title: Implications of variability in definition and reporting of major bleeding in randomized trials of oral P2Y12 inhibitors for acute coronary syndromes.
abstract: OBJECTIVE
  Various definitions of major bleeding have been used to evaluate safety in randomized controlled trials of antiplatelet therapy. We compared the definitions and rates of major bleeding in phase III randomized controlled trials of oral P2Y(12) inhibitors in the management of patients with acute coronary syndromes (ACS).
  
  
  RESULTS
  Electronic searches identified six phase III randomized controlled oral P2Y(12) inhibitor trials published between 2001 and 2010 involving 119 020 patients with ACS. The trials compared clopidogrel standard-dose (300-mg loading dose, 75-mg daily thereafter) vs. placebo (CURE, CLARITY-TIMI 28, COMMIT), clopidogrel standard-dose vs. prasugrel (TRITON-TIMI 38) or ticagrelor (PLATO) and clopidogrel standard-dose vs. clopidogrel double-dose (600-mg loading dose, 150-mg daily for 6-days, 75-mg daily thereafter) (CURRENT-OASIS 7). Using the trial definition, major bleeding rates in patients treated with standard-dose clopidogrel ranged from 0.6% in COMMIT to 11.2% in PLATO. The contrast in bleeding rates of standard-dose clopidogrel among the trials was attenuated when using the thrombolysis in myocardial infarction (TIMI) definition for major bleeding (range 1.1-7.7%) and bleeding rates in all the trials were less than 2% when comparing 30 day rates of non-coronary artery bypass graft surgery-related TIMI major bleeding (range 0.3-1.9%).
  
  
  CONCLUSIONS
  Differences in major bleeding rates between trials of P2Y(12) inhibitors in patients with ACS are minimized after standardization of bleeding definitions, timing of reporting of bleeding outcomes, and procedure rates. Interpretation of the risk of bleeding associated with different P2Y(12) inhibitors would be facilitated by a consistent approach to the definition and reporting of bleeding.
authors.affiliation: Department of Radiology, Kings College Hospital, London, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Quinlan
authors.forename: John W
authors.initials: JW
authors.lastname: Eikelboom
authors.forename: Shaun G
authors.initials: SG
authors.lastname: Goodman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Welsh
authors.forename: David H
authors.initials: DH
authors.lastname: Fitchett
authors.forename: Pierre
authors.initials: P
authors.lastname: Théroux
authors.forename: Shamir R
authors.initials: SR
authors.lastname: Mehta
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000241:Adenosine / Q000009:adverse effects / Q000031:analogs & derivatives; D017326:Clinical Trials, Phase III as Topic; D000077144:Clopidogrel; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013876:Thiophenes; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives
chemical_list: D010879:Piperazines; D058921:Purinergic P2Y Receptor Antagonists; D013876:Thiophenes; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine