title: Inactivations, deletions, non-adjudications, and downgrades of clinical endpoints on ticagrelor: serious concerns over the reliability of the PLATO trial.
abstract: OBJECTIVE
  Ascertain platelet inhibition and patient outcomes (PLATO) trial conduct.
  
  
  METHODS
  We examined information from the FDA complete response review.
  
  
  RESULTS
  FDA Medical Review indicated that (1) patients on ticagrelor monitored by the study sponsor had a lower odds ratio for the primary endpoint (p = 0.0004) versus ticagrelor patients monitored by a third party Clinical Research Organisation (CRO) independent of the study sponsor, (2) a significant interaction existed between ticagrelor and regions monitored by the study sponsor for all cause mortality through study end in favor of ticagrelor (p = 0.006), (3) ticagrelor faired worse than clopidogrel when regions were monitored independent of the study sponsor by a third party Contract Research Organisation (United States, Russia and Georgia), (OR = 1.21, 95% CI: 0.91 to 1.59, p = 0.2022), (4) 46% of all primary endpoint events favoring ticagrelor came from just two countries (Poland and Hungary), (5) PLATO was easy to unblind by breaking open a clopidogrel/dummy clopidogrel tablet with at least 452 patients being unblinded prior to the database lock, (6) significantly more cardiac events submitted for clopidogrel counted in the primary analysis as a myocardial infarction (MI) compared to those submitted for ticagrelor (p < 0.0001), (7) significantly more ticagrelor subjects hospitalized after an index event/hospitalization were not being reported as having a primary event compared to clopidogrel (p = 0.002 in favor of ticagrelor), (8) site-reported MI was not significantly reduced with ticagrelor versus clopidogrel, (9) an estimated 23 definite or possible cardiovascular events or deaths on ticagrelor were either not submitted for adjudication, inactivated, deleted or were downgraded to "softer" endpoints (this was not shown in the FDA review for clopidogrel), and (10) four FDA reviewers voted for non-approval of ticagrelor.
  
  
  CONCLUSIONS
  The FDA report highlights what appear to be multiple serious deficiencies in the reporting of the PLATO results, which clinicians will not have gleaned from the primary publication alone. Individual clinicians may therefore wish to carefully reconsider their practice of ticagrelor prescription for this indication. Guideline bodies should also evaluate the information in its totality.
authors.affiliation: Wegmans Pharmacy, Ithaca, NY, United States; Department of Neurology, Charles University in Prague, 2nd Faculty of Medicine, University Hospital Motol, Czech Republic. Electronic address: jjdinicol@gmail.com.
authors.forename: James J
authors.initials: JJ
authors.lastname: DiNicolantonio
authors.forename: Ales
authors.initials: A
authors.lastname: Tomek
mesh_terms: D054058:Acute Coronary Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D023381:Endpoint Determination / Q000379:methods / Q000592:standards*; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use; D015203:Reproducibility of Results; D000077486:Ticagrelor; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration / Q000592:standards*
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000077486:Ticagrelor; D000241:Adenosine
keywords: Acute coronary syndrome; Clopidogrel; Myocardial infarction; Ticagrelor