Genotype-guided Strategy for Antithrombotic Treatment in Peripheral Arterial Disease. (GENPAD)

Genotype-guided Strategy for Antithrombotic Treatment Versus Conventional Clopidogrel Therapy in Peripheral Arterial Disease.

Rationale: Peripheral arterial disease (PAD) is a common presentation of atherosclerosis. For the prevention of adverse events related to arterial thrombosis in PAD patients, clopidogrel is recommended. Clopidogrel in itself is inactive and needs to be metabolized by cytochrome P450 2C19 (CYP2C19) into the active metabolite. About 30% of PAD patients receiving clopidogrel is carrying one or two CYP2C19 loss-of-function allele(s) and do not or to a limited extent convert the prodrug into its active metabolites, and are therefore at increased risk of adverse clinical events related to arterial thrombosis. We hypothesize that genotype-guided prescription of antithrombotic treatment reduces adverse clinical events related to arterial thrombosis.

Objective: The primary aim of the GENPAD study is to evaluate the ability of genotype-guided antithrombotic treatment to reduce adverse clinical events related to arterial thrombosis in PAD patients. Secondary objectives are to evaluate the ability of genotype-guided antithrombotic treatment to reduce the separate elements of the primary composite outcome and to assess the risk of clinically relevant bleedings in patients allocated to the genotype-guided antiplatelet treatment versus standard clopidogrel prescription.

Study design: A randomized, controlled, open label, multicenter trial. Study population: Patients (n=2276) with PAD consulting a vascular surgeon for diagnosis and/or treatment, receiving clopidogrel according to the guidelines.

Intervention: Testing for carriage of the CYP2C19*2 and *3 loss-of-function alleles, followed by a genotype guided antithrombotic treatment with either clopidogrel 75mg once daily (normal metabolizers), clopidogrel 75mg twice daily (intermediate metabolizers), or low-dose rivaroxaban plus acetylsalicylic acid (poor metabolizers).

Comparator: All patients receive clopidogrel 75mg once daily without pharmacogenetic guidance.

Main study parameters/endpoints: The primary combined outcome is the occurrence of adverse clinical events related to arterial thrombosis at 24 months. The occurrence of major adverse cardiovascular events, major adverse limb events, death and clinically relevant bleedings are the secondary endpoints.

Study Overview

• Status: Recruiting
• Conditions: Peripheral Arterial Disease
• Intervention / Treatment: Genetic: Direct CYP2C19 genotyping; Drug: Poor metabolisers; Drug: Intermediate metabolisers; Drug: Normal metabolisers and unknown metaboliser state; Genetic: CYP2C19 genotyping at the end of the study

Detailed Description

Rationale: Peripheral arterial disease (PAD) is a common presentation of atherosclerosis, resulting in intermittent claudication, pain at rest or gangrene. For the prevention of adverse events related to arterial thrombosis in PAD patients, clopidogrel is recommended. Clopidogrel in itself is inactive and needs to be metabolized by cytochrome P450 2C19 (CYP2C19) into the active metabolite. About 30% of PAD patients receiving clopidogrel is carrying one or two CYP2C19 loss-of-function allele(s) and do not or to a limited extent convert the prodrug into its active metabolites, and are therefore at increased risk of adverse clinical events related to arterial thrombosis and subsequent cardiovascular death. We hypothesize that genotype-guided prescription of antithrombotic treatment reduces adverse clinical events related to arterial thrombosis.

Objective: The primary aim of the GENPAD study is to evaluate the ability of genotype-guided antithrombotic treatment to reduce adverse clinical events related to arterial thrombosis in PAD patients. Adverse clinical events of interest are major adverse cardiovascular events (myocardial infarction, stroke, transient ischemic arrack), major adverse limb events (acute/chronic limb ischemia of peripheral vascular intervention including amputation) and death. Secondary objectives are to evaluate the ability of genotype-guided antithrombotic treatment to reduce the separate elements of the primary composite outcome and to assess the risk of clinically relevant bleedings in patients allocated to the genotype-guided antiplatelet treatment versus standard clopidogrel prescription. Other objectives are to evaluate cost-effectiveness, to explore health state scores and health-related quality of life between study groups and metabolizer states and to set-up a biobank.

Study design: A randomized, controlled, open label, multicenter trial. Study population: Patients (n=2276) with PAD consulting a vascular surgeon for diagnosis and/or treatment, receiving clopidogrel according to the guidelines.

Intervention: Testing for carriage of the CYP2C19*2 and *3 loss-of-function alleles, followed by a genotype guided antithrombotic treatment with either clopidogrel 75mg once daily (normal metabolizers), clopidogrel 75mg twice daily (intermediate metabolizers), or low-dose rivaroxaban plus acetylsalicylic acid (poor metabolizers).

Comparator: All patients receive clopidogrel 75mg once daily without pharmacogenetic guidance.

Main study parameters/endpoints: The primary combined outcome is the occurrence of adverse clinical events related to arterial thrombosis at 24 months. The occurrence of major adverse cardiovascular events, major adverse limb events, death and clinically relevant bleedings are the secondary endpoints. Health state, quality of life and medical consumption will be measured with validated questionnaire. Questionnaires will be used to assess which antithrombotic treatment the participant is receiving during follow-up, medication adherence and the occurrence of extramural adverse events at 6, 12, 24 and 36 months.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Participants will visit the hospital once for informed consent procedure, blood sample withdrawal and/or buccal sample collection This visit will be combined with a routine visit to the vascular surgeon or vascular laboratory. Patients might experience some discomfort while taking blood samples and buccal sample collection for a short amount of time. The follow-up of participants will range from 6 months (minimum) to 36 months (maximum). Participants are sent questionnaires at baseline and at 6, 12, 24 and 36 months, dependent on the duration of their follow-up. Completing the questionnaires will take approximately 30 minutes. Risks regarding the study are negligible and consist of the possible adverse events related to doubling the daily dose of clopidogrel or related to rivaroxaban and acetylsalicylic acid.

• Study Type: Interventional
• Enrollment (Anticipated): 2276
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Loes H Willems, MD; Phone Number: 0031 24 361 5333; Email: genpad.heel@radboudumc.nl
• Study Contact Backup: Name: Josephine Kranendonk, MD; Phone Number: 0031 24 361 5333; Email: genpad.heel@radboudumc.nl

Study Locations

• Netherlands
  • Apeldoorn, Netherlands
    • Not yet recruiting
    • Gelre Ziekenhuizen
    • Contact: Hessel CLJ Buscher, PhD
  • Arnhem, Netherlands, 6815
    • Recruiting
    • Rijnstate
    • Contact: Michel MPJ Reijnen, Prof
  • Ede, Netherlands
    • Recruiting
    • Ziekenhuis Gelderse Vallei
    • Contact: Hans JEM Sybrandy, MD
  • Eindhoven, Netherlands
    • Not yet recruiting
    • Maxima Medisch Centrum
    • Contact: Maarten JA Loos, PhD
  • Enschede, Netherlands
    • Not yet recruiting
    • Medisch Spectrum Twente
    • Contact: Theo P Menting, PhD
  • Groningen, Netherlands, 9713 GZ
    • Not yet recruiting
    • UMC Groningen
    • Contact: Clark JAM Zeebregts, Prof
  • Groningen, Netherlands
    • Not yet recruiting
    • Ommelander Ziekenhuis
    • Contact: Martijn L Dijkstra, PhD
  • Maastricht, Netherlands
    • Not yet recruiting
    • Maastricht University Medical Center
    • Contact: Barend ME Mees, Ass. Prof
  • Nijmegen, Netherlands, 6525 GA
    • Recruiting
    • Radboudumc
    • Contact: Michiel C Warlé, PhD
  • Nijmegen, Netherlands, 6532 SZ
    • Recruiting
    • Canisius Wilhelmina Hospital
    • Contact: Bianca Bendermacher, PhD
  • Uden, Netherlands, 5406 PT
    • Recruiting
    • Bernhoven
    • Contact: Andre S van Petersen, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 16 years
• Obtained written informed consent
• Indication for monotherapy clopidogrel 75mg once daily
• Ankle-brachial index < 0.9 and/or toe brachial index < 0.5
• Current or previous symptoms due to insufficient vascularization of one or two lower extremities, including intermittent claudication, pain at rest and/or gangrene (Rutherford category 1-6)
• Consulting a vascular surgeon for diagnosis, treatment and/or follow-up of PAD

Exclusion Criteria:

• known CYP2C19 genotype or metabolizer state
• treated with coumarins, Non-vitamin K Oral Anti-Coagulants, unfractionated heparin, low molecular weight heparins or double antiplatelet therapy with acetylsalicylic acid and a P2Y12 inhibitor for other indications
• contraindication for clopidogrel, acetylsalicylic acid and/or rivaroxaban
• pregnant or breastfeeding women
• unable to give informed consent (including not being able to understand the Dutch language)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group; The intervention includes testing of patients for carriage of the CYP2C19*2 and *3 allele (loss-of-function (LOF) alleles), followed by a genotype guided antithrombotic treatment with either clopidogrel 75mg (without LOF allele, normal metabolizers), clopidogrel 150mg (one LOF allele, intermediate metabolizers), or rivaroxaban 2.5mg twice daily plus acetylsalicylic acid 100mg (two LOF alleles, poor metabolizers).	Genetic: Direct CYP2C19 genotyping; CYP2C19 genotype will be determined by the Spartan RX CYP2C19 point-of-care system.; Drug: Poor metabolisers; Acetylsalicylic acid 100mg once daily plus rivaroxaban 2.5mg twice daily; Drug: Intermediate metabolisers; Clopidogrel 75mg twice daily; Drug: Normal metabolisers and unknown metaboliser state; Clopidogrel 75mg once daily
Active Comparator: Comparison group; The comparison group will not be prescribed clopidogrel 75mg without preceding testing for carriage of the CYP2C19*2 and *3 loss-of-function alleles. CYP2C19 genotyping will be performed at the end of the study.	Drug: Normal metabolisers and unknown metaboliser state; Clopidogrel 75mg once daily; Genetic: CYP2C19 genotyping at the end of the study; Blood-based CYP2C19 genotyping will be performed at the end of the study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of participants that experienced major adverse events	The number of participants that experienced a major adverse cardiovascular events, major adverse limb events or death from any cause.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of participants that experienced major adverse cardiovascular events	The number of participants that experienced a myocardial infarction, stroke, transient ischemic attack or cardiovascular death.	24 months
The number of participants that experienced major adverse limb events	The number of participants that experienced acute limb ischemia, chronic limb ischemia or peripheral vascular intervention	24 months
The number of participants that experienced major bleeding	The number of participants that experienced major bleeding, including: 1) fatal bleeding, 2) symptomatic bleeding into a critical organ, 3) bleeding causing a fall in hemoglobin level of 20 g L-1 (1.24 mmol L-1) or more or leading to transfusion of two or more units of whole blood or red cells, and 4) bleeding into a surgical site requiring a second intervention.	24 months
The number of participants that experienced clinically relevant bleeding	The number of participants that experienced clinically relevant bleeding, including bleeding that led to: 1) hospitalization (including presentation to an acute care facility without an overnight stay), 2) a physician guided medical or surgical treatment for bleeding, or 3) a change in antithrombotic treatment.	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The cost-effectiveness of a CYP2C19 genotype-guided antithrombotic treatment strategy versus standard clopidogrel treatment	The costs per adverse event avoided for CYP2C19 genotype-guided antithrombotic treatment strategy compared to standard clopidogrel treatment	24 months
The difference in mean health state scores	Health state score measured by the EuroQol five-dimensional questionnaire five-level (EQ-5D-5L) will be determined at baseline and during follow-up. Patients score five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) on 5 levels (no problems, slight problems, moderate problems, severe problems and extreme problems), resulting in a descriptive score of 5 consecutive numbers. The validated Dutch tariff for the EQ-5D-5L will convert the descriptive score to a continuous score (range -1 to 1) in which a higher value represents a better health state than a lower value..	24 months
The difference in health-related quality of life scores	Health-related quality of life measured by the abbreviated World Health Organization Quality of life questionnaire (WHOQoL-Bref) will be determined at baseline and during follow-up. Patients score their quality of life with 26 questions on 4 domains (physical, psychological, social relationships and environment). Each question can be answered by 1 to 5. Scores are scaled in a positive direction (i.e. higher scores denote higher quality of life). The mean score of individual items within each domain, multiplied by 4, represents the domain score (range 4 to 20). The mean of the domain scores is the health-related quality of life score (range 4 to 20).	24 months

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Rijnstate Hospital; Academisch Ziekenhuis Groningen; Canisius-Wilhelmina Hospital; Bernhoven Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Anticipated): June 30, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: November 2, 2020
• First Submitted That Met QC Criteria: November 2, 2020
• First Posted (Actual): November 6, 2020

Study Record Updates

• Last Update Posted (Actual): April 20, 2022
• Last Update Submitted That Met QC Criteria: April 19, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Arterial Disease; Peripheral Vascular Diseases
• Other Study ID Numbers: NL2020-7057

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Data will be accessible through the Data Archiving and Networked Services Electronic Archiving System (DANS EASY) repository, using Dublin Cor metadata scheme
• IPD Sharing Time Frame: Immediately after publication of the main paper for at least 15 years.
• IPD Sharing Access Criteria: A steering committee, programme committee or project leader will be charged with approving data requests.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No