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

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;

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.

Informations de copyright

Copyright: © 2022 The Author(s). Published by IMR Press.

Déclaration de conflit d'intérêts

The authors declare no conflict of interest. Victor Serebruany is serving as one of the Editorial Board members of this journal. We declare that Victor Serebruany had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Mattia Galli and Domenico D’Amario. At the time of NDA 22-433 review, the senior author of this paper was a Medical Team Leader for the FDA cardio-renal division. HeartDrug™ Research LLC (Wilmington, DE) owned by Victor Serebruany supported communications, and travel. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.