A Pharmacodynamic Study Comparing Prasugrel Versus Ticagrelor in Patients Undergoing PCI With CYP2C19 Loss-of-function:

A Pharmacodynamic Study Comparing Prasugrel Versus Ticagrelor in Patients With Coronary Artery Disease Undergoing PCI With CYP2C19 Loss-of-function Genotypes: A Feasibility Study With Point-of-care Pharmacodynamic and Genetic Testing

Numerous studies have shown that pharmacodynamics (PD) response profiles vary among clopidogrel treated patients and that individuals with reduced response have an increased risk of recurrent ischemic events. There are multiple factors contributing to clopidogrel response variability, including genetic variations of the cytochrome P450 (CYP) 2C19 enzyme. In particular, loss-of-function (LOF) alleles of the CYP2C19 enzyme reduce transformation of clopidogrel pro-drug into its active metabolite. Thus, patients carrying LOF alleles have lower levels of clopidogrel's active metabolite as well as diminished platelet inhibition, which translates into an increased rate of adverse cardiovascular events, particularly in the setting of percutaneous coronary intervention (PCI). Prasugrel and ticagrelor are novel generation P2Y12 receptor inhibitors characterized by greater PD potency and reduced ischemic event rates compared with clopidogrel, and are not affected by CYP2C19 LOF polymorphisms. However, to date there are limited head-to-head PD comparisons between these two new P2Y12 receptors blockers, and there are no studies assessing on how these agents behave among CYP2C19 LOF carriers. The aim of the present study is to compare the PD effects of prasugrel versus ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles using the novel point-of-care genetic testing Spartan RX-CYP2C19 which permits accurate and rapid identification of CYP2C19 genetic status.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Prasugrel; Drug: Ticagrelor

Detailed Description

Clopidogrel is the most broadly utilized platelet P2Y12 receptor inhibitor. However, numerous studies have shown that pharmacodynamics (PD) response profiles vary among clopidogrel treated patients and that individuals with reduced response have an increased risk of recurrent ischemic events. There are multiple factors contributing to clopidogrel response variability. Among these, genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key contributor to clopidogrel metabolism, have been involved. In particular, loss-of-function (LOF) alleles of the CYP2C19 enzyme reduce transformation of clopidogrel pro-drug into its active metabolite. Thus, patients carrying LOF alleles have lower levels of clopidogrel's active metabolite as well as diminished platelet inhibition, which translates into an increased rate of adverse cardiovascular events, particularly in the setting of percutaneous coronary intervention (PCI). Because of these findings, drug regulating authorities have provided a boxed warning on the product label of clopidogrel on the potential for reduced efficacy of clopidogrel among CYP2C19 LOF carriers and suggested considering alternative antiplatelet therapies for these individuals. Prasugrel and ticagrelor are novel generation P2Y12 receptor inhibitors characterized by greater PD potency and reduced ischemic event rates compared with clopidogrel, and are not affected by CYP2C19 LOF polymorphisms. However, to date there are limited head-to-head PD comparisons between these two new P2Y12 receptors blockers, and there are no studies assessing on how these agents behave among CYP2C19 LOF carriers. Tailoring antiplatelet therapy according to results of genetic testing has been limited in real world clinical practice because of not having readily accessible results of individual's genetic makeup. The aim of the present study is to compare the PD effects of prasugrel versus ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles using the novel point-of-care genetic testing Spartan RX-CYP2C19 which permits accurate and rapid identification of CYP2C19 genetic status.

• Study Type: Interventional
• Enrollment (Actual): 65
• 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 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• Inclusion criteria:

  1. Patients scheduled for left heart catheterization and undergoing PCI
  2. Age 18-75 years
  3. On aspirin (81mg) or aspirin (81mg) and clopidogrel (75mg/day)
  4. Presence of at least one 2C19 LOF allele

• Exclusion criteria:

  1. Known allergies to aspirin, prasugrel, ticagrelor, or clopidogrel
  2. Age >75 years
  3. Weight <60kg
  4. Considered at high risk for bleeding
  5. History of ischemic or hemorrhagic stroke or transient ischemic attack
  6. Known severe hepatic dysfunction
  7. On treatment with oral anticoagulant therapy (Vitamin K antagonists, dabigatran, apixaban, rivaroxaban)
  8. Use of glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban)
  9. Blood dyscrasia or bleeding diathesis
  10. Platelet count <80x106/mL
  11. Hemoglobin <10 g/dL.
  12. Active bleeding or hemodynamic instability
  13. Creatinine Clearance <30 mL/minute
  14. Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection.
  15. Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with Ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin.
  16. 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 Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ticagrelor; The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers.	Drug: Prasugrel; Comparison of platelet reactivity between prasugrel and ticagrelor; Other Names: Effient
Experimental: Prasugrel; The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers.	Drug: Ticagrelor; Comparison of platelet reactivity between prasugrel and ticagrelor; Other Names: Brilinta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet Reactivity	The primary endpoint is P2Y12 reaction unit (PRU) measured by the Verify Now P2Y12 assay 24hours/hospital discharge post randomization to prasugrel vs ticagrelor. PRU is is an arbitrary unit of measure to assess ADP-induced platelet aggregation.	24 hours post loading dose

Collaborators and Investigators

• Sponsor: University of Florida

Publications and helpful links

General Publications

• Franchi F, Rollini F, Rivas J, Rivas A, Agarwal M, Briceno M, Wali M, Nawaz A, Silva G, Shaikh Z, Maailiki N, Been L, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Bass TA, Angiolillo DJ. Prasugrel Versus Ticagrelor in Patients With CYP2C19 Loss-of-Function Genotypes: Results of a Randomized Pharmacodynamic Study in a Feasibility Investigation of Rapid Genetic Testing. JACC Basic Transl Sci. 2020 Mar 25;5(5):419-428. doi: 10.1016/j.jacbts.2020.02.009. eCollection 2020 May.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): April 22, 2019
• Study Completion (Actual): April 22, 2019

Study Registration Dates

• First Submitted: February 12, 2014
• First Submitted That Met QC Criteria: February 14, 2014
• First Posted (Estimate): February 19, 2014

Study Record Updates

• Last Update Posted (Actual): September 16, 2020
• Last Update Submitted That Met QC Criteria: August 27, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Coronary Artery Disease; Percutaneous Coronary Intervention; Pharmacodynamic; Genetic Polymorphism
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor; Prasugrel Hydrochloride
• Other Study ID Numbers: UFJ 2014-12; IRB201702750 (Other Identifier: UF IRB)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No