High Prasugrel Reloading Dose Best for Suppressing Platelet Reactivity Prior to PCI

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Reloading with a 60-mg dose of prasugrel suppresses platelet reactivity more effectively than lower doses prior to percutaneous coronary intervention (PCI) in patients who are already on maintenance therapy with the new antiplatelet agent, according to pharmacodynamic findings published in the May 8, 2012, issue of the Journal of the American College of Cardiology.

For the prospective study, researchers led by Dominick J. Angiolillo, MD, PhD, of the University of Florida College of Medicine-Jacksonville (Jacksonville, FL), looked at 64 patients on prasugrel maintenance therapy (10 mg/day) at least 14 days following PCI. Patients were randomized to 1 of 3 prasugrel loading doses (10 mg, 30 mg, or 60 mg) prior to a subsequent PCI procedure. Pharmacodynamic testing by VASP assay (BioCytex, Marseille, France), VerifyNow P2Y12 assay (Accumetrics, San Diego, CA), and light transmission aggregometry (LTA, Chrono-Log, Havertown, PA) was performed at 1 and 4 hours after prasugrel reloading.

Improvements in the platelet reactivity index (PRI) at both 1 hour (table 1) and 4 hours (primary endpoint, table 2) were shown with the 30-mg and 60-mg doses but not with the 10-mg dose.

Table 1. VASP PRI Measurements at 1 Hour

Prasugrel Dose

Baseline

1 Hour

P Value

10 mg

31.6 ± 3.3%

26.5 ± 3.1%

0.355

30 mg

29.5 ± 3.5%

17.8 ± 3.2%

0.006

60 mg

26.6 ± 3.4%

11.5 ± 3.2%

0.004


Table 2. VASP PRI Measurements at 4 Hours

Prasugrel Dose

Baseline

4 Hours

P Value

10 mg

31.6 ± 3.3%

28.8 ± 2.8%

0.776

30 mg

29.5 ± 3.5%

11.0 ± 2.9%

< 0.001

60 mg

26.6 ± 3.4%

2.8 ± 2.7%

< 0.001


The improvements from 1 to 4 hours were also significant for the 30-mg (P = 0.044) and 60-mg (P = 0.002) groups. Moreover, 60 mg of prasugrel was more effective than both 30 mg (P < 0.05) and 10 mg (P < 0.001) in lowering PRI values at 4 hours.

The 60-mg dose showed a trend toward reducing P2Y12 reaction units (P = 0.064) and percent inhibition of platelet aggregation (P = 0.094) at 4 hours compared with 30 mg on VerifyNow P2Y12 analysis, but both doses showed similar reductions in platelet reactivity on LTA measurements. The 60-mg and 30-mg doses were more effective than 10 mg at all time points according to all assay measurements.

Dr. Angiolillo and colleagues pointed out that the differences in results between assays can be explained by the fact that VASP and VerifyNow are more specific in assessing effects on P2Y12 receptor signaling, while ADP LTA results “are more reflective of overall purinergic-mediated platelet aggregation.”

“Ultimately,” the researchers conclude, “a 60 mg dose was associated with rapid effects as demonstrated by the levels of platelet reactivity achieved at 1 h[our], which were either similar or greater than those achieved by a 30 mg dose at 4 h[ours].”

Clues from Clopidogrel?

The authors draw a parallel between the current study and previous ones investigating clopidogrel reloading showing that strategy to be associated with additional platelet inhibition and reduced ischemic events including stent thrombosis. “Therefore, the results of the present pharmacodynamic investigation using prasugrel may also have potential clinical implications,” they note.

In an e-mail communication with TCTMD, Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), affirmed that, “This study shows that reloading and higher reloading dose give better acute platelet inhibition with prasugrel, important for PCI.” Still, he added, “We need more studies on reloading and switching to guide antiplatelet and anticoagulation therapy.”

The authors cite a growing number of patients undergoing PCI while on chronic prasugrel therapy. “That has raised concerns with regard to the optimal dosing of prasugrel in the peri-PCI period,” they write.

Dr. Bates, though, indicated that reloading is controversial, with both positive and negative studies. “I do it with clopidogrel and now I will do it with prasugrel, but others don’t,” he said, adding that clinicians should not need to worry about pharmacodynamic interactions that fail to translate to ischemic outcomes.

“The only impact would be on periprocedural events,” Dr. Bates said. “So this is a different story than the pharmacodynamic drug-drug interactions with maintenance dose therapy that have gained a lot of attention, but are probably time-limited because the active metabolite eventually accumulates while platelet activation decreases in parallel.”

 


Source:
Tello-Montoliu A, Tomasello SD, Ferreiro JL, et al. Pharmacodynamic effects of prasugrel dosing regimens in patients on maintenance prasugrel therapy: Results of a prospective randomized study. J Am Coll Cardiol. 2012;59:1681-1687.

 

 

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Jason R. Kahn, the former News Editor of TCTMD, worked at CRF for 11 years until his death in 2014…

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Disclosures
  • The study was funded by a research grant provided by Daiichi-Sankyo and Lilly to the University of Florida College of Medicine-Jacksonville.
  • Dr. Angiolillo reports receiving honoraria for lectures, consulting fees, and research grants and funding from numerous pharmaceutical companies, including Daiichi-Sankyo and Lilly.
  • Dr. Bates reports serving on advisory boards for AstraZeneca, Bristol-Myers Squibb/Sanofi-Aventis, and Daiichi-Sankyo and Lilly.

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