Document Detail


Inactivations, deletions, non-adjudications, and downgrades of clinical endpoints on ticagrelor: Serious concerns over the reliability of the PLATO trial.
MedLine Citation:
PMID:  23911266     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
DISCUSSION: 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:
James J Dinicolantonio; Ales Tomek
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-8-1
Journal Detail:
Title:  International journal of cardiology     Volume:  -     ISSN:  1874-1754     ISO Abbreviation:  Int. J. Cardiol.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-8-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8200291     Medline TA:  Int J Cardiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013.
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.
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