Ticagrelor, clopidogrel show similar benefits for PAD patients

mainart_smallrevPatients who have peripheral artery disease will likely respond equally well whether treated with ticagrelor or clopidogrel as monotherapy, according to results from the Examining Use of Ticagrelor in PAD trial. Investigators reported that the two drugs produced nearly identical rates of cardiovascular death, myocardial infarction or ischemic stroke in patients who are symptomatic for PAD. EUCLID results were presented Nov. 13 as a late-breaking clinical trial during Scientific Sessions 2016.

“PAD of the lower extremities is very common, more than 200 million patients worldwide, with a high risk for cardiovascular events,” said EUCLID lead author Manesh Patel, MD, from the Duke Clinical Research Institute at Duke University Medical Center in Durham, North Carolina. “Antiplatelet therapy is recommended for all patients with PAD, but our evidence in these patients is limited.”

The CAPRIE trial, published in 1996, showed that clopidogrel is superior to aspirin for MI, ischemic stroke or vascular death. In patients with acute coronary syndrome, ticagrelor is superior to clopidogrel in reducing cardiovascular death, myocardial infarction or stroke, Patel noted. Many assumed that ticagrelor would be similarly superior to clopidogrel in PAD, but there have been no firm data to support that assumption.

EUCLID was designed to detect differences in the composite outcome of cardiovascular death, MI or ischemic stroke in patients with symptomatic PAD treated with ticagrelor versus clopidogrel as long-term monotherapy. A key secondary endpoint combined the primary composite endpoint with acute limb ischemia requiring hospitalization while safety was evaluated in terms of thrombolysis in MI major bleeding.

EUCLID enrolled 13,885 patients across 811 sites in 28 countries. The double-blind, double-dummy design randomized patients to either 90 mg ticagrelor twice daily or 75 mg clopidogrel once daily. Patients who were poor metabolizers for CYP2C19 or who required dual anti-platelet therapy were excluded.

Both arms showed very good follow-up, with the proportion of potential patients years of follow-up at about 98%. The median follow-up period was 30 months.

There was no difference in the primary efficacy endpoint between ticagrelor and clopidogrel. In both arms, 12.5 percent of patients reached the primary endpoint (p=0.65).

There was no significant difference in cardiovascular death (p=0.40), MI (p=0.48) or the secondary endpoint that combined the primary composite endpoint with acute limb ischemia requiring hospitalization (p=0.74). But there was a higher rate of ischemic stroke in the clopidogrel arm, 2.4 percent, versus ticagrelor, 1.9 percent (p=0.03).

The primary safety outcome, TIMI major bleeding, was infrequent and identical, seen in 1.6 percent of patients in both arms (p=0.49). TIMI minor bleeding was also similar, 1.2 percent for ticagrelor and 1.0 percent for clopidogrel (p=0.09).

There were statistically significant differences in adverse events leading to discontinuation, Patel said. In the ticagrelor arm, 4.8 percent of patients discontinued its use due to dyspnea versus 0.8 percent in the clopidogrel arm (p<0.001). Ticagrelor also showed a higher rate of bleeding leading to discontinuation, 2.4 percent versus 1.6 percent for clopidogrel (p<0.001).

“We have limited antithrombotic medical options for patients with PAD,” Patel said. “Clopidogrel and ticagrelor have comparable efficacy and safety. This trial teaches us that we should exercise caution in extrapolating evidence from coronary artery disease patients and trials to peripheral artery disease. We need individual studies in PAD patients.”