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

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

Dual pathway inhibition as compared to acetylsalicylic acid monotherapy in relation to endothelial function in peripheral artery disease, a phase IV clinical trial

Objective: Dual pathway inhibition (DPI) by combining acetylsalicylic acid (ASA) with low-dose rivaroxaban has been shown to reduce cardiovascular events in patients with peripheral arterial disease (PAD) when compared to ASA monotherapy. A potential explanation is that inhibition of factor Xa improves endothelial function through crosstalk between coagulation and inflammatory pathways, subsequently attenuating the occurrence of cardiovascular events. We hypothesize that the addition of rivaroxaban to ASA in PAD patients leads to improved endothelial function. Design: An investigator-initiated, multicentre trial investigating the effect of DPI on endothelial function. Methods: Patients, diagnosed with PAD, were enrolled in two cohorts: cohort A (Rutherford I-III) and cohort B (Rutherford IV-VI). Participants received ASA monotherapy for a 4-weeks run-in period, followed by 12 weeks of DPI. Macro- and microvascular endothelial dysfunction were studied by measuring carotid artery reactivity upon sympathetic stimulus and by measuring plasma endothelin-1 concentrations, respectively. All measurements were performed during the use of ASA (baseline) and after 12 weeks of DPI. Results: 159 PAD patients (111 cohort A, 48 cohort B) were enrolled. Twenty patients discontinued study drugs early. Carotid artery constriction upon sympathetic stimulation at baseline (ASA) and after 12 weeks of DPI was similar in the total group, 22.0 vs. 22.7% (p = 1.000), and in the subgroups (Cohort A 22.6 vs. 23.7%, p = 1.000; cohort B 20.5 vs. 20.5%, p = 1.000), respectively. The mean concentration of plasma endothelin-1 at baseline and after 12 weeks of DPI did not differ, 1.70 ± 0.5 vs. 1.66 ± 0.64 pmol/L (p = 0.440) in the total group, 1.69 ± 0.59 vs. 1.62 ± 0.55 pmol/L in cohort A (p = 0.202), and 1.73 ± 0.53 vs. 1.77 ± 0.82 pmol/L in cohort B (p = 0.682), respectively. Conclusion: Macro- and microvascular endothelial dysfunction, as reflected by carotid artery reactivity and plasma endothelin-1 concentrations, are not influenced in PAD patients by addition of low-dose rivaroxaban to ASA monotherapy for 12 weeks. Trial registration: https://clinicaltrials.gov/ct2/show/NCT04218656

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

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