CYP2C19 genotype-guided antithrombotic treatment versus conventional clopidogrel therapy in peripheral arterial disease: study design of a randomized controlled trial (GENPAD).

Abstract

BACKGROUND:

Clopidogrel is recommended in international guidelines to prevent arterial thrombotic events in patients with peripheral arterial disease (PAD). Clopidogrel itself is inactive and metabolism is dependent on the CYP2C19 enzyme. About 30% of Caucasian PAD patients receiving clopidogrel carry 1 or 2 CYP2C19 loss-of-function allele(s) and do not or to a limited extent convert the prodrug into its active metabolite. As a result, platelet inhibition may be inadequate which could lead to an increased risk of adverse clinical events related to arterial thrombosis. A CYP2C19 genotype-guided antithrombotic treatment might be beneficial for PAD patients.

METHODS:

GENPAD is a multicenter randomized controlled trial involving 2,276 PAD patients with an indication for clopidogrel monotherapy. Patients with a separate indication for dual antiplatelet therapy or stronger antithrombotic therapy are not eligible for study participation. Patients randomized to the control group will receive clopidogrel 75 mg once daily without pharmacogenetic guidance. Patients randomized to the intervention group will be tested for carriage of CYP2C19 *2 and *3 loss-of-function alleles, followed by a genotype-guided antithrombotic treatment with either clopidogrel 75 mg once daily for normal metabolizers, clopidogrel 150 mg once daily for intermediate metabolizers, or acetylsalicylic acid 80 mg once daily plus rivaroxaban 2.5 mg twice daily for poor metabolizers. The primary outcome is a composite of myocardial infarction, ischemic stroke, cardiovascular death, acute or chronic limb ischemia, peripheral vascular interventions, or death. The secondary outcomes are the individual elements of the primary composite outcome and clinically relevant bleeding complications.

CONCLUSION:

The aim of the GENPAD study is to evaluate the efficacy, safety, and cost-effectiveness of a genotype-guided antithrombotic treatment strategy compared to conventional clopidogrel treatment in PAD patients.

• Authors: J Kranendonk, L H Willems, Rj van der Vijver-Coppen, M Coenen, E Adang, R Donders, C J Zeebregts, Vhm Deneer, Mmpj Reijnen, C Kramers, M C Warlé
• Journal: American heart journal (Am Heart J) Vol. 254 Pg. 141-148 (Dec 2022) ISSN: 1097-6744 [Electronic] United States
• PMID: 35988587 (Publication Type: Randomized Controlled Trial, Multicenter Study, Journal Article)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Clopidogrel
• Platelet Aggregation Inhibitors
• Cytochrome P-450 CYP2C19
• Aspirin
• CYP2C19 protein, human

Topics

• Humans
• Clopidogrel (therapeutic use)
• Platelet Aggregation Inhibitors (therapeutic use)
• Cytochrome P-450 CYP2C19 (genetics)
• Aspirin (therapeutic use)
• Peripheral Arterial Disease (drug therapy, genetics)
• Myocardial Infarction (drug therapy)
• Genotype
• Thrombosis (drug therapy)
• Treatment Outcome