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Pharmacodynamic study hints at optimal prasugrel reloading dose before PCI

Reuters Health • The Doctor's Channel Daily Newscast

NEW YORK (Reuters Health) – For patients on maintenance prasugrel (Effient) therapy having percutaneous coronary intervention (PCI), a dose of 60 mg in the peri-PCI period achieves “faster and higher” platelet inhibition compared to lower doses, according to results of a randomized open-label pharmacodynamic study published May 8 in the Journal of the American College of Cardiology.

“The reason we conducted this study is because there has been increased utilization of prasugrel in clinical practice, particularly in high risk ACS [acute coronary syndrome] patients undergoing PCI,” Dr. Dominick Angiolillo from University of Florida College of Medicine in Jacksonville explained in an email to Reuters Health.

“Many of these patients may still require revascularization procedures down the road either because of staged procedures (for example in patients with STEMI after treating the culprit lesions) or due to chronic progression of their coronary atherosclerotic disease. Therefore, there are a growing number of patients undergoing PCI while on chronic prasugrel therapy raising the question on the optimal dosing of prasugrel in the peri-PCI period,” he further explained.

“This is a very similar situation as we had almost a decade ago with regards to patients already on clopidogrel therapy and now, thanks to studies done in the past, most of us re-load with clopidogrel. Similarly, our study with prasugrel shows that if you reload the patient on chronic prasugrel therapy using a 60 mg loading dose regimen you are going to get more rapid and potent platelet inhibition compared with a 30 mg or 10 mg dose,” Dr. Angiolillo said.

Sixty four patients receiving aspirin (81 mg/day) and maintenance prasugrel (10 mg/day for at least 14 days) were enrolled in the study and randomly assigned to a 10 mg, 30 mg, or 60 mg dose of prasugrel.

The researchers collected blood samples for pharmacodynamic assessment using multiple assays at baseline and one and four hours after dosing. The morning of their baseline visit, patients didn’t’ take their prasugrel dose so that their last maintenance dose of the drug was 18 to 24 hours before baseline blood sampling.

There were no between-group differences in baseline platelet reactivity index (PRI) (p=0.577).

Intragroup comparisons showed that the 60-mg dose reduced the PRI significantly after one hour (p=0.004) and four hours (the primary endpoint; p<0.001). The 30-mg dose also significantly reduced the PRI at one and four hours (p=0.006 and p<0.001). The 10-mg dose had a nonsignificant reduction in the PRI at one and four hours (p=0.355 and p=0.776).

Intergroup comparisons showed that at one hour after dosing, PRI levels were reduced significantly using 60 mg, whereas there was a large but nonsignificant decrease with the 30 mg vs 10 mg dose (p=0.058); there were no marked differences in PRI levels between 60 mg and 30 mg at one hour (p=0.171). At four hours after dosing, 60 mg and 30 mg continued to have lower PRI levels than 10 mg (p< 0.001 for 60 mg vs 10 mg and 30 mg vs 10 mg).

The researchers say, “Trend analyses observed better platelet inhibitory effects with higher prasugrel doses at both one hour and four hours.”

“Although the study does not have clinical endpoints, this pharmacodynamic study suggests that a 60 mg loading dose of prasugrel in patients undergoing PCI while on chronic prasugrel therapy may be a reasonable option and this is what I do in my practice,” Dr. Angiolillo told Reuters Health.

The researchers say they didn't see any bleeding complications or adverse events up to seven days after the study ended. They caution, however, that this was a pharmacodynamic study, it was not conducted in patients undergoing PCI and was not powered to assess safety or efficacy. “Hence, the lack of bleeding complications, including extrapolations to arterial access site complications, in this study should be interpreted with caution.”

“The clinical implications of prasugrel reloading in patients on maintenance prasugrel therapy undergoing PCI warrant further investigation,” they conclude.

This investigator-initiated study was funded by a research grant provided by Daiichi Sankyo and by LillyUSA to the University of Florida College of Medicine, Jacksonville. Several of the authors have disclosed financial relationships with various drug companies including Daiichi Sankyo and Eli Lilly. A complete list can be found with the original article.

SOURCE:

J Am Coll Cardiol 2012;59:1681-1687