Switching from Clopidogrel to Prasugrel in patients undergoing PCI: A meta-analytic overview

Despite the demonstrated benefits of Prasugrel, a new generation thienopyridine, in the prevention of thrombotic complications after percutaneous coronary interventions (PCI) for Acute Coronary Syndromes (ACS), its use is still precluded to those many patients arriving to the cath lab pre-treated with Clopidogrel. Conclusive data on the strategy of switching from Clopidogrel to Prasugrel are still missing, therefore we aimed to perform a meta-analysis of current studies evaluating the safety and efficacy of switching from Clopidogrel to Prasugrel (PS) as compared to a standard thienopyridine therapy with Clopidogrel or Prasugrel in patients undergoing PCI. Literature archives and main scientific sessions’ abstracts were scanned for studies comparing a switching strategy from Clopidogrel to Prasugrel vs. Prasugrel or Clopidogrel. Primary efficacy endpoint was overall mortality. Secondary endpoints were: non-fatal myocardial infarction and definite/probable stent thrombosis. Safety endpoint was the rate of major bleedings according to a per-protocol definition. A total of 12 studies, involving 3956 patients, were included. Among them, 1396 patients (35.3%), received Prasugrel after a Clopidogrel treatment (PS), while 2560 (64.7%) received either Prasugrel or Clopidogrel. The switch from Clopidogrel to Prasugrel was in the majority of the studies periprocedural. The mortality was numerically lower, but not statistically significant, in the PS group as compared with patients who did not switch (1.7% vs. 3.8%, OR [95% CI]?=?0.68 [0.40,1.15], p?=?0.15, p_het?=?0.61), without any relationship with patients’ risk profile (r?=??0.68 [?2.09, 0.73], p?=?0.35). Similar results were obtained for secondary efficacy endpoints and at sensitivity analysis in the majority of subgroups evaluated. Moreover, the PS strategy did not increase major bleedings as compared with standard therapy (1.4% vs. 2.5%, OR [95% CI?=?0.70 [0.39, 1.25], p?=?0.23, p_het?=?0.6). The present meta-analysis confirms that, among patients undergoing PCI, switching from Clopidogrel to Prasugrel may be safely performed and therefore should be encouraged among patients eligible to Prasugrel.     

P2Y12 receptor inhibitors for secondary prevention of ischemic stroke

Introduction: Ischemic stroke (IS) is a major cause of death and disability worldwide. The P2Y₁₂ receptor plays a critical role in the formation of a stable thrombus leading to ischemic complications. Therefore, P2Y₁₂ receptor inhibitors constitute a major antiplatelet strategy in the secondary prevention of IS.

Areas covered: We searched articles about P2Y₁₂ receptor inhibitors and stroke in PubMed published until December 2014. This is a comprehensive review of the role of P2Y₁₂ receptor inhibitors alone and in combination with aspirin in the secondary prevention of noncardioembolic stroke.

Expert opinion: The potential benefit of more potent antiplatelet therapy for secondary stroke prevention must be weighed against the risk of bleeding in patients with IS. Short-term (≤ 3 months) dual antiplatelet therapy with clopidogrel and aspirin that is initiated early after IS or transient ischemic attack due to large artery atherosclerosis appears most efficient.     

氯吡格雷抵抗的临床处理

急性冠状动脉综合征的患者尽管接受了标准剂量的氯吡格雷治疗,仍有部分患者发生缺血性心血管事件,称为氯吡格雷抵抗。氯吡格雷抵抗引起的广泛关注使个体化抗血小板药物成为这些患者改善预后的治疗策略。在遗传学检测的辅助下,新型P2Y12受体拮抗剂普拉格雷、替卡格雷和坎格雷拉以及糖蛋白Ⅱb/Ⅲa受体拮抗剂和高剂量氯吡格雷是可能的应对措施。就现有的临床试验研究证据对氯吡格雷抵抗患者的个体化治疗做一综述。     

The influence of body size on the pharmacodynamic and pharmacokinetic response to clopidogrel and prasugrel: A retrospective analysis of the FEATHER study

Introduction

Patients treated with clopidogrel who have higher body size exhibit greater platelet reactivity than patients with lower body size. In a retrospective analysis of the FEATHER trial, we examined the relationship between platelet response to thienopyridines clopidogrel 75 mg (Clop-75), prasugrel 5 mg (Pras-5), and prasugrel 10 mg (Pras-10) using 3 body size indices: body weight (BW), body mass index (BMI), and body surface area (BSA). Relationships were assessed as continuous variables and as 4 incremental body size groups.

Materials and Methods

Aspirin-treated patients with stable coronary artery disease (N = 72) and a BW range of 45-134 kg received Clop-75, Pras-5, and Pras-10 in a 3-period, blinded, cross-over study. Platelet assays included maximum platelet aggregation (MPA) to 20 μM ADP by light transmission aggregometry, VerifyNow-P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). Exposure to active metabolites (AMs) was also assessed.

Results

Body size was a determinant of AM exposure and residual platelet reactivity regardless of type and dose of thienopyridine. BW and BSA demonstrated marginally stronger correlations with platelet reactivity; VASP-PRI demonstrated a stronger correlation with the body size than the other tests. Correlation coefficients ranged from a high of 0.64 (BW vs. PRI on Pras-5) to a low of 0.34 (BMI vs. MPA on Pras-10), but all were statistically significant (p < 0.01).

Conclusions

Using a comprehensive selection of body size indices, AM exposures, platelet function tests, and thienopyridine doses, we demonstrated a consistent inverse relationship between body size and response to clopidogrel and prasugrel.     

Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease

Objective:  The pharmacokinetic (PK) and pharmacodynamic (PD) responses to prasugrel were compared in three studies of healthy subjects vs. those with moderate or end-stage renal impairment.
Methods:  Two of the three protocols were parallel-design, open-label, single dose (60-mg prasugrel) studies in subjects with end-stage renal disease (ESRD; n  = 12) or moderate renal impairment ( n  = 10) and matched healthy subjects with normal renal function ( n  = 10). The third protocol was an open-label, single-dose escalation (5, 10, 30 and 60 mg prasugrel) study in subjects with ESRD ( n  = 16) and matched healthy subjects with normal renal function ( n  = 16). Plasma concentrations of prasugrel's active metabolite were determined and pharmacokinetic parameter estimates were derived. Maximum platelet aggregation (MPA) was measured by light transmission aggregometry using 20 μ m adenosine diphosphate as agonist.
Results:  Across all studies, prasugrel's C _max and AUC_{0– t} were 51% and 42% lower in subjects with ESRD than in healthy subjects. AUC_{0– t} did not differ between healthy subjects and subjects with moderate renal impairment. The magnitude of change and time-course profiles of MPA was similar for healthy subjects compared with subjects with moderate renal impairment and those with ESRD. Prasugrel was well-tolerated in all subjects.
Conclusion:  There was no difference in pharmacokinetics or PD responses between subjects with moderate renal impairment and healthy subjects. Despite significantly lower exposure to prasugrel's active metabolite in subjects with ESRD, MPA did not differ between healthy subjects and those with ESRD.