Pharmacodynamic assessment of prasugrel and clopidogrel in patients with non-cardioembolic stroke: a multicenter, randomized, active-control clinical trial.

Prasugrel, a novel P2Y12 receptor antagonist, has been shown to be more effective than clopidogrel for preventing cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary intervention. We investigated the dose-response antiplatelet effects of prasugrel compared with clopidogrel in Japanese patients with non-cardioembolic stroke. The influence of cytochrome P450 (CYP) polymorphisms on the antiplatelet effects of both drugs was also compared. In this multicenter randomized active-control comparative study, patients were randomized to receive prasugrel 2.5 mg, 5 mg, or 7.5 mg (double blind) or clopidogrel 75 mg (open label) once daily for 14 days. The primary endpoint was inhibition of platelet aggregation (IPA) in response to adenosine diphosphate 20 µM within 8 h of study drug administration on day 14. Of the 66 patients randomized, data from 63 (prasugrel 2.5 mg, 5 mg, and 7.5 mg groups, n = 14, 16, and 18, respectively; clopidogrel group, n = 15) were used in the pharmacodynamic assessment. IPA (arithmetic mean ± SD) after prasugrel administration increased dose-dependently (33 ± 9%, 44 ± 11%, and 53 ± 14%, at 2.5 mg, 5 mg, and 7.5 mg, respectively) and was higher in these groups than after clopidogrel (23 ± 16%). In a subgroup of CYP2C19 intermediate metabolizers, IPA was higher in the prasugrel 5 mg and 7.5 mg groups than in the clopidogrel group. No death or serious adverse events were reported. Prasugrel was well tolerated at doses up to 7.5 mg/day and had antiplatelet effects higher than those of clopidogrel 75 mg/day. CYP2C19 polymorphisms may have reduced clopidogrel-induced IPA.

Efficacy and Safety of Clopidogrel, Prasugrel and Ticagrelor in ACS Patients Treated with PCI: A Propensity Score Analysis of the RENAMI and BleeMACS Registries.

INTRODUCTION: Real-life data comparing clopidogrel, prasugrel, and ticagrelor for unselected patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) are lacking, as are data for the temporal distribution of ischemic and bleeding risks. METHODS: A total of 19,825 patients were enrolled from the RENAMI and BleeMACS registries. Both were multicenter, retrospective, observational registries including the data and outcomes of consecutive patients with ACS who underwent primary PCI and were discharged with dual antiplatelet therapy (DAPT). We evaluated the long-term outcome stratified by the different antiplatelet agents. RESULTS: A total of 14,105 patients (71.2%) were treated with clopidogrel, 2364 patients (11.9%) with prasugrel and 3356 patients (16.9%) with ticagrelor. After propensity score matching, at 1 year, prasugrel reduced the incidence of net adverse clinical events (NACE; a composite endpoint of all-cause death, myocardial infarction [MI] and Bleeding Academic Research Consortium [BARC] 3-5 bleeding) (4.2% vs.7.6%, p = 0.002) and of major adverse cardiovascular events (MACE; a composite endpoint of death and MI) compared with clopidogrel (2.6% vs. 5.2%, p = 0.007). Ticagrelor decreased rates of MACE compared with clopidogrel (2.7% vs. 6.2%, p < 0.001), but not of NACE (6.6% vs. 8.7%, p = 0.07). Ticagrelor presented similar performance in terms of MACE compared with prasugrel (2.8% vs. 2.4%, p = 0.56), with a trend towards a reduction in MI (0.2% vs. 0.4%, p = 0.56), but with higher risk of BARC 3-5 bleedings (3.8% vs. 1.7%, p = 0.04). In the daily risk analysis, clopidogrel presented a binomial distribution with a peak of ischemic risk at 3 months, which decreased towards bleedings; prasugrel had a constant equivalence between opposite risks; and ticagrelor constantly reduced recurrent MIs despite higher risk of BARC 3-5 events. CONCLUSION: In real life, ticagrelor is more effective in reducing ischemic events during the first year after ACS, despite an increased risk of major bleedings, while prasugrel assures a better balance between ischemic and bleeding recurrent events.

Pharmacodynamic Assessment of Platelet Reactivity After a Loading Dose of Prasugrel or Clopidogrel in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Few studies have compared the platelet reactivity of prasugrel and clopidogrel in the acute phase of ST-segment elevation myocardial infarction (STEMI).Methods and Results:Primary percutaneous coronary intervention (PCI) was performed in 78 patients with STEMI within 12 h of onset. Patients were randomly assigned to receive a Japanese standard loading dose of prasugrel 20 mg or clopidogrel 300 mg. Platelet reactivity was serially assessed using the VerifyNow-P2Y12 assay, the results of which were expressed as P2Y12-reaction-units (PRU). PRU values were significantly lower in the prasugrel group (n=38) than in the clopidogrel group (n=40) at 3 h, 24 h, and 14 days after loading (191±101 vs. 271±50, 147±80 vs. 261±57, and 171±67 vs. 221±70, respectively, P<0.05), although the PRU levels at baseline (231±57 vs. 237±58, P=0.65) and 1 h after loading (282±65 vs. 291±62, P=0.54) were similar. As compared with the baseline values, the PRU levels at 1, 3 and 24 h after clopidogrel loading were significantly higher (respectively, P<0.05), whereas only the PRU at 1 h after prasugrel was elevated (P<0.001). CONCLUSIONS: In Japanese patients with STEMI who undergo primary PCI, prasugrel provides stronger platelet inhibition than clopidogrel from 3 h after loading, whereas platelet reactivity remained elevated within 24 h after clopidogrel loading. (Circ J 2016; 80: 2520-2527).