BMJ Investigation Revives Questions About PLATO, Ticagrelor

A BMJ investigation is delving once again into questions over the quality and conduct of the PLATO trial that launched ticagrelor (Brilinta; AstraZeneca) 15 years ago. It’s also reinvigorating a discussion about whether the P2Y12 inhibitor maintains an advantage over other generic options in contemporary practice.

Published last week, the article by Peter Doshi, a BMJ senior editor, recaps the ticagrelor saga, starting with the publication of the PLATO results in 2009. That pivotal trial showed ticagrelor reduced the rate of vascular death, MI, or stroke (the primary endpoint) compared with clopidogrel in patients with ACS while increasing major bleeding not related to CABG.

Those results supported US Food and Drug Administration approval of the drug in 2011, a move that came despite a subgroup analysis showing that US patients fared worse with ticagrelor, as well as concerns raised by some FDA scientists. Ticagrelor has since gained strong recommendations in international guidelines.

As Doshi recounts, however, the conduct of the PLATO trial has been called into question repeatedly over the years and was the subject of a US Department of Justice probe from 2013 to 2014. That ended because the allegations of problems with the trial “lacked sufficient merit,” according to a spokesperson for the US Attorney’s Office for the District of Columbia who was quoted by Doshi.

Now, Doshi endeavors to throw new light on specific PLATO trial endpoints—including MI and death—that he suggests were assessed in a manner that favored ticagrelor. To that end, he reviewed primary PLATO trial records and unpublished data obtained through a Freedom of Information Act request. In his interpretation, these sources show “an imbalance among 20 death category decisions that the adjudication committee was in ‘major’ disagreement over and ultimately could not resolve,” and that the cause of death ultimately recorded for these cases favored ticagrelor. In addition, Doshi indicates that some site-level death records he reviewed did not match the FDA’s and that several deaths were not included in the initial publication of the trial results.

Doshi’s paper ends with a quote from Victor Serebruany, MD, PhD, who has long criticized AstraZeneca and the PLATO trial, calling for the Department of Justice to reopen its case.

PLATO Investigators Push Back

But whether the new effort throws fresh light on the controversy or merely reamplifies earlier concerns is unclear.

Lars Wallentin, MD, PhD (Uppsala Clinical Research Center, Sweden), co-chair of PLATO’s executive committee, defended the study, suggesting that the BMJ has not added anything of merit. “As far as I can see, there is no new information in the BMJ article. Personally, I have nothing new to add in addition to what already is in the public domain,” he told TCTMD via email, adding that he supports current guideline recommendations regarding P2Y12 inhibitors in patients with ACS.

My clinical impression is, at this point in time, with a much lower ischemic risk associated with PCI or ACS, that any potential benefit ticagrelor had 15 years ago has probably disappeared. Eric Bates

Similarly, Robert Harrington, MD (Weill Cornell Medicine, New York, NY), who was at the Duke Clinical Research Institute in Durham, NC, when he co-chaired the PLATO executive committee, told TCTMD via email: “The PLATO group stands by the publication as well as dozens of subsequent ones. We have also responded to these and similar accusations multiple times in the peer-reviewed literature over the early years following the publication of the trial results and the FDA review of the drug.”

He continued, “I’m not sure about the rationale for the questions being raised 15 years after publication of the original data and after multiple papers detailing our responses on vital status of the participants and other questions.”

Declining Ischemic Risk

In the years since PLATO came out, “a host of observational and randomized studies have failed to replicate PLATO’s results,” Doshi writes. A large US and Korean database study, a real-world study from England, and several others have called ticagrelor’s supremacy into question, including, more recently, a review of ticagrelor trials published earlier this year in the Journal of the American Heart Association.

Eric Bates, MD (University of Michigan, Ann Arbor), who co-authored that review, told TCTMD that the treatment landscape has changed over the last 15 years, with thinner stents, better drug coatings and delivery systems, and increased use of intracoronary imaging to guide procedures, and this may explain why newer studies have failed to show an advantage with ticagrelor.

“With a number of treatment advances, the ischemic risk has gone down and the bleeding risk has become more important, so the risk-benefit balance has changed,” he said.

One of the tipping points in the move away from ticagrelor, Bates said, was the ISAR-REACT 5 trial, which showed that prasugrel provided better outcomes than ticagrelor in ACS patients headed for revascularization. Even though it may have some pharmacodynamic advantages over other agents, the twice-a-day dosing, side effects (like dyspnea), and high costs are also deterrents to use. In addition, both ticagrelor and prasugrel have higher bleeding risks compared with clopidogrel.

“Being a practical clinician, I’m not sure there’s a big advantage of prasugrel and ticagrelor over clopidogrel, and if there is, it’s in the first month after an ACS event. . . . After that, I think clopidogrel is probably as good as anything,” Bates said.

The principal investigators are two of the most highly thought of cardiologists in the world and their integrity is without question. Lloyd Klein

Lloyd Klein, MD (UCSF Medical Center, San Francisco, CA), who also commented on the issues in Doshi’s piece, agreed that a trend toward lower ischemic risk in patients treated today versus 15 years ago could be contributing to the difficulty of finding an advantage for ticagrelor in studies conducted since PLATO.

“I just don’t think we know,” he told TCTMD, adding, however, that numerous papers—as reviewed by Bates and discussed in one of Klein’s editorials from earlier this year—“suggest that right now in everyday practice, if you’re getting very much from [ticagrelor], nobody can find it.”

Klein said he does use ticagrelor, especially after stenting, but also uses prasugrel and clopidogrel. “I don’t think in clinical practice anybody I know of can discern any difference amongst the three,” he said. “But none of us have done 18,000-patient trials. So we wouldn’t know.”

He stressed that he doesn’t think Harrington or Wallentin were behind any of the issues being raised with the trial. “The principal investigators are two of the most highly thought of cardiologists in the world and their integrity is without question,” Klein added.

Cost Amid Choices

As the BMJ story makes clear, questions have emerged over the years about whether, in current practice, ticagrelor truly has advantages over other P2Y12 inhibitors, including prasugrel and clopidogrel, which are generic medications. Generic versions of ticagrelor are coming but have not yet hit the market. According to Doshi, ticagrelor currently accounts for less than 10% of P2Y12 inhibitor prescriptions—based on data from the US Centers for Medicare & Medicaid Services (CMS)—but about two-thirds of the cost, with the US government spending more than $750 million on the drug in 2022.

Dipti Itchhaporia, MD (University of California, Irvine), a past president of the American College of Cardiology, cited the adherence challenges related to increased bleeding risks and side effects like dyspnea, as well as cost considerations, around use of ticagrelor.

Itchhaporia, to TCTMD, said that there could be specific populations in which the drug could be valuable, including a patient with a high thrombotic risk and low bleeding risk or one who is resistant to clopidogrel. Nonetheless, “when you think about it, when you think about cost sensitivity, then I think clopidogrel is still going to be preferred,” Itchhaporia said.

Although she does use ticagrelor in some of her patients, it’s typically for a short period of time, she said. For an ACS patient with moderate bleeding risk, for example, she would initiate ticagrelor during the hospitalization and continue it in the early postdischarge phase, but then transition the patient to clopidogrel after 3 months if the patient is stable.

Time to Reconsider the Guidelines?

Though Doshi’s article claims that Bates is calling for a reappraisal of the guidelines recommending ticagrelor—some of which he helped write—Bates told TCTMD that’s not accurate: “I’m not here jumping up and down, waving a flag.”

Instead, he said, “my challenge is to the thought experts who keep misrepresenting the data in favor of ticagrelor, because I think that’s a false representation. And my clinical impression is, at this point in time, with a much lower ischemic risk associated with PCI or ACS, that any potential benefit ticagrelor had 15 years ago has probably disappeared by the lower event rate and our increased clinical recognition of bleeding as an equal and important endpoint.”

Asked to comment on the need to reevaluate the guidelines, the American Heart Association (AHA) referred questions to Marc Sabatine, MD (Brigham and Women’s Hospital, Boston, MA), chairman of the TIMI Study Group. He said via email that “these recycled attacks on the PLATO trial data are entirely without scientific merit, and thus I see no compelling reason to reevaluate the recommendation of ticagrelor over clopidogrel in patients with ACS.” He noted that his practice is moving toward a strategy of dropping aspirin over the long term to reduce bleeding risk without increasing risk of ischemic events.

These recycled attacks on the PLATO trial data are entirely without scientific merit, and thus I see no compelling reason to reevaluate the recommendation of ticagrelor over clopidogrel in patients with ACS. Marc Sabatine

Frank Sellke, MD (Warren Alpert School of Medicine of Brown University, Providence, RI), also referred by the AHA, said that guidelines are frequently reevaluated in the face of new evidence, adding that the decision about whether evidence on ticagrelor warrants such a reassessment will be made by the guideline committees. “Improved technology and factors such as better coronary stents or improved secondary prevention should always enter into the discussion and need for reevaluation,” he said.

For his part, Harrington, a past president of the AHA and current member of the group’s board of directors, said such questions about the need for reevaluation “should apply to much of the older literature and studies and not just antiplatelet therapies. How does one respond to the changes in practice, including concomitant meds and new technologies? And can we create an evidence-generation system that is more continuously reassessing outcomes as things change? It’s a big and bold set of questions.”

It might make sense to use ticagrelor in select groups of patients moving forward “rather than kind of carte blanche, changing the whole guideline,” Itchhaporia suggested.

Klein, however, feels more strongly about the need to provide clarity on the issues around PLATO and ticagrelor. “If PLATO was flawed and if the results weren’t what was published, the first step is the record has to be clarified and the guidelines committees have to change the guidelines to reflect the fact that there are no confirmatory studies in modern practice,” he said.

He added, too, that “as an American citizen who pays for my insurance and a taxpayer whose income in part pays for CMS, I’d like to be reassured that the expensive drug I helped pay for, for others, was a wise use of the money. And if it wasn’t, then I would think the government and the insurance companies would expect restitution.”

To that end, he agreed with Serebruany that the Department of Justice should take another look at the PLATO trial and some of the issues raised in Doshi’s story.

“I’m disappointed that medical professionals have dropped the ball on this and haven’t looked at it,” Klein said. “And if it has to be the Department of Justice, then it has to be the Department of Justice. But somebody’s got to investigate thoroughly what happened.”

Responding to a request for comment from TCTMD, a spokesperson from AstraZeneca said the company is aware of the BMJ publication, “which reiterates themes consistent with prior coverage of this matter. We are confident in the integrity of the PLATO trial and the benefits Brilinta/Brilique offers to patients and have no additional comment to share outside of our previous statement.”