Prasugrel Inhibits Platelet Function Better Than High-Dose Clopidogrel in Diabetics

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In patients with type 2 diabetes and coronary artery disease (CAD), the recently approved antiplatelet agent prasugrel suppresses platelet reactivity more effectively than a double dose of the standard thienopyridine clopidogrel, with fewer poor responders and no increase in bleeding events, according to a small randomized trial published online January 20, 2011, ahead of print in the European Heart Journal.

For the OPTIMUS (Optimizing anti-Platelet Therapy In diabetes MellitUS)-3 trial, Researchers led by Dominick J. Angiolillo, MD, PhD, of the University of Florida College of Medicine-Jacksonville (Jacksonville, FL), randomized 35 patients with type 2 diabetes and CAD to prasugrel (60-mg loading dose; 10-mg maintenance dose for 7 days) or double-dose clopidogrel (600-mg loading dose; 150-mg maintenance dose for 7 days). This was followed by a 2-week washout period and then a crossover phase in which each group received the alternate drug regimen, thereby serving as self-controls. Patients were continued on aspirin throughout the study.  

Multiple Assays, Same Result

Numerous platelet function tests were used to determine the level of platelet inhibition achieved with each drug. Patients with a recent ACS, PCI or CABG were excluded since halting antiplatelets was deemed inadvisable for the washout period in such individuals.  

Using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA), inhibition of platelet aggregation 4 hours post loading dose (primary endpoint) was significantly greater with prasugrel compared with clopidogrel. The findings were similar after a week of maintenance therapy (table 1), and at all time points measured in between.

Table 1. Inhibition of Platelet Aggregation by VerifyNow

  

Prasugrel
(n = 18)

Clopidogrel
(n = 17)

P Value

4 hrs Post Loading

89.3%

27.7%

< 0.0001

After 1 wk Maintenance

61.8%

44.2%

< 0.0001

Platelet function studies at 4 hours and 1 week via light transmission aggregometry (LTA) and vasodilator-stimulated phosphoprotein (VASP) phosphorylation analysis (Biocytex, Marseille, France) showed similar benefits with prasugrel (table 2). 

Table 2. Platelet Function Measurements

  

Prasugrel
(n = 18)

Clopidogrel
(n = 17)

P Value

LTA

     4 hrs Post Loading,  MPA (20 µM ADP)

   1 wk Maintenance,   MPA (20 µM ADP)


22.4%

 

38.3%

  

57.5%

  

50.7%

  

< 0.0001

  

< 0.0001

VASP

    4 hrs Post Loading,  PRI

    1 wk Maintenance,PRI

  

 14.5%

  27.4%

  

 67.5%

42.3%

  

 < 0.0001

0.0012

Abbreviations: MPA, maximum platelet aggregation; PRI, platelet reactivity index.

At all time points measured and by multiple definitions, the rates of poor responders were lower with prasugrel than clopidogrel (P < 0.05 for each comparison):

  • 4 hrs post loading dose: 0-3.1% with prasugrel, 35.3-82.9% with clopidogrel
  • 24 hrs post loading dose: 0% with prasugrel, 51.5-78.8% with clopidogrel
  • 7 days: 2.9-21.2% with prasugrel, 23.5-52.9% with clopidogrel

While the trial was not powered to determine differences in safety outcomes, there was no TIMI major or minor bleeding with either drug regimen. In addition, there were no deaths or serious adverse events. The overall rate of adverse events was 14.7% with prasugrel and 25.7% with clopidogrel.

“In patients with type 2 [diabetes] and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel,” the researchers conclude.

Questions from TRITON-TIMI

The study authors explained that diabetics continue to have a higher risk of recurrent ischemic events compared with nondiabetics despite use of clopidogrel, possibly due to inadequate P2Y12 inhibition with current recommended antiplatelet regimens. Previously, in the diabetic subanalysis of the TRITON-TIMI 38 trial, it was determined that prasugrel reduced the risk of the primary composite endpoint (CV death, nonfatal MI or nonfatal stroke) by 30% compared with clopidogrel without any increase in major bleeding. But the clopidogrel regimen used in that study was the standard 300-mg loading dose, with 75-mg per day maintenance, leaving open the question as to whether a double dose of clopidogrel would close the gap.

“This study is another piece in the puzzle suggesting it may not be only about the dosing, it may be about the drug itself, because when you give clopidogrel at the highest doses, it just does not match prasugrel,” said Michael E. Farkouh, MD, MSc, of Mount Sinai Medical Center (New York, NY), in a telephone interview with TCTMD.

Findings Translate to ACS Patients?

Dr. Farkouh added that the current results also may be applicable to the ACS population, which was not included in the current trial. “I think the evidence in this paper could inform us about ACS,” he said. “That’s another very important question because ACS is a different patient population than a stable population, so it may mean that the results would be more dramatic, that the differences would be more profound.”

The current results, though, should be regarded only as hypothesis generating, he cautioned. “We shouldn’t say that clopidogrel at this dose is not adequate,” Dr. Farkouh said. “That’s a step I don’t think clinicians are ready to take because we have not proven yet that VerifyNow or any of the platelet assays can really help us drive our clinical care. We’ve learned from GRAVITAS and other trials that we really need outcome trials.”

Nevertheless, the data to date are starting to look persuasive, he added. “I believe that for diabetics with ACS, the current dose of prasugrel (60 mg loading, 10 mg daily maintenance) appears to have excellent outcomes compared with the usual dose of clopidogrel,” Dr. Farkouh said. “That’s the data we have head-to-head, so there is a role for prasugrel in these patients.”

Meanwhile, regarding the current results with the higher clopidogrel dose, “without a clinical correlate, they’re confirmatory of what we’ve known before, that prasugrel appears more potent in its blockade of the platelet,” he added.

  

Source:

Angiolillo DJ, Badimon JJ, Saucedo JF, et al. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: Results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 trial. Eur Heart J. 2011:Epub ahead of print.

  

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

Disclosures
  • OPTIMUS-3 was supported by Daiichi Sankyo and Eli Lilly.
  • Dr. Angiolillo reports financial relationships with numerous drug and device companies.
  • Dr. Farkouh reports no relevant conflicts of interest.

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