PLATO Ticagrelor Controversy: Journal Editor Enters the Fray

Marlene Busko

May 30, 2014

COVENTRY, UK — For years, the International Journal of Cardiology (IJC) has been publishing papers critical of the Platelet Inhibition and Patient Outcomes (PLATO) trial of ticagrelor (Brilinta, AstraZeneca). Fed up with the accusations, PLATO investigators published a rebuttal last December that also reproached the journal for publishing the critical papers in the first place.

Now, in the latest twist in this long-running controversy, the IJC's editor has published an editorial defending the journal's decisions and arguing that it behooves journals to help the scientific community by publishing controversial articles[1].

PLATO, as reported by heartwire , was the phase 3 trial that led to ticagrelor's approval. For years, the trial has been panned in a series of articles by Drs Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD) and/or Dr James DiNicolantonio (Wegmans Pharmacy, Ithaca, NY), the majority published in IJC. Last December, PLATO investigators, led by Dr Lars Wallentin (Uppsala University, Sweden), published their scathing rebuttal.

As such, the editorial is partly a rebuttal to the Wallentin rebuttal, IJC editor in chief Dr Andrew J Stewart Coats (Monash University, Australia) told heartwire . "We are just publishing both sides of the story," he explained. The editorial is coauthored by Drs Darrel Francis and Sukh Nijjer (both Imperial College London, UK), "since we have previously analyzed the field of many things that are 'better than clopidogrel 300 mg,' " Francis told heartwire .

The editorial lays out the reasons that, both generally and specifically, the IJC has continued to publish the papers critical of PLATO.

"The main point is the medical literature has an absolute responsibility to bring to the scientific community areas where there's disagreement and argument," Coats explained. "The second main point is that the peer-review process itself is not sufficiently detailed and rigorous to pick up discrepancies. We do require whistleblowers . . . because the initial peer-review process does not have access to raw source data."

Dogged by Controversy

The 2009 PLATO trial of more than 18 000 patients with ACS found that the rate of MI/stroke/CV death was significantly reduced in patients who received the oral antiplatelet agent ticagrelor as opposed to clopidogrel.

European regulators approved the drug in December 2010 and the US Food and Drug Administration in July 2011. It is now authorized for use in more than 100 countries.

From the outset, however, the trial has been dogged by concerns about worse outcomes at North American sites, the potential for unblinding, regional differences in trial conduct, and difficulties in diagnosing MI—some of which were broached in the Coats rebuttal.

"It remains the duty of all physicians, scientists, and [caregivers] to be vigilant to the possibility of harm or of an overemphasis of benefit of a new therapy even after guidelines and local authorities have accepted [it] as efficacious and worthy to be endorsed," Coats and colleagues write.

Even important studies published by major journals may be subject to revision, they add, noting that "the willingness to investigate already-published work and retract unreliable findings represents the self-correcting nature of science at work."

Not "Controversy," but Unbalanced Critiques

As far as Wallentin and colleagues are concerned, "There exists no 'controversy.' " Rather, he continues, there has been "a series of currently 33 articles with PLATO criticism . . . based on highly selective data extracts from open sources by two persons (DiNicolantonio and/or Serebruany)," Wallentin, on behalf of the PLATO publications committee, told heartwire in an email.

Coats and colleagues, however, note that positive articles about PLATO outnumber critiques by more than two to one, since there are "16 critiques by DiNicolantonio for 38 positive publications by the PLATO leadership, [although] it is difficult to know what this ratio means scientifically, if anything."

The saga is likely to continue. According to Wallentin, after the ICJ published the PLATO investigators' rebuttal in December, it then published two new papers from the two critics, triggering another rebuttal from Wallentin et al, submitted to the journal on April 9, 2014.

"Thus, as long as some journals find it interesting to repeatedly publish the same critical comments disregarding any contrasting facts, answers, and arguments from the PLATO group, the false debate will most likely be continuing," he noted. From the PLATO investigators' perspective, it would be better to wait for new scientific evidence from real-life registries and the new ticagrelor trials. Topping the list is the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin (PEGASUS) trial, which enrolled 21 000 patients. Results are eagerly expected later this year.

PLATO Investigators Respond to IJC

The PLATO investigators have three main issues with the new editorial. First, the papers by DiNicolantonio and Serebruany were not "provided in an honest, open, and scientifically sound forum." Second, "the large number of similar publications by [these authors] . . . contain information that is misleading or incorrect, and yet the peer review process has allowed them to proceed to publication, not just once but multiple times. . . . Third, it is very surprising that the IJC editor in this editorial claims that regulatory agencies from some countries may not provide adequate scrutiny of the data to support approval of drugs. We suggest that the IJC editor reference the source . . . and openly state which agencies are remiss."

As reported by heartwire , in October 2013 the US Department of Justice issued a civil investigative demand "seeking documents and information regarding PLATO," which AstraZeneca did. More recently, as reported by heartwire , a Wall Street Journal article in February 2014 reported that Serebruany filed a complaint under the False Claims Act in US district court in the District of Columbia, contending that cardiovascular events in the PLATO "may have been manipulated," which the US attorney's office in Washington, DC, is currently investigating.

Neither Wallentin nor Coats had insights into when these investigations would wrap up or what they might yield.

In the meantime, "Clinicians can be confident that the rigorously collected, regulatory-agency–scrutinized and peer-reviewed published data from the PLATO trial are reported without bias and accurately reflect the clinical outcomes in participating patients," Wallentin said. "Therefore, clinicians can confidently use ticagrelor as a first-line treatment in the majority of patients with acute coronary syndrome to prolong life and reduce the risk of recurrent events in accordance with international and local treatment guidelines."

Coats and colleagues agree with the PLATO investigators that new data might settle any concerns once and for all. "Time will tell, as raw data of further studies come to light," Coats said.

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