Clinical trial NCT01612884
Conditions: Thrombosis Coronary Artery Disease
Sponsor: Indiana University
Start date: 2011-08-01; Completion date: 2017-03-01
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Personalized treatment approaches and antiplatelet drug choice have been proposed to optimize safety of coronary stenting by reducing heart attacks and repeat interventions while simultaneously minimizing adverse bleeding events. This study compares the efficacy of two laboratory guided treatment algorithms to personalize antiplatelet medication choice after coronary stenting

Detailed description:

Arms: arm 1: Clopidogrel non-response defined as MA≥69 Clopidogrel response defined as MA\<69 arm 2: Clopidogrel non-response defined as MPA ADP \>42.9% Clopidogrel response defined as MPA ADP \<42.9%
Interventions: intervention 1: Prasugrel intervention 2: Clopidogrel
Intervention descriptions: intervention 1: Prasugrel 60mg loading dose at time of PCI if clopidogrel non-responder intervention 2: Clopidogrel 300mg loading dose at time of PCI if clopidogrel responder

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
Antiplatelet therapy guided by thrombelastography in patients with 
acute coronary syndromes (TEGCOR Study) 
 
 
 
Principal Investigator: 
 
Rolf P. Kreutz, M.D. 
Krannert Institute of Cardiology 
1701 N. Senate Blvd, ME-400 
Indianapolis, IN 46202 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
A. 
INTRODUCTION 
Platelet aggregation and activation mediated by various agonists are fundamental in the 
development of ischemia in patients with coronary artery disease. 
Activated platelets mediate vessel wall inflammation, and thrombin generated by 
procoagulant factors and tissue injury initiates fibrin generation. Platelet-platelet 
aggregates cross-linked by fibrin and fibrinogen eventually mechanically obstruct the 
vessel lumen in patients with acute coronary syndromes. Dual antiplatelet therapy with 
aspirin and clopidogrel and more recently aspirin and prasugrel have become standard of 
care for patients undergoing percutaneous coronary intervention (PCI) and stent 
placement for acute coronary syndromes. Despite significant reduction in ischemic 
complications, concern remains regarding the occurrence of thrombotic events after 
coronary interventions and stenting. Specifically, high posttreatment platelet reactivity 
after coronary stenting measured by ex vivo platelet assays with clopidogrel have been 
repeatedly associated with high rates of stent thrombosis and myocardial infarction post 
PCI, events with high mortality and morbidity [1-3]. The significant interindividual 
variation in the extent of clopidogrel platelet inihibition is to a great degree founded in 
genetic interindividual differences in CYP450 metabolism or other drug-drug interactions 
that inhibit hepatic isoenzyme activity [4,5]. In particular reduced function 
polymorphisms of CYP 2C19 have been found to significantly impair the 
pharmacodynamic effects of clopidogrel and have been associated with worse clinical 
outcomes in several large studies of patients after coronary stent implantation [6]. These 
findings have supported the development of more efficacious and predictive P2Y12 
inhibitors, such as prasugrel and ticlopidine, both of which have been shown to be 
associated with reduced rates of stent thrombosis as compared to clopidogrel.  
Thrombelastography (TEG) is an ex-vivo method that measures the viscoelastic 
properties of whole blood clot formation in response to various agonists [2] . In essence, 
the device features a stationary pin suspended by a torsion wire which is lowered into a 
rotating sample cup containing whole blood and various agonists. The device then 
measures the forces between the pin and the cup generated by the developing fibrin and 
platelet-fibrin clots.   
Thus, the method enables the measurement of various parameters of coagulation and 
aggregation, including thrombin activity by measuring the time to fibrin generation, but 
also the relative contribution of platelet-platelet aggregate formation and fibrin generation 
on tensile clot strength. As we have shown previously, elevated whole blood clot strength 
appears to be a significant predictor for adverse ischemic events after coronary stenting 
with a relative adjusted OR of 22.6 for the occurrence of ischemic events in patients with 
highest quartile clot strength [2]. Inhibition of GpIIb/IIIa receptors by eptifibatide 
significantly reduces MA and also periprocedural myocardial infarctions associated with 
coronary stenting. It appears that high tensile whole blood clot strength on clopidogrel 
therapy appears to be a significant risk factor for recurrent ischemic events that may be 
only partially explainable by insufficient P2Y12 receptor inhibition. The ex-vivo 
phenotype of high tensile clot strength is probably multifactorial, but may be due to 
release of tissue factor and increased velocity of thrombin generation in patients with 
acute coronary syndromes. Not surprisingly, it is these patients that are clinically known 
to be at highest risk for recurrent thrombotic events and cardiac death. Accordingly, we 
have previously demonstrated that high clot strength phenotype was associated with 


 
 
elevated levels of fibrinogen, tissue factor, vWF, C-reactive protein, TNF-a and IL-8 and 
was found more frequent in patients with acute coronary syndromes as compared to 
patients with stable coronary artery disease [7,8]. These findings suggest that TEG may 
be a unique testing modality that is able to identify and specifically target patients at 
elevated clinical risk.  
Although increased P2Y12 receptor inhibition with prasugrel is more efficient in reducing 
ischemic events than clopidogrel, it also carries an increased risk for significant bleeding. 
Personalized treatment approaches should ideally be able to identify patients at need for 
higher or lower intensity of platelet P2Y12 inhibition in an attempt to optimize the 
risk/benefit ratio for each patient. However, currently only one study prospectively 
compared a personalized dosing approach of clopidogrel vs. standard dosing in 162 
patients prior to coronary stenting [9].  
In addition to the currently available antiplatelet drugs that inhibit ADP mediated platelet 
aggregation by inhibiting P2Y12, several oral thrombin receptor protease-activated 
receptor-1 (PAR-1) inhibitors (platelet thrombin receptor) have been developed. Two oral 
PAR-1 inhibitors have completed phase 2 clinical trials and the eventual addition of these 
drugs to standard dual antiplatelet therapy may in the future further increase bleeding risk 
for patients on several antiplatelet drugs. Theoretically, thrombelastography may provide 
an ideal methodology to identify patients at highest risk for thrombin mediated ischemic 
events or identify patients at risk of bleeding. In the surgical field, thrombelastography 
has been used successfully to predict postoperative bleeding risk and guide post surgical 
and trauma related transfusion requirements. 
 
Currently controversy exists as to the optimal method to identify patients at risk for 
ischemic events after coronary interventions and several point of care assays measuring 
platelet inhibition are currently in use in large prospective clinical trials. These currently 
employed methods focus on the specific amount of ADP mediated platelet aggregation 
measured ex-vivo to guide risk prediction and intensity of P2Y12 inhibition by either dose 
adjustment of clopidogrel or switching therapy to prasugrel. Therefore, as a control group 
we will include a group of patients which will be assigned to prasugrel or clopidogrel 
therapy based on LTA measurements pre-cath using a cutoff that has been validated as a 
predictor of ischemic events in several other large studies [1]. 
 
The purpose of this study is to assess the pharmacodynamic effects of high intensity 
P2Y12 receptor inhibition by prasugrel in patients with high clot strength and assess the 
interrelationship with clopidogrel non-response as defined by light transmittance 
aggregometry. Pharmacogenetic analyses will aid in understanding the impact of 
CYP450 metabolism and other polymorphisms in the coagulation cascade on the high 
clot strength phenotype.  
Data from this study may be used in the design of personalized therapeutic trials of 
antiplatelet drugs and guide the use of next generation PAR-1 inhibitors. 
 
 
B. 
SPECIFIC AIMS 
The aim of the current study is to evaluate the impact of increased P2Y12 inhibition by 
prasugrel on the physical properties of whole blood clot formation in patients with 


 
 
persistent high fibrin-platelet clot strength on clopidogrel and compare the TEG guided 
treatment approach to a platelet aggregation guided approach of personalized antiplatelet 
therapy. 
Pharmacogenetic analyses of revelant genetic polymorphisms and genes involved in 
thrombosis are intended to support pharmacodynamic conclusions drawn from the results 
of this study. 
 
Primary hypothesis 
High tensile clot strength as measured by TEG and defined as MA ≥ 69 on clopidogrel is 
partially due to inadequate P2Y12 inhibition and can be overcome by switching to 
prasugrel 
 
Primary Endpoint: 
Persistence of high tensile clot strength measured by TEG 16-24 hours after reloading of 
either clopidogrel or prasugrel. 
 
Secondary Endpoints: 
a) 
Occurrence of ischemic events over 6 month follow-up period as defined by 
death, recurrent myocardial infarction, recurrent unstable angina, repeat coronary 
intervention (exclusion of staged interventions) 
b) 
Occurrence of bleeding events according to TIMI minor/major criteria over 6 
months follow-up. 
 
C. 
METHODS 
1.0 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria:  
- Patients admitted with acute coronary syndrome (unstable angina, non-ST elevation 
myocardial infarction) and referred for coronary angiography. 
- Current therapy with clopidogrel (at least 300mg loading dose, or 75mg po daily for >5 
days)  
- Age range 21-75 years.  
 
Exclusion Criteria: 
- Unable to give consent 
- Age younger than 21 years, greater than 75 years 
- History of stroke 
- Body weight <60 kg 
- Acute STEMI,  
- Thrombocytopenia<100’000, 
-  requirement for chronic warfarin therapy 


 
 
 
2.0 
Enrollment/Randomization 
 
The current study will be an open label study. Subjects will be enrolled among patients 
who are admitted with an acute coronary syndrome (unstable angina, non-STEMI) and 
who are being referred for coronary angiography and possible percutaneous coronary 
intervention. All study candidates must have received at least 300mg of clopidogrel 
loading dose since admission, or have been on clopidogrel 75mg daily for >5 days at time 
of enrollment.  
Subjects will be enrolled before undergoing diagnostic angiography using written 
informed consent after screening for appropriate candidates. Patients will have the first 
study blood draw performed prior to coronary angiography. In case significant coronary 
disease is found and the patient proceeds with percutaneous coronary intervention, the 
patient will be randomized to either a TEG guided or LTA guided strategy. The subject 
with then be switched to prasugrel or continue on clopidogrel according to the results of 
the pre-cath TEG or LTA measurements.  Patients in the TEG guided arm with high 
physical clot strength (MA≥69) will be assigned to prasugrel, whereas patients with 
lower clot strength (MA<69) will continue on clopidogrel. This cutoff reflects the 50th 
percentile of clot strength based on data from a prior cohort of patients undergoing PCI 
and was determined as cutoff for ischemic risk in prior studies.  
Patients in the LTA guided arm with high on treatment platelet reactivity to ADP 
(PA>42.9%) will be assigned to prasugrel, whereas patients with low on treatment 
platelet reactivity (PA≤42.9%) will continue on clopidogrel. This value was determined 
as a significant cutoff for ischemic risk in prior studies. If the decision is made to proceed 
with percutaneous revascularization, patients assigned to remain on clopidogrel will 
receive 300mg clopidogrel loading dose in the cath lab, and then remain on 75mg po 
daily. Patients assigned to prasugrel will receive 60mg po loading dose, and then remain 
on 10mg po daily.  
 
Telephone follow-up will be conducted after 6 months to assess for ischemic and 
bleeding events.  
 
The enrollment and study process is depicted in a Fig 1. 
 
We plan on enrolling 100 subjects, with 50 subjects randomized to each arm: 
 
 
3.0 
Study Procedures 
 
After signing of informed consent, patients are asked to fill out a short questionnaire 
regarding demographics, risk factors, family history and dietary history that will take 5 
minutes to complete. 
 
Venous blood will be collected through peripheral venous puncture (~ 20ml) prior to 
cardiac catheterization and again 16-24 hours post PCI. 


 
 
Thrombelastography measurements and light transmittance aggregometry will be 
performed using several agonists on both occasions. 
The remaining buffy coat will be collected and frozen at -80°C for DNA extraction and 
analysis. Analysis of candidate genes involved in metabolism of thienopyridines, platelet 
aggregation, and coagulation will be performed. 
 
Patient records from the Indiana Network for Patient Care (INPC) will be accessed for 
analysis of cardiovascular outcomes. 
Data that will be collected for database analyses includes the following (not exclusive): 
 
Demographics 
Age 
Gender 
Weight 
Height 
 
Race/ Ethnicity 
Self reported 
Risk factors/Co-morbidities 
Diabetes mellitus 
Hypertension 
Hyperlipidemia 
PVD 
COPD/Asthma 
Renal failure/Dialysis 
Smoking history 
Valvular disease 
Hx of arrhythmias 
Nutritional History 
Caffeine consumption  
Alcohol use 
 
Medications 
Current medication list  
History of Present Illness 
Reason for referral for cardiac cath 
 
Laboratory 
Most recent laboratory data prior to stress 
test will be obtained from INPC to include: 
Cardiac markers (troponin, CK, CKMB) 
Complete blood count 
Basic metabolic profile 
Liver function tests (if available) 
Lipid profile 
Electrocardiogram 
As per standard of care 
 
Cardiac catheterization 
Cines/Images from cardiac catheterizations 
performed  
 
 
 


 
 
4.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
4.1 Data Safety Monitoring Board 
A data safety monitoring board consisting of two physicians not directly involved with 
the study will monitor the progress of the study at least annually. 
 
4.2. Reporting mechanisms for adverse events to the IRB, FDA, NIH. 
 
The principal investigator and study coordinator will review the clinical course for 
immediate adverse events directly related to the study procedure. Unanticipated serious 
adverse events as defined below or loss of anonymity will be reported to the IRB within 
10 days after discovery in writing. Anticipated adverse events of coronary interventions 
will be reported during continuing annual review to the IRB. 
 
4.3. Plan for unanticipated AE reporting 
 
Unanticipated serious adverse events must be reported to the IRB within 10 days of 
discovery. Unanticipated serious adverse events are events (including adverse events, 
injuries, side effects during a study) that caused harm to one or more subjects or others, 
or placed one or more subjects or others at increased risk of harm, AND were unexpected 
(the frequency or severity of the event is not accurately reflected in the informed consent 
document for the cardiac catheterization or is inconsistent with available literature, e.g. 
drug brochure, protocol) , AND were related (e.g. > 51% chance) to the research 
procedures, AND require revision to the informed consent document. 
 
4.4. Plan for annual reporting of AEs   
 
Based upon continuing review, all adverse events will be reported to the Clarian IRB 
annually in writing. 
 
4.5 
Study Withdrawal/Discontinuation 
 
Participants may withdraw from the participation in the study at any time. This requires a 
written request to the principal investigator.   
 
5 
Statistical Considerations 
Sample size calculation was performed assuming an estimated prevalence of 50% of MA 
≥ 69 in the general patient population with ACS on clopidogrel referred for cardiac 
catheterization according to previous studies. It was assumed that switching to prasugrel 
would reduce the maximal clot strength in 60% of these patients with baseline MA ≥ 69 
resulting in 20% prevalence of high tensile clot strength. Assuming a power of 0.8 and 
alpha 0.05 with a loss of 5% of follow-up, a sample size of 50 in each arm and a total 
sample size of n=100 was calculated accordingly. 
 


 
 
 
6 
Privacy/Confidentiality Issues 
 
All information will be collected and kept on a customized database on computers of the 
investigators and on a secure network server at the Krannert Institute of Cardiology. 
Access to the database is password protected and computers will be kept in locked offices 
at the Krannert Institute and Wishard Hospital.  Access to the offices housing the 
information is only available via keys possessed by the investigators. Only the listed 
investigators of the study will have access to review information and to analyze data.  
Data sent for analysis will be de-identified. The names of the patients will not be revealed 
if the results of this study lead to a publication. 
The genetic information found through the course of the study will not be revealed to the 
study participants or their family members.  
Blood samples are stored in a secured biospecimen storage facility that has secured 
access. Biospecimens are deidentified and do not allow identification of patients. 
 
 
7 
Follow-up and Record Retention 
 
The study will last for at least 6 months after enrollment of the last study subject. Records 
and samples will be kept as required by the IRB and federal legislation and until 
completion of all study related analyses. 
 
 
D. 
FACILITIES AVAILABLE 
The cardiac catheterization laboratories at Wishard Hospital and Methodist Hospital will 
be used as study locations as required for the clinical care of the patients. Standard 
hospital care will be provided. 
Laboratory analyses including platelet studies, thrombelastography, as well as DNA 
analysis will be performed in the laboratories of the Division of Clinical Pharmacology, 
Indiana University School of Medicine. 
 
E. 
SUPPORTING INFORMATION 
The proposed research strives to further the cause of delivering personalized care to 
patients undergoing invasive and high risk procedures in the cardiac catheterization 
laboratory. Personalizing antiplatelet drug therapy by adjusting drugs and dosing 
according to measurements of platelet inhibition has been proposed as a future approach 
to optimally balance desired therapeutic effects as well as unwanted adverse effects and 
thus deliver optimal patient care. Patients enrolled in this study will benefit from 
advanced laboratory testing and likely improved outcomes after coronary stenting 
compared to standard treatment. Findings from this study may be useful in the design of 
future clinical research studies.   
 
 
 


 
 
References: 
1. 
Bonello L et al. Consensus and Future Directions on the Definition of High on 
Treatment Platelet Reactivity to ADP. J Am Coll Cardiol 2010;56:919-33 
2. 
Gurbel PA, Bliden KP, Guyer K, Cho PW, Zaman KA, Kreutz RP, Bassi AK, 
Tantry US. Platelet Reactivity in Patients and Recurrent Events Post-Stenting: Results of 
the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005;46(10):1820-1826 
3. 
Gurbel PA, Bliden KP, Cohen E, Navickas IA, Singla A, Antonino MJ, Fissha M, 
Kreutz RP, Bassi AK, Tantry US. Race and Sex Differences in Thrombogenicity: Risk of 
Ischemic Events Following Coronary Stenting. Blood Coagul Fibrinolysis 2008;19:268-
275. 
4. 
Kreutz RP, Stanek EJ, Aubert R, Yao J, Breall JA, Desta Z, Skaar TC, Teagarden 
JR, Frueh FW, Epstein RS, Flockhart DA. Impact of Proton Pump Inhibitors on the 
effectiveness of Clopidogrel Following Coronary Stent Placement:  The Clopidogrel 
Medco Outcomes Study. Pharmacotherapy 2010,30(8):787-96. 
5. 
Shuldiner AR et al. Association of cytochrome P450 2C19 genotype with the 
antiplatelet effect and clincal efficacy of clopidogrel. JAMA 2009; 302(8):849-858 
6. 
Mega JL et al. Cytochrome P450 polymorphisms and response to clopidogrel. N 
Engl J Med 2009; 360:354-62 
7. 
Gurbel PA, Bliden KP, Kreutz RP, Dichiara J, Antonino MJ, Tantry US. The link 
between heightened thrombogenicity and inflammation: pre-procedure characterization 
of the patient at high risk for recurrent events after stenting. Platelets 2009;20(2):97-104. 
8. 
Tantry US, Bliden KP, Suarez TA, Kreutz RP, Dichiara J, Gurbel 
PA.Hypercoagulability, platelet function, inflammation and coronary artery disease 
acuity: Results of the Thrombotic RIsk Progression (TRIP) Study. Platelets 
2010;21(5):360-7. 
9. 
Bonello L et al. Adjusted Clopidogrel loading doses according to VASP index 
decrease rate of major cardiovascular events in patients with clopidogrel resistance. J Am 
Coll Cardiol 2008;51:1404-11 
 
 


 
 
Fig 1.
 

SAP_001.pdf: 
Effects of intensified oral P2Y12 inhibition on 
elevated fibrin-platelet clot strength in patients 
with acute coronary syndromes  
(TEGCOR Study)  
 
 
 
 
Principal Investigator: 
 
Rolf P. Kreutz, M.D. 
Krannert Institute of Cardiology 
1701 N. Senate Blvd, ME-400 
Indianapolis, IN 46202 
 


Statistical Analysis Plan 
 
Comparison of clot strength measured by Thrombelastography in whole blood (TEG-MA) will 
be made with 2-sided Student’s T-test after reloading of clopidogrel or prasugrel at 16-24 hours. 
Comparison of outcome events (death, recurrent myocardial infarction, recurrent unstable 
angina, repeat coronary intervention up to 6 months) will be made by Chi-Square test. All tests 
are performed two-sided with p<0.05 as significance threshold.