Switching from clopidogrel to prasugrel or ticagrelor: tips and tricks

This editorial refers to ‘A head-to-head pharmacodynamic comparison of prasugrel vs. ticagrelor after switching from clopidogrel in patients with coronary artery disease: results of a prospective randomized study’†, by F. Rollini et al. on page 2722. Clopidogrel is a thienopyridine prodrug, the active metabolite of which (CAM) inhibits the interaction of ADP with its platelet P2Y12 receptor, which plays a central role in platelet activation and thrombus formation.1 In combination with aspirin, it is recommended for patients with acute coronary syndromes (ACS) and for those undergoing percutaneous coronary interventions (PCIs) to reduce the risk of subsequent cardiovascular events such as stent thrombosis or other major adverse cardiovascular events (MACE).1 Its clinical utility is hampered by the wide interindividual variability of pharmacological response, with a significant proportion of subjects (∼30%) who are poor responders, displaying high on-treatment platelet reactivity (HPR).2,3 Impaired transformation of the prodrug to CAM by hepatic cytochrome P450 (CYP) is among the most important causes of HPR. Because patients with HPR are at increased risk of MACE,2,3 alternative P2Y12 antagonists displaying a lower degree of interindividual variability of platelet inhibition are necessary in order to protect the large majority of patients from stent thrombosis and MACE. Hypothesis of P2Y12 receptor occupancy up to 24 h after a loading dose (LD) and 7 days after maintenance doses (MDs) of prasugrel or ticagrelor given to patients on maintenance treatment with clopidogrel. 1. Maintenance treatment with 75 mg/day clopidogrel accomplishes partial, irreversible inhibition of the platelet P2Y12 receptors; 24 h after the last dose of clopidogrel, virtually no active metabolite of clopidogrel (CAM) will be present in the circulation, due its very short half-life. 2. Two hours after an LD of prasugrel or ticagrelor, high concentrations of the active metabolite of prasugrel (PAM) and ticagrelor are present in the circulation and occupy the P2Y12 receptors on platelets that had not already been occupied by CAM. 3. Twenty-four hours after an LD of prasugrel, virtually no PAM will be present in the circulation, but virtually all P2Y12 receptors will be occupied by either CAM or PAM; 24 h after an LD of ticagrelor, fewer molecules of ticagrelor will be present in the circulation, but virtually all P2Y12 receptors will be occupied by either CAM or ticagrelor (especially if the first MD of ticagrelor is given 12 h after the LD). 4. Seven days after MDs of prasugrel or ticagrelor, virtally no platelets with P2Y12 occupied by CAM will be present in the circulation, due to the replacement of CAM-inhibited platelets by newly formed platelets; virtually all P2Y12 receptors will be occupied by PAM or ticagrelor; PAM will be virtually absent in the circualtion due to its short half-life. Prasugrel is a newer generation thienopyridine with more rapid and less variable inhibitory effects on platelet aggregation than clopidogrel, due to its peculiar chemical structure which permits conversion to its active metabolite (PAM) with less dependence on CYP enzymes than clopidogrel.1 Ticagrelor belongs to the new chemical class cyclopentyl-triazolo-pyrimidines: it does not require conversion to an active metabolite and has a half-life of ∼8.5 h.1 After oral administration, it rapidly and reversibly inhibits P2Y12 with a much lower interindividual variability compared with clopidogrel. Both prasugrel and ticagrelor were shown to reduce the incidence of stent thrombosis and MACE in randomized clinical trials, compared with clopidogrel.4,5 Although ticagrelor has an additional mechanism of action that is mediated by increased bioavailability of adenosine, which might contribute to its clinical efficacy,6 it is likely that the greater antithrombotic efficacy of ticagrelor and prasugrel compared with clopidogrel can be explained by the lower interindividual variability of response to these drugs.7 As a matter of fact, more patients treated with prasugrel or ticagrelor than patients treated with clopidogrel display optimal inhibition of platelet function and, as a consequence, are protected from stent thrombosis and MACE. For the same reason, treatment with prasugrel or ticagrelor is associated with increased incidence of bleeding complications not associated with coronary artery bypass surgery, because effective inhibition of P2Y12 impairs platelet-dependent haemostasis. Despite the increased incidence of bleeding complications, the net clinical benefit of both prasugrel and ticagrelor was superior to that of clopidogrel. The comparative safety and efficacy profiles of prasugrel and ticagrelor are unknown because no direct comparisons in clinical trials with clinical endpoints have been conducted. Several comparative studies with pharmacodynamic endpoints have been performed: although many of them showed that ticagrelor achieved greater degrees of P2Y12 inhibition compared with prasugrel, this finding was not consistent across all studies.8,9 Moreover, only one type of platelet function assay was generally used and the effects of maintenance doses (MDs) of the drugs were prevalentely evaluated, generally at one time point only.8,9 Thus, further studies comparing the pharmacodynamics of prasugrel and ticagrelor in large cohorts of patients are necessary. Notwithstanding the more favourable clinical profile of prasugrel and ticagrelor, clopidogrel is still the most widely used P2Y12 antagonist in clinical practice. Attempts are still being made to identify poor responders to clopidogrel, based on the results of laboratory tests exploring platelet function in vitro, with the aim of treating them with alternative treatments that could increase the degree of inhibtion of platelet function.2 Unfortunately the two large-scale randomized, double-blind clinical trials that have been completed and published so far failed to demonstrate that this strategy is effective in reducing the incidence of stent thrombosis and MACE.10,11 Of note, clopidogrel is very widely used for upfront treatment of patients with ACS, despite the fact that the benefits of early inhibition of P2Y12 are still controversial. This practice poses the problem to treating physicians of how to switch from clopidogrel to prasugrel or ticagrelor.12 Theoretically, switching to prasugrel or ticagrelor from clopidogrel, whose active metabolite (CAM) has a very short half-life and irreversibly inhibts P2Y12, should not pose particular problems. PAM, the active metabolite of prasugrel, whose half-life and potency are identical to those of CAM,13 will have the same effects on P2Y12, although the number of inhibited P2Y12 receptors will be higher, due to the higher concentrations of PAM reached in vivo compared with CAM (Figure 1). Switching from clopidogrel to ticagrelor should not raise any problems either, despite the differences between the two drugs: ticagrelor does not need to be metabolized into an active metabolite to exert its action, it has a longer half-life than CAM, and it reversibly inhibts the receptor.1 Ticagrelor will not compete with CAM at the P2Y12 receptor level, when administered 12/24 h after clopidogrel, because CAM will be already cleared from the circulation by that time (Figure 1). In addition, ticagrelor, independently of whether or not its binding site on platelets is the same as that of CAM,14,15 will antagonize the receptors that have not been occupied by CAM. The studies that have been published so far basically confirmed this hypothetical expectation. In this issue of the journal, Rollini et al. publish the results of an elegant study that compared the degree of inhibition of platelet function by loading dose (LD) and MD of ticagrelor and prasugrel administered to patients on chronic treatment with clopidogrel.16 The main characteristics of the study were the following: (i) a prospective, randomized, parallel design, open-label study of a large number of patients (n = 110) with angiographically proven coronary artery disease on treatment with low-dose aspirin (<100 mg/day) and clopidogrel (75 mg/day) for at least 1 month; (ii) patients were randomly assigned (1:1) to either prasugrel (LD 60 mg + MD 10 mg/day) or ticagrelor (LD 180 mg + MD 90 mg b.i.d; (iii) the first MD of ticagrelor was given 24 h after the LD, but in a second phase of the study, which involved only 27 patients who agreed to participate, it was given 12 h after the LD; (iv) the pharmacodynamic effects of switching to prasugrel or ticagrelor were studied at different time points: baseline, 30 min, 2 h, 24 h, and 1 week; and (v) platelet function was tested using three different assays: vasodilator-stimulated phosphoprotein (VASP) phosphorylaion assay, VerifyNow P2Y12, and light transmission aggregometry (LTA). Platelet reactivity, independently of the laboratory test used to measure it, significantly decreased 30 min after the LD of prasugrel or ticagrelor, further decreased at 2 h, and remained low for up to 1 week of treatment with MDs of the drugs. No statistically significant differences between the two treatment arms were observed, with the exceptions of the 30 min time point (LTA only) and the 24 h time point (all tests) of the first phase of the study, when platelet reactivity was significantly lower in prasugrel-treated patients. Platelet reactivity at 24 h was lower and similar to that achieved with prasugrel in the subgroup of patients who participated in the second phase of the study, to whom the first MD of ticagrelor was given 12 h, instead of 24 h after the LD. The analysis for repeated measures adjusted for baseline values indicated that there was a trend towards lower levels of platelet reactivity with VASP and VerifyNow-P2Y12, which reached statistical significance with LTA, in prasugrel-treated patients. The prevalence of HPR varied according to the assay used, confirming the poor agreement between different tests of platelet function for the identification of this phenotype,2 and decreased substantially after switching from clopidogrel to prasugrel or ticagrelor, with no statistically significant differences bewteen the two arms. In conclusion, the carefully performed study by Rollini et al. indicates that, in patients on maintenance treatment with clopidogrel, switching to prasugrel or ticagrelor decreases platelet reactivity significantly, with no major statistically significant differences between the two drugs. Consistently, the prevalence of HPR was also similarly decreased by prasugrel and ticagrelor. The study also suggests that, when switching to ticagrelor, the MD regimen should be started 12 h after the LD in order to achieve a degree of inhibition of platelet reactivity 24 h post-LD that is comparable with that observed with prasugrel. Conflict of interest: none declared.