Efficacy and Safety of Dabigatran Compared with Warfarin in Relation to Baseline Renal Function in Patients with Atrial Fibrillation: A RE-LY Trial Analysis

Background — Renal impairment increases the risk of stroke and bleeding in patients with atrial fibrillation. In the RE-LY trial dabigatran, with approximately 80% renal elimination, displayed superiority over warfarin for prevention of stroke and systemic embolism in the 150 mg dose, and significantly less major bleeding in the 110 mg dose in 18,113 patients with non-valvular atrial fibrillation. This pre-specified study investigates these outcomes in relation to renal function. Methods and Results — Glomerular filtration rate (GFR) was estimated with the Cockcroft-Gault, CKD-EPI and MDRD equations in all randomized patients with available creatinine at baseline (n=17,951), cystatin C based GFR was estimated in a subpopulation with measurements available (n=6190). A GFR (cid:149) 80, 50-<80, and <50 ml/min was estimated in 32.6%, 47.6%, 19.8%, and 21.6%, 59.6%, 18.8% based on Cockcroft-Gault and CKD-EPI, respectively. Rates of stroke or systemic embolism, major bleeding and all-cause mortality increased as renal function decreased. The rates of stroke or systemic embolism were lower with dabigatran 150 mg and similar with 110 mg twice daily, than those with warfarin without significant heterogeneity in subgroups defined by renal function (interaction p>0.1 for all). For the outcome of major bleed, there were significant interactions between treatment and renal function according to CKD-EPI and MDRD equations respectively (p<0.05). The relative reduction of major bleed with either dabigatran dose compared to warfarin was greater in patients with GFR (cid:149) 80 mL/min. coonnsnsistent witthohoututu anynyy ssigigignninififificcacantntt ininnteteraracctioonsnss forr rreenaalal iiimpmppaaiirmrmmenntnt ccononnccernrnnininingg isisschchchemememiccc sstrtrokokokes pp>0>0>0.66.69)9)9) aandndnd aallll---caauausesee mmmorortaaalilltytyty (((p<p<p<0.0.050505 wwwiitith h CoCoCockckkcrcrofofoft-t-t-GGaGaululult tt bbubuttt nonontt t siiigngngififificiccanantt t bbabaseeed onon continuous aanananalylylysisisisss ororr wwwheeen n n usuuinining g g thththe ototoheheherr r eGeGeGFRFRR eeeququqatatatioioionsnsns).).). ThThThe e rereresususultltltsss fofofr r boboboththth dddababaigatran grgrananntt sususupppppororot ccononossultant lectctturuue BBrBrissstotl-Myerers MsMsMs AAAndndnderererssssssononon rreeppororortstst nnoo ccoconnfliiictctctss s ofofof iintnttereeesesest.t.t DDDr CoConnnnnnololollylyly rrrepeppoorortststs eeeceeeiviing coonsnsullttinnng ffeeees, lleecctutuuree feeeees anannd ggrraannt suupppppororrt t t frfrfromomom Booeoehhringgegerr InInnggeelhlheiim.m.m DDDr EiEikekelblblboooooommm hhahas s rererecececeivivvededed gggrarntntt sssupupupppoportrt;; hohohonononorararaririria;a;a; aaandndn fefefeeseses