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

Coronary Artery Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02065479
• Other study ID #: UFJ 2014-12
• Secondary ID: IRB201702750
• Status: Completed
• Phase: Phase 4
• Start date: March 2014
• Est. completion date: April 22, 2019

Study information

• Verified date: August 2020
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: April 22, 2019
• Est. primary completion date: April 22, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 74 Years

Eligibility

• 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.

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia

Intervention

Drug:
• Prasugrel
Comparison of platelet reactivity between prasugrel and ticagrelor
• Ticagrelor
Comparison of platelet reactivity between prasugrel and ticagrelor

Locations

Country	Name	City	State
United States	University of Florida	Jacksonville	Florida

Sponsors (1)

Lead Sponsor	Collaborator
University of Florida

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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