The FDA and PLATO Investigators death lists: Call for a match

Serebruany, Victor L.; Tanguay, Jean‐François; Marciniak, Thomas A.

doi:10.1111/ijcp.14105

Cited by 4 publications

(4 citation statements)

References 11 publications

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“…Both data sets identify a single PDC, which we would expect to be identical [ 5 , 6 , 7 ]. The PDC may be “unknown” or “other” but there should be just one PDC.…”

Section: Resultsmentioning

confidence: 99%

“…Not only is suicide (PLATO code 12-5) a valid PDC, which cannot be substituted, but both “missing” patients are from the clopidogrel arm. We directly approached PLATO Investigators with detailed specific inquiries regarding these 2 suicides unreported to the FDA, but we received no response or any explanation on these 2 extra deaths in the DRTI [ 6 ]. Not solving such a simple issue not only raises questions regarding inaccurate vascular deaths but also challenges the claimed all-cause mortality benefit of ticagrelor, which has not been observed in later clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…It was our hypothesis that these two lists would match precisely with the exception of 33 fatalities removed from the broader DRFDA. We repeatedly tried to gain access to the original DRTI for the optimal match [ 6 ], but our requests were ignored. However, the PDC data based on DRTI counts were presented by the PLATO Investigators in several good quality papers [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Primary Causes of Death Reported to the FDA Suggest Less Ticagrelor Mortality Benefit than the List Issued to the PLATO Trial Investigators

Serebruany¹,

Tanguay²,

Marciniak³

2022

Rev. Cardiovasc. Med.

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Background:The PLATO trial data set reported to the FDA (DRFDA) revealed that some primary deaths causes (PDC) were inaccurately reported favoring ticagrelor. Trial Investigators (DRTI) received different data set with more ticagrelor mortality advantage. We compared these two death lists for the match in PDC. Methods and Results: The DRFDA contains 938 deaths, while the DRTI contains 905. We matched "vascular", "non-vascular", "unknown", "missed", and "other" causes of death between DRFDA and DRTI. The DRFDA used 14 vascular, 9 non-vascular, 1 unknown and 1 other PDC codes, while the DRTI used 14 but different vascular, 14 non-vascular but no unknown or other PDC codes. We observed a significant mismatch for the PDC codes between the DRFDA and DRTI data sets. Most DRFDA deaths were vascular (n = 677), fewer non-vascular (n = 159) and unexpectedly many unknown (n = 95) or other (n = 7) PDC. Surprisingly, the shorter DRTI contains more vascular (n = 795), fewer non-vascular (n = 110), but no unknown, other, or missed causes. There were more sudden deaths in DRTI than in DRFDA (161 vs. 138; p < 0.03), twice as many post-myocardial infarction deaths (373 vs. 178; p < 0.001) but fewer heart failure deaths (73 vs. 109; p = 0.02). The reported non-vascular PDC match better except for 2 extra suicides in the clopidogrel arm of the DRTI. Conclusions: Over 100 "unknown", "missed", or "other" PDC events reported by the trial sponsor to the FDA were omitted from the investigator data set contributing to the inflated differences in vascular mortality benefit of ticagrelor reported in numerous PLATO publications. Synchronization of PDC reporting between regulatory agencies and investigators was lacking in PLATO but remains mandatory to ensure quality for future indication-seeking trials.

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“…Both data sets identify a single PDC, which we would expect to be identical [ 5 , 6 , 7 ]. The PDC may be “unknown” or “other” but there should be just one PDC.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Primary Causes of Death Reported to the FDA Suggest Less Ticagrelor Mortality Benefit than the List Issued to the PLATO Trial Investigators

Serebruany¹,

Tanguay²,

Marciniak³

2022

Rev. Cardiovasc. Med.

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“…We finally gained access to the detailed FDA-issued dataset of PLATO deaths, which has been matched with local patient-level data from sites controlled by the sponsor, revealing that the actual existence, precise dates, and proper causes of some deaths in PLATO were inaccurately reported in favor of ticagrelor [5]. Moreover, there is a significant discrepancy between primary death causes reported to the FDA, and those utilized by the PLATO for numerous secondary reports published in top journals for over a decade [6]. We here examined the validity and reporting patterns of cancer deaths in PLATO.…”

Section: Introductionmentioning

confidence: 99%

Misreported Cancer Deaths in PLATO Trial

Serebruany

Tanguay

2021

JCM

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The potential link between antiplatelet agents and anticoagulants with excess cancer deaths (CD) was reported first for prasugrel (TRITON, DAPT), clopidogrel (DAPT), vorapaxar (TRACER), apixaban (APPRAISE-2), and later ticagrelor (PEGASUS). However, verified CD in the ticagrelor indication-seeking PLATO were not public. We obtained the complete list of deaths and their primary causes in PLATO, matched that dataset against local site records, and analyzed the patterns of CD reporting. The FDA-issued spreadsheet contains 31 precisely detailed CD (PLATO code 12-3). We obtained local site evidence for four CD and matched them with FDA-reported. We also assessed the patterns of how CD were reported among non-vascular death database column “S” by scrolling the FDA Excel file down among 938 PLATO entries. Clopidogrel CD (n = 17) were reported exclusively by sponsor, while independent CRO’s reported only ticagrelor CD (3 out of 14 PLATO total). Among four matched verified outcomes, one ticagrelor CD was correct, second ticagrelor CD was unreported, and two (ticagrelor and clopidogrel) CD were reported inaccurately. Of the remaining 16 clopidogrel CD six were reported as three separate next in line paired entries in Denmark (236–237), Poland (597–598), Romania (679–680), and as two more fatalities in South Africa (786) and Spain (789), while patients 787 and 788 received ticagrelor out of 938 records suggesting possible late addition of incorrect clopidogrel CD reports. We conclude that some CD were misreported in PLATO, favoring ticagrelor. Such mismatch may require reevaluation of this critical outcome in the trial focusing on the exact death cause reported by site investigators.

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Infections Deaths in the PLATO Trial

Serebruany

Tanguay

2021

TH Open

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Background Cardiovascular benefits of aggressive dual antiplatelet therapy may be associated with extra risks including bleeding, cancer, and infections discovered first for prasugrel in the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel (TRITON) trial. Ticagrelor in PLATO also caused slightly more infections but surprisingly less sepsis-related deaths (SRD) than clopidogrel. However, verified infection fatalities in PLATO were lacking from the public domain. We obtained the complete Food and Drug Administration (FDA)-issued primary causes death list, matched it with the few local site records dataset and analyzed the patterns of infections and deaths reported in PLATO. Methods Among infections, the FDA spreadsheet contains only two primary death codes for pneumonia (12–2) and SRD (12–8). We obtained local evidence for two pneumonia and two SRD and matched those with the FDA records. We assessed how SRD patterns were reported among nonvascular death's dataset. Results The FDA PLATO records indicate that clopidogrel caused numerically less (n = 8) primary pneumonia deaths than ticagrelor (n = 10) but over three times more SRD (n = 23/7). Among matched verifiable outcomes, both pneumonia deaths were correct, but two clopidogrel SRD were incorrect. Of the remaining 21 clopidogrel SRD, 6 were reported as two separate closed paired entries in Brazil (lines 76 and 78 and 86 and 88) and India (lines 436 and 440), suggesting last minute addition of potentially incorrect SRD reports. Four ticagrelor SRD (lines 24,193,467 and 650) were “compensated” with close or next in line clopidogrel SRD entries (lines 22,195,468 and 651). Conclusion The FDA-issued evidence suggests no benefit of ticagrelor in preventing deaths from infections with slightly more pneumonia deaths, with possible misreporting of SRD in PLATO. These findings require an in-depth precise review of sepsis deaths in this trial.

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The FDA and PLATO Investigators death lists: Call for a match

Cited by 4 publications

References 11 publications

Primary Causes of Death Reported to the FDA Suggest Less Ticagrelor Mortality Benefit than the List Issued to the PLATO Trial Investigators

Primary Causes of Death Reported to the FDA Suggest Less Ticagrelor Mortality Benefit than the List Issued to the PLATO Trial Investigators

Misreported Cancer Deaths in PLATO Trial

Infections Deaths in the PLATO Trial

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