the first choice in this setting [1-4]. However, 
in STEMI patients undergoing PPCI there is a delayed onset of action of oral P2Y12 receptor 
inhibitors, including prasugrel and ticagrelor, which require more than 2 hours to exert their full 
antiplatelet effects, and thus exposing these high-risk patients to an increased risk of early 
thrombotic complications [5-8]. The mechanism of this delayed onset of antiplatelet effect is 
likely multifactorial due to the presence in the setting of STEMI of specific conditions that 
translate into delayed drug absorption which in turn affect the pharmacokinetic (PK) and 
pharmacodynamic (PD) profiles of oral P2Y12 receptor inhibitors [5-8]. Crushing prasugrel and 
ticagrelor improves their PK and PD profiles as it favors drug absorption and onset of antiplatelet 
effects and because of this, it is commonly used in STEMI patients undergoing PPCI [9,10]. 
However, despite the use of crushed tablets, up to one-third of patients may still have high on-
treatment platelet reactivity (HPR) within the first 2 hours after loading dose (LD) administration 
of these oral agents [9,10]. These findings support the need for intravenous agents with more 
rapid platelet inhibiting effects.  
Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of 
action associated with a greater reduction in ischemic events, including stent thrombosis, 


 
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compared with clopidogrel in P2Y12 receptor naïve patients undergoing PCI (including stable 
coronary artery disease, non-STE-ACS and STEMI) [4,11,12]. To date most studies have 
explored cangrelor in the setting of PCI subjects treated with clopidogrel and the clinical profile 
of cangrelor among patients treated with prasugrel or ticagrelor is currently unknown. This is 
noteworthy because ACS patients, in particular STEMI undergoing PPCI, are commonly treated 
with either prasugrel or ticagrelor. Moreover, cangrelor is also more likely to be used in these 
higher risk settings. PD investigations conducted in vitro or ex vivo in stable patients have shown 
cangrelor to be associated with enhanced platelet inhibition compared with that induced by 
prasugrel and ticagrelor [13-15]. However, the PD effects of cangrelor in STEMI patients 
undergoing PPCI treated with a newer generation P2Y12 receptor inhibitor and how this 
compares with a crushed formulation of the oral drug is unexplored. Because of a potential for 
drug-drug interactions with thienopyridines, drug regulating authorities only recommend that 
ticagrelor, and not prasugrel, be administered concomitantly with cangrelor [16-18]. 
Accordingly, ticagrelor is being chosen to test our study hypothesis in this investigation and will 
be administered as a crushed formulation as this has shown to be associated with fastest onset of 
effects of an oral formulation agent.  
 
Study Aim 
The aim of this prospective randomized study is to investigate the PD effects of cangrelor 
in STEMI patients undergoing PPCI treated with crushed ticagrelor.  
 
 
 


 
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Research plan 
Research Design  
The proposed investigation is a prospective, randomized, double-blind, parallel design 
PD study. This study will be performed at the University of Florida Health Jacksonville - 
Division of Cardiology. Patients will be recruited and consented at the Emergency Department or 
Catheterization Laboratory of our Institution. Patients will be screened by cardiology research 
staff, who will verify that all candidates meet inclusion criteria. After providing written informed 
consent, STEMI patients undergoing PPCI will be eligible for randomization. After diagnostic 
angiography and prior to commencement of the PCI procedure, patients will be randomly 
assigned 1:1 to receive either cangrelor (30 μg/kg bolus followed by 4 μg/kg/min infusion) or 
matching placebo (normal saline bolus and infusion). The bolus will be administered at the same 
time of a 180mg crushed ticagrelor LD and infusion will be continued for 2 h. The 180-mg LD 
of ticagrelor will consist in 2 ticagrelor 90-mg tablets that will be crushed using a commercially 
available syringe crusher. After, 5 rotations of the crushing mechanism, 25mL water will be 
aspirated into the syringe and mixed by shaking for 30 seconds. This suspension will be 
dispensed into a 165mL dosing cup.  The syringe crusher will be rinsed using additional 25 mL 
water, which will be added to the dosing cup for a total of 50mL suspension administered orally 
to patient. Patients will be administered the ticagrelor LD in the cardiac catheterization 
laboratory after diagnostic angiography and before starting PPCI (before passing the wire 
through the target lesion).  
All patients will be treated as per local standard of care, which includes 325 mg aspirin 
LD and 4000 IU of unfractioned heparin at time of presentation. The choice of intravenous 
anticoagulant during PPCI (heparin or bivalirudin) will be at discretion of the physician 


 
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performing PPCI. After PCI, all patients will receive aspirin 81 mg/d indefinitely and ticagrelor 
90 mg bid for at least 12 months. The PCI procedure will be performed as per local practice 
standards, including the route of access (femoral vs. radial), use of aspirations device, and stent 
type. Patients receiving glycoprotein IIb/IIIa inhibitors before the primary end point time point 
will be excluded due to their interference with the VerifyNow assay. 
PD assessment will be performed at the following 8 time points: baseline (before LD 
administration), 5 minutes, 30 minutes, 1 hour, and 2 hours after bolus, at the end of PCI (when 
the guide catheter was removed at procedure completion), and 1 hour and 2 hours after stopping 
the infusion. A flow diagram of the study is presented below. 
 
Study Population 
Inclusion criteria: 
 Patients with STEMI undergoing primary PPCI 
 Age > 18 years old  
 
Exclusion criteria: 
 
 Inability to provide written informed consent 
 Known history of prior intracranial bleeding 


 
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 On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, 
ticagrelor) in the prior 10 days  
 Known allergies to aspirin, ticagrelor or cangrelor 
 On treatment with oral anticoagulant 
 Treatment with glycoprotein IIb/IIIa inhibitors before the primary end point time point 
 Fibrinolytics within 24 hours 
 Active bleeding 
 High risk of bleeding 
 Known platelet count <80x106/mL 
 Known hemoglobin <10 g/dL 
 Intubated patients (prior to randomization) 
 Known creatinine clearance <30 mL/minute or on hemodialysis. 
 Known severe hepatic dysfunction 
 Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker 
protection 
 Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction 
with ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, 
ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin. 
 Pregnant or lactating females.  
 
Blood sampling and Laboratory assessments 
Blood samples (10 mL) will be drawn through the arterial access sheet used for the PCI 
procedure for time points (until the end of PCI) while patient are in the cath lab; post-cath lab 
samples will be drawn through venous sampling. Samples will be collected in anticoagulated and 
serum tubes at each study time point for all PD assessments. The first 2-4 mL of blood will be 
discarded to avoid spontaneous platelet activation. 
 
 


 
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Laboratory assessments will include 2 PD assays: 
1. VerifyNow PRU assay 
2. VASP-PRI assay 
 
Description of laboratory assays 
1) VerifyNow PRU: The VerifyNow System is a turbidimetric based optical detection system 
which measures platelet induced aggregation as an increase in light transmittance (Accumetrics, 
San Diego, CA) and will be utilized according to manufacturer’s instructions, as previously 
described [5]. The assay is based on microbead agglutination and uses specific reagents for the 
pathways of interest. The VerifyNow PRU assay, by combining ADP+PGE1, measures changes 
in platelet function specific to P2Y12 receptor inhibitors. The assay is based upon the ability of 
activated platelets to bind fibrinogen. Fibrinogen-coated microparticles aggregate in proportion 
to the number of GP IIb/IIIa receptors expressed. Microbead aggregation is more rapid and 
reproducible if platelets are activated; therefore the reagents are incorporated into the assay 
channel to induce platelet activation without fibrin formation. Light transmittance increases as 
activated platelets bind and aggregate fibrinogen-coated beads. The instrument measures this 
change in optical signal and reports results in P2Y12 Reaction Units (PRU). 
2) Whole blood vasodilator-stimulated phosphoprotein (VASP):  VASP phosphorylation (VASP-
PRI) is a marker of P2Y12 receptor reactivity, which is the target for ticagrelor. VASP will be 
assessed according to standard protocol using labeled monoclonal antibodies by flow cytometry 
with the Platelet VASP-FCM kit (Biocytex Inc., Marseille, France) as previously described [5]. 
PGE1 increases VASP-P levels by stimulation of adenylate cyclase. Binding of ADP to P2Y12 
leads to Gi-coupled inhibition of adenylate cyclase. Therefore, the addition of ADP to PGE1-


 
8 
 
stimulated platelets reduces PGE1-induced VASP-P levels. If P2Y12 receptors are successfully 
inhibited by ticagrelor or cangrelor, addition of ADP will not reduce the PGE1-stimulated 
VASP-P levels. The platelet reactivity ratio (PRI) will be calculated after measuring VASP-P 
levels after stimulation with PGE1 (MFI PGE1) and also PGE1 + ADP (MFI PGE1 + ADP). The 
P2Y12 reactivity ratio = ([MFI PGE1] – [MFI PGE1 + ADP]/[MFI PGE1]) x 100%. 
 
Primary and secondary objectives 
The primary end point of our study is the comparison in platelet reactivity measured by 
VerifyNow PRU between crushed ticagrelor LD plus cangrelor infusion and crushed ticagrelor 
LD (plus placebo infusion) at 30 min after the LD and cangrelor (or placebo) bolus. We 
hypothesize that adding cangrelor will significantly reduce PRU in patients with STEMI 
undergoing PPCI. Secondary objectives will include: 1) the comparison in PRU between 
cangrelor and placebo at the other time points; 2) the comparison in PRI at all time points; 3) the 
comparison in rates of HPR between cangrelor and placebo at all time points. According to 
consensus definition, HPR will be defined as PRU>208 or PRI >50% [19]. 
 
Sample Size Computation, Power Analysis and Statistical Analysis 
Assuming a common standard deviation of 70 PRU, a sample size of 20 patients per 
group will allow to detect a 70 PRU difference between groups (~160 PRU with ticagrelor vs 
~90 PRU with ticagrelor plus cangrelor) with 85% power and a two-sided α = 0.05. Considering 
the 2 arms and a possible ~25% rate of invalid results due to hemolysis, technical problems, or 
drop-out, we plan to randomize up to 50 patients, in order to have complete data for the primary 


 
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end point analysis. Our sample size is based on data derived from previously published studies 
[10,20,21]. 
The PD population will include all patients with PD data and without a major protocol 
deviation thought to affect significantly the PD of ticagrelor or cangrelor. The PD population 
will be used for analysis of all primary and secondary PD variables. Erroneously treated patients 
(e.g., those randomized to one treatment but actually given the other) will be accounted for based 
on the actual treatment received. 
Categorical variables will be expressed as frequencies and percentages. Continuous 
variables will be presented as mean ± SD or median [IQR]. Continuous variables will be 
analyzed for normal distribution with the Kolmogorov-Smirnov test. Comparisons between 
categorical variables will be performed using two-tailed Fisher’s exact test or the Pearson's chi-
square test. Student´s t test, Mann-Whitney U-test and Wilcoxon test will be used to compare 
continuous variables when appropriate. An analysis of covariance will be used to evaluate the 
primary end point and all between-group comparisons in platelet reactivity. A mixed linear 
model will be used to evaluate the overall difference between groups over time and within-group 
comparisons. A p value <0.05 will be considered statistically significant for superiority analyses. 
Statistical analysis will be performed using a SPSSv22.0 software (SPSS Inc. Chicago, IL). 
 
Publication Strategy/Additional Information  
Subjects will be identified with a number and data collection sheets will all be stored in a 
locked area. Data will be kept for 6 years after enrollment ends to comply with HIPAA 
regulations. Patients will receive a handout with the names and telephone numbers of the doctors 
involved in the study. Study subjects will be identified first (months 1-12): we expect to 


 
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randomize 4-5 subjects monthly and complete enrollment in 12 months (total: 50 subjects 
randomized). Months 13-14 will be implied for statistical analysis and manuscript preparation. 
Results will be presented at the first available major cardiovascular meeting (e.g. AHA, ACC, 
ESC), and final manuscript will be submitted to publication to one of major cardiovascular 
journals (e.g. JACC, Circulation, European Heart Journal). 
 
Possible Discomforts and Risk 
In clinical trials, the most common clinical side effect of cangrelor was bleeding. 
Severe/moderate bleeding occurred in 0.8% of patients receiving cangrelor, as compared to 0.6% 
of those receiving placebo. Other side effects include dyspnea (1.3%), worsening renal function 
(3.2% of patients with severe renal impairment), and hypersensitivity (0.05%) [11,12].  
All clinical events described above, if they were to occur, as well as death, myocardial 
infarction, stroke, and urgent revascularization procedure with PCI or coronary artery bypass 
grafting will be recorded. Bleeding data will be collected using BARC definitions [22]. Clinical 
events will be evaluated by a local committee, comprised of 2 faculty members (2 cardiologists), 
not directly involved in the research. In the event of a report of a serious adverse event the local 
committee will meet and antiplatelet treatment management will be managed according to 
physician recommendation. 
 
Definition of Adverse Events 
An adverse event is any unintended or undesirable experience that occurs during the 
course of the clinical investigation whether or not it is considered to be therapy related.  This 
includes any newly occurring event or previous condition that has increased in severity or 


 
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frequency since the initiation of study treatment.  Adverse events will be followed until 
resolution while the patient remains on-study.  Once the patient is removed from study, events 
thought to be related to the study therapy will be followed until resolution or until the patient 
starts a new treatment regimen. 
Serious Adverse Events (SAE): An adverse event occurring while on study and considered 
related (reasonable possibility that the study treatment caused the adverse experience) to the 
study treatment that results in any of the following outcomes: 
- Death 
- A life-threatening adverse experience. 
- A persistent or significant disability, incapacity, or is a congenital anomaly, or birth defect. 
- Requires inpatient hospitalization, or prolongation of existing hospitalization. 
The definition of serious adverse event also includes ‘important medical event’.  Medical and 
scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the patient and/or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the definition above.  These 
should also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse. 
 
Conflict of Interest 
Dr. Angiolillo is a consultant for Chiesi, the maker of cangrelor, and Astra Zeneca, the maker of 
ticagrelor. 


 
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