Prasugrel Noninferior to Ticagrelor, but Both Achieve Poor Platelet Inhibition at Two Hours

April 09, 2013

FLORENCE, ITALY — A study comparing ticagrelor (Brilinta, AstraZeneca) and prasugrel (Effient, Lilly/Daiichi-Sanyo) in patients with ST-segment-elevation MI (STEMI) undergoing primary PCI has shown prasugrel to be noninferior to ticagrelor in terms of residual platelet reactivity measured two hours after the loading dose[1].

The study, known as the Rapid Activity of Platelet Inhibitor Drugs Study (RAPID), also showed that four hours is needed to achieve effective platelet inhibition in most patients, with just 50% of treated patients achieving effective platelet inhibition two hours after receiving the drugs.

"This means that the majority of the procedures of stenting of the infarct-related artery were performed without functional evidence of a significant antiplatelet effect," according to lead investigator Dr Guido Parodi (Careggi Hospital, Florence, Italy). "In a previous study, it has been demonstrated that a nontrivial number of acute coronary syndrome patients do not achieve optimal platelet inhibition despite the use of prasugrel loading dose and that such patients have a higher risk of major adverse cardiac events."

Published in the April 16, 2013 issue of the Journal of the American College of Cardiology, the pharmacodynamic study included 25 STEMI patients undergoing primary PCI with bivalirudin randomized to receive a 60-mg loading dose of prasugrel and 25 patients randomized to receive a 180-mg loading dose of ticagrelor.

Measured two hours after receiving the antiplatelet agents, the platelet reactivity units (PRU), which were the study's primary end point, were 217 and 275 in the prasugrel- and ticagrelor-treated patients, respectively. This met the study's prespecified noninferiority end point. At two hours, however, 44% of patients treated with prasugrel and 60% of those treated with ticagrelor had high residual platelet reactivity (HRPR), defined as PRU >240. For those treated with prasugrel and ticagrelor, the time required to achieve a PRU <240 was three hours and five hours, respectively. The use of morphine significantly affected the activity of prasugrel and ticagrelor, with morphine use shown to be an independent predictor of HRPR two hours after the loading doses were administered (odds ratio 5.29; p=0.012).

"Our data revealed a wide variability of drug response, suggesting that the gastrointestinal absorption of orally administered drugs may be limited or delayed in STEMI patients because of multiple reasons, including reduced or delayed drug adsorption in patients with hemodynamic disarrangement, systemic vasoconstriction, adrenergic activation, and high risk of vomiting," according to Parodi and colleagues. In addition, advanced age, increased body weight, and the use of multiple medications for other conditions might be additional factors that influence the time to drug-effect onset, they add.

The results are in line with a previous study, reported by heartwire , showing that ticagrelor and prasugrel failed to bring about adequate platelet inhibition at the time of primary PCI in STEMI patients. Those researchers, led by Dr Dimitrios Alexopoulos (Patras University Hospital, Greece), expected ticagrelor to have a faster onset of antiplatelet effect than prasugrel because it is a direct-acting agent, but that was not the case. At the time, Alexopoulos emphasized the importance of time in STEMI patients, noting these patients are typically loaded with prasugrel or ticagrelor 20 to 30 minutes before primary PCI, but this does not appear to be sufficient.

In this newest study, Parodi et al note that the PRUs in the present study were higher than those observed in previous pharmacokinetic analyses of healthy volunteers or those with stable coronary artery disease. The majority of STEMI patients needed at least four hours to achieve a significant drug effect with a loading dose of the two antiplatelet agents. They suggest these results highlight a "significant time window after primary PCI in which many patients are at high risk of stent thrombosis."

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