Pharmacodynamic effects of adjunctive cilostazol therapy in patients with coronary artery disease on dual antiplatelet therapy: Impact of high on-treatment platelet reactivity and diabetes mellitus status

Authors


  • Conflict of interest: Honoraria for lectures from Bristol Myers Squibb, sanofi-aventis, Eli Lilly and Co., and Daiichi Sankyo, Inc; Astra Zeneca; consulting fees from Bristol-Myers Squibb, sanofi-aventis, Eli Lilly and Co., Daiichi Sankyo, Inc., The Medicines Company, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, Merck, Abbott Vascular, and Astra Zeneca; and research grants from Bristol Myers Squibb, sanofi-aventis, GlaxoSmithKline, Otsuka, Eli Lilly and Co., Daiichi Sankyo, Inc., The Medicines Company, Portola, Accumetrics, Schering-Plough, Astra Zeneca, Eisai, and Johnson and Johnson (D.J.A.); Honoraria for lectures from Eli Lilly and Co., and Daiichi Sankyo, Inc. (T.A.B); Honoraria for lectures from Abbott, Bristol Myers Squibb, sanofi-aventis, Eli Lilly and Co., and Daiichi Sankyo, Inc, Pfizer; and research grants from Millenium and Astellas (M.Z.Z.); Honoraria for lectures from Daiichi Sankyo, Inc.; Eli Lilly Co. (J.L.F.).

Abstract

Background

In patients on dual antiplatelet therapy with aspirin and clopidogrel, the adjunctive use of cilostazol is associated with enhanced platelet inhibition. However, if cilostazol exerts different pharmacodynamic (PD) effects according to levels of on-treatment platelet reactivity remains unknown. This study aimed to determine the PD effects of cilostazol in patients with and without high on-clopidogrel platelet reactivity (HPR) according to diabetes mellitus (DM) status.

Methods

This is a post-hoc analysis derived from patients (n = 79) enrolled in a prospective, randomized, double-blind, double-dummy, crossover study comparing cilostazol with placebo in stable coronary artery disease patients on aspirin and clopidogrel therapy. In the present analysis, patients were divided according to the presence or absence of HPR (HPR and non-HPR). HPR was defined as a P2Y12 units (PRU) > 240 as assessed by the VerifyNow P2Y12 assay. The PD effects of cilostazol were evaluated in patients with and without HPR according to DM status.

Results

Significant absolute changes in PRU values were observed after adjunctive cilostazol in both HPR [53.4 (95% CI 24.7–82.1), P = 0.001] and non-HPR [40.8 (95% CI 28.7–52.8), P < 0.0001] patients. This difference was statistically significant in HPR patients with DM (P = 0.001), but not without DM (P = 0.24), and in non-HPR patients with and without DM (P = 0.0001 for both). The greatest mean reduction in PRU was observed in HPR patients with DM (72.9; 95% CI 33.7–112.0). Thrombin generation was not affected by cilostazol, irrespective of HPR status.

Conclusion

Cilostazol reduces platelet reactivity both in HPR and non-HPR patients, although these PD effects are enhanced in HPR patients with DM. Nevertheless, larger studies are needed to better evaluate possible differential effects of cilostazol on platelet reactivity by diabetes status. © 2012 Wiley Periodicals, Inc.

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