A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial

Dominick J Angiolillo, Juan Jose Badimon, Jorge F Saucedo, Andrew L Frelinger, Alan D Michelson, Joseph A Jakubowski, Baojin Zhu, Clement K Ojeh, Brian A Baker, Mark B Effron, Dominick J Angiolillo, Juan Jose Badimon, Jorge F Saucedo, Andrew L Frelinger, Alan D Michelson, Joseph A Jakubowski, Baojin Zhu, Clement K Ojeh, Brian A Baker, Mark B Effron

Abstract

Aims: Patients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM.

Methods and results: Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind, crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n= 35) were randomly assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was assessed by VerifyNow® P2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNow® P2Y12 was achieved by prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P< 0.0001; primary endpoint). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7 days (P < 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in fewer poor responders at all time points irrespective of definition used.

Conclusion: In patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel.

Trial registration: ClinicalTrials.gov NCT00642174.

Figures

Figure 1
Figure 1
(A) Study design. (B) Patient disposition.
Figure 2
Figure 2
Platelet function by VerifyNow® P2Y12. (A) Inhibition of platelet aggregation. (B) VerifyNow® P2Y12 PRU. Values are expressed as the least-squares mean and 95% confidence intervals. Prasugrel and clopidogrel values from each treatment period have been combined. Time 0 is the baseline value (combined for each treatment period). ***P< 0.0001.
Figure 3
Figure 3
Platelet aggregation by light transmission aggregometry. (A) Maximum platelet aggregation to 20 μM ADP; (B) maximum platelet aggregation to 5 μM ADP; (C) inhibition of platelet aggregation in response to 20 μM ADP; (D) inhibition of platelet aggregation in response to 5 μM ADP. Values are expressed as the least-squares mean and 95% confidence intervals. Prasugrel and clopidogrel values from each treatment period have been combined. Time 0 is the baseline value (combined for each treatment period). *P= 0.0002, **P = 0.0001, ***P < 0.0001.
Figure 4
Figure 4
Platelet function by vasodilator-stimulated phosphoprotein. Vasodilator-stimulated phosphoprotein platelet reactivity index values are expressed as the least-squares mean and 95% confidence intervals. Prasugrel and clopidogrel values from each treatment period have been combined. Time 0 is the baseline value (combined for each treatment period). **P< 0.01, ***P< 0.0001.
Figure 5
Figure 5
Individual response profiles. VerifyNow® P2Y12 PRU was measured at 0 h (baseline) and 4 h post-loading dose of prasugrel or clopidogrel. (A) Patients dosed with clopidogrel first and then crossed over to prasugrel. (B) Patients dosed with prasugrel first and then crossed over to clopidogrel. Baseline (0 h) values for the second treatment period were measured after the 2-week washout period. BL, baseline.
Figure 6
Figure 6
Poor responders. Poor responder analyses were conducted at (A) 4 h post-loading dose; (B) 24 h post-loading dose; and (C) 7 days by VerifyNow® (PRU >235), light transmission aggregometry (MPA >50% and IPA ≤20%), or vasodilator-stimulated phosphoprotein phosphorylation (PRI >50%) platelet function assays. P-values for comparison between treatment groups for each assay are indicated. MPA, maximum platelet aggregation to 20 µM ADP by light transmission aggregometry; IPA, inhibition of platelet aggregation with 20 µM ADP by light transmission aggregometry.

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