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, 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.