Clinical trial NCT03489863
Conditions: Coronary Artery Disease
Keywords: clopidogrel prasugrel ticagrelor
Sponsor: University of Florida
Start date: 2018-05-30; Completion date: 2019-03-20
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Polymorphisms of the cytochrome P450 (CYP) 2C19 enzyme has been consistently shown to modulate clopidogrel response. Accordingly, the Food and Drug Administration (FDA) has issued a warning on the potential for reduced efficacy of clopidogrel among carriers of loss-of-function alleles (LOF) for CYP2C19 and suggest considering alternative antiplatelet therapies for these individuals.

The pharmacodynamic (PD) effects of prasugrel and ticagrelor are not affected by CYP2C19 genetic polymorphisms. However, to date there are no head-to-head PD comparisons between these agents among patients with different CYP2C19 genetic polymorphisms, which is currently under investigation in CAD patients undergoing PCI at UF Health-Jacksonville (UFJ 2014-12, NCT 02065479). In order to rule out play of chance findings, pharmacogenetic investigations require external validation cohorts to support the study findings. Therefore, the present randomized study is designed to serve as an external validation cohort conducted in patients with established CAD not undergoing PCI testing the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 LOF allele carriers.

Detailed description:
Therapeutic inhibition of platelet activation is essential for the management of ischemic cardiovascular disease. The use of platelet adenosine diphosphate (ADP) P2Y12 receptor antagonists (clopidogrel, prasugrel, and ticagrelor) in addition to aspirin are associated with a decrease in cardiovascular events in high-risk coronary artery disease (CAD) patients. Clopidogrel is the most broadly utilized P2Y12 receptor antagonist. However, among clopidogrel treated patients, there is broad variability in antiplatelet drug response which is known carry prognostic implications. Polymorphisms of the cytochrome P450 (CYP) 2C19 enzyme has been consistently shown to modulate clopidogrel response. Accordingly, the Food and Drug Administration (FDA) has issued a warning on the potential for reduced efficacy of clopidogrel among carriers of loss-of-function alleles (LOF) for CYP2C19 and suggest considering alternative antiplatelet therapies for these individuals.

The pharmacodynamic (PD) effects of prasugrel and ticagrelor are not affected by CYP2C19 genetic polymorphisms. However, to date there are no head-to-head PD comparisons between these agents among patients with different CYP2C19 genetic polymorphisms which is currently under investigation in CAD patients undergoing PCI at UF Health-Jacksonville (UFJ 2014-12, NCT 02065479). In order to rule out play of chance findings, pharmacogenetic investigations require external validation cohorts to support the study findings. Therefore, the present randomized study is designed to serve as an external validation cohort conducted in patients with established CAD not undergoing PCI testing the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 LOF allele carriers.

Arms: arm 1: Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose). arm 2: Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose).
Interventions: intervention 1: Prasugrel intervention 2: Ticagrelor
Intervention descriptions: intervention 1: Maintenance dose will be maintained for 10±3 days. intervention 2: Maintenance dose will be maintained for 10±3 days.

Protocol documents:
Prot_SAP_000.pdf: 
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Pharmacodynamic comparison of prasugrel versus ticagrelor in patients with 
CYP2C19 loss-of-function genotype:  
a validation study in patients with stable coronary artery disease  
 
 
 
 
 
 
 
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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Abstract 
Therapeutic inhibition of platelet activation is essential for the management of ischemic 
cardiovascular disease. The use of platelet adenosine diphosphate (ADP) P2Y12 receptor 
antagonists (clopidogrel, prasugrel, and ticagrelor) in addition to aspirin are associated with a 
decrease in cardiovascular events in high-risk coronary artery disease (CAD) patients. 
Clopidogrel is the most broadly utilized P2Y12 receptor antagonist. However, among clopidogrel 
treated patients, there is broad variability in antiplatelet drug response which is known carry 
prognostic implications. Polymorphisms of the cytochrome P450 (CYP) 2C19 enzyme has been 
consistently shown to modulate clopidogrel response. Accordingly, the Food and Drug 
Administration (FDA) has issued a warning on the potential for reduced efficacy of clopidogrel 
among carriers of loss-of-function alleles (LOF) for CYP2C19 and suggest considering 
alternative antiplatelet therapies for these individuals.   
The pharmacodynamic (PD) effects of prasugrel and ticagrelor are not affected by 
CYP2C19 genetic polymorphisms. However, to date there are no head-to-head PD comparisons 
between these agents among patients with different CYP2C19 genetic polymorphisms which is 
currently under investigation in CAD patients undergoing PCI at UF Health-Jacksonville (UFJ 
2014-12, NCT 02065479). In order to rule out play of chance findings, pharmacogenetic 
investigations require external validation cohorts to support the study findings. Therefore, the 
present study is designed to serve as an external validation cohort conducted in patients with 
established CAD not undergoing PCI testing the non-inferiority in platelet reactivity of prasugrel 
versus ticagrelor among CYP2C19 LOF allele carriers.  
 
 


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Background and Significance 
Therapeutic inhibition of platelet activation is essential for the management of ischemic 
cardiovascular disease [1,2]. In particular, the use of platelet adenosine diphosphate (ADP) 
P2Y12 receptor antagonists (clopidogrel, prasugrel, and ticagrelor) in addition to aspirin are 
associated with a decrease in cardiovascular events in high-risk coronary artery disease (CAD) 
patients [3-5]. Clopidogrel is a second-generation thienopyridine and inhibits ADP-induced 
platelet activation [1]. Clopidogrel is an inactive form of pro-drug requiring a 2-step oxidation 
process by the hepatic cytochrome P450 (CYP) system to be in its active form. Clopidogrel is the 
most broadly utilized P2Y12 receptor antagonist, including in patients with acute coronary 
syndromes (ACS) and/or undergoing percutaneous coronary interventions (PCI) [6-8]. However, 
among clopidogrel treated patients, there is broad variability in antiplatelet drug response and 
patients with poor clopidogrel response are at increased risk of thrombotic complications [9-11]. 
Inter-individual variability in clopidogrel response is a multi-factorial process, including clinical, 
cellular, and genetic factors [9-11]. Among the latter, polymorphisms of the CYP2C19 enzyme 
has been consistently shown to modulate clopidogrel response [12-17].  
 Various studies have demonstrated that carriers (heterozygotes and homozygotes) of 
loss-of-function (LOF) alleles have reduced clopidogrel metabolism leading to lower levels of its 
active metabolite and reduced platelet inhibition [12-17]. The most common LOF alleles include 
the CYP2C19*2 and CYP2C19*3 alleles which are found in approximately 15-40% of patients 
with a prevalence which may vary according to ethnicity (about 15 % in Caucasians and 
Africans, and range between 30% and 40% in Asians) [18-20]. Importantly, carriers of any LOF 
allele have an increased rate of cardiovascular adverse events, particularly in the setting of PCI 


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[12]. These observations have led the Food and Drug Administration (FDA) to issue a warning 
on the potential for reduced efficacy of clopidogrel among CYP2C19 LOF carriers and suggest 
considering alternative antiplatelet therapies for these individuals [21]. 
The new-generation ADP P2Y12 receptor blockers, prasugrel and ticagrelor, have more 
potent, prompt, and predictable antiplatelet effects compared with clopidogrel, which translate 
into greater reduction of cardiovascular events in ACS patients albeit at the expense of a higher 
risk of bleeding [4,5]. Importantly, the pharmacodynamic (PD) effects of both drugs have not 
shown to be affected by CYP2C19 genetic polymorphisms [22-25]. Moreover, post-hoc analyses 
of two large, international trials have not shown any clinical interaction between CYP2C19 LOF 
polymorphisms and ticagrelor or prasugrel [26,27]. Although, PD investigations have shown 
equipoise between prasugrel and ticagrelor [28], to date there are no head-to-head PD 
comparisons between these agents among patients with CYP2C19 LOF alleles.  
Tailoring antiplatelet therapy according to results of genetic testing has been limited in 
real world clinical practice of patients by having readily accessible results of individual’s genetic 
makeup. Recently, a new rapid genotyping assay for the CYP2C19 LOF polymorphisms, 
SpartanRX (Spartan Bioscience, Ottawa, Canada), has been developed [29,30]. This technology 
is currently being testing in a prospective, randomized fashion the comparative PD effects of 
prasugrel vs. ticagrelor in CAD patients with CYP2C19 LOF alleles undergoing PCI at UF 
Health-Jacksonville (UFJ 2014-12, NCT 02065479). In order to rule out play of chance findings, 
pharmacogenetic investigations require external validation cohorts to support the study findings 
[13,31-33]. Therefore, in line with these recommendations, the present study is designed to serve 
as an external validation cohort to UFJ 2014-12 which is testing the non-inferiority in platelet 


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reactivity of prasugrel versus ticagrelor among CYP2C19 LOF allele carriers. This validation 
cohort will be composed of patients with established CAD not undergoing PCI.   
 
Specific aim and study hypothesis  
The primary aim of the present study is to compare the PD effects of prasugrel and 
ticagrelor in patients with established CAD (not in the setting of PCI) and CYP2C19 LOF 
alleles. This study will serve as an external validation cohort to UFJ 2014-12 which is currently 
ongoing and assessing the same objective in the context of patients undergoing PCI. In 
particular, this will allow for an external validation cohort composed of CAD patients without 
the confounding factors related to the PCI procedure itself, including peri-procedural intravenous 
antithrombotic therapy as well the prothrombotic milieu generated by the coronary intervention. 
The study hypothesis is the non-inferiority in platelet reactivity at 24 hours of prasugrel versus 
ticagrelor among CYP2C19 LOF allele carriers.  
 
Research Design and Methods  
Study Population 
CYP2C19 genotyping is currently being performed in patients undergoing cardiac 
catheterization as part of an implementation program at UF Health Jacksonville. This program 
has allowed for the results of CYP2C19 genotyping to be available in our electronic medical 
records (i.e., EPIC) providing the opportunity to clinicians to consider this information to aid 
their decision making on the choice of antiplatelet therapy to be used. Therefore, patients 
meeting study entry criteria will be identified from EPIC. These patients will be contacted by 


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phone (see attached script for description of the phone call). Patients will also be identified 
during their routine clinic visits. Specific study inclusion and exclusion criteria are provided 
below.   
• Inclusion criteria: 
1. Patients with CAD [defined as the presence of at least a 50% stenosis in a major 
epicardial vessel or major branch, or any prior coronary revascularization (PCI or 
coronary bypass graft surgery)] on treatment with either aspirin (81mg/day) or aspirin 
and clopidogrel (75m/day) for at least 30 days as per standard of care  
2. Age 18-75 years 
3. Participated in UFJ 2016-14 study with genetic buccal swab test and have  at least one 
CYP 2C19 LOF allele (CYP2C19*2 and CYP2C19*3) 
 
• Exclusion criteria:  
1. Known allergies to prasugrel or ticagrelor 
2. Age >75 years 
3. Weight <60kg 
4. Considered at high risk for bleeding 
5. Currently active bleeding 
6. History of ischemic or hemorrhagic stroke or transient ischemic attack, or intracranial 
hemorrhage 
7. Known severe hepatic dysfunction 
8. On treatment with oral anticoagulant therapy (Vitamin K antagonists, dabigatran, 
apixaban, rivaroxaban)  
9. Platelet count <80x106/mL 
10. Hemoglobin <10 g/dL. 
11. Creatinine Clearance <30 mL/minute 
12. Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker 
protection. 


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13. Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction 
with ticagrelor): CYP3A Inhibitors (ketoconazole, itraconazole, voriconazole, 
clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and 
telithromycin) and CYP3A Inducers (rifampin, phenytoin, carbamazepine, and 
phenobarbital) 
14. Pregnant or breastfeeding females* 
*Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while 
participating in the study. 
 
Lab results performed within the past 90 days will be considered valid for screening purposes. 
Individuals who do not have lab results during this time frame will require screening labs to 
verify that study entry criteria are met.  
 
Research design 
Patients must fulfill specific study entry criteria described above. Carriers of *2 or *3 
LOF allele [homozygotes (*2/*2, *3/*3 or *2/*3) or heterozygotes (*1/*2, *1/*3, *2/*17, 
*3/*17)] will be eligible for randomization. Patients will be randomly (1:1) assigned to receive 
FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or 
ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose). Maintenance dose will be 
maintained for 10±3 days. Prasugrel and ticagrelor will be provided to study participants. 
Patients will maintain aspirin during the conduct the study. Patients on clopidogrel will 
discontinue the drug 24 hours prior to randomization; patients will remain off clopidogrel for the 
duration of the study. Afterwards, patients will continue with the antiplatelet therapy 
recommended by the treating cardiologist. A follow-up call will be made 10±3 days after 


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conclusion of the study to confirm that patients have resumed their standard of care antiplatelet 
medication and to rule out any adverse effects. The study design is represented in the figure 
below. 
 
 
 
 
 


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Blood sampling 
In patients meeting study entry criteria, blood sampling will be performed at 5 time points: 
a) baseline (prior to loading dose administration of antiplatelet therapy); b) 30 minutes after 
loading dose administration; c) 2 hours after loading dose administration; d) 24 hours after loading 
dose administration (before the morning dose of either prasugrel or ticagrelor, in order to measure 
trough levels of platelet inhibition); e) after 10±3 days of maintenance dose antiplatelet therapy 
(blood will be drawn before the morning dose of either prasugrel or ticagrelor).  
 
Platelet Function Assay: 
VerifyNow Point-of-care Testing: The VerifyNow System is a turbidometric 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 [34,35]. The assay is based on microbead agglutination and uses specific reagents 
for the pathways of interest. The instrument measures this change in optical signal and reports 
results in P2Y12 Reaction Units (PRU). High on-treatment platelet reactivity (HPR) is defined by 
PRU >208 [36]. 
 
Study Endpoints and Determination of Sample Size: 
The primary endpoint is the non-inferiority in platelet reactivity, measured as PRU, at 24 
hours of prasugrel versus ticagrelor among LOF allele carriers. Under the assumption of 0 
difference at 24 hours in mean PRU between ticagrelor and prasugrel and a common standard 
deviation of 50 PRU, a sample size of 22 patients per group allows for the 95% CI to stay within 


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± 45 PRU with a 90% power and alpha = 0.05. Considering the two arms of treatment and a 
possible drop out of 10-15%, we will randomize a total 50 patients to ensure that complete data 
will be available for analysis. Secondary endpoints include: differences in PRU between 
prasugrel and ticagrelor at 30 minutes, 2 hours, and 10±3 days, and rates of HPR at all study time 
points.   
 
Statistical Analysis: 
  
The PD population will include all patients with PD data and without a major protocol 
deviation thought to significantly affect PD profiles. All patients who received at least 1 dose of 
study drug will be included in the safety population. Erroneously treated patients (e.g., those 
randomized to 1 treatment, but actually given the other) will be accounted for on the basis of 
actual treatment received. All continuous variables will be expressed as mean values ± standard 
deviations. Categorical variables will be expressed as frequencies and percentages. The SPSS 
software (ver. 21.0 for Window; SPSS, Chicago, IL) will be used for all analyses. An 
independent Student’s t-test or Wilcoxon rank-sum test will be used to compare continuous 
variables between groups. Comparisons between categorical variables will be performed using 
McNemar test or binomial exact test. Missing data will not be imputed. A p values less than 0.05 
were considered statistically significant. 
 
Possible Discomforts and Risk 
The most important adverse effect associated with the use of prasugrel is bleeding [5]. 
The risk of non-surgical bleeding is 2.4%. The most common side effects of prasugrel were 


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blurred vision, dizziness, headache, nervousness. The most important adverse effect associated 
with the use of ticagrelor is also bleeding [4]. The risk of non-surgical bleeding is 2.8%. Also, 
the most common clinically side effects of ticagrelor were dyspnea (13.8%), headache (6.5%), 
cough (4.9%), dizziness (4.5%), and nausea (4.3%), principally. However, these rates are those 
reported after 1 year of treatment with events that accrue over time, while this study is limited to 
only 10±3 days of treatment thus reducing the risk of these events. All clinical events, if they 
were to occur, including myocardial infarctions both fatal and non-fatal, strokes, peripheral 
vascular disease, bypass surgery (coronary or peripheral vascular), repeated hospitalizations, and 
bleeding will be recorded. 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 (major bleeding – defined as life-threatening: fatal, symptomatic 
intracranial hemorrhage, leading to a drop in hemoglobin of at least 5 g/dL, significant 
hypotension requiring intravenous inotropes, requiring surgical intervention, or requiring 
transfusion of 4 or more units of blood; non–life-threatening: substantially disabling, intraocular 
bleeding leading to vision loss, or requiring at least 2 units of blood; thrombocytopenia <50,000), 
the local committee will meet and antiplatelet treatment will be withdrawn. 
 
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 
frequency since the initiation of study treatment. Adverse events will be followed until resolution 


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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 dyscrasia 
or convulsions that do not result in hospitalization; or development of drug dependency or drug 
abuse. 
 
 


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Possible benefits 
The present investigation is aimed to evaluate the PD differences between ticagrelor and 
prasugrel in patients with stable CAD and CYP2C19 LOF alleles. Although, this study is not 
designed to evaluate differences in clinical outcomes, the results obtained from this study may 
prompt further large scale clinical investigation. 
 
Potential Financial Risks 
None 
 
Potential Financial Benefits 
None 
 
Conflict of Interest 
Dr. Angiolillo is a consultant for Eli-Lilly/Daiichi-Sanyo, the makers of prasugrel (Effient), and 
Astra Zeneca, the makers of ticagrelor (Brilinta). 
 


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