title: Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
abstract: BACKGROUND
  Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes.
  
  
  METHODS
  We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71,683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity.
  
  
  RESULTS
  42,411 participants received a new oral anticoagulant and 29,272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73-0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38-0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85-0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39-0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01-1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59-0·81 vs 0·93, 0·76-1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84-1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43-1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02-1·60; p=0·045).
  
  
  CONCLUSIONS
  This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk-benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.
  
  
  BACKGROUND
  None.
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: cruff@partners.org.
authors: Christian T
authors: CT
authors: Ruff
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors: Robert P
authors: RP
authors: Giugliano
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors: Eugene
authors: E
authors: Braunwald
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors: Elaine B
authors: EB
authors: Hoffman
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors: Naveen
authors: N
authors: Deenadayalu
authors: Jefferson Medical College, Philadelphia, PA, USA; Cardiovascular Research Foundation, New York, NY, USA.
authors: Michael D
authors: MD
authors: Ezekowitz
authors: St George's University, London, UK.
authors: A John
authors: AJ
authors: Camm
authors: McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
authors: Jeffrey I
authors: JI
authors: Weitz
authors: Lady Davis Carmel Medical Center, Haifa, Israel.
authors: Basil S
authors: BS
authors: Lewis
authors: Institute of Cardiology, Kiev, Ukraine.
authors: Alexander
authors: A
authors: Parkhomenko
authors: The Cardiovascular Institute, Tokyo, Japan.
authors: Takeshi
authors: T
authors: Yamashita
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors: Elliott M
authors: EM
authors: Antman
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy*; D004617:Embolism / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin