Clinical trial NCT03708588
Conditions: Percutaneous Coronary Intervention
Keywords: Ticagrelor Stent
Sponsor: Wake Forest University Health Sciences
Start date: 2018-09-19; Completion date: 2021-07-31
Enrollment: 112 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Hypothesis The primary question the investigators propose to answer is whether all patients undergoing percutaneous coronary intervention (PCI) with stent deployment who receive chewed ticagrelor will demonstrate more rapid drug absorption and decreased platelet reactivity as compared to integral pill form 1 hour after drug administration.

Detailed description:
Hypothesis The primary question the investigators propose to answer is whether all patients undergoing PCI with stent deployment who receive chewed ticagrelor will demonstrate more rapid drug absorption and decreased platelet reactivity as compared to integral pill form 1 hour after drug administration.

Secondary Hypotheses:

1. Major adverse cardiac and cerebrovascular event (MACCE) rate at 30 days and 1 year.

   1. Death
   2. Repeat myocardial infarction
   3. Need for urgent revascularization
   4. Cerebrovascular accident
2. Rate of stent thrombosis and in-stent stenosis at 30 days and 1 year.
3. Bleeding: Defined as major, minor, or minimal bleeding based on thrombolysis in myocardial infarction (TIMI) criteria.

Arms: arm 1: Drug: Ticagrelor chewed pills. The loading dose will be administered as soon as possible by Catheterization Lab staff after a baseline P2Y12 platelet reaction units (PRU) level is drawn and before the end of the PCI. Patients will be asked to chew, but not swallow, allowing for sublingual absorption. (Loading dose 180mg) arm 2: Drug: Ticagrelor integral pills. The loading dose will be administered as soon as possible by Catheterization Lab staff after a baseline P2Y12 platelet reaction units (PRU) level is drawn and before the end of the PCI. Patients will swallow the loading dose followed by 25-50mL (milliliter) of water. (180mg)
Interventions: intervention 1: Ticagrelor intervention 2: Ticagrelor
Intervention descriptions: intervention 1: Chewed intervention 2: Integral

Protocol documents:
Prot_SAP_000.pdf: 
Version date: 8 OCT2020 
Page 1 
 
Cover Page 
 
Study Title:  Chewed versus integral pill of ticagrelor in in selected patients undergoing 
coronary angiography --a platelet reactivity study and patient outcomes study. 
NCT number:  NCT03708588 
Document/version date: 10/08/2020 


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Project title: Chewed versus integral pill of ticagrelor in in selected patients undergoing 
coronary angiography --a platelet reactivity study and patient outcomes study. 
Principal Investigator: Suhail Allaqaband, MD 
Adress: 2801 W. Kinnickinnic River Parkway,    Suite 440,  Milwaukee, WI 53215 
Phone: (414) 649-3491    
 
Email: Suhail.allaqaband@aurora.org 
 
Lead Fellow: Thomas Wilson, MD 
 
BACKGROUND 
Patients with acute coronary syndrome (ACS) and stable coronary artery disease usually 
require percutaneous coronary intervention (PCI) with stent deployment to open stenosed 
or occluded coronary arteries. Ticagrelor (Brilinta) is an orally administered third 
generation thienopyridine and reversible P2Y12 receptor antagonist and has been shown 
to improve patient outcomes as compared to other anti platelet medications. In the PLATO 
trial published in 2009, for example, patients with ACS treated with ticagrelor experienced a 
significantly lower rate of death, repeat myocardial infarction, and stroke. 
Despite advancements in medical therapy, studies have demonstrated delayed antiplatelet 
effects of oral P2Y12 inhibitors and higher than expected platelet reactivity hours after drug 
administration.  Due to elevated risk of peri-procedural thrombotic events in patients 
undergoing PCI, the goal of achieving platelet inhibition more rapidly should be addressed. 
The delayed antiplatelet effects of medications like ticagrelor are likely related to impaired 
drug absorption.  Many patients presenting with acute coronary syndromes have decreased 
gastrointestinal motility.  Additionally, if morphine is administered by medical providers for 
chest pain absorption of antiplatelet medications such as ticagrelor may be delayed.  
Research performed to date has demonstrated more rapid absorption and platelet inhibition 
when ticagrelor is administered in crushed or chewed form to patients with ST segment 
elevation MI (STEMI) 
In December 2017, a trial compared a chewed sublingual form of ticagrelor to standard pill 
form in patients with STEMI.  It also showed more rapid absorption and platelet inhibition 
within hours of drug administration.  To our knowledge, our study will be the first to 
compare platelet reactivity in non ST segment elevation acute coronary syndrome (NSTE-
ACS) and patients with stable CAD undergoing PCI who received chewed ticagrelor. 


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Specific Aims:  
To compare the effect of ticagrelor chewed pills with the effect of equal dose of integral pills in 
decreasing platelet reactivity and adverse event rates in all patients being treated for NSTE-ACS 
and stable coronary artery disease, undergoing percutaneous coronary intervention. 
Primary objective:  
Determine platelet inhibition at baseline, and early at 1 hour and 4 hours after loading dose.  
Secondary objective:  
Assess major adverse cardiac and cerebrovascular event (MACCE) rate at 30 days and 1 
year. 
1. Death; 
2. Repeat myocardial infarction; 
3. Need for urgent revascularization; 
4. Cerebrovascular accident;  
5. Rate of stent thrombosis and in-stent stenosis at 30 days and 1 year; 
6. Bleeding: Defined as major, minor, or minimal bleeding based on TIMI criteria. 
Hypothesis:  
Chewed ticagrelor pill is superior to integral pill in decreasing platelet reactivity. 
Primary Outcome Measures: 
Residual platelet reactivity by Platelet Reactivity Units (PRU) VerifyNow 1 hour and 4 hours 
after ticagrelor loading dose (LD) and percent of patients with a high residual platelet reactivity 
(PRU > 208) 1 hour and 4 hours after ticagrelor LD. 
Secondary Outcome Measures: 
1. Bleeding events: Major, minor, minimal bleeding (TIMI criteria) events. 
2. Occurrence of dyspnea and/or symptomatic bradycardia. 
3. Major adverse cardiac and cerebrovascular event (MACCE) rate: Death, Myocardial 
infarction, Stent Thrombosis, Urgent revascularization, Cerebrovascular accident at 30 
days and 1 year. 


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STUDY DESIGN 
This will be an interventional study to evaluate the superiority of chewed ticagrelor in 
comparison to integral pill form.  Superiority will be defined as a reduction of platelet 
reactivity in both groups undergoing PCI. 
Study population will include 132 patients.  They will be stratified into 2 groups: Patients with 
NSTE-ACS and patients with stable coronary artery disease (CAD) undergoing coronary 
angiography for non-urgent reasons. 
Inclusion criteria: 
1. Patients presenting with NSTEMI-ACS or stable CAD undergoing coronary 
angiography for urgent or non-urgent reasons.  
Exclusion criteria: 
1. Age <18 years or Age >90 years; 
2. Known coagulopathy, bleeding diathesis, or active bleeding; 
3. Known chronic therapy with clopidogrel, prasugrel, or ticagrelor; 
4. Known history of intracranial bleed or intracranial neoplasm; 
5. Suspected aortic dissection; 
6. Severe hemodynamic instability, cardiogenic shock; 
7. Life expectancy <1 year; 
8. Known severe liver or renal disease (CrCl < 30, or dialysis dependent); 
9. Taking drugs known to interfere with CYP3A4 metabolism (Azoles, Clarithromycin, 
Ritonavir, Saquinavir, Nelfinavir, Indinavir, Atazanavir); 
10. Any use of GP llb-llla inhibitors 48-hours before the procedure or any use during the 
procedure; 
11. Any use of Cangrelor during or after the procedure; 
12. Hemoglobin <10 g/dL, PLT <80x10"9/L; 
13. Pregnant or lactating females; 


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14. Known allergy to study medication; 
15. Fibrinolytic use within past 48 hours; 
16. Inability to give consent; 
17. Known sick sinus syndrome (SSS) or high degree AV block without pacemaker 
protection. 
Written informed consent:  
Patients presenting for both urgent and elective left heart catheterization will be consented 
by the personnel delegated by the investigator before any study-related activity.  
Randomization: 
Patients will be randomized prior to PCI.  Patients from each strata (NSTE—ACS, and 
patients with stable CAD) will be randomized in a 1:1 fashion to receive a loading dose of 
180mg ticagrelor in integral pill form (swallowed) or chewed form. 
Study procedures:  
Patients admitted to the inpatient cardiology service with NSTE-ACS meeting eligibility 
criteria are often treated medically before reaching the catheterization suite for coronary 
angiography and possible percutaneous coronary intervention. These patients often receive 
the loading dose of 180mg ticagrelor on the medical floor. In order to enroll these patients, 
the baseline PRU level blood draw, can be obtained on the floor before that loading dose is 
administered. The subsequent 1-hour and 4-hour blood draws can be obtained on the 
medical floor or in catheterization suite.  
Patients scheduled to undergo and elective (non-urgent) coronary angiography for stable 
CAD who meet eligibility criteria will have blood drawn for a baseline PRU level prior to 
administration of the study drug.  After the procedure, two subsequent blood draws will be 
taken at precise times: 1 hour +/-60 minutes, and 4 hours +/- 90 minutes after loading dose 
administration.  All other procedures are considered standard of care. 
 
Arm 
Intervention/Treatment 
Arm One: Chewed 
ticagrelor pills (Loading 
dose 180mg) 
Drug: Ticagrelor chewed pills.  The loading dose will be administered 
as soon as possible by hospital floor nurse or Catheterization Lab 
staff after a baseline PRU level is drawn.Patients will be asked to 


Version date: 8 OCT2020 
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chew and swallow followed by 25-50mL of water. 
Arm Two: Integral pill 
form of ticagrelor 
(Loading dose 180mg) 
Drug: Ticagrelor integral pills.  The loading dose will be administered 
as soon as possible by hospital floor nurse or Catheterization Lab 
staff after a baseline PRU level is drawn. and before the end of the 
PCI.  Patients will swallow the loading dose followed by 25-50mL of 
water. 
 
Subject will have orders to continuing ticagrelor during admission status. After the 4th hour 
blood draw the primary outcome will be complete.  Patients will be encouraged to remain on 
ticagrelor with an outpatient prescription to measure secondary outcomes.    


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Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
Patient’s EMR will be reviewed at 30 days and at 1 year to document any primary or 
secondary outcome measures. Duration of the study is one year.  
Patients undergoing coronary angiography for NSTE-ACS 
or Stable CAD. 
NSTE--ACS patients 
Stable CAD 
Arm1: Chewed 
ticagrelor pills 
(Loading dose 
180mg) 
Arm 2: Integral pill 
form of ticagrelor 
(180mg) 
Arm 1: Chewed 
ticagrelor pills 
(Loading dose 
180mg) 
Arm 2: Integral pill 
form of ticagrelor 
(180mg) 


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Data collection 
Baseline Characteristics 
Gender  
 
Body mass index, kg/m2 
Current smoker 
 
Hypertension 
 
Diabetes mellitus  
Dyslipidemia 
 
Prior coronary artery 
disease 
Prior aspirin 
 
Prior beta-
blockers 
 
Prior statins 
 
LVEF (%) 
 
Creatinine clearance, 
mL/min 
Hemoglobin 
(gr/dl) 
 
Platelet count, 1,000/mm3 
Low-density lipoprotein 
(mg/dl) 
High-density lipoprotein 
(mg/dl) 
 
Procedure Related 
information 
Post-procedure Related 
Information 
Consenting 
Randomization 
Baseline PRU test 
Loading dose administration 
Access (femoral, Radial) 
Start catheterization 
Culprit vessel 
Type of stent 
Number of stents 
Fluoro time/dose 
Contrast volume 
Narcotic use 
 
PRU 1 hour  
PRU 4 hours  
Length of stay 
Date of death 
Repeat MI 
Stent thrombosis 30 
days 
CVA 
Urgent 
Revascularization 
 
TIMI Minimal bleeding 
TIMI Minor bleeding 
TIMI Major bleeding 
Access site 
complication 
(hematoma, 
pseudoaneurysm, need 
for surgical or 
percutaneous repair) 
 
 
 
Data will be collected by the personnel delegated by the PI. Preliminary data will be 
analyzed after enrollment of 65 patients. 


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Page 10 
 
Timeline /Schedule of events 
 
Visit 1  
 
Baseline 
Visit 2  
 
Procedure 
Visit 3     
 
Post 
Procedure 
Visit 4 
 
Discharge 
Visit 5          
30 day follow 
up- 
(+/- 14 d) 
 
EMR-Chart 
review 
Visit 6         
1 yr follow up- 
(+/- 14 d) 
 
EMR-Chart 
review 
Inclusion/  
Exclusion 
X 
 
 
 
 
 
Informed 
Consent 
Obtained 
X 
 
 
 
 
 
Demographics, 
Medical 
History,       
Con Meds 
X 
 
 
 
 
 
Angiography 
/PCI Procedure 
 
X 
 
 
 
 
Blood draw for 
PRU 
X 
baseline, 
1-hour 
and 4-
hour 
levels can 
be 
collected 
before 
coronary 
angiograp
hy for 
patients 
admitted 
to  
hospital 
floor 
X  
1 h after 
PCI 
4h after 
PCI 
 
 
 


Version date: 8 OCT2020 
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before 
procedure 
MAACE  Event 
documentation 
 
 
 
X 
X 
X 
 
 
 


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Statistical Analysis 
Patient characteristics will be presented as proportions for categorical variables and mean ± 
standard deviation (SD) and or Median [lower quartile (01) - upper quartile (03)] for 
continuous variables.  Comparison of categorical variables for patients who will receive 
integral pill form of ticagrelor and the other the chewed form will be performed using the 
chi-square and Fisher's exact test while the two sample t test will be done to assess 
differences in continuous patient characteristics.  Visual displays of event free Survival and 
cumulative incidence curves will be generated by the Kaplan-Meier approach and event free 
survival among groups compared using the log rank test.  In addition to time point analysis, 
an alternating logistic regression (ALR) will be fitted to evaluate P2Y12 reaction units 
(PRU) levels at baseline (before LD), 1 hour, and 4 hours.  Further analysis will entail fitting 
both univariate and multivariate Cox proportional-hazards models to examine the 
association between baseline characteristics and each of outcomes: In-stent thrombosis and 
restenosis, MACCE, and the need for repeat revascularization within 1-year separately.  All 
analyses will be done using SAS Version 9.4 (SAS Institute, Cary, NC) and tests performed 
at a 5% level of significance. 
Monitoring Plan  
The goal of monitoring in this study is primarily to make sure that the primary data are collected 
and recorded properly and consenting process was done.  
The Principal Investigator will be responsible for monitoring the safety environment of the 
participants, and will ensure that   
a) Only subjects who meet the study eligibility criteria will be enrolled. All subject 
inclusion/exclusion criteria were reviewed and verified with source documents, when 
applicable. 
b) The informed consent process will be obtained prior to proceeding with any study 
procedures.  Any problems with informed consent will also be documented, and reported to 
the IRB, if required. 
c) Data is collected and analyzed as specified in the protocol. 
d) Adverse events are reviewed promptly and reported as required. 
e) Privacy and confidentiality of subjects is maintained.  Consent forms will be stored in a 
room accessible only to research personnel.  
f) Subject withdrawals will be documented for the reason of withdrawal.  
g) Subjects will be informed during the informed consent process that study results may be 
disseminated in the form of presentations at conferences and publications in journals. The 
data/results that will be presented will only include anonymous/aggregate data,nothing that 
will identify subjects. 
h) A regulatory binder will be kept to document: IRB approvals, protocol versions, informed 
consents (all versions), all formal communications with the IRB (approval letters, 


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acknowledgements), Delegation of Authority Log. 
 
This study will be listed on ClinicalTrials.gov prior to enrollment of subjects. 
https://clinicaltrials.gov/ct2/manage-recs/fdaaa  
 
Human Protections 
This prospective randomized trial may require patients to undergo additional lab draws 
at intervals described above if samples cannot be taken from peripheral intravenous (IV) 
lines already in place. Risks associated with lab draws include, but are not limited to, 
bleeding, infection, and patient discomfort. Highly trained technicians will be drawing 
blood, if required, to mitigate the risks described above. Breaching patient 
confidentiality will be minimized by storing subject information in password-protected 
devices and by limiting access to data to those named on the IRB form. Additionally, data 
will be reported in aggregate form only. 
Dissemination and Future Funding Plan 
Results of the study will be submitted to multiple peer-reviewed journals for review.  No 
study of this kind known at the time of submission has compared to platelet reactivity and 
patient outcomes in NSTE-ACS and patients with stable CAD undergoing percutaneous 
coronary intervention (PCI).  Potential targets for publication include, but are not limited to, 
the journal of the American College of Cardiology, European Heart Journal, Circulation, and 
the Journal of interventional Cardiology. 
References 
D. Lindholm, C. Varenhorst, et al. Ticagrelor vs. clopidogrel in patients with non-ST-elevation 
acute coronary syndrome with or without revascularization: results from the PLATO trial. 
European Heart Journal, Volume 35, Issue 31, 14 August 2014, Pages 2083-2093. 
L. Wallentin, R. Becker, et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary 
Syndromes. New England Journal of Medicine 2009; 361: 1045-1057, September 10, 2009. 
A.A Heestermans, J.W. van Werkum, D. Taubert, et al. Impaired bioavailabiHty of clopidogrel in 
patients with a ST-segment elevation myocardial infarction. Thromb Res, 122 (2008), pp. 776-781 
Teng R., Carlson G., Hsia J. (2014) Crushing ticagrelor tablets accelerates exposure compared with 
intact tablets (abstr). J Am Coll Cardiel 63(Suppl 12):A22 


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G. Parodi, B. Bellandi, I. Xanthopoulou, et al. Morphine is associated with a delayed activity of 
oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing 
primary percutaneous coronary intervention. Circ Cardiovasc lnterv, 8 (2014), p. e001593 
G. Parod,i I. Xanthopoulou, 8. Bellandi, et al. Ticagrelor crushed tablets administration in STEMI 
patients: the MOJITO study. J Am Coll Cardiol, 65 (2015), pp. 511-512 
Asher E, Tai S, Mazin I, et al. Effect of Chewing vs Swallowing Ticagrelor on Platelet Inhibition in 
Patients Wrth ST-Segment Elevation Myocardial Infarction A Randomized Clinical Trial. JAMA 
Cardiol. 2017;2(12):1380-1384. Doi:10.1001/jamacardio.2017.3868 
Zafar M.U., Farkouh M.E., Fuster V., et al. (2009) Crushed clopidogrel administered via nasogastric 
tube has faster and greater absorption than oral whole tablets. J lnterv Cardiol 22:385-389. 
Crean B., Finnie C., Crosby A. (2013) Evaluation of crushed ticagrelor tablet doses: recovery 
following crushing and naso-gastric tube passage ex vivo. Drugs 13:153-157. 
Parodi G., Valenti R., Bellandi 8., et al. (2013) Comparison of prasugrel and ticagrelor loading 
doses in ST- segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet 
Inhibitor Drugs) primary PCI study. J Am Coll Cardiol 61:1601-1606. 
D. Alexopoulos, V. Gkizas, S. Patsilinakos, et al. Double versus standard loading dose of ticagrelor: 
onset of antiplatelet action in patients with STEM! undergoing primary PCI. J Am Coll Cardiel, 62 
(2013), pp. 940-941. 
D. Alexopoulos, N. Barampoutis, V. Gkizas, et al. Crushed versus integral tablets of ticagrelor in 
ST-segment elevation myocardial infarction patients: a randomized 
pharmacokinetic/pharmacodynamic study. Clin Pharmacokinet, 55 (2016), pp. 359-367.