Pharmacological Effects of Crushing Prasugrel in STEMI Patients

Pharmacodynamic and Pharmacokinetic Profiles of Prasugrel in Patients With ST Elevation Myocardial Infarction: A Randomized Comparison of Standard Versus Crushed Formulation

Prasugrel has shown to be superior to clopidogrel, in adjunct to aspirin, in preventing recurrent ischemic events. Prasugrel is approved in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) at a dosage of 60 mg loading dose (LD) followed by 10 mg/day. However, a delay in the onset of its antiplatelet effects in this particular setting has been consistently shown. administration of clopidogrel and ticagrelor crushed tablets has been tested and a faster and greater bioavailability compared to the whole tablets has been observed. However, if the administration of a crushed prasugrel LD may overcome the above limitation is still unknown and represents the aim of our study. The proposed investigation will have a prospective, randomized, design in which STEMI patients undergoing primary PCI will be randomized to receive two different formulation of prasugrel LD (60 mg whole tablets and 60 mg crushed tablets). Pharmacodynamic testing will be performed at several time points to test our study hypothesis that crushed LD regiment will achieve more prompt and enhanced platelet inhibitory effects.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: prasugrel

Detailed Description

Dual antiplatelet therapy consisting of aspirin and a P2Y12 receptor antagonist is the cornerstone of treatment for prevention of thrombotic events in patients with acute coronary syndromes (ACS). Prasugrel, a third generation thienopyridine, is an orally administered prodrug that needs single-step hepatic biotransformation into its active metabolite to irreversibly block the P2Y12 receptor. Prasugrel has shown to be superior to clopidogrel, in adjunct to aspirin, in preventing recurrent ischemic events. Prasugrel is approved in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) at a dosage of 60 mg loading dose (LD) followed by 10 mg/day. However, a delay in the onset of its antiplatelet effects in this particular setting has been consistently shown. The STEMI setting is characterized by conditions, such as impaired absorption and hepatic metabolism, patients either intubated, in shock or unable to swallow, which may affect the pharmacoki¬netic and pharmacodynamic effects of orally administered antiplatelet drugs. The administration of clopidogrel and ticagrelor crushed tablets has been tested and a faster and greater bioavailability compared to the whole tablets has been observed. However, if the administration of a crushed prasugrel LD may overcome the above limitation is still unknown and represents the aim of our study. The proposed investigation will have a prospective, randomized, design in which STEMI patients undergoing primary PCI will be randomized to receive two different formulation of prasugrel LD (60 mg whole tablets and 60 mg crushed tablets). Pharmacodynamic testing will be performed at several time points to test our study hypothesis that crushed LD regiment will achieve more prompt and enhanced platelet inhibitory effects. This study will provide insights on the pharmacodynamic effects of crushed prasugrel LD and will help clinicians choose the most appropriate treatment to avoid complications related to inadequate platelet inhibition in the early phase of patients with STEMI undergoing primary PCI.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Patients with ST-elevation myocardial infarction undergoing primary PCI
• Age between 18 and 75 years old

Exclusion criteria:

• Age >75 years
• Weight <60 Kg
• On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) in past 7 days
• Known allergies to aspirin or prasugrel
• Considered at high risk for bleeding
• History of ischemic or hemorrhagic stroke or transient ischemic attack
• On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran, rivaroxaban, apixaban)
• Treatment with IIb/IIIa glycoprotein inhibitors
• Fibrinolytics within 24 hours
• Known blood dyscrasia or bleeding diathesis
• Known platelet count <80x106/mL
• Known hemoglobin <10 g/dL
• Active bleeding
• Hemodynamic instability
• Known creatinine clearance <30 mL/minute
• Known severe hepatic dysfunction

• Pregnant females*

  • Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prasugrel crush; Prasugrel 60mg loading dose as crushed tablets	Drug: prasugrel; the effects of whole tablets versus crushed tablets will be compared; Other Names: Effient
Active Comparator: Prasugrel tablets; Prasugrel 60 mg loading dose as whole tablets	Drug: prasugrel; the effects of whole tablets versus crushed tablets will be compared; Other Names: Effient

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
P2Y12 Reaction Units (PRU)	The primary end-point of the study is the comparison in platelet reactivity expressed as PRU determined by VerifyNow P2Y12 between prasugrel 60 mg and crushed prasugrel 60 mg at 2 hours after LD administration	2 hrs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet Reactivity Index (PRI)	The secondary end-point of the study is the comparison in platelet reactivity expressed as PRI determined by whole blood vasodilator-stimulated phosphoprotein (VASP) between prasugrel 60 mg and crushed prasugrel 60 mg at 2 hours after LD administration	2 hrs

Collaborators and Investigators

• Sponsor: University of Florida

Publications and helpful links

General Publications

• Rollini F, Franchi F, Hu J, Kureti M, Aggarwal N, Durairaj A, Park Y, Seawell M, Cox-Alomar P, Zenni MM, Guzman LA, Suryadevara S, Antoun P, Bass TA, Angiolillo DJ. Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention: The CRUSH Study. J Am Coll Cardiol. 2016 May 3;67(17):1994-2004. doi: 10.1016/j.jacc.2016.02.045. Epub 2016 Mar 21.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: August 6, 2014
• First Submitted That Met QC Criteria: August 6, 2014
• First Posted (Estimate): August 8, 2014

Study Record Updates

• Last Update Posted (Estimate): December 28, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: prasugrel; pharmacokinetic; pharmacodynamic; ST-elevation myocardial infarction
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Myocardial Infarction; Infarction; Coronary Artery Disease; ST Elevation Myocardial Infarction; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride
• Other Study ID Numbers: Prasugrel-CRUSH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO