Clinical trial NCT02065479
Conditions: Coronary Artery Disease
Keywords: Coronary Artery Disease Percutaneous Coronary Intervention Genetic Polymorphism Pharmacodynamic
Sponsor: University of Florida
Start date: 2014-03-01; Completion date: 2019-04-22
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Numerous studies have shown that pharmacodynamics (PD) response profiles vary among clopidogrel treated patients and that individuals with reduced response have an increased risk of recurrent ischemic events. There are multiple factors contributing to clopidogrel response variability, including genetic variations of the cytochrome P450 (CYP) 2C19 enzyme. In particular, loss-of-function (LOF) alleles of the CYP2C19 enzyme reduce transformation of clopidogrel pro-drug into its active metabolite. Thus, patients carrying LOF alleles have lower levels of clopidogrel's active metabolite as well as diminished platelet inhibition, which translates into an increased rate of adverse cardiovascular events, particularly in the setting of percutaneous coronary intervention (PCI). Prasugrel and ticagrelor are novel generation P2Y12 receptor inhibitors characterized by greater PD potency and reduced ischemic event rates compared with clopidogrel, and are not affected by CYP2C19 LOF polymorphisms. However, to date there are limited head-to-head PD comparisons between these two new P2Y12 receptors blockers, and there are no studies assessing on how these agents behave among CYP2C19 LOF carriers. The aim of the present study is to compare the PD effects of prasugrel versus ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles using the novel point-of-care genetic testing Spartan RX-CYP2C19 which permits accurate and rapid identification of CYP2C19 genetic status.

Detailed description:
Clopidogrel is the most broadly utilized platelet P2Y12 receptor inhibitor. However, numerous studies have shown that pharmacodynamics (PD) response profiles vary among clopidogrel treated patients and that individuals with reduced response have an increased risk of recurrent ischemic events. There are multiple factors contributing to clopidogrel response variability. Among these, genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key contributor to clopidogrel metabolism, have been involved. In particular, loss-of-function (LOF) alleles of the CYP2C19 enzyme reduce transformation of clopidogrel pro-drug into its active metabolite. Thus, patients carrying LOF alleles have lower levels of clopidogrel's active metabolite as well as diminished platelet inhibition, which translates into an increased rate of adverse cardiovascular events, particularly in the setting of percutaneous coronary intervention (PCI). Because of these findings, drug regulating authorities have provided a boxed warning on the product label of clopidogrel on the potential for reduced efficacy of clopidogrel among CYP2C19 LOF carriers and suggested considering alternative antiplatelet therapies for these individuals. Prasugrel and ticagrelor are novel generation P2Y12 receptor inhibitors characterized by greater PD potency and reduced ischemic event rates compared with clopidogrel, and are not affected by CYP2C19 LOF polymorphisms. However, to date there are limited head-to-head PD comparisons between these two new P2Y12 receptors blockers, and there are no studies assessing on how these agents behave among CYP2C19 LOF carriers. Tailoring antiplatelet therapy according to results of genetic testing has been limited in real world clinical practice because of not having readily accessible results of individual's genetic makeup. The aim of the present study is to compare the PD effects of prasugrel versus ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles using the novel point-of-care genetic testing Spartan RX-CYP2C19 which permits accurate and rapid identification of CYP2C19 genetic status.

Arms: arm 1: The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers. arm 2: The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers.
Interventions: intervention 1: Prasugrel intervention 2: Ticagrelor
Intervention descriptions: intervention 1: Comparison of platelet reactivity between prasugrel and ticagrelor intervention 2: Comparison of platelet reactivity between prasugrel and ticagrelor

Protocol documents:
Prot_SAP_000.pdf: 
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A Pharmacodynamic study comparing prasugrel versus ticagrelor in patients with coronary 
artery disease undergoing PCI with CYP2C19 loss-of-function genotypes:  
A feasibility study with point-of-care pharmacodynamic and genetic testing 
 
 
 
 
 
 
 
 
Investigators 
Dominick J Angiolillo, MD, PhD 
Fabiana Rollini, MD 
Francesco Franchi, MD  
Jennifer Dover, RN, BSN 
 
 


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Project Overview 
Clopidogrel is the most broadly utilized platelet P2Y12 receptor inhibitor. However, numerous 
studies have shown that pharmacodynamics (PD) response profiles vary among clopidogrel treated 
patients and that individuals with reduced response have an increased risk of recurrent ischemic 
events. There are multiple factors contributing to clopidogrel response variability. Among these, 
genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key contributor to clopidogrel 
metabolism, have been involved. In particular, loss-of-function (LOF) alleles of the CYP2C19 
enzyme reduce transformation of clopidogrel pro-drug into its active metabolite. Thus, patients 
carrying LOF alleles have lower levels of clopidogrel’s active metabolite as well as diminished 
platelet inhibition, which translates into an increased rate of adverse cardiovascular events, 
particularly in the setting of percutaneous coronary intervention (PCI). Because of these findings, 
drug regulating authorities have provided a boxed warning on the product label of clopidogrel on the 
potential for reduced efficacy of clopidogrel among CYP2C19 LOF carriers and suggested 
considering alternative antiplatelet therapies for these individuals. Prasugrel and ticagrelor are novel 
generation P2Y12 receptor inhibitors characterized by greater PD potency and reduced ischemic event 
rates compared with clopidogrel, and are not affected by CYP2C19 LOF polymorphisms. However, 
to date there are limited head-to-head PD comparisons between these two new P2Y12 receptors 
blockers, and there are no studies assessing on how these agents behave among CYP2C19 LOF 
carriers. Tailoring antiplatelet therapy according to results of genetic testing has been limited in real 
world clinical practice because of not having readily accessible results of individual’s genetic 
makeup. The aim of the present study is to compare the PD effects of prasugrel versus ticagrelor in 
patients undergoing PCI with CYP2C19 LOF alleles using the novel point-of-care genetic testing 
Spartan RX-CYP2C19 which permits accurate and rapid identification of CYP2C19 genetic status.  


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Background and Significance: 
Dual antiplatelet therapy consisting of aspirin and clopidogrel is the cornerstone of treatment 
for prevention of thrombotic events in patients with coronary artery disease (CAD) who have an acute 
coronary syndrome (ACS) or undergo percutaneous coronary intervention (PCI) [1]. However, there 
are a considerable number of patients who continue to have recurrent ischemic events despite this 
treatment regimen [2,3]. In fact, variability in the pharmacodynamic (PD) response to clopidogrel is 
well recognized, and patients with high on-treatment platelet reactivity (HPR) are at increased risk of 
adverse cardiovascular events [4]. Variability in clopidogrel response is a multifactorial process. One 
of the contributing factors is the variability in its metabolism. Clopidogrel is a prodrug and needs to 
undergo biotransformation to become an active metabolite to exert its antiplatelet effects. Clopidogrel 
is metabolized by the hepatic cytochrome P450 (CYP) system in two steps and CYP 2C19 is involved 
in both steps [5]. Multiples studies have demonstrated that both heterozygotes and homozygotes for 
loss-of-function (LOF) alleles have lower levels of the active clopidogrel metabolite as well as 
diminished platelet inhibition [6]. Moreover, carriers of any LOF allele have an increased rate of 
cardiovascular adverse events, particularly in the setting of PCI [7]. Because of these findings, drug 
regulating authorities have provided a boxed warning on the product label of clopidogrel on the 
potential for reduced efficacy of clopidogrel among CYP2C19 LOF carriers and suggested 
considering alternative antiplatelet therapies, which include prasugrel and ticagrelor, for these 
individuals [8,9]. However, to date there are no head-to-head comparisons between these agents 
among CYP2C19 LOF carriers. 
Recently, new P2Y12 receptor blockers, prasugrel and ticagrelor, have been approved for 
clinical use [10,11]. Both new P2Y12 receptor antagonists have more potent PD effects compared with 
clopidogrel, which has translated into better clinical outcomes in patients with ACS [12,13]. The PD 


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effects of both drugs have not shown to be affected by CYP2C19 genetic status and both agents 
achieve more potent platelet inhibitory effects than clopidogrel in healthy volunteers with CYP2C19 
LOF alleles [6,14]. These PD findings have also been shown in patients with CAD and post-hoc 
analyses of two large, international trials have not shown any clinical interaction between ticagrelor 
or prasugrel and CYP2C19 LOF polymorphisms [15-20]. However, to date there are no head-to-head 
PD comparisons between these two new P2Y12 receptors blockers 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 undergoing PCI by having readily accessible results of 
individual’s genetic makeup. Recently, a new point-of-care genotyping assay for the CYP2C19 LOF 
polymorphisms, Spartan RX, has been developed and approved by the Food and Drug Administration 
(FDA) as a feasible bedside tool [21,22]. The Rapid Gene study showed that point-of-care genetic 
testing permits accurate identification of CYP2C19 LOF carriers. Moreover, the use of Spartan RX 
as genetic testing may facilitate the rapid personalization of anti-platelet therapy as demonstrated with 
the reduction of HPR in the rapid genotyping group using prasugrel on those patients who showed to 
be LOF carriers [18,20]. The present investigation will compare the PD effects of prasugrel and 
ticagrelor in PCI-treated patients with CYP2C19 LOF using the Spartan RX device. 
 
Specific Aim and study hypothesis:  
The primary aim of the present study is to compare the PD effects of prasugrel and ticagrelor 
in patients undergoing PCI presenting with CYP2C19 LOF alleles. The study hypothesis is the non-
inferiority in platelet reactivity at 24 hours of prasugrel versus ticagrelor among LOF allele carriers. 
 
 


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Research Design and Methods:  
Research design 
Patients scheduled for left heart catheterization (LHC) with intent to undergo PCI will be 
screened for the study.  Patients will be screened in our inpatient and outpatients services referring 
patients to our cardiac catheterization laboratories to undergo LHC. Patients must fulfill all specific 
inclusion and exclusion criteria described below. A rapid genetic testing using the point-of-care 
genotyping (Spartan RX) will be performed in these patients to define carriers of LOF alleles. In 
particular, this point-of-care assay enables assessment of the following alleles: *1,*2,*3 and *17. The 
most common LOF alleles are *2 and *3. Therefore, carriers of *2 or *3 LOF carrier status 
[homozygotes (*2/*2, *3/*3 or *2/*3) or heterozygotes (*1/*2, *1/*3, *2/*17, *3/*17)] will be 
eligible for randomization. Patients who are non-carriers of LOF alleles (*1/*1, *1/*17 or *17/*17) 
will not be eligible for randomization and considered as screen failures and treated per standard of 
care. Also, screened patients with CYP2C19 LOF alleles who do not undergo PCI will be considered 
as screen failures and treated per standard of care. 
Screened patients, either on aspirin monotherapy or on dual antiplatelet therapy (DAPT) with 
aspirin and clopidogrel as per standard of care, defined to be carriers of LOF and undergoing PCI will 
be randomized. Patients will be randomly (1:1 randomization) 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). Randomization will be stratified according to baseline 
antiplatelet therapy (aspirin alone vs. DAPT with aspirin and clopidogrel). Loading dose 
administration will be given immediately after PCI as per standard of care. Maintenance dose will be 


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maintained for up to 30 days. Afterwards, patients will continue with the antiplatelet therapy 
recommended by the treating cardiologist (clopidogrel, prasugrel or ticagrelor).  
 
Study Population 
• Inclusion criteria: 
1. Patients scheduled for left heart catheterization and undergoing PCI  
2. Age 18-75 years 
3. On aspirin (81mg) monotherapy or on DAPT with aspirin (81mg) and clopidogrel (75mg) as 
per standard of care  
4. Presence of at least one 2C19 LOF allele  
 
• Exclusion criteria:  
1. Known allergies to aspirin, prasugrel, ticagrelor, or clopidogrel 
2. Age >75 years 
3. Weight <60kg 
4. Considered at high risk for bleeding 
5. History of ischemic or hemorrhagic stroke or transient ischemic attack 
6. Known severe hepatic dysfunction 
7. On treatment with oral anticoagulant therapy (Vitamin K antagonists, dabigatran, apixaban, 
rivaroxaban)  
8. Use of glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) 
9. Blood dyscrasia or bleeding diathesis 
10. Platelet count <80x106/mL 


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11. Hemoglobin <10 g/dL. 
12. Active bleeding or hemodynamic instability 
13. Creatinine Clearance <30 mL/minute 
14. Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker 
protection. 
15. Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with 
Ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, 
saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin. 
16. Pregnant females* 
*Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while 
participating 
in 
the 
study. 
 
The 
study design is 
detailed 
in 
the 
following figure. 
 
 
 
 
 
 
 


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Blood sampling 
In patients meeting study entry criteria and undergoing PCI, blood sampling will be performed 
at 5 time points: a) baseline (prior to initiating the PCI procedure and 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 or hospital discharge (whichever comes 
first); e) during routine follow-up clinical visit 1 – 4 weeks after PCI while on maintenance dose 
antiplatelet therapy.  Time points will have a 10% window. 
 
Genetic Testing 
Spartan RX point-of-care rapid genotyping: Spartan RX (Spartan Bioscience Inc., Ontario, Canada) 
is the point-of-care determining the CYP2C19 (*1,*2,*3,*17) allele status within 1 hour. This test 
consisted of four separate steps intended to be done in less than 8 minutes: acquisition of a buccal 
swab; insertion of the swab into the cartridge; insertion of the reaction solution into the device; and 
analysis of CYP2C19 genotype triggered by a button on the device. In this study, patients with the *2 
or *3 LOF carrier status [homozygotes (*2/*2, *3/*3 or *2/*3) or heterozygotes (*1/*2, *1/*3, 


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*2/*17, *3/*17)] will be eligible for randomization. Patients who are non-carriers of LOF alleles 
(*1/*1, *1/*17 or *17/*17) will be treated per standard of care [21]. 
 
Platelet Function Assays: 
VerifyNow Point-of-care Testing: 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 [23]. 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 [4]. 
 
Study Endpoints and Determination of Sample Size: 
The primary endpoint is the non-inferiority in platelet reactivity, measured as PRU, at 24 hours 
or hospital discharge (whichever comes first) of prasugrel versus ticagrelor among LOF allele carriers 
in each cohort. Under the assumption of 0 difference in mean PRU between treatments and a common 
standard deviation of 50 PRU, a sample size of 60 patients will allow for the 95% CI to stay within ± 
40 PRU with a 85% power and alpha=0.025. Considering a 25% rate of invalid results due to 
hemolysis or drop-out (based on our prior experience), we will randomize a total of 80 patients to 
ensure complete data for analysis. Non-inferiority will be assessed using a 95% CI of the difference 
in mean PRU between the 2 groups.  Secondary endpoints will include: differences in PRU between 
prasugrel and ticagrelor at 30 minutes, 2 hours, and 1-4 weeks (during maintenance therapy); rates of 
HPR at all study time points. Subgroup analyses will be performed according to baseline antiplatelet 
therapy (aspirin alone vs. DAPT with aspirin and clopidogrel) 


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Statistical Analysis: 
Continuous variables will be expressed as a mean ± SD or median [IQR] as appropriate. Categorical 
variables will be expressed as frequencies and percentages. Comparisons between continuous 
variables will be performed using Student t-test or Wilcoxon rank-sum test. Comparisons between 
categorical variables will be performed using McNemar test or binomial exact test. Missing data will 
not be imputed. An analysis of covariance method with a general linear model, with treatment as the 
main effect and baseline values of platelet reactivity as a covariate, will used to evaluate the primary 
endpoint as well as all between-group comparisons at each time point. Least squares mean (LSM) 
differences in PRU between groups and the corresponding 2-sided 95% CI for the difference will be 
obtained based on the analysis of covariance model. The PD population will include all patients with 
PD data and without a major protocol deviation thought to affect significantly the PD effects of 
ticagrelor or prasugrel. 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. Statistical analysis will be 
performed by our group using SPSSv24.0 software (SPSS Inc. Chicago, IL). 
 
Possible Discomforts and Risk 
In clinical trials, the most common clinical side effects of prasugrel were blurred vision, 
dizziness, headache, nervousness; infrequent events included intracranial hemorrhage (0.79%) and 
severe neutropenia (< 0.1%). The most important adverse effect associated with the use of prasugrel 
is bleeding [11]. The risk of non-surgical bleeding is 2.4%. On the other hand, the most common 
clinically side effects of ticagrelor were dyspnea (13.8%), headache (6.5%), cough (4.9%), dizziness 


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(4.5%), and nausea (4.3%), principally. Also, the most important adverse effect associated with the 
use of ticagrelor is bleeding [10]. The risk of non-surgical bleeding is 2.8%. 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 3 
faculty members (2 cardiologists and 1 non-cardiologist), 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 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: 


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- 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. 
 
Possible benefits 
The present investigation is aimed to evaluate the PD differences between ticagrelor and prasugrel in 
patients with CYP2C19 LOF alleles. Although, this study is not designed to evaluate differences in 
clinical outcomes, the results obtained may prompt further large scale clinical investigation. 
 
Potential Financial Risks 
None 
 
Potential Financial Benefits 
None 


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Conflict of Interest 
Dr. Angiolillo is a consultant for Bristol Myers Squibb/Sanofi-Aventis, the makers of clopidogrel 
(Plavix), Eli-Lilly/Daiichi-Sanyo, the makers of prasugrel (Effient), and Astra Zeneca, the makers of 
ticagrelor (Brilinta). 


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DrugSafetyInformationforPatientsandProviders/ucm203888.htm. Accessed April 28, 2010. 
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label 
package: 
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Providers/UCM264004.pdf Accessed on August 2011 
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22.- 
FDA 
Spartan 
RX 
CYP2C19 
Test 
System 
label 
package: 
http://www.accessdata.fda.gov/cdrh_docs/reviews/k123891.pdf 


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23.-  Malinin A, Pokov A, Spergling M, et al. Monitoring platelet inhibition after clopidogrel with 
the VerifyNow-P2Y12(R) rapid analyzer: the VERIfy Thrombosis risk Assessment (VERITAS) 
study. Thromb Res. 2007;119:277-84.