Switching to potent P2Y12 receptor inhibitors reduces high platelet reactivity rates
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
BackgroundFor 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 . 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 .
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:
- Whole blood vasodilator-stimulated phosphoprotein (VASP) with results quantified by the platelet reactivity index (PRI)
- VerifyNow P2Y12 (VN-P2Y12) with results reported as P2Y12 reaction units (PRU)
- 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)
- 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)
• 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)
ConclusionPrasugrel 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
1. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol 2015;12:30–47
2. Wiviott SD, Braunwald E, McCabe CH, et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–2015
3. Wallentin L, Becker RC, Budaj A, et al. PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–1057
4. Rollini F, Franchi F, Angiolillo DJ. Switching antiplatelet therapies with P2Y12 receptor inhibitors in coronary artery disease patients. Nat Rev Cardiol 2016;13:11–2.
5. Angiolillo DJ, Saucedo JF, Deraad R, et al. SWAP Investigators. Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: results of the SWAP (SWitching Anti Platelet) study. J Am Coll Cardiol 2010;56:1017–1023
6. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 2010;121:1188–1199
7. Diodati JG, Saucedo JF, French JK, et al. Effect on platelet reactivity from a prasugrel loading dose after a clopidogrel loading dose compared with a prasugrel loading dose alone: Transferring From Clopidogrel Loading Dose to Prasugrel Loading Dose in Acute Coronary Syndrome patients (TRIPLET): a randomized controlled trial. Circ Cardiovasc Interv. 2013;6:567–574
8. Lhermusier T, Lipinski MJ, Tantry US, et al. Meta-analysis of direct and indirect comparison of ticagrelor and prasugrel effects on platelet reactivity. Am J Cardiol 2015;115:716–723
9. Lemesle G, Schurtz G, Bauters C, et al. High on-treatment platelet reactivity with ticagrelor versus prasugrel: a systematic review and meta-analysis. J Thromb Haemost 2015;13:931–942