title: Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial.
abstract: BACKGROUND
  Rivaroxaban is established for the treatment and secondary prevention of venous thromboembolism, but whether it is useful in patients with antiphospholipid syndrome is uncertain.
  
  
  METHODS
  This randomised, controlled, open-label, phase 2/3, non-inferiority trial, done in two UK hospitals, included patients with antiphospholipid syndrome who were taking warfarin for previous venous thromboembolism, with a target international normalised ratio of 2·5. Patients were randomly assigned 1:1 to continue with warfarin or receive 20 mg oral rivaroxaban daily. Randomisation was done centrally, stratified by centre and patient type (with vs without systemic lupus erythematosus). The primary outcome was percentage change in endogenous thrombin potential (ETP) from randomisation to day 42, with non-inferiority set at less than 20% difference from warfarin in mean percentage change. Analysis was by modified intention to treat. Other thrombin generation parameters, thrombosis, and bleeding were also assessed. Treatment effect was measured as the ratio of rivaroxaban to warfarin for thrombin generation. This trial is registered with the ISRCTN registry, number ISRCTN68222801.
  
  
  RESULTS
  Of 116 patients randomised between June 5, 2013, and Nov 11, 2014, 54 who received rivaroxaban and 56 who received warfarin were assessed. At day 42, ETP was higher in the rivaroxaban than in the warfarin group (geometric mean 1086 nmol/L per min, 95% CI 957-1233 vs 548, 484-621, treatment effect 2·0, 95% CI 1·7-2·4, p<0·0001). Peak thrombin generation was lower in the rivaroxaban group (56 nmol/L, 95% CI 47-66 vs 86 nmol/L, 72-102, treatment effect 0·6, 95% CI 0·5-0·8, p=0·0006). No thrombosis or major bleeding were seen. Serious adverse events occurred in four patients in each group.
  
  
  CONCLUSIONS
  ETP for rivaroxaban did not reach the non-inferiority threshold, but as there was no increase in thrombotic risk compared with standard-intensity warfarin, this drug could be an effective and safe alternative in patients with antiphospholipid syndrome and previous venous thromboembolism.
  
  
  BACKGROUND
  Arthritis Research UK, Comprehensive Clinical Trials Unit at UCL, LUPUS UK, Bayer, National Institute for Health Research Biomedical Research Centre.
authors: Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK; Haemostasis Research Unit, Department of Haematology, University College London, London, UK. Electronic address: hannah.cohen@ucl.ac.uk.
authors: Hannah
authors: H
authors: Cohen
authors: Department of Thrombosis and Haemophilia, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK; Department of Haematology, King's College London, London, UK.
authors: Beverley J
authors: BJ
authors: Hunt
authors: Haemostasis Research Unit, Department of Haematology, University College London, London, UK.
authors: Maria
authors: M
authors: Efthymiou
authors: Haemostasis Research Unit, Department of Haematology, University College London, London, UK.
authors: Deepa R J
authors: DR
authors: Arachchillage
authors: Haemostasis Research Unit, Department of Haematology, University College London, London, UK.
authors: Ian J
authors: IJ
authors: Mackie
authors: Comprehensive Clinical Trials Unit, University College London, London, UK.
authors: Simon
authors: S
authors: Clawson
authors: Comprehensive Clinical Trials Unit, University College London, London, UK.
authors: Yvonne
authors: Y
authors: Sylvestre
authors: Haemostasis Research Unit, Department of Haematology, University College London, London, UK.
authors: Samuel J
authors: SJ
authors: Machin
authors: Academic Department of Vascular Surgery, Cardiovascular Division, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors: Maria L
authors: ML
authors: Bertolaccini
authors: Lupus Research Unit, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK.
authors: Maria
authors: M
authors: Ruiz-Castellano
authors: Comprehensive Clinical Trials Unit, University College London, London, UK.
authors: Nicola
authors: N
authors: Muirhead
authors: Comprehensive Clinical Trials Unit, University College London, London, UK.
authors: Caroline J
authors: CJ
authors: Doré
authors: Lupus Research Unit, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK; Lupus Research Unit, Division of Women's Health, King's College London, London, UK.
authors: Munther
authors: M
authors: Khamashta
authors: Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London, UK; Centre for Rheumatology, Division of Medicine, University College London, London, UK.
authors: David A
authors: DA
authors: Isenberg
mesh_terms: D000925:Anticoagulants / Q000627:therapeutic use; D016736:Antiphospholipid Syndrome / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology; D000074099:Equivalence Trials as Topic; D065427:Factor Xa Inhibitors / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D000069552:Rivaroxaban / Q000627:therapeutic use*; D015996:Survival Rate; D013927:Thrombosis / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology; D016896:Treatment Outcome; D006113:United Kingdom / Q000453:epidemiology; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D014859:Warfarin; D000069552:Rivaroxaban