Physicians' Academy for Cardiovascular Education

Switching to potent P2Y12 receptor inhibitors reduces high platelet reactivity rates

Rollini F et al., Eur Heart J 2016

 
A head-to-head pharmacodynamic comparison of prasugrel vs. ticagrelor after switching from clopidogrel in patients with coronary artery disease: results of a prospective randomised study

 
Rollini F, Franchi F, Cho JR, et al.
Eur Heart J 2016; published online ahead of print
 

Background

For patients suffering an acute coronary syndrome, dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor is standard of care, independently of whether they are treated with a percutaneous coronary intervention, or not [1]. Clopidogrel, prasugrel, and ticagrelor are the P2Y12 receptor inhibitors used in this setting. While clopidogrel is most frequently used, prasugrel and ticagrelor prevent more atherothrombotic events, and are associated with an increased risk of bleeding [2,3].
Switching P2Y12 inhibiting agents has represented a clinical concern due to the potential for drug interactions [4-7]. Conflicting data exist regarding the comparative efficacy and safety of prasugrel versus ticagrelor [8,9]. Moreover, ticagrelor has a plasma half-life of 8–12 h, thus requiring twice daily administration. However, in clinical practice, the first maintenance dose of ticagrelor is either initiated 12 h after the loading dose, or the following morning [1].
In this study the pharmacodynamic effects of prasugrel versus ticagrelor after switching from clopidogrel therapy was investigated in patients with coronary artery disease, using three different platelet function assays:
  1. Whole blood vasodilator-stimulated phosphoprotein (VASP) with results quantified by the platelet reactivity index (PRI)
  2. VerifyNow P2Y12 (VN-P2Y12) with results reported as P2Y12 reaction units (PRU)
  3. Light transmittance aggregometry (LTA) following 5 and 20 µM adenosine diphosphate (ADP) stimuli with results reported as maximum platelet aggregation (MPA).
 

Main results

• The platelet reactivity of patients on clopidogrel at baseline were similar between groups:
  • VASP-PRI (P = 0.483), VN-P2Y12 (P = 0.427), MPA 20 µM (P = 0.414)
• After the administration of a prasugrel loading dose (60 mg) and a ticagrelor loading dose (180 mg):
  • platelet reactivity was reduced within 30 min, which was maintained up to 1 week (P < 0.001 after correction for multiple comparisons)
  • platelet reactivity with all assays was lower with prasugrel compared with ticagrelor at 24 h after the loading dose administration (P < 0.001)
• Levels of platelet reactivity were similar between groups with all assays at 30 min, 2 h, and 1 week (P > 0.05 for all), with the exception of MPA at 30 min which was lower with prasugrel (P = 0.003).
• Repeated measures analysis adjusted for baseline values of platelet reactivity showed that over time with prasugrel there was a trend towards lower levels of PRI (ANCOVA P = 0.054), PRU (ANCOVA P = 0.151), MPA (ANCOVA P < 0.001).
• When a ticagrelor maintenance dose (90 mg/b.i.d.) was initiated 12 h after the administration of a loading dose
  • no significant differences were seen between groups in repeated measures analyses adjusted for baseline levels of platelet reactivity
  • at 24 h platelet reactivity was lower than in the cohort of patients who initiated ticagrelor maintenance dose 24 h after the loading dose in the first phase
  • at 24 h platelet reactivity was similar to the prasugrel group (P < 0.05 for all assays)
• Rates of high platelet reactivity (HPR) were markedly reduced and similar between groups.
 

Conclusion

Prasugrel and ticagrelor achieved similar levels of P2Y12 inhibition in patients with stable coronary artery disease who were on chronic clopidogrel therapy. Both P2Y12 inhibitors achieved more potent pharmacodynamic effects compared with clopidogrel that translated into reduced high platelet reactivity rates, which is a marker of risk for recurrent atherothrombotic events. These pharmacodynamics effects were reached within 30 minutes following a loading dose and were preserved with the maintenance dose. Moreover, in this study no drug interactions were observed when switching from clopidogrel to either prasugrel or ticagrelor.
Last but not least, the initiation of the ticagrelor maintenance dose 24 h after the loading dose administration resulted in higher platelet reactivity than that observed among patients who initiated the maintenance dose 12 h after the loading dose, supporting the recommendation of starting the twice daily maintenance regimen 12 h after the loading dose.
 
Find this article online at Eur Heart J
 

References

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