Clopidogrel for Atherothrombotic Event Management in Patients with Peripheral Arterial Disease (COOPER) Study: Safety and Efficacy of Clopidogrel versus Ticlopidine in Japanese Patients

Abstract

Background: Peripheral arterial disease (PAD) has been recognized as an independent risk factor for vascular events and contributes to an adverse prognosis. Long-term administration of clopidogrel is recommended to prevent atherothrombotic events for patients with established PAD. We investigated the benefits of clopidogrel treatment in Japanese patients with PAD.

Materials and methods: COOPER (Clopidogrel for atherOthrombOtic event management in patients with PERipheral arterial disease) was a multicenter, randomized, double-blind study to evaluate the safety and efficacy of clopidogrel (75 mg/day) compared to ticlopidine (200 mg/day) in Japanese patients with PAD. The primary endpoint was the cumulative incidence of "safety events of interest" comprising clinically significant bleeding, blood disorders, hepatic dysfunction and other serious adverse events up to 12 weeks. The other safety events and vascular events were also assessed. Patients were followed up to 52 weeks.

Results: A total of 431 patients with PAD were randomly assigned to receive either clopidogrel or ticlopidine. The cumulative incidences of "safety events of interest" at 12 weeks were 2.4% and 13.6% of patients who received clopidogrel and ticlopidine, respectively (adjusted hazard ratio, 0.161; 95% confidence interval, 0.062 to 0.416; p <0.0001). Bleeding and vascular events were similar in both groups.

Conclusion: Clopidogrel demonstrated a favorable benefit/risk profile than ticlopidine in Japanese patients with PAD. (

Trial registration: ClinicalTrials.gov, Identifier: NCT00862420).

Keywords: antiplatelets; clinical study; clopidogrel; peripheral arterial disease; vascular event.

Figures

Fig. 1

Study design. R: randomization; o.d.: once daily

Fig. 2

Patient flow diagram.

Fig. 3

Kaplan-Meier curves of first events up to 12 weeks and 52 weeks: all randomized population. A: The cumulative incidence of “safety events of interest” in the clopidogrel group was significantly lower than that of the ticlopidine group (2.4% [95% CI, 0.3% to 4.4%] vs. 13.6% [95% CI, 9.0% to 18.2%] at 12 weeks; adjusted HR, 0.161; 95% CI, 0.062 to 0.416; p <0.0001). B: The cumulative incidence of “safety events of interest” for the CLOP-CLOP group up to 52 weeks (4.8% [95% CI, 1.9% to 7.8%]). C: The cumulative incidence of bleeding adverse events for the CLOP-CLOP group up to 52 weeks (19.1% [95% CI, 13.8% to 24.4%]). D: The cumulative incidence of serious adverse events for the CLOP-CLOP group up to 52 weeks (16.7% [95% CI, 11.7% to 21.8%]). E: The cumulative incidence of vascular events of cerebral infarction, MI or other CV death for the CLOP-CLOP group up to 52 weeks (0.5% [95% CI, 0.0% to 1.4%]). F: The cumulative incidence of vascular events of cerebral infarction, MI, other CV death or hospitalization due to an ischemic event for the CLOP-CLOP group up to 52 weeks (4.3% [95% CI, 1.6% to 7.1%]).