Clinical Question

Is edoxaban (Lixiana) as safe and effective as warfarin (Coumadin) for the prevention of thromboembolic events in patients with atrial fibrillation?

Bottom Line

Edoxaban provides similar effectiveness and a somewhat lower rate of major gastrointestinal and intracranial bleeding than warfarin. It is worth reading the supplemental appendices to this report for a look at the subgroups. For almost all subgroups, low-dose edoxaban caused less major bleeding than warfarin, and was better than high-dose edoxaban. But when you look at the effectiveness outcome, almost every point estimate for low-dose edoxaban in every subgroup favors warfarin. This warfarin advantage was statistically significant for patients who had previously taken a vitamin K antagonist (i.e., warfarin) and for those who were not using aspirin at baseline. Thus, the benefit of edoxaban is much murkier, and is not as clear as the authors claim. (Level of Evidence = 1b)

Synopsis

Edoxaban is yet another oral direct inhibitor of factor Xa that is awaiting U.S. Food and Drug Administration approval. The researchers identified adults with atrial fibrillation diagnosed within the previous 12 months. They excluded anyone with severely impaired renal function; a high risk of bleeding; moderate to severe mitral stenosis; and acute coronary syndromes, coronary revascularization, or stroke within the 30 days before randomization. The participants were randomized to receive warfarin (international normalized ratio target = 2.0 to 3.0) or one to two doses of edoxaban (30 or 60 mg by mouth once daily). After randomization, patients with a creatinine clearance of 30 to 50 mL per minute per 1.73 m² (0.50 to 0.83 mL per second per m²); patients taking quinidine, verapamil, or dronedarone (Multaq); and patients weighing 132 lb (60 kg) or less had their dose halved.

Outcomes were adjudicated by a committee masked to the treatment assignment of each patient. Analysis was modified intention to treat (only patients receiving at least one dose of the study drug were included), but included 99.6% of patients originally enrolled in the study. This was a noninferiority trial; that is, it was designed to show that edoxaban was as good as warfarin. Those in the warfarin group spent 68% of their time in range, which is pretty typical for usual practice. The median age of participants was 72 years, 38% were women, and 25% had paroxysmal rather than chronic atrial fibrillation. Approximately 78% had a CHADS₂ (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and stroke or transient ischemic attack) score of 3 or less, indicating low risk of venous thromboembolism, whereas the remainder were at higher risk. The primary effectiveness end point was the composite of stroke or systemic embolic event, and the primary safety end point was the occurrence of major bleeding. Patients were followed for a median of 2.8 years, with slightly more than 7,000 persons in each group.

There was also an open-label continuation period, but we will focus on the double-blinded portion of the trial. For the comparison of high-dose edoxaban with warfarin, the former was slightly more effective regarding the primary outcome (1.18% vs. 1.5% per year; P = .02; number needed to treat [NNT] = 312 per year). There was no difference between low-dose edoxaban and warfarin regarding the primary outcome (1.61% vs. 1.5%). Most of the benefit came from a reduction in hemorrhagic (not embolic) stroke, which is actually a complication of anticoagulation rather than a byproduct of the atrial fibrillation. Major bleeding episodes were less common with high-dose edoxaban (2.75% vs. 3.43%; P < .001; NNT = 147) and low-dose edoxaban (1.61% vs. 3.43%; P < .001; NNT = 55). This benefit was observed for intracranial and gastrointestinal bleeds, as well as any bleed into a critical organ site. Adverse events other than bleeding were similar between groups.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Allocation: Concealed

Setting: Outpatient (any)

Reference: GiuglianoRPRuffCTBraunwaldEet alENGAGE AF-TIMI 48 InvestigatorsEdoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med.2013; 369( 22): 2093– 2104.