title: Characterising and predicting bleeding in high-risk patients with an acute coronary syndrome.
abstract: OBJECTIVE
  In the Apixaban for Prevention of Acute Ischemic Events (APPRAISE-2) trial, the use of apixaban, when compared with placebo, in high-risk patients with a recent acute coronary syndrome (ACS) resulted in a significant increase in bleeding without a reduction in ischaemic events. The aim of this analysis was to provide further description of these bleeding events and to determine the baseline characteristics associated with bleeding in high-risk post-ACS patients.
  
  
  METHODS
  APPRAISE-2 was a multinational clinical trial including 7392 high-risk patients with a recent ACS randomised to apixaban (5 mg twice daily) or placebo. Bleeding including Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding, International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant non-major (CRNM) bleeding, and any bleeding were analysed using an on-treatment analysis. Kaplan-Meier curves were plotted to describe the timing of bleeding, and a Cox proportional hazards model was used to identify predictors of ISTH major or CRNM bleeding and any bleeding. Median follow-up was 241 days.
  
  
  RESULTS
  The proportion of patients who experienced TIMI major or minor, ISTH major or CRNM, and any bleeding was 1.5%, 2.2% and 13.3%, respectively. The incidence of bleeding was highest in the immediate post-ACS period (0.11 in the first 30 days vs 0.03 after 30 days events per 1 patient-year); however, >60% of major bleeding events occurred >30 days after the end of the index hospitalisation. Gastrointestinal bleeding was the most common cause of major bleeding, accounting for 45.9% of TIMI major or minor and 39.5% of ISTH major or CRNM bleeding events. Independent predictors of ISTH major or CRNM bleeding events included older age, renal dysfunction, dual oral antiplatelet therapy, smoking history, increased white cell count and coronary revascularisation.
  
  
  CONCLUSIONS
  When compared with placebo, the use of apixaban is associated with an important short-term and long-term risk of bleeding in high-risk post-ACS patients, with gastrointestinal bleeding being the most common source of major bleeding. The baseline predictors of major bleeding appear to be consistent with those identified in lower-risk ACS populations with shorter-term follow-up.
  
  
  BACKGROUND
  NCT00831441.
authors.affiliation: Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Razi
authors.initials: R
authors.lastname: Khan
authors.affiliation: Duke Clinical Research Institute, Duke Medicine, Durham, North Carolina, United States.
authors.forename: Renato D
authors.initials: RD
authors.lastname: Lopes
authors.affiliation: Duke Clinical Research Institute, Duke Medicine, Durham, North Carolina, United States.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Neely
authors.affiliation: Duke Clinical Research Institute, Duke Medicine, Durham, North Carolina, United States.
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Stevens
authors.affiliation: Stanford School of Medicine, Stanford, California, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.affiliation: ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina.
authors.forename: Rafael
authors.initials: R
authors.lastname: Diaz
authors.affiliation: Academisch Ziekenhuis Klina, Brasschaat, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Cools
authors.affiliation: University Hospital Motol, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Jansky
authors.affiliation: Institute of Cardiology, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
authors.affiliation: Oslo University Hospital, and Institute of Clinical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Dan
authors.initials: D
authors.lastname: Atar
authors.affiliation: University Hospital La Paz, Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Lopez-Sendon
authors.affiliation: Clinical Trials and Evaluation Unit, Royal Brompton Hospital and Harefield NHS Foundation Trust, London, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Flather
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Liaw
authors.affiliation: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.affiliation: Duke Clinical Research Institute, Duke Medicine, Durham, North Carolina, United States.
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
authors.affiliation: Terrence Donnelly Heart Centre, St Michael's Hospital, University of Toronto, and the Canadian Heart Research Centre, Toronto, Ontario, Canada.
authors.forename: Shaun G
authors.initials: SG
authors.lastname: Goodman
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000368:Aged; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D006470:Hemorrhage / Q000139:chemically induced / Q000145:classification / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011379:Prognosis; D016016:Proportional Hazards Models; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects; D018570:Risk Assessment; D012307:Risk Factors; D055502:Secondary Prevention / Q000379:methods; D013997:Time Factors
chemical_list: D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban