Absence of "rebound" platelet hyperreactivity following cessation of prasugrel

doi:10.1160/TH10-11-0764 Thromb Haemost 2011; 106: 174–176 Dear Sir, Recurrence of ischaemic events following cessation of clopidogrel has been suggested to be due to rebound platelet hyperreactivity (1, 2). In light of such reports, we performed a retrospective analysis to determine if this phenomenon occurs following cessation of prasugrel. Data was from an open-label, fixed-sequence, two-period, two-treatment crossover, clinical pharmacology study that included assessment of platelet reactivity (PR) before, during, and after treatment with prasugrel. It was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice, approved by an independent ethics committee, and all participants gave written informed consent prior to enrollment. Healthy male subjects (n = 23), 29 ± 11 years of age (mean ± standard deviation [SD]) with a body mass index (BMI) (mean ± SD) of 24.6 ± 2.4 kg/m2 were enrolled. Subjects received a prasugrel 60-mg loading dose (LD) followed by once-daily 10-mg maintenance doses (MD) for seven days. Blood was drawn at baseline, various time points after LD and MDs, and on days 4, 5, 6, and 16 (median, 15–30 days) after the last MD. Platelet reactivity was assessed by light transmission aggregometry (LTA) as described (3, 4). Agonists included 5 μM and 20 μM adenosine diphosphate (ADP), 2 μg/ml collagen, and 1.5 mM arachidonic acid with maximum platelet aggregation (MPA) and residual platelet aggregation (RPA) recorded (5). Vasodilator-associated phosphoprotein (VASP) phosphorylation was measured by flow cytometry (6). Rebound platelet hyperreactivity was declared if any platelet activation/aggregation measure exceeded the baseline value by >20%. Statistical analyses were performed with SAS software (version 9.1). Pharmacodynamic parameters were analysed separately by mixed-effect models at the two sided alpha = 5% level. Least squares (LS) mean differences, 90% confidence intervals (CIs), and corresponding p-values were calculated from each model for the comparisons to baseline. Following administration of prasugrel, patterns of platelet inhibition with 5 μM and 20 μM ADP were similar and confirmed that high levels of P2Y12 blockade were achieved ( Fig. 1A). At 4 hours (h) after the LD, MPA (mean ± SD) for 5 μM ADP (10.3 ± 5.0) was significantly decreased (p < 0.001) from baseline (72.8 ± 20.1) with slightly higher levels of aggregation (15.4 ± 11.3) at 4 h after the last MD, but remaining significantly decreased from baseline (p < 0.001). MPA in response to 20 μM ADP showed similar patterns of inhibition and also remained significantly decreased than baseline (p < 0.001). MPA values for 5 μM and 20 μM ADP recovered gradually between days 1 and 6 after the last MD with no evidence of rebound platelet hyperreactivity. Likewise, at washout (median 16 days after final prasugrel MD), MPA values for both concentrations of ADP (5 μM ADP = 71.3 ± 4.4 and 20 μM ADP = 85.1 ± 1.5) were not significantly different from baseline (p = 0.62 and 0.42, respectively). At no time throughout the washout period did values exceed their respective baseline values. Statistical analysis of MPA induced by 5 μM ADP and 20 μM ADP, at baseline compared to final washout showed no significant differences ( Suppl. Table 1 available online at www.thrombosis-online.com). The time course of RPA for 5 μM and 20 μM ADP was similar to that seen for MPA with no evidence of rebound hyperreactivity as evidenced by a lack of significant difference between washout values and baseline ( Suppl. Fig. 2 and Suppl. Table 2 available online at www.thrombosis-on line.com). Although assayed at fewer time points during the washout period, the MPA ob-