Pharmacodynamic Outcomes in CCS Patients Treated With an Individualized Treatment Strategy

Pharmacodynamic Outcomes in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention Treated With an Individualized Treatment STRATEGY

Patients with Chronic Coronary Syndrome (CCS) undergoing with elective percutaneous coronary intervention (PCI) are treated with dual antiplatelet therapy (DAPT), consisting of aspirin combined with clopidogrel for 6 months. The aim of DAPT is to prevent recurrent thrombotic events, i.e. death, stent thrombosis and/ or myocardial infarction (MI). However, the trade-off of thrombotic prevention by DAPT is an increased risk of bleeding.

Multiple strategies to reduce bleeding risk and optimize outcomes have been proposed. On one hand the bleeding risk can be reduced by shortening the duration of DAPT and omitting aspirin. This has been proven effective in patients with acute coronary syndromes (ACS) compared to standard DAPT, without a significant difference in thrombotic events. On the other hand, personalized medicine by means of genotyping to ensure that a patient is treated with an, for them, effective drug, can be a strategy to optimize patients outcomes. In CCS patients the preferred P2Y12-inhibitor is clopidogrel. However, clopidogrel must first be activated by the CYP2C19 enzyme in the liver. Only then can clopidogrel inhibit the P2Y12-receptor and prevent platelet activation. Almost thirty percent of patients has a genetic variation of the gene encoding this CYP2C19 enzyme. In these patients, clopidogrel is not or hardly activated, putting them at a higher risk of thrombotic events than patients who do not have this gene variation. By determining the CYP2C19 genotype, it is possible to estimate whether clopidogrel will be effective or not.

In this trial the investigators evaluate the pharmacodynamic effects of genotype guided P2Y12-inhibitor monotherapy in patients with CCS undergoing PCI. In the intervention arm the CYP2C19 genotype will be assessed using a point-of-care test device on the cardiology ward, which can be performed by (research) nurses. Patients with a CYP2C19 loss-of-function (LOF) allel will be treated with monotherapy ticagrelor or prasugrel. Patients who are non-carrier of a LOF allel will receive clopidogrel. The control arm will be treated with the current standard-of-care, which is DAPT, consisting of aspirin combined with clopidogrel for 6 months.

The main goals is to assess the antithrombotic effects of individualized P2Y12 monotherapy strategy versus clopidogrel plus aspirin in elective PCI patients.

Study Overview

• Status: Recruiting
• Conditions: Coronary Artery Disease; Platelet Reactivity
• Intervention / Treatment: Drug: CYP2C19 genotype guided P2Y12 monotherapy; Drug: Clopidogrel

Detailed Description

Rationale: Novel antithrombotic strategies, such as genotype-guided P2Y12-inhibitor selection and P2Y12-inhibitor monotherapy, instead of routine dual antithrombotic therapy (DAPT), have recently been investigated in major randomized controlled trials. It is unclear whether these therapies can also be applied to all comer patients undergoing elective percutaneous coronary (PCI) with stenting.

Objective: The aim of this study is to evaluate the pharmacodynamic response of CYP2C19-genotype-guided monotherapy in patients undergoing elective PCI. Bleeding and ischemic outcomes will also be registered.

Study design: A prospective, single center, randomized controlled trial.

Study population: Patients undergoing elective PCI

Intervention: Randomized to genotype-guided monotherapy P2Y12 inhibition or standard DAPT.

After PCI, patients will be randomised between two groups. Intervention group: P2Y12-inhibitor monotherapy. Patients without a LOF-allel will receive clopidogrel monotherapy (tablet of 75mg once daily) for 6 months. Patients with a LOF-allel will receive ticagrelor (tablet of 90mg twice daily) or prasugrel (tablet of 10mg once daily) for 6 months.

Control group: Dual antiplatelet therapy (DAPT). Patients will receive clopidogrel (tablet of 75mg once daily) for 6 months and acetylsalicylic acid (tablet 80mg one daily) for 6 months.

Main study parameters/endpoints:

• To evaluate the antithrombotic effects of ticagrelor/prasugrel or clopidogrel monotherapy versus clopidogrel plus aspirin in order to assess the feasibility and safety of individualized antithrombotic therapy after elective PCI based on CYP2C19-genotyping.

Secondary endpoints:

• The primary (safety) bleeding endpoint is the incidence of minor, moderate or severe bleeding (Bleeding Academic Research Consortium 2, 3 and 5)
• The primary efficacy endpoint is the incidence of cardiovascular mortality, myocardial infarction, stent thrombosis, and stroke)
• Individual components and combinations of the primary and secondary end points
• To evaluate the net clinical benefit (a composite of all-cause death, MI, stroke and major bleeding defined as BARC type 3 or 5 bleeding at 6 months)
• To compare the number of patients in whom the antiplatelet drug is prematurely discontinued or switched to another drug in the CYP2C19 genotype guided antiplatelet treatment versus standard DAPT treatment

• Study Type: Interventional
• Enrollment (Estimated): 88
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Wout van den Broek, MD; Phone Number: 088 320 1337; Email: w.van.den.broek2@antoniusziekenhuis.nl

Study Locations

• Netherlands
  • Utrecht
    • Nieuwegein, Utrecht, Netherlands, 3435CM
      • Recruiting
      • St. Antonius Hospital
      • Contact: Wout van den Broek, MD; Phone Number: 088 320 13 37; Email: w.van.den.broek2@antoniusziekenhuis.nl
      • Principal Investigator: Jur ten Berg, MD, PhD
      • Sub-Investigator: Wout van den Broek, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients ≥ 18 years of age
• Patients with CCS undergoing successful elective PCI
• Patients with written informed consent as approved by the ethics committee

Exclusion Criteria:

• Contraindication to aspirin, ticagrelor, prasugrel or clopidogrel
• Under the age of 18 years
• Planned cardiac valve surgery
• Need for chronic oral anticoagulation
• PCI when admitted for ACS
• Life expectancy < 1 year
• Unable or unwilling to provide informed consent
• Pregnancy
• Suboptimal result of stenting as defined by the operator, preferably explained according the complex-PCI criteria
• Treatment with a strong CYP3A4 inhibitor or inducer
• Treatment with a strong CYP2C19 inhibitor or inducer
• History of definite stent thrombosis

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
Experimental: Genotype guided P2Y12 monotherapy; Patients will be tested for the CYP2C19 genotype. Patients without a loss-of-function (LOF) allele will receive clopidogrel monotherapy (tablet of 75mg once daily) for 6 months. Patients with a LOF-allel will receive ticagrelor (tablet of 90mg twice daily) or prasugrel (tablet of 10mg once daily) for 6 months.	Drug: CYP2C19 genotype guided P2Y12 monotherapy; Patients without a LOF-allel will receive clopidogrel monotherapy (tablet of 75mg once daily) for 6 months. Patients with a LOF-allel will receive ticagrelor (tablet of 90mg twice daily) or prasugrel (tablet of 10mg once daily) for 6 months.; Other Names: Prasugrel; Clopidogrel; Ticagrelor
Active Comparator: Standard DAPT; Patients will receive clopidogrel monotherapy (tablet of 75mg once daily) for 6 months and acetylsalicylic acid (tablet 80mg one daily) for 6 months.	Drug: Clopidogrel; Standard DAPT according to current guidelines with clopidogrel (tablet of 75mg once daily) for 6 months and acetylsalicylic acid (tablet 80mg one daily) for 6 months.; Other Names: Aspirin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet reactivity	Change in P2Y12 Reaction Units (PRU) measured using the VerifyNow	Baseline and 30 days after PCI
High on-treatment platelet reactivity (HTPR)	Number of participants with high on-treatment platelet reactivity (HTPR) defined by a PRU >208	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bleeding complications	Number of participants with major or clinically relevant bleeding complications according to the Bleeding Academic Research Consortium Definition for Bleeding (BARC) classification.	6 months
Myocardial infarction	Number of participants with myocardial infarction as defined by the 4th Universal Definition of Myocardial Infarction	6 months
Stroke	Number of participants with stroke as defined by the Valve Academic Research Consortium (VARC) definitions	6 months
Stent thrombosis	Number of participants with stent thrombosis as defined by the Academic Research Consortium (ARC)	6 months
All-cause death	Number of participants with all-cause death as defined by the Academic Research Consortium (ARC)	6 months
Cardiovascular death	Number of participants with cardiovascular death as defined by the Academic Research Consortium (ARC)	6 months

Collaborators and Investigators

• Sponsor: St. Antonius Hospital
• Investigators: Principal Investigator: Jurriën ten Berg, MD, PhD, St. Antonius Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2024
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: March 7, 2023
• First Submitted That Met QC Criteria: March 7, 2023
• First Posted (Actual): March 17, 2023

Study Record Updates

• Last Update Posted (Actual): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Percutaneous Coronary Intervention; Pharmacodynamics; CYP2C19; Antithrombotic therapy; CYP2C19 guided treatment
• 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; Clopidogrel; Prasugrel Hydrochloride
• Other Study ID Numbers: 2023-504078-39

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