Concomitant administration of prasugrel with cangrelor may lead to drug-drug interaction in patients undergoing PCI

The antiplatelet effects of IV cangrelor are not affected by the concomitant prasugrel use, but this strategy is associated with a rise in platelet reactivity at the end of the cangrelor infusion—by that point, there exist low levels of the active metabolite of prasugrel remaining to bind to the previously occupied P2Y12 receptors.

Previous studies have suggested the occurrence of drug-drug interaction (DDI) when transitioning from IV (intravenous) P2Y12 inhibition with cangrelor to oral P2Y12 inhibition with prasugrel. However, its testing has not been done in patients undergoing PCI.

Francesco Franchi, University of Florida College of Medicine, Jacksonville, FL, USA, and colleagues, therefore, aimed to rule out a DDI when cangrelor and prasugrel are concomitantly administered in patients undergoing percutaneous coronary intervention in the SWAP-6 study.

The Switching Antiplatelet-6 (SWAP-6) was a prospective, randomized, 3-arm, open-label pharmacodynamic (PD) and pharmacokinetic (PK) study. The study included 77 patients undergoing PCI; they were randomized to a) prasugrel only at the start of PCI; b) cangrelor plus prasugrel concomitantly at the start of PCI; c) cangrelor at the start of PCI plus prasugrel at end of infusion. Infusion of cangrelor was maintained for 2 hours.

PD/PD assessments were done at baseline and 6-time points post-randomization. The primary endpoint was measured as the noninferiority in VerifyNow P2Y12 reaction units (PRU) measured at 4 hours post-randomization between prasugrel plus cangrelor concomitantly administered versus prasugrel only. Pharmacokinetic assessments included plasma levels of the active metabolite of prasugrel (P-AM).

The authors reported the following findings:

• Compared with prasugrel, cangrelor further enhances P2Y12 inhibitory effects.
• At 4 hours post-randomization, PRU levels were significantly lower with prasugrel only compared to cangrelor and prasugrel concomitantly administered (LSM difference 130), failing to meet the prespecified noninferiority margin.
• Findings were corroborated by multiple PD assays.
• P-AM levels were not affected by the concomitant administration of cangrelor and were low at the end of the cangrelor infusion.

"Concomitant administration of prasugrel with cangrelor in patients undergoing PCI leads to a marked increase in platelet reactivity after stopping cangrelor infusion, supporting the presence of a DDI," the researchers wrote.

These results are consistent with current drug labels but there is a lot of confusion in practice when it comes to transitioning from cangrelor to oral P2Y12 inhibitors. Studies have revealed that using ticagrelor at the same time as cangrelor is safe but that clopidogrel and prasugrel, which have shorter half-lives than ticagrelor, should be initiated at the end of cangrelor infusion to ensure that there is enough drug circulating when the P2Y12 receptors are vacated by cangrelor.

"These new findings can be used to guide the use of these agents in practice, and they are strong enough to support updated drug labels, which currently contain recommendations based on limited data," the team concluded.

Reference:

Franchi, F., Rollini, F., Ortega-Paz, L., Been, L., Giordano, S., Galli, M., Ghanem, G., Garabedian, H., Al Saleh, T., Uzunoglu, E., Rivas, A., Pineda, A. M., Suryadevara, S., Soffer, D., Zenni, M. M., Mahowald, M., Reiter, B., Jilma, B., & Angiolillo, D. J. (2023). Switching from Cangrelor to Prasugrel in Patients Undergoing Percutaneous Coronary Intervention: The Switching Antiplatelet-6 (SWAP-6) Study. JACC: Cardiovascular Interventions. https://doi.org/10.1016/j.jcin.2023.08.009