Pharmacodynamic and Pharmacokinetic Profiles of Switching Between Cangrelor and Ticagrelor Following Ticagrelor Pre-treatment: The Switching Antiplatelet -5 (SWAP-5) Study
Phase: PHASE4
Conditions: Coronary Artery Disease
Sponsor: University of Florida

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Pharmacodynamic and pharmacokinetic profiles of switching between cangrelor and 
ticagrelor following ticagrelor pre-treatment:  
The Switching Antiplatelet -5 (SWAP-5) study 
 
 
 
 
 
 
 
 
Francesco Franchi, MD 
Assistant Professor of Medicine 
Division of Cardiology 
University of Florida College of Medicine - Jacksonville 
655 West 8th Street 
Jacksonville, FL – 32209 
Tel: +1-904-244-2060, Fax: 904-244-3102 
francesco.franchi@jax.ufl.edu 
 
 
 

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PROJECT SUMMARY 
Cangrelor is an intravenous P2Y12 inhibitor utilized as a bridge to achieve adequate platelet 
inhibition until oral P2Y12 inhibitors achieve their full antiplatelet effects in patients undergoing 
coronary stenting. Although in this setting the potent oral P2Y12 inhibitor ticagrelor is commonly 
utilized, there is very limited data on the optimal approach for switching between these therapies. 
In particular, ruling out a drug-drug interaction (DDI) is critical to this extent as the presence of a 
DDI would translate into reduced or abolished antiplatelet effects exposing these acute patients 
to an increased thrombotic risk. Despite the available evidence suggesting a lack of DDI with the 
use of ticagrelor in cangrelor treated patients, most data derive from studies in which ticagrelor 
was given at the time of initiation or during cangrelor infusion. To date, there is no data to fully 
rule out a DDI when ticagrelor is given prior to starting cangrelor infusion. The need for such 
investigation is underscored by the relatively high prevalence of pretreatment with ticagrelor in 
acute settings. The methodological approach for this assessment should rely on comprehensive 
pharmacodynamics (PD) investigations aimed to assess levels of P2Y12 receptor inhibition, 
pharmacokinetic (PK) investigations to assess systemic levels of the drug/drug metabolite, and 
mechanistic investigations by assessment of levels of P2Y12 receptor gene expression. The 
overarching aim of this investigation is to rule out a DDI when ticagrelor is administered prior to 
cangrelor infusion. 
 

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BACKGROUND 
Cangrelor is an intravenous adenosine triphosphate (ATP) analogue that directly and 
reversibly inhibits ADP binding to the adenosine diphosphate (ADP) P2Y12 receptor subtype in a 
dose-dependent manner, achieving immediate potent platelet inhibition after a bolus dose [1,2]. 
The cangrelor binding site at the P2Y12 receptor level has been subject to controversy and is not 
clearly defined [3,4]. Nonetheless, cangrelor is associated with high levels of receptor occupancy 
and prevents ADP binding. Cangrelor is promptly inactivated through dephosphorylation by 
ectonucleotidase and has a very short plasma half-life (3-6 minutes) [1-4]. Therefore, recovery of 
platelet function is rapid (~60 minutes) after discontinuation of cangrelor infusion [1-4].  
Cangrelor was approved for clinical use based on the results of the CHAMPION 
(Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) 
PHOENIX trial, which showed that cangrelor significantly reduced the rate of ischemic events, 
driven by a reduction in stent thrombosis and myocardial infarction, with no significant increase 
in severe bleeding in patients undergoing percutaneous coronary intervention (PCI) [5]. Given 
the different pharmacological properties of cangrelor and the oral P2Y12 inhibitors, several 
studies have investigated the potential for drug-drug interaction (DDI) when these agents are 
concomitantly administered [6-12]. These potential DDIs are concerning as they can result in 
reduced platelet inhibition and subsequent lack of protection from thrombotic complications in 
the peri-PCI period. In a study conducted in healthy volunteers, clopidogrel administration 
during cangrelor infusion was associated with an impaired antiplatelet effect of clopidogrel after 
cangrelor discontinuation [6]. This reflects the fact that clopidogrel active metabolite cannot bind 
to the P2Y12 receptors if already largely occupied by cangrelor. In turn, the plasma 
concentrations of the unbound clopidogrel active metabolites fall rapidly to subtherapeutic levels 

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as a result of distribution to other compartments and systemic clearance. Therefore, after 
stopping cangrelor infusion, when receptors become available for binding, most of the active 
metabolite has already been eliminated from the circulation [6]. In contradistinction, 
clopidogrel’s antiplatelet effects are not diminished when it is administered after cangrelor 
infusion, because of the very fast offset of action of cangrelor and subsequent availability of 
P2Y12 receptors for binding by clopidogrel active metabolite [6]. Accordingly, across the 
CHAMPION clinical trial program, a clopidogrel loading dose (LD) was administered always 
immediately after discontinuation of cangrelor infusion [5,13-15]. 
Although cangrelor was approved based on a trial in which clopidogrel was used, in real-
world clinical practice cangrelor is more commonly utilized in high-risk patients undergoing 
PCI, in particular patients with acute coronary syndromes (ACS), in whom the newer generation 
P2Y12 inhibitors (i.e, prasugrel and ticagrelor) are recommended over clopidogrel [16-17]. 
Recommendations on how to transition from cangrelor to oral treatment with ticagrelor and 
prasugrel largely derive from pharmacodynamic (PD) studies [3,4,8,9]. Unlike that observed 
with clopidogrel, no interaction was shown when transitioning from cangrelor to ticagrelor, 
allowing for a more versatile use of ticagrelor with respect to timing of administration in relation 
to the start of cangrelor therapy [8]. The presence of an interaction between clopidogrel and 
cangrelor, but not between ticagrelor and cangrelor is probably the result of different half-lives 
of these drugs, as well as the different sites and types of binding to the P2Y12 receptor [3,4,6-
8,11,12].  
Ticagrelor reversibly binds the P2Y12 receptor at a site distinct from the ADP-binding site 
and has a half-life of 6-12 hours. Although it is unknown whether ticagrelor can bind with the 
P2Y12 receptor during cangrelor infusion, its half-life is such that drug is still systemically 

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available to bind with the P2Y12 receptor after discontinuation of cangrelor infusion [3,4,8]. This 
was most recently demonstrated in the CANTIC (The Platelet Inhibition with CANgrelor and 
Crushed TICagrelor in STEMI Patients Undergoing Primary Percutaneous Coronary 
Intervention) study, which was the first study to rule out a DDI in the setting of patients 
presenting with ST-elevation myocardial infarction undergoing primary percutaneous coronary 
intervention, in which ticagrelor, administered as a crushed formulation, was given 
concomitantly with cangrelor without any apparent DDI [18]. Overall, based on these PD 
observations, according to FDA product label, ticagrelor can be administered at any time during 
cangrelor infusion or immediately after discontinuation [19]. 
 
STUDY RATIONALE 
Despite the available evidence suggesting a lack of DDI with the use of ticagrelor in 
cangrelor treated patients, most data derive from studies in which ticagrelor was given at the time 
of initiation or during cangrelor infusion. To date there is no data to fully rule out a DDI when 
ticagrelor is given prior to starting cangrelor infusion. In fact, although a prior PD investigation 
demonstrated that ticagrelor given before cangrelor did not attenuate the PD effects of cangrelor, 
this study did not assess whether the PD effects of ticagrelor are preserved after discontinuing 
cangrelor infusion [8]. In another investigation, PD effects were studied in patients pretreated 
with ticagrelor with less than 1 hour from primary PCI or receiving ticagrelor in cath lab and 
treated with cangrelor [20]. At 30 min after end of infusion, platelet reactivity was within the 
therapeutic range for most patients and there were no differences between patients treated with 
ticagrelor prehospital or in the cath lab. Thus, the design of this study cannot rule-out a DDI due 
to several factors: the comparison was not randomized, at 30 min there is still residual effect of 

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cangrelor which warrants at least 60 minutes for complete wash-out of effects (thus not adequate 
to rule out a DDI), and 12.5% of patients had high platelet reactivity at this time point [20]. 
Moreover, in none of the above mentioned studies were pharmacokinetic (PK) assessments 
performed to characterize the impact, if any, of cangrelor on systemic levels of ticagrelor and its 
major metabolite (AR-C124910XX). Therefore, the lack of data to rule out a DDI between 
cangrelor and ticagrelor when the latter is administered prior to starting cangrelor infusion 
warrants dedicated prospective investigations. The need for such investigations is underscored by 
the relatively high prevalence of pretreatment with ticagrelor in acute settings [21,22]. 
Importantly, such acute settings represent desirable scenarios to use cangrelor. Of note, use of 
prehospital ticagrelor (i.e, pretreatment) in acute settings is endorsed by practice guidelines both 
in the United States and Europe [17]. Therefore, ruling out a DDI between cangrelor and 
ticagrelor when the latter is administered prior to starting cangrelor infusion would have 
important clinical implications for real-world practice. The methodological approach for this 
assessment should rely on comprehensive PD assessments aimed to evaluate levels of P2Y12 
receptor inhibition and thrombus formation, PK assessments to assess systemic levels of the 
drug/drug metabolite, and mechanistic assessments by measuring levels of P2Y12 receptor gene 
expression. In particular, different levels of P2Y12 receptor gene expression can modulate the PD 
effects of oral P2Y12 receptor inhibitors at a given level of drug exposure defined by PK 
profiling. 
 
 
 
 

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STUDY AIM 
The aim of this investigation is to rule out a DDI when ticagrelor is administered prior to 
cangrelor infusion. Comprehensive PK and PD assessments will be conducted to reach this study 
aim. 
 
REASERCH PLAN 
Study design 
The Switching Antiplatelet Therapy-5 (SWAP-5) study will be a prospective, 
randomized, double-blind, placebo controlled, cross-over PK and PD investigation aimed to rule 
out a DDI when ticagrelor is administered prior to cangrelor infusion. Aspirin treated patients 
with known coronary artery disease will be considered eligible for the study. The study will be 
performed at the Division of Cardiology of University of Florida Health, Jacksonville, Florida. 
Patients will be screened by Cardiology Research staff, who will verify that all candidates meet 
inclusion and exclusion criteria, and obtain their written informed consent to participate in the 
study. Results from blood tests performed within the last 90 days will be considered valid for 
screening purposes. If these are not available, a blood sample will be collected for the screening 
phase. 
Using a computer-based randomization system, patients will be randomized in a 1:1 
fashion to one of the following treatment arms: a) ticagrelor loading dose followed after 1 hour 
by cangrelor bolus and infusion or b) ticagrelor loading followed after 1 hour by placebo 
infusion. In line with FDA recommendations, ticagrelor will be administered as a 180mg loading 
dose (two 90mg tablets) [23]. Cangrelor will be used at the FDA recommended dose using a 30 
μg/kg bolus followed by 4 μg/kg/min infusion [19]. The duration of cangrelor/placebo infusion 

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will be 2 hours. After completing the first phase of the study, patients will undergo a 1-4 week 
wash-out period and then will cross-over to the alternative treatment in the second phase (i.e., 
patients assigned to treatment with cangrelor in the first phase will be assigned to placebo in the 
second phase and vice-versa). All patients will be on a background of aspirin therapy (81 mg 
daily maintenance dose). During each phase, PK and PD assessments will be conducted at 7 time 
points (total 14 time points): baseline (prior to ticagrelor loading dose; time -1 h); at start of 
cangrelor/placebo bolus and infusion (1 hour after ticagrelor loading dose); 30 minutes after 
cangrelor/placebo bolus; 1 hour after cangrelor/placebo bolus, 2 hours after cangrelor/placebo 
bolus (time of infusion discontinuation); 1 hour after discontinuation of cangrelor/placebo 
infusion; and 2 hours after after discontinuation of cangrelor/placebo infusion. Figure 1 
illustrates the overall study design. The study will have a double-blind design. Patients, research 
staff and laboratory personnel will be blinded to treatment assignments. Masking and 
randomization of medications (cangrelor and placebo) will be performed by our institutional 
research pharmacy in line with prior investigations [18]. 
Figure 1. Overall study design 
 
 
 
 
 
 
 
 
Washout  
& 
Crossover 
(1-4 weeks) 

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Study Population 
Inclusion criteria: 
• Patients with known coronary artery disease (defined as prior type I myocardial 
infarction, coronary revascularization, percutaneous or surgical, or presence of at least a 
50% stenosis in any major epicardial vessel). 
• Age > 18 years old 
• On aspirin 81mg/qd for at least 1 month 
 
Exclusion criteria:        
• Inability to provide written informed consent 
• Hemodynamic instability 
• On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, 
ticagrelor) in past 30 days  
• Known allergies to ticagrelor or cangrelor 
• Considered at high risk for bleeding 
• History of intracranial bleeding/hemorrhagic stroke 
• On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran, rivaroxaban, 
apixaban, edoxoban) within past 30 days 
• Known platelet count <80x106/mL 
• Known hemoglobin <10 g/dL 
• Active bleeding 
• Known end stage renal disease on hemodialysis 
• Known severe hepatic dysfunction 
• Acute or severe bronchial asthma or upper airway obstruction. 
• 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. 

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• Pregnant females [women of childbearing age must use reliable birth control (i.e. oral 
contraceptives) while participating in the study] 
 
Blood sampling and Laboratory assessments 
Blood samples (10 mL) will be drawn through a short venous catheter inserted into a 
forearm vein and collected in anticoagulated and serum tubes at each study time point for all 
PK/PD assessments. The first 2-4 mL of blood will be discarded to avoid spontaneous platelet 
activation. 
 
Laboratory assessments will include: 
1. VerifyNow PRU 
2. Light transmittance aggregometry 
3. Whole blood vasodilator-stimulated phosphoprotein (VASP) 
4. Total Thrombus-Formation Analysis System (T-TAS) 
5. PK 
6. P2Y12 gene receptor level expression 
 
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 (Accriva, San 
Diego, CA) and will be utilized according to manufacturer’s instructions, as previously described 
[18, 24-26]. 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 

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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) Light transmittance aggregometry (LTA): Platelet aggregation will be performed using LTA 
according to standard protocols. Blood will be collected in citrated (3.2%) tubes. LTA will be 
performed using platelet rich plasma (PRP) by the turbidimetric method in a 2-channel 
aggregometer (Chrono-Log 490 Model, Chrono-Log Corp., Havertown) as previously described 
[24-26]. Platelet agonists will include collagen (3µg/ml), ADP (20 µM) and TRAP (15 μM). PRP 
will be obtained as a supernatant after centrifugation of citrated blood at 1000 rpm for 10 
minutes. The isolated PRP will be kept at 37° C before use. Platelet poor plasma (PPP) will be 
obtained by a second centrifugation of the blood fraction at 2800 rpm for 10 minutes. Light 
transmission will be adjusted to 0% with the PRP and to 100% for the PPP for each 
measurement. Curves will be recorded for 6 minutes and platelet aggregation will be determined 
as the maximal percent change (MPA) in light transmittance from baseline using PPP as a 
reference.   
3) Whole blood vasodilator-stimulated phosphoprotein (VASP):  VASP phosphorylation (VASP-
P) is a marker of P2Y12 receptor signaling. VASP will be assessed the ELISA VASP-P kit 
(Biocytex Inc., Marseille, France) as previously described [18]. After a first step of parallel 
whole blood sample activation with PGE1 and PGE1+ADP, platelets from the sample are lysed, 
allowing released VASP to be captured by an anti-human VASP antibody, which is coated in the 

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microtiter plate. Then, a peroxidase-coupled anti-human VASP-P antibody binds to 
phosphorylated serine 239 antigenic determinant of VASP. The bound enzyme peroxidase is 
then revealed by its activity on TMB substrate over a predetermined time. After stopping the 
reaction, absorbance at 450 nm is directly related to the concentration of VASP-P contained in 
the sample.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-stimulated platelets reduces PGE1-induced VASP-P levels. If P2Y12 receptors are 
successfully inhibited, addition of ADP will not reduce the PGE1-stimulated VASP-P levels. The 
platelet reactivity index (PRI) will be calculated after measuring VASP-P levels. 
4) Total Thrombus-Formation Analysis System (T-TAS): T-TAS is an automated microchip flow 
chamber system for the quantitative analysis of the thrombus formation process under blood flow 
conditions. T-TAS allows measurement of thrombus formation using the PL-chip (Diapharma, 
West Chester Township, OH) [27]. The PL-chip contains 25 capillary channels (width 40 μm, 
depth 40 μm) coated with type I collagen and is specifically designed for quantitative analysis of 
platelet thrombus formation, including platelet adhesion and aggregation, granule secretion, and 
thrombus growth in the absence of coagulation and fibrinolysis systems. In measurements using 
the PL-chip, a blood sample collected in a hirudin containing blood sampling tube. The platelet 
aggregates gradually increase in size and, in the process, occlude the capillary, resulting in an 
increase in flow pressure. In the present study, total platelet-derived thrombogenicity is 
expressed as the area under the flow pressure curve for the first 10 min for the PL-chip tested at a 
flow rate of 18 μL/min (PL18-AUC10). Low PL18-AUC10 reflect reduced thrombus growth and 
rapid breakdown of the thrombus. 

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4) Pharmacokinetic (PK) assay: Determination of plasma concentration of ticagrelor and its 
active metabolite (AR-C124910XX) will be assessed from blood samples taken at the same time 
points of PD analysis as previously described [28]. Blood samples for measurement of drug 
concentrations will be drawn through the same cannula used for PD sampling. The blood will be 
taken into lithium heparin tubes and placed on ice until centrifugation (2800 rpm, 4°C, 10 min) 
within 30 min of sampling to collect the plasma, which will be transferred to plain polypropylene 
tubes and frozen upright at or below -20°C until analysis. For ticagrelor and its active metabolite, 
the area under the plasma concentration vs. time curve from time 0 to the last measurable 
concentration (AUC0-t), maximum plasma concentration (Cmax), and time to Cmax (tmax) will 
be estimated. 
5) P2Y12 gene receptor level expression: Gene expression in platelets will be performed using 
standard protocols. In particular, purified platelets are dissolved in Trizol reagent (Invitrogen) 
and total RNA will be extracted using RNA minipres kit (Zymos research) according to 
manufacturer’s protocol.  P2Y12 mRNA expression will be measured with real-time PCR using 
SYBR green and specific primers as previously described [29].   
 
In addition to specific assays described above, whole blood, serum and plasma samples will be 
stored for future analysis that may include genetic determinants of antiplatelet drugs response, 
alternative mRNAs, and biomarkers.  
 
Study endpoints, sample size calculation and statistical analysis 
 
The primary end point of the study will be the non-inferiority in PRU measured at 2 
hours after discontinuation of cangrelor vs. placebo. We hypothesize that in patient receiving 

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cangrelor following a ticagrelor LD platelet inhibition assessed by PRU will be non-inferior 
compared to patients receiving ticagrelor LD followed by placebo infusion. Non-inferiority will 
be assessed using a 95% confidence interval (CI) of the difference in mean PRU between the two 
arms. Under the assumption of 0 difference in mean PRU between group 1 and group 2 and a 
common standard deviation of 75 PRU, a sample size of 16 patients will allow for the 95% CI to 
stay within ± 45 PRU with a 95% power and alpha=0.05. Considering a 25% data attrition rate 
due to hemolysis, drop out or technical problems, 20 patients will need to be randomized in order 
to ensure complete available data for analysis. The sample size of this study was established 
according to results of previous PD investigations [18,30]. In line with previously reported 
investigations, 45 PRU was chosen for the noninferiority margin for the upper 95% CI limit of 
the difference [25, 31]. All other end points will be considered exploratory and will include the 
comparisons of PD and PK parameters, and P2Y12 gene receptor level expression between all 
treatment arms at each time points, as well as the comparisons of rates of high on-treatment 
platelet reactivity (HPR). HPR will be defined as PRU>208, PRI>50%, and LTA-ADP>59%, in 
line with consensus definitions [32].  
Conformity to the normal distribution will be evaluated for continuous variables with the 
Kolmogorov-Smirnov test. For baseline characteristics, continuous variables will be expressed as 
mean ± SD or median [IQR]. Treatment effects will be evaluated comparing the functional 
parameters observed in the overall patient population after cangrelor treatment with those 
achieved after placebo regardless of the sequence. All statistical comparisons of platelet function 
for the primary end point and exploratory end points with continuous variables will be conducted 
using a linear mixed-effect model with treatment group, sequence, period, and treatment-group-
by-period as fixed effects, patient as a random effect, and baseline value of the corresponding 

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platelet function test as a covariate. The comparisons of rates of HPR will be conducted using the 
McNemar test. 
Platelet reactivity results will be reported as least-square means (LSM) (95% confidence 
interval [CI]) for the above detailed analyses. LSM differences in PRU between groups and the 
corresponding 2-sided 95% CI for the difference will be obtained to assess non-inferiority based 
on the linear model. Given the exploratory nature of comparisons for secondary end points, 
correction for multiple comparisons will not be performed. A 2-tailed p value of <0.05 will be 
considered to indicate a statistically significant difference for superiority for all the analyses 
performed. Statistical analysis will be performed using SPSS version 25.0 software (SPSS Inc., 
Chicago, Illinois).  
The safety population will include all randomized patients exposed to study medication. 
The PD population will include all patients with PD data and without a major protocol deviation 
thought to affect significantly the PD and PK of cangrelor or ticagrelor. The PD population will 
be used for analysis of all primary and secondary end points. Erroneously treated patients (eg, 
those randomized to one treatment but actually given the other) will be accounted for based on 
the actual treatment received. 
 
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 1-8): we expect to 
randomize 2-3 subjects monthly and complete enrollment in 8 months (total: 20 subjects 

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randomized). Months 9 and 10 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%) [5]. In clinical 
trials, the most common clinical side effects of ticagrelor were dyspnea (13.8%), headache 
(6.5%), cough (4.9%), dizziness (4.5%), nausea (4.3%), and bradycardia (4.4%) principally. 
Infrequent events included intracranial hemorrhage (0.3%) and severe bradycardia requiring 
pacemaker insertion (0.9%) [33]. The most important adverse effect associated with the use of 
ticagrelor is bleeding. The risk of spontaneous bleeding with ticagrelor is 2.8% [32]. However, 
such bleeding prevalence occurred in the setting of a long-term (12 months) trial, while our study 
is limited to a single loading dose, thus reducing the risk of any side effect, in particular bleeding 
complications.  
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 [34]. 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 

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committee will meet and antiplatelet treatment management will be managed according to 
physician recommendation. 
 
Conflict of Interest 
Dr. Franchi (Principal Investigator) is a paid consultant for AstraZeneca pharmaceutical the 
maker of Ticagrelor, which is used in the study. Dr. Angiolillo (Sub-Investigator) is a consultant 
for Chiesi, the maker of cangrelor, and of AstraZeneca, the maker of ticagrelor 
 
 

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