Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.

International audienceBACKGROUND: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: None

Left atrial structure and function in atrial fibrillation: ENGAGE AF-TIMI 48.

International audienceAIMS: The complex relationship between left atrial (LA) structure and function, electrical burden of atrial fibrillation (AF) and stroke risk is not well understood. We aimed to describe LA structure and function in AF. METHODS AND RESULTS: Left atrial structure and function was assessed in 971 subjects enrolled in the echocardiographic substudy of ENGAGE AF-TIMI 48. Left atrial size, emptying fraction (LAEF), and contractile function were compared across AF types (paroxysmal, persistent, or permanent) and CHADS2 scores as an estimate of stroke risk. The majority of AF patients (55%) had both LA enlargement and reduced LAEF, with an inverse relationship between LA size and LAEF (R = -0.57, P < 0.001). With an increasing electrical burden of AF and higher CHADS2 scores, LA size increased and LAEF declined. Moreover, 19% of AF subjects had impaired LAEF despite normal LA size, and LA contractile dysfunction was present even among the subset of AF subjects in sinus rhythm at the time of echocardiography. CONCLUSIONS: In a contemporary AF population, LA structure and function were increasingly abnormal with a greater electrical burden of AF and higher stroke risk estimated by the CHADS2 score. Moreover, LA dysfunction was present despite normal LA size and sinus rhythm, suggesting that the assessment of LA function may add important incremental information in the evaluation of AF patients. Clinical Trial Registration: http://www.clinicaltrials.gov; ID = NCT00781391