title: Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.
abstract: BACKGROUND
  Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0-3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population.
  
  
  METHODS
  In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0-3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600.
  
  
  RESULTS
  The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1-65·5%, 65·5-72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0·036 and p=0·0006, respectively) and total mortality (interaction p=0·066 and p=0·052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR.
  
  
  CONCLUSIONS
  The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives.
  
  
  BACKGROUND
  Boehringer Ingelheim.
authors.affiliation: Uppsala Clinical Research Centre, Uppsala University, Uppsala, Sweden. lars.wallentin@ucr.uu.se
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ezekowitz
authors.forename: Marco
authors.initials: M
authors.lastname: Alings
authors.forename: Marcus
authors.initials: M
authors.lastname: Flather
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Franzosi
authors.forename: Prem
authors.initials: P
authors.lastname: Pais
authors.forename: Antonio
authors.initials: A
authors.lastname: Dans
authors.forename: John
authors.initials: J
authors.lastname: Eikelboom
authors.forename: Jonas
authors.initials: J
authors.lastname: Oldgren
authors.forename: Janice
authors.initials: J
authors.lastname: Pogue
authors.forename: Paul A
authors.initials: PA
authors.lastname: Reilly
authors.forename: Sean
authors.initials: S
authors.lastname: Yang
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Connolly
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000150:complications*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069604:Dabigatran; D004334:Drug Administration Schedule; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020521:Stroke / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D013923:Thromboembolism / Q000517:prevention & control; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D001562:Benzimidazoles; D011725:Pyridines; D014859:Warfarin; D000069604:Dabigatran