Ticagrelor was found to be “not superior” to clopidogrel at preventing cardiovascular events in the largest clinical trial to date involving patients with symptomatic peripheral artery disease (PAD), Manesh Patel, MD, reported at the American Heart Association scientific sessions.

Ticagrelor also was no better than clopidogrel at preventing acute limb ischemia in this study of 13,885 patients.

Regarding safety issues, the two drugs had identical rates of major bleeding adverse events, but ticagrelor was discontinued significantly more often than clopidogrel was, because of its other well-known adverse effects, said Dr. Patel of Duke University, Durham, N.C.

The findings of the EUCLID (Examining the Use of Ticagrelor in PAD) study were presented at the meeting and simultaneously published online Nov. 13 in the New England Journal of Medicine (2016. doi: 10.1056/NEJMoa1611688 ).

In addition, the results of a substudy of the EUCLID trial involving the 7,875 participants who had previously undergone lower-limb revascularization were reported at the meeting and simultaneously published online in Circulation (2016 Nov 13; doi: 10.1161/CIRCULATIONAHA.116.025880).

Until now, there have been no large studies comparing antiplatelet therapies in patients with PAD. Clopidogrel is considered superior to aspirin in this patient population based on limited evidence, often extrapolated from studies of acute coronary syndromes or coronary artery disease. Ticagrelor also proved beneficial in these contexts, so researchers performed the EUCLID study, comparing the two medications head to head in patients with PAD.

The manufacturer-funded double-blind trial was conducted at 811 medical centers in eight countries. Patients aged 50 years or older (median age, 66 years) were randomly assigned to receive either oral ticagrelor, 90 mg twice daily (6,930 patients), or oral clopidogrel, 75 mg once daily (6,955 patients), and were followed for a median of 30 months.

The primary efficacy endpoint – the first occurrence of any event in the composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred in 10.8% of the ticagrelor group and 10.6% of the clopidogrel group, for a hazard ratio of 1.02.

When the components of this composite endpoint were considered individually, only the rate of ischemic stroke was significantly different between the two study groups, occurring in 1.9% of patients taking ticagrelor and 2.4% of those taking clopidogrel (HR, 0.78).

Other important secondary and composite efficacy endpoints, including acute limb ischemia and revascularization, were similar between the two study groups, Dr. Patel said.

The primary safety endpoint – the rate of major bleeding events – occurred in the same percentage of both study groups (1.6%), and individual rates of fatal bleeding, intracranial bleeding, and minor bleeding were similar.

“There were numerically fewer fatal bleeding events in the ticagrelor group than in the clopidogrel group (10 vs. 20), but there were significantly more bleeding events leading to drug discontinuation with ticagrelor than with clopidogrel (168 vs. 112),” he noted.

Ticagrelor was discontinued more often than clopidogrel during the study (30.1% of patients vs. 25.9%; HR, 1.21). Discontinuation was driven mainly by the occurrence of dyspnea (4.8% vs. 0.8%) and minor bleeding, both of which are well-described adverse effects of ticagrelor, Dr. Patel said.

“Our findings show the hazards of extrapolating evidence from patients with coronary artery disease to those with peripheral artery disease,” he added.

In the separate report in Circulation, the results were similar in the substudy of EUCLID participants who had already undergone lower-extremity revascularization procedures before enrollment, said W. Schuyler Jones, MD , of Duke Clinical Research Institute, Durham, N.C.

The primary efficacy endpoint occurred in 11.4% of the ticagrelor group and 11.3% of the clopidogrel group, a nonsignificant difference (HR, 1.01). “Other key secondary and composite endpoints, including repeat revascularization, also were not different between the two study groups,” Dr. Jones said.

Regarding safety endpoints, the rates of major bleeding, fatal bleeding, intracranial bleeding, and minor bleeding all were similar between the two study groups.

“These findings suggest that patients with prior revascularization have a substantial residual rate of cardiovascular and acute limb events, despite high adherence to antiplatelet and statin medications, and require further study,” Dr. Jones noted.


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