DoJ's PLATO Investigation Closes, No Further Action to Be Taken in Ticagrelor (Brilinta) Trial

Shelley Wood

August 19, 2014

WASHINGTON, DC ( updated ) — The US Department of Justice (DoJ) has completed its probe into the Platelet Inhibition and Patient Outcomes (PLATO) trial of ticagrelor (Brilinta, AstraZeneca) in the setting of acute coronary syndromes and "is not planning any further action," according to a statement released by its manufacturer today[1]

As previously reported by heartwire , the company first announced news of the DoJ investigation in October 2013, when the DoJ's civil division sent an investigative demand "seeking documents and information regarding PLATO."

PLATO was the pivotal study released in 2009 that led to the approval of the novel antiplatelet drug in 2011. From the start, the trial was dogged by questions surrounding the apparent geographic discrepancies in the trial, most notably a trend toward worse outcomes with ticagrelor vs clopidogrel at North American sites. Other questions raised have included study site monitoring and the timing of deaths in the study.

Many of those concerns have also played out in a series of articles penned by the trial's chief critics, Drs Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD) and James DiNicolantonio (Wegmans Pharmacy, Ithaca, NY), leading to a high-profile spat in the International Journal of Cardiology.

The company, as well as the international investigators who led the study, have long insisted that the trial design and conduct were faultless and that any of the questions raised about the study had been thoroughly examined, and dismissed, by the FDA in its review.

"Good to see this news," PLATO investigator Dr Robert Harrington (Stanford University, Stanford, CA) told heartwire . "Now hopefully PLATO leadership can turn its attention to more productive activities. Maybe a few of the journals will also take a harder, more rigorous look at some of the poorly done papers masquerading as science that a few people persist in publishing."

PLATO's principal investigator, Dr Lars Wallentin (Uppsala University, Sweden), also speaking with heartwire , said that he and other PLATO investigators assume but have never had it confirmed that the DoJ was looking into the claims made by Serebruany and DiNicolantonio. He says he himself was never contacted by the DoJ, nor—to the best of his knowledge—was anyone else on the executive committee for the trial.

"We never really knew what it was [they were looking into], we only had this public criticism in a few medical journals like the [International Journal of Cardiology], and we answered them," he told heartwire . "Obviously we sincerely hope [that this news reassures doctors and patients], and we are extremely happy about this statement. I really welcome that it has been a fairly rapid decision."

He added that the PLATO investigators have never doubted their findings and, having worked together for more than a decade, have always been confident that the trial was rigorously conducted and the results reliable.

"Now the DOJ has reviewed [any] claims and from our perspective, too, there is nothing there. I think we can put these issues to rest."

Any lingering questions about ticagrelor's benefit in North American patients should be set to rest when the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin (PEGASUS) trial comes out next year. The trial completed enrollment of 21 000 patients late last year—with significant numbers of US patients enrolled—and is anticipated to be presented in early 2015.

The company press release announcing the closure of the DoJ's investigation notes that a handful of other trials are also under way or wrapping up, including SOCRATES , looking at ticagrelor in acute ischemic stroke or transient ischemic attack (TIA), and THEMIS , in patients with type 2 diabetes and atherosclerosis. Another trial, EUCLID , has also recently completed enrollment, this one looking at ticagrelor in patients with peripheral artery disease.

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