Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trial
Selected in by R. Dworakowski
Christian T Ruff MD, Robert P Giugliano, Eugene Braunwald, Elaine B Hoffman, Naveen Deenadayalu, Michael D Ezekowitz, A John Camm, Jeffrey I Weitz, Basil S Lewis, Alexander Parkhomenko, Takeshi Yamashita, Elliott M Antman
The Lancet, Volume 383, Issue 9921, Pages 955 - 962, 15 March 2014
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What is known
New oral anticoagulants (rivaroxaban, dabigatran, apixaban-NOACs) are at least as safe and effective as warfarin for stroke prevention in patients with atrial fibrillation. The balance between efficacy and safety in important clinical subgroups needs better definition. Authors aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes.
- meta-analysis of all 71 683 patients included in the four phase 3 randomised trials: RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF
- NOACs significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73—0·91; p<0·0001), this was mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38—0·64; p<0·0001)
- NOACs were associated with reduction of 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)
- a greater relative reduction in major bleeding with new oral anticoagulants was seen 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).
The main limitation of this meta-analysis is an assumption that all new oral anticoagulants are the same and work on the basis of class effect, which is not the case. Dabigatran is competitive and reversible direct thrombin inhibitor activated in the liver by cytochrome p-450 system. Its absorption is dependent to P-glycoprotein system; Rivaroxaban is a highly selective factor Xa inhibitor inhibiting both thrombin formation and development of thrombi, is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms; Apixaban is direct Xa inhibitor metabolized by CYP3A4. Inhibitors of CYP3A4 such as ketoconazole, dilatizem and naproxen increase mean apixaban concentration.
Nevertheless authors showed that NOACs are more effective and safer than warfarin across a broad range of analysed subgroups. The patients group that benefits the most from NOACs is a group with INR difficult to control.
This meta-analysis confirms findings from individual studies that new oral anticoagulants are as good as warfarin in preventing ischaemic stroke but they are safer.