title: A cross-country comparison of rivaroxaban spontaneous adverse event reports and concomitant medicine use with the potential to increase the risk of harm.
abstract: BACKGROUND
  Concerns with the safety profiles of the newer anticoagulants have been raised because of differences in treatment populations between pre-marketing studies (randomized controlled trials) and clinical practice. Little is known about the potential safety issues and the reporting in spontaneous adverse event databases associated with rivaroxaban.
  
  
  OBJECTIVE
  To analyse spontaneous adverse event reports associated with the oral anticoagulant rivaroxaban from Australia, Canada and the USA; and to examine concomitant medicine use that may increase the risk of adverse events.
  
  
  METHODS
  Spontaneous adverse event report databases from Australia, Canada and the USA were examined for all reports of adverse events associated with rivaroxaban and concomitant medicines from 1 August 2005 to 31 March 2013. Disproportionality analysis (the proportional reporting ratio [PRR] and reporting odds ratio [ROR]) was conducted for quantitative detection of signals, using the US database.
  
  
  RESULTS
  There were 244 spontaneous adverse event reports associated with rivaroxaban from Australia, 536 from Canada and 1,638 from the USA. Reporting of haemorrhage (any type) was common, ranging from 30.7% for Australia to 37.5% for Canada. Gastrointestinal haemorrhage was the most commonly reported haemorrhage, accounting for 13.9% of Australian, 16.4% of Canadian and 11.1% of US adverse event reports. Positive signals were confirmed in the US data (haemorrhage [any type] PRR 11.93, χ (2) 4,414.78 and ROR 13.41, 95% confidence interval [CI] 12.13-14.81; gastrointestinal haemorrhage PRR 12.52, χ (2) 2,018.48 and ROR 13.15, 95% CI 11.36-15.21). Reporting of concomitant use of medicines with the potential to increase bleeding risk ranged from 63.7% in Australia to 89.2% in Canada.
  
  
  CONCLUSIONS
  A large proportion of adverse event reports for rivaroxaban were associated with use of concomitant medicines, which may have increased the risk of adverse events-in particular, haemorrhage. Increased awareness of a patient's comorbidity and associated medicine use is needed when rivaroxaban is used in clinical practice.
authors.affiliation: Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471, Adelaide, SA, 5001, Australia.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: McDonald
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kalisch Ellett
authors.forename: John D
authors.initials: JD
authors.lastname: Barratt
authors.forename: Gillian E
authors.initials: GE
authors.lastname: Caughey
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000925:Anticoagulants / Q000009:adverse effects*; D001315:Australia / Q000453:epidemiology; D002170:Canada / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects*; D016017:Odds Ratio; D011358:Product Surveillance, Postmarketing / Q000706:statistics & numerical data; D018570:Risk Assessment; D000069552:Rivaroxaban; D013876:Thiophenes / Q000009:adverse effects*; D014481:United States / Q000453:epidemiology
chemical_list: D000925:Anticoagulants; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban