EUCLID trial to analyse monotherapy of ticagrelor versus clopidogrel in patients with peripheral arterial disease

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Despite “overwhelming data” demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data for antiplatelet therapy for peripheral arterial disease (PAD) are “less compelling”, according to the investigators of the EUCLID trial, which will investigate whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.

The investigators—led by Jeffrey S Berger, New York University School of Medicine, New York, USA—write in the American Heart Journal, “The current American College of Cardiology Foundation/ American Heart Association/European Society of Cardiology guidelines for PAD recommend use of either aspirin or clopidogrel for reduction in cardiovascular events. Unfortunately, these recommendations are based on the evaluation of effects in patients with PAD that were primarily subgroups in larger trials. The EUCLID trial will define the role of antiplatelet therapy in patients with symptomatic PAD.”

Citing existing data, Berger and colleagues note, “The benefit of aspirin in the setting of PAD is far from certain. A meta-analysis including nine trials of subjects with PAD did not detect a significant difference in cardiovascular events from aspirin versus placebo or control. Clopidogrel monotherapy outperformed aspirin monotherapy in patients with prior myocardial infarction, stroke or PAD. In fact, the largest reduction in cardiovascular events from clopidogrel was observed in the PAD cohort, suggesting a greater benefit of clopidogrel in the setting of PAD.”

Ticagrelor (Brilinta, AstraZeneca)—a reversibly binding, potent, oral adenosine diphosphate P2Y12 receptor blocker—“is beneficial in patients with acute coronary syndrome and prior myocardial infarction,” the authors write. The EUCLID trial will analyse its ability to reduce the incidence of atherothrombotic ischaemic events as measured by the composite end point of cardiovascular death, myocardial infarction, or ischaemic stroke in a population with established PAD.

Designed to address “the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events,” EUCLID recruitment began in December 2012 and was completed in March 2014, with a total of 13,887 patients randomised. The trial will continue until at least 1,364 adjudicated primary endpoints occur.

EUCLID is a randomised, double-blind, parallel-group, multinational study, conducted at 821 sites in 28 countries. Patients with established PAD will be randomised at a 1:1 ratio to 90mg of ticagrelor or twice daily or 75mg of clopidogrel daily. The primary endpoint is a composite of cardiovascular death, myocardial infarction, or ischaemic stroke. Secondary endpoints address limb events including acute leg ischaemia, need for revascularisation, disease progression by ankle-brachial index and quality of life. The primary safety objective will be thrombolysis in myocardial infarction-defined major bleeding.

Patients return for study visits at two, six and 12 months during the first year, followed by in-person six-month visits thereafter until the end of the trial. There is a telephone follow-up every six months beginning at month nine until the end of the trial. During follow-up visits, patients are assessed for adverse and potential end point events. All patients are to undergo an end of treatment visit when permanently stopping therapy and a follow-up contact approximately two weeks after their last dose of the study drug. All patients’ vital status will be assessed at the end of the trial.