Comparison of antiplatelet effect and tolerability of clopidogrel resinate with clopidogrel bisulfate in patients with coronary heart disease (CHD) or CHD-equivalent risks: a phase IV, prospective, double-dummy, parallel-group, 4-week noninferiority trial.

Abstract

BACKGROUND: Clopidogrel resinate is a resinate complex of (+)-clopidogrel optical isomer, wherein the (+)-clopidogrel isomer binds to a water-soluble cation exchange resin via sulfonic acid groups. It was approved by the Korean Food and Drug Administration on the basis of a Phase I study that demonstrated the bioequivalence of clopidogrel resinate and clopidogrel bisulfate. However, there are no available data regarding efficacy and tolerability in patients with vascular disease.

OBJECTIVE: The goal of this study was to investigate the antiplatelet efficacy and tolerability of clopidogrel resinate in patients with coronary heart disease (CHD) or CHD-equivalent risks.

METHODS: This study was a Phase IV, randomized, double-blind, double-dummy, parallel-group, noninferiority trial. We prospectively recruited patients in 10 centers between March 2008 and July 2008. Patients who had documented CHD or CHD-equivalent risks were randomly assigned to 1 of 3 groups: group A, aspirin (100 mg) + clopidogrel bisulfate placebo + clopidogrel resinate placebo; group B, aspirin (100 mg) + clopidogrel bisulfate placebo + clopidogrel resinate (75 mg); or group C, aspirin (100 mg) + clopidogrel bisulfate (75 mg) + clopidogrel resinate placebo. The primary outcome was the percent P2Y(12) inhibition after medication, assessed by using a point-of-care assay. If the 1-sided 90% upper confidence limit for the difference was less than the prespecified delta value (-5.7), clopidogrel resinate would be considered noninferior to clopidogrel bisulfate. The secondary outcome, the prevalence of adverse events (AEs) associated with study medications, was assessed at each visit by direct interview.

RESULTS: A total of 314 patients (mean [SD] age, 62.2 [9.0] years; male 63.7%; weight, 67.3 [13.6] kg [range, 45-102 kg]; all Asian) were enrolled, and 287 patients finished the study (group A, n = 97; group B, n = 90; and group C, n = 100). Eight patients took no study medications and were excluded from the tolerability and efficacy analyses. Nineteen patients discontinued the study because of protocol violation (n = 15), adverse events (n = 3), or voluntary withdrawal (n = 1) and were excluded from the efficacy analysis. There were no significant differences in baseline clinical characteristics among the groups except for the frequency of a history of CHD (group A, 85.4%; group B, 73.0%; and group C, 88.3%; P = 0.01). Patients treated with either type of clopidogrel showed significant inhibition (mean [SD]) of P2Y(12) (group A, -5.9% [15.1%]; group B, 23.4% [21.9%]; and group C, 19.5% [23.8%]; P < 0.001). Differences between clopidogrel resinate and clopidogrel bisulfate in the inhibition of P2Y(12) did not exceed the predetermined value for inferiority (P for noninferiority, 0.02; 90% CI, -0.9 to 10.3). In the tolerability analysis, there was no mortality during the study period and no significant differences between groups in the frequency of AEs and serious AEs (AEs: group A, 33.0%; group B, 26.0%; and group C, 23.3% [P = 0.27]; serious AEs: group A, 1.0%; group B, 3.0%; and group C, 1.0% [P = 0.42]). One patient in group B underwent coronary stent implantation for treatment of stable angina.

CONCLUSIONS: In this small, selected Asian patient population, differences in the platelet inhibition efficacies of clopidogrel resinate and clopidogrel bisulfate did not exceed the predetermined limits for noninferiority. The differences in tolerability between the 2 drugs did not reach statistical significance.