Genotype-Guided Antithrombotic Therapy vs Clopidogrel in Patients With PAD

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A study is being conducted to determine the cost-effectiveness, safety, and efficacy of a genotype-guided antithrombotic treatment strategy in patients with PAD.

In patients with peripheral arterial disease (PAD), use of CYP2C19 genotype-guided antithrombotic therapy might prove to be beneficial compared with standard clopidogrel treatment. Information on a study exploring this hypothesis was published in the American Heart Journal.

The randomized, controlled, open-label, multicenter Genotype-guided Strategy for Antithrombotic Treatment in Peripheral Arterial Disease (GENPAD) study ( identifier: NCT04619927) is being conducted to compare the efficacy, cost-effectiveness, and safety of a CYP2C19 genotype-guided antithrombotic treatment strategy with standard clopidogrel therapy among patients with PAD.

Investigators aim to determine whether the use of a CYP2C19 genotype-guided antithrombotic treatment is superior to standard clopidogrel in reducing adverse events associated with arterial thrombosis in individuals with the PAD.  The study is being conducted at multiple medical centers located in The Netherlands.

The primary study outcome is a composite of myocardial infarction, ischemic stroke, acute or chronic limb ischemia, peripheral vascular interventions, or death. Secondary outcomes include the individual components of the primary composite outcome, along with the occurrence of major and clinically relevant bleeding complications. Major bleeding complications are defined as the following:

  • fatal bleeding
  • symptomatic bleeding into a critical organ
  • bleeding that is associated with a decrease in hemoglobin level of 20 g/L-1 (1.24 mmol/L) or more, which results in the transfusion of 2 units or more of whole blood or red blood cells
  • bleeding at a surgical site that requires reoperation

All individuals with lower extremity PAD who visit the outpatient clinic or vascular laboratory of 1 of the medical centers are screened for study participation. Patients already being treated with clopidogrel monotherapy, as well as newly diagnosed patients, are considered eligible. Study inclusion criteria are as the following:

  • prior or current ankle-brachial index of less than 0.9 and/or toe-brachial index of less than 0.5
  • prior or current symptoms due to insufficient vascularization of 1 or 2 lower extremities, including intermittent claudication, pain at rest, and/or gangrene
  • consultation with the vascular surgery department for diagnosis, treatment, and/or follow-up
  • indication for once-daily clopidogrel 75 mg monotherapy
  • aged older than 16 years

Patients with a separate indication for dual-antiplatelet therapy or for stronger antithrombotic therapy are ineligible for participation.

A total of 2276 patients with PAD and an indication for clopidogrel monotherapy are scheduled to be enrolled in the study. Participants randomly assigned to the control group will receive clopidogrel 75 mg once daily with no pharmacogenetics guidance. Those randomized to the intervention group will be tested for carriage of CYP2C19 *2 and *3loss-of-function alleles, followed by a genotype-guided antithrombotic treatment with clopidogrel 75 mg once daily in normal metabolizers, clopidogrel 150 mg once daily in intermediate metabolizers, or acetylsalicylic acid 80 mg once daily plus rivaroxaban 2.5 mg twice daily in poor metabolizers.

The first patient was enrolled in the study on March 16, 2021. To date, a total of 10 participating centers are actively enrolling patients, with 749 individuals having been included thus far. It is anticipated that study recruitment will be completed in 2023.

The GENPAD study is the first randomized clinical trial to assess the efficacy of a CYP2C19 genotype-guided antithrombotic therapeutic strategy in individuals with PAD. The investigators hypothesize that patients with PAD who have CYP2C19 loss-of-function alleles treated with clopidogrel are at increased risk for the occurrence of ischemic events.

A potential limitation of the study is that large-scale research in patients with PAD is lacking, with any existing evidence with respect to the association between clopidogrel treatment and ischemic events debatable. Further, since an interim analysis is not included in the study protocol, the trial might be underpowered if the power calculation used proves to be inaccurate.

“Pharmacogenetic testing should be implemented in daily practice and treatment strategies used in the GENPAD trial may be used to optimize treatment of CYP2C19 [loss-of-function]-carriers,” the researchers wrote. “This knowledge is required to enhance treatment of [patients with PAD], possibly leading to improved outcomes and reduced cardiovascular morbidity and mortality while reducing health care costs.”


Kranendonk J, Willems LH, Vijver-Coppen RV, et al. CYP2C19 genotype-guided antithrombotic treatment versus conventional clopidogrel therapy in peripheral arterial disease: study design of a randomized controlled trial (GENPAD). Am Heart J. Published online August 19, 2022. doi:10.1016/j.ahj.2022.08.001