title: Rivaroxaban compared with standard thromboprophylaxis after major orthopaedic surgery: co-medication interactions.
abstract: OBJECTIVE
  The aim of the present study was to analyse concomitant drug use and its association with outcome in patients (N = 17 701) receiving rivaroxaban or standard of care (SOC) for the prevention of venous thromboembolism after major orthopaedic surgery in the non-interventional, phase IV XAMOS (Xarelto® in the prophylaxis of post-surgical venous thromboembolism after elective major orthopaedic surgery of hip or knee) study.
  
  
  METHODS
  Concomitant drug use was at the discretion of the treating physician. Prespecified co-medications of interest were cytochrome P450 (CYP) 3A4/P-glycoprotein inhibitors/inducers, platelet aggregation inhibitors (PAIs) and nonsteroidal anti-inflammatory drugs (NSAIDs). Crude event incidences were compared between rivaroxaban and SOC groups.
  
  
  RESULTS
  CYP3A4/P-glycoprotein inhibitor/inducer use was infrequent, in contrast to PAI (~7%) and NSAID (~52%) use. Rivaroxaban was associated with a lower incidence of overall symptomatic thromboembolic events compared with SOC, regardless of co-medication use. In both treatment groups, PAI users, with higher age and prevalence of cardiovascular co-morbidities, had similar higher (>7-fold) incidences of symptomatic arterial but not venous thromboembolic events compared with non-users. NSAID use had no influence on thromboembolic events. However, odds ratios (ORs) for major bleeding events (European Medicines Agency definition) were higher in NSAID users compared with non-users in rivaroxaban [OR = 1.50; 95% confidence interval (CI) 1.06, 2.13] and SOC (OR = 1.70; CI 1.16, 2.49) groups. In PAI users, ORs for major bleeding events were no different from those of non-users in both the rivaroxaban (OR = 1.49; CI 0.84, 2.65) and SOC (OR = 1.46; CI 0.82, 2.62) groups.
  
  
  CONCLUSIONS
  Use of NSAIDs in XAMOS was frequent and associated with a higher frequency of bleeding events in patients receiving rivaroxaban or SOC, although the benefit-risk profile of rivaroxaban compared with SOC was maintained.
authors.affiliation: Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
authors.affiliation: Institute for Experimental Oncology and Therapy Research, Technical University of Munich, Munich, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Haas
authors.affiliation: Bayer HealthCare AG, Berlin, Germany.
authors.forename: Gerlind
authors.initials: G
authors.lastname: Holberg
authors.affiliation: Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lassen
authors.affiliation: CESP-Center for Public Health Research, University of Milan-Bicocca, Monza, Italy.
authors.forename: Lorenzo G
authors.initials: LG
authors.lastname: Mantovani
authors.affiliation: Bayer HealthCare AG, Berlin, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Department of Medicine, Hamilton Health Services, Hamilton, Ontario, Canada.
authors.forename: Alexander G G
authors.initials: AG
authors.lastname: Turpie
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019644:Arthroplasty, Replacement, Hip / Q000379:methods*; D019645:Arthroplasty, Replacement, Knee / Q000379:methods*; D015331:Cohort Studies; D004347:Drug Interactions; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069552:Rivaroxaban / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D054556:Venous Thromboembolism / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D000069552:Rivaroxaban
keywords: bleeding; major orthopaedic surgery; nonsteroidal anti-inflammatory drug; platelet aggregation inhibitor; rivaroxaban; venous thromboembolism