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

Summary

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.

Conditions

• Peripheral Arterial Disease

Interventions

GENETIC

Direct CYP2C19 genotyping

CYP2C19 genotype will be determined by the Spartan RX CYP2C19 point-of-care system.

GENETIC

CYP2C19 genotyping at the end of the study

Blood-based CYP2C19 genotyping will be performed at the end of the study

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

Sponsors & Collaborators

• ZonMw: The Netherlands Organisation for Health Research and Development

  collaborator OTHER

• Academisch Ziekenhuis Groningen

  collaborator OTHER

• Rijnstate Hospital

  collaborator OTHER

• Bernhoven Hospital

  collaborator OTHER

• Canisius-Wilhelmina Hospital

  collaborator OTHER

• Radboud University Medical Center

  lead OTHER

Principal Investigators

• Michiel C Warlé, PhD · Radboud University Medical Center

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

16 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-03-01

Primary Completion

2024-06-30

Completion

2024-12-31

Countries

• Netherlands

Study Locations