Pharmacodynamic and pharmacokinetic profiles associated with switching from cangrelor to prasugrel in patients undergoing percutaneous coronary intervention: the SWAP-6 study

Abstract

Abstract Background Cangrelor is an intravenous P2Y12 inhibitor used in patients undergoing coronary intervention (PCI). Preliminary studies have shown the potential for a drug-drug interaction (DDI) when transitioning from cangrelor to oral P2Y12 inhibition with prasugrel. However, to date this has not been prospectively tested in patients undergoing PCI. Purpose To rule out a DDI when cangrelor and prasugrel are concomitantly administered in patients undergoing PCI. Methods SWAP-6 is a prospective, randomized, 3-arm, open-label, pharmacokinetic (PK) and pharmacodynamic (PD) study conducted in patients undergoing PCI (n=77). Patients were randomized to either a) prasugrel only administered at the start of PCI; b) cangrelor plus prasugrel concomitantly administered at the start of PCI; c) cangrelor administered at the start of PCI plus prasugrel administered at the end of the cangrelor infusion. Cangrelor (30 μg/kg bolus followed by 4 μg/kg/min infusion) was maintained for 2 hours and all patients were on a background of aspirin therapy. Prasugrel was administered as a 60 mg loading dose. PK analysis included plasma levels of prasugrel active metabolite, and PD assessments included VerifyNow PRU, total thrombus-formation analysis system (T-TAS), and vasodilator-stimulated phosphoprotein (VASP), at baseline and 6 time points after prasugrel/cangrelor administration. The primary end point was non-inferiority in PRU measured at 4 hours after prasugrel/cangrelor loading (2 hours after stopping cangrelor infusion) of cangrelor plus prasugrel concomitantly administered versus prasugrel only. The noninferiority margin was defined as 45 PRU. Results Cangrelor achieved lower PRU levels than prasugrel only as early as 30 minutes and up to 2 hours after bolus administration (Figure). At 3 hours after prasugrel/cangrelor loading, PRU levels were higher with cangrelor compared to prasugrel only. At 4 hours after loading (2 hours after stopping cangrelor infusion), PRU levels were significantly lower with prasugrel only compared to cangrelor and prasugrel concomitantly administered (LSM difference 130; 95% CI: 85-176), failing to meet the prespecified noninferiority primary end point (Figure). At this time point, cangrelor followed by prasugrel at the end of the infusion had higher PRU than prasugrel only, but lower than cangrelor and prasugrel concomitantly. Platelet reactivity by T-TAS and VASP showed consistent findings. PK analysis tracked PD results (data not shown). Conclusions In patients undergoing PCI, cangrelor is associated with more potent platelet inhibition than prasugrel alone. However, concomitant administration of prasugrel with cangrelor leads to a marked increase in platelet reactivity after stopping cangrelor infusion, supporting the presence of a DDI. This underscores the importance of administering prasugrel not until the end of cangrelor infusion, a strategy which mitigates the increase in platelet reactivity.