Prasugrel versus clopidogrel in aspirin-treated patients with CAD

December 15, 2008
Christoph Varenhorst

We studied platelet adenosine diphosphate P2Y12 receptor antagonism and inhibition of platelet aggregation in patients with stable coronary artery disease.

In combination with aspirin, clopidogrel is currently the drug of choice for patients with acute coronary syndromes (ACS) and those undergoing stent implantation.1 There is evidence of an increase in the speed of onset and greater platelet inhibition with a 600-mg clopidogrel loading dose compared with the approved 300-mg loading dose.2 Current data show that 5% to 44% of clopidogrel-treated patients respond poorly to treatment,3 and poor response seems to increase the risk of cardiovascular events.4 The reasons for the poor response to clopidogrel are unclear, but several mechanisms have been proposed.3

We assessed the pharmacodynamic and pharmacokinetic effects of prasugrel 60-mg loading dose and 10-mg maintenance dose compared with clopidogrel 600-mg loading dose and 75-mg maintenance dose in aspirin-treated patients with coronary artery disease (CAD). We also investigated the mechanisms of poor response with the addition of clopidogrel’s active metabolite to patients’ plasma samples ex vivo.

Subjects and methods

We conducted a randomized, double-blind, double-dummy, parallel-group trial that included 110 male and female patients, aged 40 to 75 years, with stable CAD. Following a lead-in period on aspirin, subjects were assigned to treatment with either clopidogrel 600-mg loading dose and a 75-mg maintenance dose or prasugrel 60-mg loading dose and a 10-mg maintenance dose. There was no significant difference between treatment groups in baseline clinical characteristics except for a small difference in age (<3 years). The study was conducted according to the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines.

Adenosine diphosphate (ADP)-induced platelet aggregation was measured using light transmission aggregometry (LTA) and vasodilator-stimulated phosphoprotein (VASP) assay. Measurements were taken on day 1 at baseline (predose); up to 24 hours after administration of the loading dose and during the maintenance dose period; day 14 ± 3; and day 29 ± 3. Platelet inhibition measured by LTA and VASP assay was expressed as maximal platelet aggregation (MPA, %) and platelet reactivity index (PRA, %), respectively.

Plasma concentrations of the prasugrel active metabolite and clopidogrel active metabolite were analyzed in samples obtained at predefined time points and assayed using validated liquid chromatography.5 Clopidogrel’s active metabolite (10M) was added ex vivo to samples collected at baseline (pre-loading dose) and on day 29. Platelet inhibition was then characterized using both LTA and VASP assay.


As measured by LTA, mean MPA values induced by 20M ADP were significantly lower with prasugrel in the first sample, which was taken 30 minutes after administration of the loading dose, and at all time points thereafter (P <.001). At 2 hours, the mean MPA was 31% with prasugrel compared with 54.7% for clopidogrel (P <.001). During maintenance-dose treatment (day 14 and day 29), the MPA values were still significantly lower in the prasugrel group compared with the clopidogrel group (P <.001; Figure 1A). Similar differences in platelet inhibition between treatments were observed using the VASP assay. There was a significantly greater reduction in PRI (P2Y12 receptor blockade represented by a lower PRI) at 1, 2, and 24 hours after the prasugrel loading dose was administered (PRI of 16.0%, 8.3%, and 8.7%, respectively) compared with the clopidogrel loading dose (PRI of 68.5%, 55.9%, and 50.2%, respectively; P <.001). The reduction in PRI was also significantly greater after administration of the prasugrel maintenance dose compared with the clopidogrel maintenance dose (Figure 1B).

Inhibition of platelet aggregation induced by 20 μM ADP over time following administration of prasugrel 60-mg loading dose and 10-mg maintenance dose versus clopidogrel 600-mg loading dose and 75-mg maintenance dose, as measured by MPA (%; A) or PRI (%; B). LD indicates loading dose, MD = maintenance dose, SD = standard deviation.

Figure 1.

Following the prasugrel 60-mg loading dose, active metabolite concentrations peaked at early time points (30 minutes) and were higher than those after the clopidogrel 600-mg loading dose. Similarly, active metabolite concentration for prasugrel was also higher than those of clopidogrel during maintenance-dose treatment (Figure 2). Clopidogrel’s active metabolite added ex vivo to patient blood samples taken before the loading or maintenance doses led to a lower level of PRI in all samples, including those from patients with a poor response to the clopidogrel loading dose (Figure 3).

Plasma concentrations of prasugrel and clopidogrel active metabolites after administration of a single loading dose and during maintenance dosing of thienopyridines. LD indicates loading dose, h = hours, MD = maintenance dose, SD = standard deviation.

Figure 2.

Platelet reactivity index (PRI, %) before and after ex vivo addition of clopidogrel’s active metabolite for subjects on clopidogrel or prasugrel. The bottom of each box represents the first quartile, the top of the box represents the third quartile, and the line in the box represents the median. AM indicates active metabolite, LD = loading dose, MD = maintenance dose.

Figure 3.


The results of our study clearly demonstrate that a prasugrel 60-mg loading dose provides a more rapid onset and greater inhibition of ADP-induced platelet aggregation than those achieved with a clopidogrel 600-mg loading dose. The greater speed of onset and magnitude of the platelet inhibitory effect with prasugrel might be clinically important in the treatment of ACS patients, especially those undergoing percutaneous coronary interventions.6

After administration of the prasugrel 10-mg maintenance dose, MPA values remained significantly lower compared with the clopidogrel 75-mg maintenance dose, although during maintenance dosing, the difference was halved compared with the results observed after administration of the prasugrel loading dose. The maintenance doses of both prasugrel and clopidogrel were selected for the completed phase 3 TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-TIMI 38) study based on estimates of optimal balance between safety and efficacy from earlier trials.7-9

LTA using ADP as the agonist for assessing P2Y12 effects is confounded because ADP-receptor subtypes other than P2Y12 can be activated and contribute to platelet aggregation.10 Flow cytometric assessment of VASP phosphorylation is a relatively new assay that measures P2Y12 function more directly. This assay is less dependent than ADP-induced LTA on other pathways to yield the final assay end point; thus, it is more suitable for comparing specific P2Y12 inhibitory effects of thienopyridines.11 Results from the VASP analyses illustrated a larger difference in P2Y12 inhibition between the treatments than the LTA measurements. This difference was most likely due to that LTA also reflecting P2Y1-receptor—mediated aggregation, which is not inhibited by clopidogrel or prasugrel. Our results show earlier, higher peak levels, and greater exposure to prasugrel’s active metabolite compared with clopidogrel and provide the mechanistic basis for the faster onset and greater inhibition of P2Y12-mediated platelet aggregation with prasugrel.

Ex vivo addition of clopidogrel’s active metabolite to blood samples resulted in a decrease in PRI for all subjects, including those who were poor pharmacodynamic responders. This suggests that all patients’ P2Y12 receptors respond to thienopyridine inhibition if the concentration of the active metabolite reaches an adequate level. Addition of active metabolite to samples from patients administered a clopidogrel loading dose led to a further reduction in PRI values, indicating that P2Y12 receptors were not maximally inhibited but receptive to blockade. This was not observed for samples taken after administration of the prasugrel loading dose, indicating that P2Y12 receptor blockade was already maximal and could not be further inhibited. Together, these results indicated that the variable inhibition of platelet aggregation observed with clopidogrel results from lower exposure to the active metabolite, rather than the presence of P2Y12 receptor heterogeneity.12,13


A 60-mg loading dose of prasugrel followed by a 10-mg maintenance dose provided faster onset and more pronounced inhibition of P2Y12 receptor-mediated platelet aggregation than a high (600 mg) clopidogrel loading dose followed by a 75-mg maintenance dose in aspirin-treated CAD patients. This difference resulted from faster, greater, and more efficient generation of the active metabolite from prasugrel than clopidogrel. Addition of the active metabolite ex vivo led to maximal inhibition of aggregation in all patients; thus, a poor response to clopidogrel is explained by ineffective generation of the active metabolite, rather than P2Y12 receptor heterogeneity.


We would like to thank John T. Brandt, MD, of Eli Lilly and Company for his scientific support in conducting this study and to Vivian T. Thieu for her writing assistance. We’d also like to thank the statisticians, Sylvia Olofsson, MSc, Uppsala Clinical Research Centre, and Timothy M. Costigan, PhD, Eli Lilly and Company, for their assistance with data analysis.

Varenhorst, Wallentin, James, Erlinge, Braun, and Siegbahn received an institutional grant from Daiichi Sankyo Company Ltd and Eli Lilly and Company to conduct this research. Winters, Jakubowski, and Brandt are employees and stockholders of Eli Lilly and Company. Sugidachi is an employee and stockholder of Daiichi Sankyo Company Ltd