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New Paper Disputes MI Count in TRITON, RECORD, and PLATO


August 6, 2012 (Towson, Maryland) — In three large cardiology trials--TRITON TIMI-38, RECORD, and PLATO--the number of MIs reported by the clinical events committees (CECs) differed from those reported by individual trial sites, all favoring the study drug. Did the study sponsors mishandle the data? This is the bold question posed by Dr Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD) andDr Dan Atar (Oslo University Hospital, Oslo, Norway) in a new analysis and commentary published online July 26, 2012 in Thrombosis and Hemostasis [1].
Dr Freek Verheugt (Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands), writing in an accompanying editorial, finds these discrepancies in MI outcomes "disturbing" [2].
But responding to the new paper, several of the trial investigators and CEC leaders insisted to heartwire that there is "no discrepancy," saying the viewpoint authors are the ones who used "bad science" and made "flawed analyses."
Viewpoint Implies Sponsors Manipulated Data
The authors compared the number of MIs reported by central CEC adjudicators and submitted to the US Food and Drug Administration (FDA) as part of the drug-approval process vs data from individual clinical-trial sites that were part of FDA secondary analyses.
Central adjudicating committees applied three strategies in MI reporting, which improved the MI outcomes with the investigational drugs, they report.
  • In TRITON TIMI-38, the MI definition was switched to a more liberal one toward the trial end, and the "extra" MIs were distributed equally to the prasugrel and clopidogrel (comparator) arms, making the numeric differences significant (from 72 to 144 MIs).
  • In PLATO, the CEC found an extra 45 MIs in the clopidogrel (comparator) arm but none in the ticagrelorarm.
  • In RECORD, 16 "silent" MIs were disallowed.
"It is difficult to deny that the results of adjudication--at least in these three examples--in fact formally favored the study sponsors," they write. "Without this adjudication . . . the three trials' primary efficacy outcomes were not significant," Serebruany told heartwire .
Physicians need to know the complete picture to make clinical decisions, he added. "In order to keep physicians informed, all future trial applications should mandatorily include site-reported events, so . . . physicians would know what actually investigators find out."
Editorial: "Provocative Analysis," "Astonishing Findings"
Verheugt acknowledges that adjudicators and investigators were dealing with blinded data, although RECORD was an open-label study. He finds the viewpoint analysis "provocative" and the findings "astonishing and possibly shocking."
"For the authors of the current analysis as well as many others, it cannot be completely ruled out that the sponsors of these studies had access to the data with possible manipulation of the study results as a consequence," he writes.
TIMI Investigators Poke Holes in Viewpoint
Others involved in the studies, however, take a dim view of Serebruany and Atar's conclusions.
"There is no 'discrepancy,' " Dr Christopher Cannon (Harvard Medical School, Boston, MA), senior investigator of the TIMI study group, told heartwire . "There were many periprocedural MIs that are only diagnosed via review of the centrally run biomarkers post-PCI, and thus the investigators are not supposed to find these MIs; only the CEC is," he noted. "Thus, it is a simple explanation and totally different from the wild and uninformed speculation of the authors of this very biased piece."
[There is] a simple explanation and totally different from the wild and uninformed speculation of the authors of this very biased piece.
"It is too simplistic to simply compare site and central numbers," Dr Stephen Wiviott (Brigham and Women's Hospital, Boston, MA), investigator of the TIMI study group, and chair of the TIMI study group CEC, similarly told heartwire . "In some PCI trials (for example, in TRITON-TIMI 38) biomarkers may be collected locally but analyzed and adjudicated centrally to identify MI--rather than asking sites to run uniform assays, interpret trial-specific definitions, and report such events," he explained. In other trials, the number of transfusions and specific bleeding sites might be collected without asking investigators to assign specific categories such as "major" or "minor."
"In each case, an analysis of site-reported vs central event rates would differ, with central rates [being] higher, not as a result of malfeasance or changing or reassigning events, but as a function of the data-collection and trial process," he said.
PLATO Investigators Highlight Viewpoint's "Bad Science"
PLATO trialists had a similar response.
The current "analyses are based on incomplete data, flawed assumptions, and inappropriate analyses," echoedDr Robert Harrington (Stanford University, Stanford, CA) cochair of the executive committee for PLATO, in a comment to heartwire . "While I respect open discussion and dialogue, this paper is just plain bad science," he continued. "But the tragedy is that [Serebruany] has taken a very important clinical-trial topic that warrants serious debate and discussion and trivialized it by his ongoing tirades on the topic."
"Event adjudication is an important aspect of trials, and we do need to have open dialogue about the issues raised by the authors," Dr Kenneth W Mahaffey (Duke Clinical Research Institute, Durham, NC), CEC chair for PLATO, concurred to heartwire . However, the "current analyses were flawed, because the authors did not use the patient-level data," he noted. "In PLATO, there were events that were reported by the investigators that were not called 'events' by the CEC, because they did not meet the protocol definition for the end point, [and in turn] the CEC found events that were not reported by the investigators as end points."
"The authors [also] fail to acknowledge several publications that have previously investigated the issues about disagreements between site investigators and a CEC, as well as trials in which the CEC end-point results were less favorable to the experimental arm than the site-reported end-point results," he pointed out.
Serebruany is listed as an inventor of and received compensation for US patent application P-17232, “Method for treating vascular diseases with prasugrel," assigned to Lilly, and “Treating cardiac arrhythmias, heart failure, peripheral artery disease, and stroke with cyclopentyl-triazolo-pyrimidine or derivative thereof" (USN 61/253 829) assigned to HeartDrug Research. He received funding for research studies with prasugrel and clopidogrel and consultant fees from the clopidogrel and ticagrelor manufacturers. Atar has no disclosures. Verheugt has received grants from Bayer, Roche, Lilly, and Boehringer Ingelheim. He has received consultancy/ speaker fees from Bayer, Daiichi Sankyo, Lilly, Merck, and the Medicines Company. Cannon reports receiving research grants/support from Accumetrics, AstraZeneca, Essentialis, GlaxoSmithKline, Merck, and Takeda; serving on advisory boards for Bristol-Myers Squibb/Sanofi, Novartis, and Alnylam (funds donated to charity); receiving honoraria for development of independent educational symposia from Pfizer and AstraZeneca; and serving as a clinical advisor to, with equity in, Automedics Medical Systems. Wiviott has previously disclosure receiving research funding from Eli Lilly, Daiichi Sankyo, and Schering Plough; consulting fees from Bristol-Myers Squibb, Sanofi, AstraZeneca, ARENA, and Medco; and independent continuing medical education speaking fees from Eli Lilly, Daiichi Sankyo, and Schering Plough. Disclosures for Harrington are available here. Mahaffey previously has disclosed receiving consulting fees from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Ortho/McNeill, Sanofi, Schering-Plough, Pfizer, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Novartis, and Polymedix; and grants from AstraZeneca, Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Eli Lilly,Johnson & Johnson, Merck, Novartis, Portola, Pozen, Regado, Schering-Plough, the Medicines Company, Daiichi Sankyo, GlaxoSmithKline, Momenta Pharmaceuticals, and Sanofi.

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