Ticagrelor Not Superior to Clopidogrel for Reducing Cardiovascular Events

In the largest study of patients with peripheral artery disease (PAD), ticagrelor was not superior to clopidogrel in reducing cardiovascular events. The safety profile of the 2 drugs was comparable, with both drugs having similar rates of major bleeding.

The study was simultaneously published online in the New England Journal of Medicine and presented by Manesh R. Patel, MD, chief of the Duke Division of Cardiology, at the Scientific Sessions of the American Heart Association held November 12 to 16, 2016, in New Orleans, LA.

Coauthors of the study from Duke included Gretchen Heizer, MS, W. Schuyler Jones, MD, and Craig Reist, PhD.

Ticagrelor is approved for use in patients with acute coronary syndrome and post–myocardial infarction (MI) based on the findings of studies in which the combination of ticagrelor and aspirin showed evidence of benefiting patients with PAD.

“Given the initial evidence, ticagrelor was considered a novel and potent agent with potential benefit in patients with PAD,” said Patel. “Our trial demonstrates the hazards of extrapolating evidence from coronary artery disease populations to patients with PAD.”

The study included 13,855 patients treated at 811 sites in 28 countries. The patients were randomly assigned to receive twice-daily ticagrelor 90 mg (n = 6,930) or once-daily clopidogrel 75 mg (n = 6,955). The primary efficacy end point was a composite of cardiovascular death, MI, or ischemic stroke, and the primary safety end point was major bleeding.

Patients with symptomatic PAD were eligible for the trial if they had an abnormal ankle-brachial index of 0.80 or less or revascularization in their lower extremities. Patients were excluded if they were determined to be poor metabolizers of clopidogrel (homozygous for CYP2C19 mutation).

The composite rates of cardiovascular death, MI, or ischemic stroke were 10.8% in the ticagrelor group and 10.6% in the clopidogrel group. No significant difference was observed between the 2 groups in terms of cardiovascular-related death or MI alone (Table).

Table. Efficacy Outcomes

Outcome Ticagrelor (n = 6,930), n (%) Clopidogrel (n = 6,955), n (%) HR
(95% CI)
P Value 
Primary outcomea 751 (10.8) 740 (10.6) 1.02 (0.92-1.13) .65
Cardiovascular death 363 (5.2) 343 (4.9) 1.07 (0.92-1.23) .40
MI 349 (5.0) 334 (4.8) 1.06 (0.91-1.23) .48
Ischemic stroke 131 (1.9) 169 (2.4) 0.78 (0.62-0.98) .03
Key secondary outcomeb 839 (12.1) 833 (12.0) 1.02 (0.92-1.12) .74

aComposite of cardiovascular death, MI, or ischemic stroke.
bComposite of cardiovascular death, MI, ischemic stroke, or acute limb ischemia requiring hospitalization.
CI = confidence interval, HR = hazard ratio, MI = myocardial infarction.

Ticagrelor was shown to be more effective than clopidogrel in patients with a history of coronary or carotid revascularization or a history of coronary stent implantation.

In terms of safety, the rate of major bleeding was the same for both groups (1.6%). However, Patel noted that ticagrelor was associated with a higher rate of adverse events leading to discontinuation. Dyspnea led to discontinuation in 4.8% of study participants assigned to ticagrelor compared with 0.8% assigned to clopidogrel (P < .001), and bleeding led to treatment discontinuation in 2.4% and 1.6%, respectively (P < .001).

Patel reported that the findings demonstrate that ticagrelor could be considered a reasonable alternative for patients who could not take clopidogrel, but new treatments are needed to give patients more options.

“There are limited antithrombotic medical options for patients with PAD,” said Patel. “Future trials should evaluate well-defined PAD populations and take into account the procedures, drugs, and devices used to treat symptomatic PAD.”

This trial received funding from AstraZeneca.

Source: Patel MR; EUCLID Executive and Steering Committee and Investigators. Effects of ticagrelor compared with clopidogrel in patients with PAD (EUCLID). Presented at: American Heart Association Scientific Sessions 2016; November 12-16, 2016; New Orleans, LA. Abstract LBCT.01.