FDAs delay of prasugrel decision raises dosing questions for researcher

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FDA remains undecided about prasugrel. Image Source: The InVivo Blog  

Three months ago, the FDA said it would make a decision about prasugrel, an oral antiplatelet agent, by Sept. 26. Late that Friday afternoon, Daiichi Sankyo and Eli Lilly issued a statement saying the FDA’s review was still ongoing.

While the path toward FDA approval for prasugrel—to be branded Effient—has been a long one, Victor L. Serebruany, MD, PhD, believes the drug would have passed muster by now if only the researchers had chosen a lower maintenance dose to be used in the trials. 

Serebruany, who owns HeartDrug Research in Towson, Md., is on faculty at Johns Hopkins University and was a principal investigator in an early platelet study of prasugrel, said that he favored a 3 mg maintenance dose of the drug, used for patients with acute coronary syndromes (ACS) after stent implantation, rather than the 10 mg ultimately used by researchers. He said that he showed to Lilly the JUMBO trial platelet data of potential profound bleeding at the 10 mg dose.

“A high-dose long-term strategy works well with statins and blood pressure medication, but not for platelet inhibitors,” said Serebruany, who has been contacted by the FDA during the review process.

“Historically, clopidogrel substituted nicely for ticlopidine not because of better efficacy in preventing vascular outcomes, or more potent antiplatelet properties, but due to a better safety profile with regard to bone marrow toxicity,” Serebruany said. He added that researchers could have taken a similar tack with prasugrel, proving its safety with a lower dose, and enhancing its chances of FDA approval.

In the TRITON-TIMI trial, 10 mg of prasugrel was tested against the conventional 75 mg maintenance dose of clopidogrel (Plavix), along with aspirin, in ACS patients who had undergone PCI. In the TRILOGY-ACS study, which is evaluating the two drugs in ACS patients who are medically managed, investigators are using a 5 mg maintenance dose of prasugrel. Serebruany said that even 5 mg of prasugrel is slightly more potent than 75 mg of clopidogrel and will most likely result in more bleeding events.

At the CRT conference earlier this year, Deepak Bhatt, MD, then associate director of the Cardiovascular Coordinating Center at the Cleveland Clinic, concluded that prasugrel presents a benefit in reducing MI and stent thrombosis. And despite an increase in serious bleeding, Bhatt said that there is still a net clinical benefit in the majority of the population studied.

Serebruany said, however, that the reduction of non-fatal MI shown by prasugrel should be questioned because researchers changed the definition of MI during various phases of prasugrel’s development. He said that the changes were made to capture more events to make the difference between the two drugs look larger.

“Since a self-made definition was used to calculate the MI rate in the TRITON trial, and this rate is very high in the clopidogrel arm, a conventional definition with independent adjudication of events is warranted,” he said.

Serebruany has other problems with the drug’s testing. He said the bleeding risk was underestimated because researchers used the most conservative TIMI (thrombolysis in MI) scale that did not capture some severe bleeding events or nuisance bleeds such as from shaving or brushing teeth. The risk from nuisance bleeds could result in “gross noncompliance,” he said.

Since there was no mortality difference, it will be critical to plot the deaths after clopidogrel versus prasugrel to make sure that mortality spreads similarly between the drugs. “I am afraid that it will be more early deaths with clopidogrel, and delayed deaths after prasugrel. If this is the case, then the prasugrel maintenance dose is definitely wrong from the efficacy standpoint as well,” he said.

Serebruany also said that the design of the trial put the standard of care with clopidogrel at a “gross disadvantage.” While the American Heart Association guidelines mandate pretreatment with clopidogrel, in the TRITON trial, about one-quarter of patients received the drug only after PCI, he said, despite the pre-required exclusion of heart surgery.

“This was to make a difference in outcome. The longer they hold people without clopidogrel, the more MIs and reperfusion injuries will happen,” he said.

Other disadvantages include a suboptimal loading dose (300 mg vs. 600 mg) and the lack of protection with GP IIb/IIIa