The Effects of Crushed Ticagrelor Versus Eptifibatide Bolus +Clopidogrel in Troponin-Negative ACS Patients Undergoing Coronary Intervention
Phase: PHASE2
Conditions: Acute Coronary Syndrome, Angina, Unstable
Sponsor: University of Alabama at Birmingham

Ticagrelor versus Clopidogrel and Eptifibatide Bolus in Patients 
with Stable or Unstable Angina Undergoing Coronary 
Intervention: A Randomized Pharmacodynamic Study 
 
 
     Study Protocol & Statistical Analysis Plan  
 
 
 
 
   
 
 
 
 
        NCT02925923 
 
 
 
 
 
 
 
 
 
 
 
    December 17, 2019 
 
 
 
 
Massoud A. Leesar, M.D., Principal Investigator 
 
 
  University of Alabama at Birmingham 
 
 
 
 
Birmingham, AL 35294 
 
 
 

 
 
 
 
 
 Ticagrelor versus Clopidogrel and Eptifibatide Bolus in 
Patients with Stable or Unstable Angina Undergoing 
Coronary Intervention: A Randomized Pharmacodynamic 
Study 
 
 
 
Moazez Marian, PhD, Olseun Alli, MD, Firas Al soliman, MD; Mark Sasse, MD, Arka 
Chatterjee, MD, Himanshu Aggarwal, MD, Andrew Kurtlinsky, MD Massoud 
Leesar, MD 
Division of Cardiology, UAB Center for Thrombosis Research, University of 
Alabama, Birmingham 
 
 
 
Address for Correspondence: 
Massoud A. Leesar, MD 
 
 
 
Division of Cardiology 
 
 
 
 
 
University of Alabama-Birmingham 
 
 
 
 
 
Birmingham, AL, 35294 
 
 
 
 
 
Telephone: (205) 975-0816 
 
 
 
 
 
E-mail: mleear@uab.edu 
 
 
 
 
 
 

 
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In the Ad Hoc percutaneous coronary intervention (PCI) study (Presented at the SCAI meeting, 
2015), 100 patients with troponin-negative acute coronary syndrome were randomized to receive 
ticagrelor (180mg loading dose [LD] and 90mg after 12hr) or clopidogrel (600mg LD and 75 mg 
after 12 h) with aspirin 75–100mg daily. P2Y12 reactivity unit [PRU] using VerifyNowTM assay was 
measured pre-LD, and at 0.5, 2 and 8 h post LD. At 2 h, PRU was lower with ticagrelor vs. 
clopidogrel (98.4 ± 95.4 vs. 257.5 ± 74.5, respectively; p<0.001). PRU diverged as early as 0.5 h 
post ticagrelor LD and there was a significant reduction in the PRU level with ticagrelor. The rate 
of high on-treatment PRU level was significantly reduced with ticagrelor compared with 
clopidogrel at 2 h (13.3% vs. 78.3%, respectively ;p<0.001). However, ticagrelor still did not cover 
the first 30 min of the procedure.  
 
The Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for Coronary 
Treatment (ISAR-REACT) study reported that pretreatment with 600 mg clopidogrel provides 
outcomes similar to those achieved with a strategy of pretreatment with the addition of abciximab 
[1] However, an important consideration in the decision for pretreatment is the associated risk of 
bleeding in those patients requiring coronary bypass surgery. The Clopidogrel Loading with 
Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS study) [2] showed  that the 
administration of eptifibatide with either a 300 mg or 600 mg of clopidogrel provides the most 
sustained platelet inhibition and was associated with the lowest incidence of myonecrosis 
compared with those who received clopidogrel alone. The incremental increase in myonecrosis 
observed in patients with higher levels of post-treatment platelet reactivity lend strong support to 
the concept that activated platelets during PCI play a central role in the mediation of post-stent 
myonecrosis. However, the findings of ISAR-REACT trial is not relevant when physicians decide 
not to pretreat patients whose coronary anatomy is unknown before the stenting. 
Since stenting and the use of thienopyridines have become routine, there has been a decrease 
in the incidence of acute closure, but because of concern with respect to bleeding complications 
after PCI, adopting a bolus injection or brief infusion of glycoprotein inhibitors (GPI) has reduced 
such complications. In this respect, Kini et al [3] demonstrated that among patients undergoing 
PCI, GPI bolus only reduced vascular/bleeding complications with similar MACE and reduced 
cost when compared with GPI bolus plus continuous infusion. In addition, GPI bolus only 
improved ambulatory PCI and reduced length of stay.  Marmur et al. [4] compared long-term 
mortality after bolus only administration of abciximab, eptifibatide, and tirofiban during PCI and 
demonstrated that eptifibatide, when given as bolus-only during PCI, improved the long-term 
survival compared to abciximab. Furthermore, Fung et al. [5] demonstrated that in patients 
undergoing non-emergent PCI, the post-procedural infusion of eptifibatide can be abbreviated to 
<2 h and that was not inferior to 18-h infusion in preventing ischemic events. Furthermore, they 
concluded that the abbreviated infusion of eptifibatide reduced both cost and post-procedural 
major bleeding.  
 
We recently randomized 70 patients with Non-ST-Segment Myocardial Infarction (NSTEMI) to 
ticagrelor 190 mg loading and eptifibatide bolus-only (TEP) vs. ticagrelor loading and eptifibatide 
bolus plus 2 h infusion (TEPI) administrated before stenting [Fig. 1]. Light transmission 
aggregometry was performed and percent inhibition of platelet aggregation (%IPA) was calculated 
at baseline, and at 2 , 6 , and 24 h using ADP,TRAP, collagen, and arachidonic acid (AA). Cardiac 
enzymes, hemoglobin and hematocrit were measured at baseline and at 24 h. The event rates 
were determined at 30-day follow-up. We demonstrated that in patients randomized to TEP vs. 
TEPI, there were no significant difference in the %IPA values at 2 h and 6 h with ADP 5 μM (100% 
± 0.01 vs. 99% ± 0.25 and 99% ± 2.4 vs. 99% ± 1.2, respectively) and with ADP 20 μM as well as 
with collagen. However, %IPA was lower at 24 h (still >60% platelet inhibition) compared with that 
at 2 h and 6 h. Percent IPA with TRAP 10 or 20 μM was higher at 6 h in patients randomized to 

 
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TEPI vs. TEP (87% ± 13 vs. 74% ± 17; P<0.01, respectively), but this had no bearing on outcomes 
since ADP was highly inhibited by ticagrelor at 6 h. There were no significant differences in 
troponin or hemoglobin levels among the groups. During follow- up, and there was no stent 
thrombosis or myocardial infarction. 
 
 
We concluded that %IPA values with ADP and collagen were not significantly different comparing 
ticagrelor with eptifibatide bolus only vs. ticagrelor and eptifibatide bolus plus 2 h infusion. 
Eptifibatide bolus only highly inhibited platelets aggregation while allowing bridging to the 
antiplatelet effect of ticagrelor and circumventing the need for continuous eptifibatide infusion. 
There was no significant difference in bleeding or MI between the 2 groups. 
RATIONALE 
The antiplatelet effect of clopidogrel is slow in onset, variable, and irreversible; approximately 15 
to 30% of patients are non-responsive [6]. Furthermore, a 75-mg/d clopidogrel maintenance dose 
requires at least 5 days, and a 600-mg loading dose of clopidogrel requires up to 8 hours to 
achieve a 50% steady state of inhibition of ADP-induced platelet aggregation [7-9]. The difference 
in the clinical effects of ticagrelor compared with clopidogrel lies in the fact that ticagrelor exerts 
more rapid, more potent, and more consistent inhibition of platelets [10,11].  In the CLEAR 
Fig. 1 

 
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PLATELETS study [2], administration of eptifibatide with either a 300 mg or 600 mg of clopidogrel 
provided the most sustained platelet inhibition and was associated with the lowest incidence of 
myonecrosis compared with 600 mg loading dose of clopidogrel administered in the cath lab . 
The Platelet Inhibition and Patient Outcomes (PLATO) trial [12] demonstrated that dual 
antiplatelet therapy with aspirin and ticagrelor was superior to aspirin and clopidogrel in reducing 
thrombotic complications in patients with acute coronary syndrome undergoing PCI. Glycoprotein 
IIb/IIIa inhibitors (GPI) bolus and infusion was used with ticagrelor in 40% of patients in the PLATO 
trial. However, GPI use was not randomized and the benefit of which cannot be substantiated. 
On the other hand, the CLEAR PLATELET study showed clopidogrel and eptifibatide bolus and 
infusion was associated with reduced myonecrosis. In addition, they showed that platelet 
inhibition was significantly higher with 600 mg vs. 300 mg of clopidogrel. In the Ad Hoc PCI study, 
ticagrelor or clopidogrel was administered before PCI in patients with unstable angina and there 
was a significant reduction in the PRU level with ticagrelor as compared with clopidogrel. We 
demonstrated that %IPA with ticagrelor and eptifibatide bolus was not significantly different than 
ticagrelor and eptifibatide bolus and short infusion.  
The inhibition of platelets is significantly faster and stronger with Ticagrelor than clopidogrel.  We 
hypothesized that inhibition of platelet aggregation with ticagrelor alone will be non-inferior to that 
of clopidogrel and eptifibatide bolus. The present study will be the first to investigate the 
pharmacodynamic effects of ticagrelor vs. clopidogrel plus eptifibatide bolus in patients 
undergoing elective PCI in patients with troponin negative unstable angina or stable angina. If 
ticagrelor alone is indeed non-inferior to clopidogrel and eptifibatide bolus, this will pave the way 
for a large randomized study to demonstrate the safety and efficacy of ticagrelor alone as 
compared with concomitant administration of clopidogrel and eptifibatide.  
Study Hypothesis: To compare the percent inhibition of platelet aggregation with ticagrelor 
compared with clopidogrel and eptifibatide bolus in patients with stable angina or in patients with 
troponin-negative unstable angina.  
 
Inclusion Criteria:  
Patients with stable angina with evidence for at least >10% perfusion defect (moderate to large 
ischemia) or patients with troponin-negative unstable angina.  
 
Exclusion Criteria: A need for oral anticoagulation therapy; an increased risk of bradycardia, 
and concomitant therapy with a strong cytochrome P-450 inhibitors; surgery<4 weeks; The use 
of any thienopyridines prior to randomization; upstream use of GP IIb/IIIa inhibitors;  
bleeding diathesis or major bleeding episode within 2 weeks; thrombocytopenia; incessant chest 
pain; hemodynamic instability; NSTEMI as evidenced by elevation of troponin levels; renal failure 
with a serum creatinine >2.0 mg/dL; and anemia with HCT<30%. 
 
Methods   
In this study, 100 patients with stable angina or troponin negative unstable angina, will be 
randomized to ticagrelor loading dose versus clopidogrel loading dose and eptifibatide bolus only 
administrated before PCI. Platelet function testing will be performed at baseline, at 30 min post-
loading dose, 2 h, and 4 h, and 24 h. All patients will be started on aspirin 81 mg prior to procedure 
. Heparin 60 units/kg will be administered intravenously before PCI. PCI will be performed in 
accordance with standard clinical practice. Please see Fig. 2, Design of the study below and Table 
1. 
 
 

 
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Fig. 2 
 
Blood Sampling for Platelet Function Testing 
Blood will be collected from an antecubital vein into vacutainer tubes (Becton-Dickinson, Franklin 
Lakes, NJ) that contain 3.2% trisodium citrate for light-transmittance aggregometry. All 
measurements will be performed at the UAB thrombosis research laboratory.  
 
Light-Transmittance Aggregometry 
Platelet aggregation induced by ADP (5 and 20 m), TRAP (10 and 20 m) platelet-rich plasma 
will be measured with a Chronolog Optical Aggregometer (model 490-4D; Chronolog Corporation, 
Havertown, Pa). The final extent of aggregation, measured at 6 minutes after agonist addition, 
and the maximal extent of aggregation will be expressed as the percent change in light 
transmittance from baseline with platelet-poor plasma as a reference. Inhibition of platelet 
aggregation (IPA) will be  calculated as follows:  
 
 
IPA(%)=100% X PAt - PAb 
PAb 
Where PA is platelet aggregation, b is predosing, and t is postdosing. 
 
Statistical Analysis 
The present study is an exploratory trial to investigate the percent inhibition of platelet activity 
(%IPA) (measured by light-transmittance aggregometry) comparing the loading dose of ticagrelor 

 
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with loading dose of clopidogrel and 2 boluses of eptifibatide measured at all time-points. Since 
there are no preliminary data available, no power calculation was performed. Statistical analysis 
will be performed using the Statistical Package for Social Sciences, version 22.0, software 
package for Windows (SPSS, Inc., Chicago, Illinois). Data will be presented as mean ± 1 SD or 
frequencies; a value of P< 0.05 will be considered statistically significant. %IPA of ticagrelor and 
2 boluses of eptifibatide vs. loading dose of clopidogrel and 2 boluses of eptifibatide will be 
compared at all time-points using repeated measures ANOVA. Continuous variables will be 
compared between the 2 treatment groups with Student t test. For comparisons of categorical 
data, the Chi-Square test will be performed.  
 
End-Points 
The primary end point of the study is to compare %IPA induced by ADP at 2 h, in patients 
randomized to the loading dose of ticagrelor with loading dose of clopidogrel and 2 boluses of 
eptifibatide measured at 2 h post loading dose. Secondary endpoints of the study are to 
compare %IPA induced by ADP and TRAP in patients randomized to the loading dose of ticagrelor 
with loading dose of clopidogrel and 2 boluses of eptifibatide  at all time-points.  Other secondary 
outcomes include: 1) the occurrence of post-procedural myonecrosis comparing the 2 groups. 
Ischemic myonecrosis will be defined as elevated post-procedure troponin-1 level >0.26 µg/l; and 
2) the rate minor (a fall in hemoglobin of 3 to <5 g/dL) and major bleeding ( a fall in the hemoglobin 
>5 g/dL) between the groups. 
 
Anticipated Findings  
Since platelet inhibition with ticagrelor starts rapidly, we expect that %IPA at 2 h will be no 
significantly different than clopidogrel and eptifibatide bolus. In addition, since eptifibatide half-life 
is short, we expect that %IPA at 24 h will be higher with ticagrelor than clopidogrel and eptifibatide 
bolus.  
We anticipate the results of the present study will set the stage for a large randomized trial 
comparing myonecrosis, stent thrombosis, death, myocardial infarction, bleeding, and costs in 
patients randomized to ticagrelor only vs. loading dose of clopidogrel and 2 boluses of eptifibatide.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1: Schedule of treatment  
 
Index Hospitalization 
 

 
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Time-range 
Baseline 
Procedure 
Discharge 
4 weeks 
Time range for completion 
Same day 
prior 
 
During 
 1 week 
Point of Interest 
Hospital 
 
Physician  
office 
Informed consent 
X 
 
 
 
History 
X 
 
 
 
Physical exam 
X 
 
 
X 
ECG 
X 
 
X 
X 
Hgb/Hct 
X 
 
X 
X 
Troponin 
X 
Q 8 h 
X 
 
Platelet function testing 
X 
X 
 
 
Adverse Event assessment 
including chest pain score 
and number of antianginal 
medications 
 
X 
X 
X 
 
 
 

 
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