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NEW ORLEANS -- The potent antiplatelet agent ticagrelor (Brilinta) didn't improve outcomes or reduce bleeding compared with clopidogrel (Plavix) for symptomatic peripheral arterial disease (PAD) patients, the double-blind EUCLID trial showed.

The two drugs had similar rates of the primary efficacy endpoint of adjudicated cardiovascular death, MI, or ischemic stroke, (10.8% versus 10.6% clopidogrel, HR 1.02, 95% CI 0.92-1.13), , of Duke University Medical Center in Durham, N.C., and colleagues found.

The same was true for the primary safety endpoint of major bleeding events, which occurred in 1.6% of patients in both groups (P=0.49), the group reported online in the and here at the American Heart Association meeting.

Fatal bleeds, intracranial bleeds, and TIMI minor bleeding were all also similar between arms, although ticagrelor had more discontinuations than did clopidogrel due to side effects (mainly dyspnea and minor bleeding). Acute limb ischemia rates were in 1.7% in both treatment groups (P=0.85).

Click here for more video comments from authors of the Hot Lines trials, and leading cardiologists from around the world providing daily commentary.

The only significant outcome difference between the two groups was fewer ischemic strokes with ticagrelor (1.9% vs 2.4%, HR 0.78, 95% CI 0.62-0.98). Subgroup analysis also showed that patients with a prior coronary or carotid revascularization or coronary stenting did better with ticagrelor.

The trial included 13,885 patients with symptomatic peripheral artery disease randomized double-blind to monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients had to have an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs but could not be homozygous for loss-of-function alleles to clopidogrel before randomization.

As to why EUCLID failed to find superiority for ticagrelor when two other trials had done so -- PEGASUS and PLATO in MI and acute coronary syndrome (ACS), respectively, along with subgroup findings suggesting consistently greater benefit in concomitant peripheral artery disease in those trials -- the researchers noted that "clopidogrel represents an effective active comparator."

"Furthermore, the results of the suggest that clopidogrel may be particularly effective in patients with peripheral artery disease," they added. "In addition, the patients in our trial were enrolled on the basis of having peripheral artery disease, with a minority having concomitant clinical coronary artery disease. These patients may have important phenotypic and biologic differences from those with predominantly acute and chronic coronary artery disease."

The exclusion of the clopidogrel poor metabolizers -- about a quarter of patients, based on prior evidence -- was key, , of the University of Florida in Gainesville, said as discussant at a press conference for the late-breaking clinical trial session.

"EUCLID succeeded in making clopidogrel equivalent, or the same response, as we saw with ticagrelor," he said.

The failure of the drug in EUCLID came as "a big surprise," coauthor , of NYU-Langone Medical Center in New York City, commented in an email to MedPage Today. But, he added, "an important bright spot was the lack of major bleeding in ticagrelor versus clopidogrel in this setting."

"Currently the advantage of clopidogrel is that it's available as a generic, so it's less expensive at this point in time," , president of the American College of Cardiology, told MedPage Today. "On the other hand for some situations, including patients who are post-acute coronary syndrome, there may be an advantage to the use of ticagrelor. It depends very much on the clinical situation in which one sees the patient.

"But in an era when we have to be looking at cost effective care, this may steer our treatment at least in the patient in whom we're using the agent specifically for peripheral vascular disease, not one who's had a recent MI or acute coronary syndrome."

Initially, the big sell of ticagrelor was that it was a "fast on, fast off" antiplatelet that would be easier for patients.

That "pharmacodynamic story remains valid," Berger argued. "PLATO tested ticagrelor in the acute coronary syndrome setting, which is very different than peripheral artery disease (a much more chronic setting). EUCLID does not take anything away from PLATO -- the ticagrelor story in the ACS setting (PLATO) and post-MI (PEGASUS) still holds true and is very important."

, of the University of Edinburgh, agreed: "The 'fast on, fast off' properties of ticagrelor are not so relevant to the PAD population. EUCLID does not detract from the benefits of ticagrelor over clopidogrel in the ACS population, but it does raise questions about the value of a single antiplatelet strategy."

However, , of the University Hospital, Nijmegen, the Netherlands, didn't see it as such a surprise, given the failure of dual antiplatelet therapy to do better than monotherapy in PAD patients in the CHARISMA trial.

Regarding stronger antiplatelet attack, he concluded in an interview, "It's not the way to go in patients with symptomatic peripheral arterial disease."

"I think in the future we should move to other measures," Verheugt said -- perhaps anticoagulants, now being tested in the .

Overall, PAD patients need better treatment options, the researchers concluded: "In our trial, the observed cardiovascular event rates in the two groups (4.42% per 100 patient- years) combined with the rates of acute limb ischemia (0.83% per 100 patient-years) show the need for continued clinical improvement."

EUCLID got the ball rolling as the first very large multinational trial in PAD, Berger said. "I hope we learn from these data and learn a lot more about these very high risk patients."

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