A Randomized Controlled Trial of Patients Undergoing Percutaneous Coronary Intervention Who Receive Ticagrelor and Fentanyl
Phase: PHASE4
Conditions: Percutaneous Coronary Intervention
Sponsor: The Guthrie Clinic

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A Randomized Controlled Trial of patients undergoing Percutaneous Coronary 
Intervention who receive Ticagrelor and Fentanyl 
 
FACTPCI (Fentanyl and Crushed Ticagrelor PCI) trial 
 
 
Protocol dated October 28, 2019 
 
 
Principal Investigator: Sudhakar Sattur MD 
 
Sub-Investigators:  
Safi Khan MD, Abdel Rahman Omer MD, Daniel Sporn MD and Edo Kaluski MD. 
 
The Guthrie Clinic 
One Guthrie Square 
Sayre, PA  18840 
 
 
 
Background: 
Ticagrelor is an orally administered P2Y12 receptor antagonist in patients undergoing 
percutaneous coronary intervention (PCI).1 Ticagrelor inhibits platelet activation and 
aggregation. Fentanyl is routinely administered as conscious sedation during the PCI 
procedures. Recent studies have shown that Opioid analgesics delay P2Y12 receptor 
antagonist mediated platelet aggregation.2 Delay in platelet aggregation could lead to 
increased adverse events including stent thrombosis, myocardial infarction and death. In 
a recent trial, impact of Fentanyl on Ticagrelor mediated platelet aggregation was 
evaluated. 3 There was delayed platelet aggregation with increased adverse clinical 
events in patients receiving Fentanyl and Ticagrelor. This was felt to be related to 
decreased absorption of Ticagrelor leading to delayed platelet aggregation. However, a 
recent study showed that crushed Ticagrelor has more bioavailability and reaches peak 
earlier than oral Ticagrelor.4, 5 Based on these results, it could be hypothesized that 
crushed Ticagrelor might mitigate some of the ill effects of Fentanyl. Hence, we propose 
this trial to assess the impact of Fentanyl on platelet aggregation in patients receiving 
crushed Ticagrelor during PCI. 
 
 
Objective: 
The primary objective is to test the influence of Fentanyl on pharmacodynamics of 
crushed vs non-crushed ticagrelor in patients who are undergoing PCI. 
 
 
 
 

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Methods & design: 
Single center, randomized clinical trial designed to assess the influence of Fentanyl on 
pharmacodynamics of crushed vs non- crushed ticagrelor in patients undergoing PCI at 
Robert Packer Hospital. The plan is to enroll 80 patients in this study. Forty patients each 
in the elective and non-elective PCI groups.  Further In each group, patients will be 
randomized in a 1:1 ratio to either crushed or non-crushed Ticagrelor arms.  
 
 
 

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Inclusion criteria: 
• Patients ≥ 18 years of age 
• Undergoing clinically indicated elective or non-elective PCI 
• Able to swallow oral medications 
 
Exclusion criteria: 
• Contraindications to ticagrelor or fentanyl (or other opiates) 
• Pregnancy 
• Any us of P2Y12 inhibitors within 14 days 
• Known coagulation disorders 
• Pre-procedural treatment with an anticoagulant (oral anticoagulant or low 
molecular weight heparin) 
• Platelet count < 100,000/mm3 
• Impaired renal function (Estimated glomerular filtration < 45 ml/min/1.73 m2) 
• Impaired hepatic function (Based on medical history) 
• Prior or planned transcatheter aortic valve replacement 
  
Treatment protocol 
• All patients will be medicated with at least Fentanyl 25 mcg Intravenously prior to 
start of the procedure. Additional sedation will be at the discretion of the treating 
physician. 
• In the crushed Ticagrelor arm, subjects will receive 180 mg of crushed Ticagrelor, 
which will be crushed using EZY CRUSH pill crusher and mixed with 30 cc of 
drinking water, whereas patients in the other arm will receive an integral tablet of 
Ticagrelor loading dose (180 mg).  
• Platelet function testing (PFT) in each patient will be performed (platelet 
vasodilator-stimulated phosphoprotein assay, multiple electrode aggregometry, 
Verify Now assay).  
• The PFT will be performed at randomization, 30 mins, 2, 4, and 6-hour intervals 
from the time of Ticagrelor administration.  Blood (2cc filled completely) will be 
collected in blue top tubes (coag sodium citrate 3.29). The platelets must not be 
disturbed by jarring after collection.  The blood must not be shaken after collection, 
and it must be hand carried to the lab. At each sampling time point a second blue 
top tube will be collected for sampling assurance. The first sample at each time 
point will be processed.  If a testing error occurs the second sample will be 
processed for data purposes. 
• Patients will be treated according to current American Heart Association / 
American College of Cardiology guidelines.  
• The choice of the access of the procedure (radial or femoral) and the type of 
implanted stent will be at the discretion of the operator. 
• All patients will receive maintenance doses of ticagrelor (90 mg) twice daily post 

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PCI.  
 
Risks: 
It is expected that the risk of taking Ticagrelor crushed is the same as taking Ticagrelor 
not-crushed.  The crushed tablet may enter the blood stream faster.  There may be risks 
that are not known. The risks of Ticagrelor are provided in the package insert 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022433s020lbl.pdf 
 
Benefits: 
The potential benefit to patients is that crushed Ticagrelor may have more bioavailability 
and reach peak earlier than non-crushed Ticagrelor. Crushed Ticagrelor may be useful 
to use following conscious sedation with Fentanyl, and may counter the delay in P2Y12 
receptor antagonist mediated platelet aggregation that is associated with Fentanyl.  
Improved inhibition of platelet aggregation may lead to reduced adverse events 
including stent thrombosis, myocardial infarction and death. 
For patients who are randomized to receive the non-crushed Ticagrelor, there is no 
anticipated benefit as this would be what is routinely done. 
Study endpoints:  
• The primary endpoint is the area under the PFT-time curve (AUC (0–6)) for the 
first 6 hours after the loading dose of Ticagrelor 
• The secondary end points at discharge and 30 days are as follows - 
o Stent thrombosis  
o Recurrent myocardial infarction 
o All-cause mortality 
o Stroke 
o TIMI minor and major  
Data Collection: 
Information regarding patient characteristics will be obtained from the electronic medical 
record.  Data will include: medical record number; age; sex; race; BMI; and medical 
history; date of PCI; radial or femoral access of the procedure; type of implanted stent; 
crushed or non-crushed ticagrelor; platelet function testing at baseline, 30 min, 2, 4,and 
6, hours.  Data will be collected at discharge and 30 days to include events of: stent 
thrombosis, recurrent myocardial infarction, all-cause mortality, stroke, or TIMI. 
 
Statistics  
• All continuous data will be expressed as mean ± standard deviation and compared 

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using a two-tailed Student’s t-test when appropriate or the Mann–Whitney U test.  
• Categorical variables will be expressed as a percentage and compared using chi-
square or Fisher’s exact test when appropriate.  
 
Discussion:  
This study is expected to provide crucial data on the influence of Fentanyl on crushed vs 
non-crushed Ticagrelor associated platelet function in patients undergoing PCI. The 
findings of this study would have a major impact on clinical practice as Fentanyl is 
currently used as sedation in more than 95% of patients undergoing PCI. 
 
 
 
References: 
 
1. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat 
Rev Cardiol. 2015;12:30-47.  
2. Rollini F, Franchi F. The Conundrum of Platelet P2Y12 Inhibition in ST-Segment 
Elevation Myocardial Infarction. Circ J. 2016;80:2429-2431.  
3. McEvoy et al. Effect of Intravenous Fentanyl on Ticagrelor Absorption and Platelet 
Inhibition Among Patients Undergoing Percutaneous Coronary Intervention: The 
PACIFY Randomized Clinical Trial. Circulation. 2017;CIRCULATIONAHA.117.031678 
4.  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 Interv 
Cardiol 22:385–389. 
5.  Teng R., Carlson G., Hsia J. (2014) Crushing ticagrelor tablets accelerates exposure 
compared with intact tablets (abstr). J Am Coll Cardiol 63(Suppl 12):A229. 
 
6.  Ibrahim K, Goli R, Shah R, Resar J, Schulman S, McEvoy J (2018) Effect of 
intravenous fentanyl on ticagrelor absorption and platelet inhibition among patients 
undergoing percutaneous coronary intervention: Design, rationale, and sample 
characteristics of the PACIFY randomized trial. Contemporary Clinical Trials 64: 8-12.