EUCLID: Ticagrelor, Clopidogrel in PAD Similar for CV Events, Bleeding

Larry Hand

November 13, 2016

NEW ORLEANS, LA — Ticagrelor (Brilinta/Brilique, AstraZeneca) did not prove to be superior to clopidogrel in patients with peripheral artery disease (PAD) in the Examining Use of Ticagrelor in PAD (EUCLID) trial, according to results presented at the American Heart Association (AHA) 2016 Scientific Sessions and published simultaneously in the New England Journal of Medicine[1].

"I would say, hopefully, more patients with PAD get treated with clopidogrel. Ticagrelor is very effective in patients with coronary artery disease. It's comparable in PAD, but I'm not sure it's going to change our practice," Dr Manesh R Patel (Duke University Medical Center, Durham, NC) told heartwire from Medscape.

Patel and colleagues conducted a double-blind clinical trial involving 13,855 patients randomized to either ticagrelor (n=6930) 90 mg twice daily or clopidogrel (n=6955) 75 mg daily at 811 sites in 28 countries.

They had a primary efficacy end point of a composite of cardiovascular death, MI, or ischemic stroke and a primary safety end point of major bleeding.

The researchers included patients with symptomatic PAD plus either ankle brachial index of ≤80 at screening or prior lower-extremity revascularization at least 30 days earlier. They excluded patients who were homozygous to cytochrome P450C219.

Patient median age was 66 years, 72% were men, 30% were current smokers, and 38% had diabetes. Mean baseline ankle-brachial index was 0.71 in all patients, and 76.6% of them had claudication.

During 14 months of treatment and 30 months of follow-up ending in May 2016, the primary efficacy occurred in 751 of 6930 (10.8%) ticagrelor patients and 740 of 6955 (10.6%) clopidogrel patients (hazard ratio [HR] 1.02, 95% CI 0.92–1.13; P=0.65).

However, the only significant between-group difference was the rate of ischemic stroke, which was 1.9% for ticagrelor and 2.4% clopidogrel (HR 0.78, 95% CI 0.62–0.98; P=0.03).

Major bleeding occurred in 1.6% of patients in both groups (HR 1.10, 95% CI 0.84–1.43; P=0.49), and acute limb ischemia occurred in 1.7% of both groups (HR 1.03, 95% CI, 0.79-1.33; P=0.85).

In a secondary analysis of patients with prior revascularization, published in Circulation[2], statistically significantly higher rates of MI occurred in patients with revascularization compared with patients enrolled based on abnormal ABI (HR 1.29, 95% CI 1.08-1.55; P=0.005). No between-group differences occurred for the primary efficacy end point.

In EUCLID, "adverse events leading to discontinuation occurred more frequently with ticagrelor," Patel said during the presentation, with discontinuation coming to 30.1% for ticagrelor and 25.9% for clopidogrel, mainly driven by dyspnea and bleeding.

Dr Manesh Patel

In summary, Patel said, "In patients with symptomatic peripheral artery disease, ticagrelor was not superior."

Dr Carl Pepine (University of Florida Health, Gainesville), the discussant during the presentation, said, "What EUCLID adds is that in PAD patients the same result was found with clopidogrel as with ticagrelor in terms of preventing events. In addition, there's this very interesting signal for stroke reduction."

He told heartwire , "PAD amplifies the central blood pressure, so that what's recorded at the brachial blood pressure office recording site is exceeded in the central vasculature, and that's the signal that the brain sees relative to stroke risk. I think it's reasonable to suspect that at least part of the stroke benefit seen with ticagrelor in EUCLID was related to blood-pressure reduction."

However, blood-pressure data were not available from the trial at the meeting.

"Clearly many knowledge gaps remain," he said. "We need more studies like EUCLID to determine the optimal antiplatelet therapy as well as other drugs to prevent ischemic events as well as limb-driven events."

AstraZeneca sponsored the EUCLID trial. Patel reported receiving research support and consulting fees from AstraZeneca during the conduct of the study; grant support from Johnson & Johnson, HeartFlow, Maquet, and the National Heart, Blood, and Lung Institute; grants and personal fees from CSL Behring, Janssen, and Medtronic; and personal fees from Bayer, Genzyme, and Merck. Disclosures for the coauthors are listed on the journal website.

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