A Pharmacodynamic Comparison of Prasugrel Versus Ticagrelor in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-4 Study
Background—Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events, underscoring the importance of effective platelet inhibiting therapies. Prasugrel and ticagrelor reduce thrombotic complications to a greater extent than clopidogrel. Subgroup analyses of pivotal clinical trials testing prasugrel and ticagrelor versus clopidogrel showed DM patients to have benefits that were consistent with the overall trial populations, although the magnitude of the ischemic risk reduction appeared to be enhanced with prasugrel. Whether these findings may be attributed to differences in the pharmacodynamic (PD) profiles of these drugs in DM patients remains poorly explored and represented the aim of this study.
Methods—In this prospective, randomized, double-blind, double-dummy, cross-over PD study, aspirin-treated DM patients (n=50) with coronary artery disease (CAD) were randomized to receive prasugrel [60mg loading dose (LD)/10mg maintenance dose (MD) qd] or ticagrelor (180mg LD/90mg MD bid) for 1 week. PD assessments were conducted using 4 different assays, including VerifyNow P2Y12, VASP, light transmittance aggregometry and Multiplate, which allowed to explore ADP- and non-ADP-induced (arachidonic acid-, collagen-, thrombin receptor activating peptide-induced) platelet signaling pathways. The acute (baseline, 30 min and 2 h post-LD) and maintenance (1-week) effects of therapy were assessed. The primary end-point of the study was the comparison of P2Y12 reaction units (PRU) determined by VerifyNow P2Y12 at 1-week between prasugrel and ticagrelor.
Results—ADP- and non-ADP-induced measures of platelet reactivity reduced significantly with both prasugrel and ticagrelor LD and MD. PRU defined by VerifyNow were similar between prasugrel and ticagrelor at 30 min and 2 h post-LD. At 1-week PRU was significantly lower with ticagrelor compared with prasugrel (52 [32-72] vs 83 [63-103]; LSM difference: -31; 95% CI: -57 to -4; p=0.022; primary endpoint). PD assessments measured by VASP, light transmittance aggregometry and Multiplate were similar between prasugrel and ticagrelor at each time point, including at 1-week. Rates of high on-treatment platelet reactivity were similar between groups with all assays at all time points.
Conclusions—In DM patients with CAD, ticagrelor exerts similar or greater inhibition of ADP-induced platelet reactivity compared to prasugrel in the acute and chronic phases of treatment, while the inhibition of measures of non-ADP-induced platelet reactivity were not significantly different between the two agents
Clinical Trial Registration—URL: http://www.clinicaltrials.gov Unique identifier: NCT01852214.
- Received May 9, 2016.
- Revision received July 15, 2016.
- Accepted July 25, 2016.