Previously published meta-analyses have compared trials of new oral anticoagulants with warfarin in patients with atrial fibrillation (AF), but the current meta-analysis is the first to include data for edoxaban, a novel direct oral factor Xa inhibitor. The analysis included four phase III RCTs of patients with AF (n=71,683; RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF–TIMI 48 trials) which were powered to address their primary endpoints. The outcomes of interest were stroke and systemic embolic events (primary efficacy outcome), ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding (primary safety outcome), intracranial haemorrhage, and gastrointestinal bleeding. Furthermore, the comparative efficacy and safety for stroke or systemic embolic events and for major bleeding (the primary efficacy and safety outcomes) were assessed in the following subgroups: age (<75 vs ≥75 years), sex, history of previous stroke or transient ischaemic attack, history of diabetes, renal function (creatinine clearance <50 mL/min, 50–80 mL/min, >80 mL/min), CHADS2 risk score (0–1, 2, 3–6), vitamin K antagonist status at study entry (naive or experienced), and centre-based time in therapeutic range (threshold of <66% vs ≥66%). [The analysis did not address the question of which novel oral anticoagulant is best, whether from an efficacy or safety perspective.]
The following results were reported:
• 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).
• No heterogeneity for stroke or systemic embolic events were noted in the 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).
The authors concluded that compared to warfarin, the new oral anticoagulants had similar efficacy for the prevention of stroke, were associated with a significant reduction in all cause-mortality and had a favourable safety profile but with an increase in gastrointestinal bleeding. These findings are consistent across a wide range of patients with AF known to be at high risk for both ischaemic and bleeding events.
An accompanying editorial notes that these indirect comparative data provide a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population. The authors suggest that “the drug could be fitted to the patient, or the patient to the drug, dependent on a focus on safety or efficacy, and on other patient factors, such as renal function and drug compliance.”