Effect of Chewing Vs Swallowing Ticagrelor On

STUDY PROTOCOL

Chewing versus Traditional Oral Administration of Ticagrelor in ST-elevation Myocardial Infarction - A Platelet Reactivity Study

PRINCIPAL INVESTIGATOR:

Elad Asher, M.D, M.H.A Interventional Cardiologist, CICU Leviev Heart Center, Sheba Medical Center, Tel Hashomer 52621 , Israel

M: +972-526-667131 P: +972-3-5302504 F: +972-3-5302171 [email protected] [email protected]

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Background The P2Y12-receptor amplifies platelet activation in response to ADP (1). Dual anti-platelet therapy (DAPT) with a P2Y12-receptor antagonist and aspirin is the standard of care for the treatment of ischemic patients (2-5). The co- administration of a P2Y12-receptor inhibitor and aspirin reduces platelet reactivity to a greater extent than each drug can achieve separately (6-7). Clopidogrel is a second-generation thienopyridine. It is orally administered, and requires two metabolic transformations to effect platelets (8). The third- generation thienopyridine prasugrel is also a prodrug, but requires only a single- step oxidation in the liver by CYP to become active (9). The metabolic conversion of prasugrel is more efficient, and results in higher in vivo availability (10). Ticagrelor is also administrated orally but in contrast to clopidogrel and prasugrel is not a prodrug and hence does not require activation (9). Ticagrelor directly inhibits the platelet P2Y12-receptor through allosteric modulation (9). In the PLATO trial, ticagrelor therapy was also superior to clopidogrel treatment in patients with recurrent cardiovascular events, STEMI, diabetes mellitus, chronic kidney disease, with or without loss-of-function polymorphisms in CYP2C19, aged >75 years, with a body mass <60 kg, and with a history of stroke or transient ischemic attack (11-14). In order to further achieve platelets inhibition a recent trial has evaluate the superiority of ticagrelor 180 mg LD crushed pills versus integral tables of equal dose in decreasing residual platelet reactivity 1 hour after the administration in ST elevation myocardial infarction patients (15). However, no trial has evaluated the efficacy of ticagrelor administrated sub lingual in ACS patients.

Objective To examine chewing versus traditional oral administration of ticagrelor in ST- elevation Myocardial Infarction (STEMI) patients on platelet reactivity.

Design The proposed study is a randomized-controlled, conducted among STEMI patients treated with ticagrelor. All patients will be treated with ticagrelor

Downloaded From: https://jamanetwork.com/ on 09/25/2021 loading dose (180 mg/day) and aspirin (100mg/day) according to the contemporary guidelines for treating STEMI. Eligible patients will be recruited during hospitalization due to STEMI.

Inclusion Criteria: 1. Patients presenting with STEMI 2. Informed, written consent

Exclusion Criteria: 1. Age < 18 years or Age > 90 years 2. Active bleeding; bleeding diathesis; coagulopathy 3. Increased risk of bradycardic events 4. History of gastrointestinal or genitourinary bleeding <2 months 5. Major surgery in the last 6 weeks 6. History of intracranial bleeding or structural abnormalities 7. Suspected aortic dissection 8. Any other condition that may put the patient at risk or influence study results or investigator's opinion (severe hemodynamic instability, unconsciousness, known malignancies or other comorbid conditions with life expectancy <1 year) 9. Administration in the week before the index event of clopidogrel, ticlopidine, prasugrel, ticagrelor, thrombolytics, bivalirudin, low-molecular weight heparin or fondaparinux. 10. Concomitant oral or IV therapy with strong CYP3A inhibitors or strong CYP3A inducers, CYP3A with narrow therapeutic windows 11. Known relevant hematological deviations: Hb <10 g/dl, PLT<100x10^9/l 12. Use of coumadin derivatives within the last 7 days 13. Chronic therapy with ticagrelor, prasugrel, clopidogrel or ticlopidine 14. Known severe liver disease, severe renal failure 15. Known allergy to the study medications 16. Pregnancy 17. Human immunodeficiency virus treatment 18. The use of IIBIIIA receptor antagonists in the 48 hours before enrollment (if abciximab use then in the last 14 days).

Downloaded From: https://jamanetwork.com/ on 09/25/2021 19. If the patients cannot sign percutaneous coronary intervention (PCI) informed consent for any reason.

Baseline characteristics and in-hospital therapy will be recorded, including, comorbidities, medications, clinical presentation, ECG data, blood test results including troponin and CPK levels, hemoglobin and renal function test, angiographic characteristics and therapy and in-hospital events such as arrhythmias, heart failure, recurrent ischemia and bleeding.

Randomization will be performed on admission. Patients will be randomized to receive loading dose of either 180mg chewing ticagrelor or 180mg orally ticagrelor. Platelet reactivity will be assessed during hospitalization [during enrollment at 30 min, 1 hour (or before administration of IIBIIIA inhibitors during percutaneous coronary intervention-PCI), 4-6 hours following initiation of ticagrelor therapy (or after 48 hours if IIBIIIA inhibitors were administrated during percutaneous coronary intervention)]. Patients will then receive oral ticagrelor (90mg bid) without any interruption for the entire study period.

Patients will be followed up by telephone/clinic at 30 days

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Study Flow-chart

* Or before administration of IIBIIIA inhibitors during percutaneous coronary intervention.

** Or after 48 hours if IIBIIIA inhibitors were administrated during percutaneous coronary intervention.

Platelet function tests will include: Platelet reactivity with the VerifyNow® PRUTest™ Accumetrics

End-points Primary Outcome Measures: Residual platelet reactivity by Platelet Reactivity Units (PRU) VerifyNow 1 hour after ticagrelor loading dose (LD).

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Secondary Outcome Measures: 1. The percent of patients with a high residual platelet reactivity (PRU > 208) 30 min, 1 hour and 4-6 hours after ticagrelor LD. 2. Bleeding events: Major, minor, minimal bleeding (TIMI criteria) events. 3. Occurrence of dyspnea and/or symptomatic bradycardia. 4. Major adverse cardiac and cerebrovascular event (MACCE) rate at 30 days (Death, Myocardial infarction, Urgent revascularization, Cerebrovascular accident). 5. Stent Thrombosis rate at 30-day.

Estimated Enrollment: 100 patients.

Statistical Analysis The primary and secondary endpoints of the study will be assessed by treatment allocation on an intention-to-treat basis. The required sample size is based on the primary end point of the study, with the use of a meaningful difference between sublingual and oralloading dose groups of one standard deviation from mean baseline values. Using a 1:1 randmization design, a total of 100 patients will be required to obtain at least 80% power and a 5% one-sided type I error , assuming ≤15% withdrawal rate following enrollment. Student’s t-test will be used to test for a difference in prespecified endpoints between the 2 randomized groups in an intention-to-treat bassis. In the analysis, if the assumption of normality is violated, a nonparametric test (Mann–Whitney test or Wilcoxon signed-rank test) will be performed. The effect of treatment allocation on the clinical secondary end points will be assessed using Cox proportional hazards regression analysis.

Downloaded From: https://jamanetwork.com/ on 09/25/2021

References 1. Storey, R. F., Newby, L. J. & Heptinstall, S. Effects of P2Y1 and P2Y12 receptor antagonists on platelet aggregation induced by different agonists in human whole blood. Platelets 12, 443–447 (2001). 2. Anderson, J. L. et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non‑ST‑elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 61, e179–e347 (2013). 3. O’Gara, P. T. et al. 2013 ACCF/AHA guideline for the management of ST‑ elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 61, e78–e140 (2013). 4. Hamm, C. W. et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST‑segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST‑segment elevation of the European Society of Cardiology (ESC). Eur. Heart J. 32, 2999–3054 (2011). 5. Steg, P. G. et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST‑segment elevation: Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur. Heart J. 33, 2569–2619 (2012). 6. Cadroy, Y. et al. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation 101, 2823–2828 (2000). 7. Altman, R., Scazziota, A., Rouvier, J. & Gonzalez, C. Effects of ticlopidine or ticlopidine plus aspirin on platelet aggregation and ATP release in normal volunteers: why aspirin improves ticlopidine antiplatelet activity. Clin. Appl. Thromb. Hemost. 5, 243–246 (1999).

Downloaded From: https://jamanetwork.com/ on 09/25/2021 8. Angiolillo, D. J. The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs 72, 2087–2116 (2012). 9. Ferreiro, J. L. & Angiolillo, D. J. New directions in antiplatelet therapy. Circ. Cardiovasc. Interv. 5, 433–445 (2012). 10. Sugidachi, A. et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite. J. Thromb. Haemost. 5, 1545–1551 (2007). 11. Kohli, P. et al. Reduction in first and recurrent cardiovascular events with ticagrelor compared with clopidogrel in the PLATO study. Circulation 127, 673– 680 (2013). 12. Steg, P. G. et al. Ticagrelor versus clopidogrel in patients with ST‑elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation 122, 2131–2141 (2010). 13. James, S. et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Eur. Heart J. 31, 3006–3016 (2010). 14. James, S. et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 122, 1056–1067 (2010). 15. Parodi G, Xanthopoulou I, Bellandi B. et al. Ticagrelor Crushed Tablets Administration in STEMI patients: The Mashed Or Just Integral Tablets of ticagrelOr (MOJITO) study (ECS 2014).

Downloaded From: https://jamanetwork.com/ on 09/25/2021