Included Studies

The systematic search of the literature identified one study for inclusion. The ENGAGE AF-TIMI 48 study was a phase III, noninferiority (NI), double-blind, randomized, active-controlled, parallel-group trial. Investigators randomized 21,105 NVAF patients, who had a CHADS₂ (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, and prior stroke or transient ischemic attack or thromboembolism) score of at least 2, to edoxaban 60 mg, edoxaban 30 mg, or warfarin. This review will only focus on the approved edoxaban dose of 60 mg. The study primary efficacy outcome was the incident of stroke or SEE; major bleeding was a primary safety outcome. The study continued until 672 primary efficacy–related events were collected. At the end of the double-blind treatment period, all patients transitioned to an open-label anticoagulation therapy of their choice.

ENGAGE AF-TIMI 48 employed an NI design with a hierarchal approach to test for superiority if NI was achieved. To satisfy NI, the upper boundary of the one-sided 97.5% confidence interval (CI) of edoxaban compared with warfarin had to be lower than 1.38. This margin was based on six historical studies of warfarin versus placebo and should have maintained at least 50% of the efficacy of warfarin over placebo. NI testing was conducted using the modified intention-to-treat analysis set from the treatment period. All superiority testing was conducted using the intention-to-treat analysis set from the overall study period. Treatment effects were reported using the hazard ratio (HR). The analysis was performed by employing a Cox proportional hazard model that included treatment groups and randomization stratification factors.

To address the lack of comparative evidence of edoxaban and other direct oral anticoagulants (DOACs), the CADTH Common Drug Review reviewed one manufacturer-submitted indirect comparison (IDC), as well as seven published IDCs that assessed the efficacy and safety of different DOACs for the prevention of stroke and SEEs in patients with NVAF.

Efficacy

The results from the ENGAGE AF-TIMI 48 study met the pre-specified NI margin. Overall, patients treated with edoxaban had a lower event rate of stroke or systemic embolism than patients treated with warfarin (HR edoxaban versus warfarin = 0.79; 95% CI, 0.63 to 0.99), the median per-site warfarin international normalized ratio–time in therapeutic range was 68.4%. The pre-specified superiority analysis failed to show superiority. Failure to show superiority at this point should have constituted a stop sign in the predefined hierarchal pathway of outcomes testing. In other words, no further statistical comparisons regarding efficacy outcomes should have been carried out. Subgroup analyses were performed for the primary efficacy outcome of stroke or SEE on the basis of baseline characteristics (age, gender, race, body weight, creatinine clearance, CHADS₂ score, dose reduction, prior vitamin K antagonist status, and various comorbidities). The findings from subgroup analyses were reported as being consistent with the base-case results.

Although all the reviewed IDCs share the same limitations, specifically the use of a fixed-effects model in the presence of clinical heterogeneity and our inability to test and assess basic IDC assumptions because of the insufficient number of DOAC trials, the results are consistent with the notion that edoxaban may have a similar efficacy and safety profile to other DOACs.

Harms

Major bleeding represents the biggest safety concern associated with antithrombotic drugs. The incidence of major bleeding (modified International Society on Thrombosis and Haemostasis criteria) was lower with edoxaban 60 mg than with warfarin (418 patients, 2.75%, versus 524 patients, 3.43%; HR = 0.80; 95% CI, 0.71 to 0.91). The incidence of various key aspects of major bleeding — fatal bleeding and hemorrhagic stroke — were lower with edoxaban 60 mg than with warfarin, but there were more patients with gastrointestinal hemorrhage in the edoxaban 60 mg arm than in the warfarin arm. Although ENGAGE AF-TIMI 48 was able to detect a statistically significant difference in major bleeding, the interpretation of this relative value into the absolute number of patients who will experience this lower risk of bleeding can be challenging.

Overall, there were fewer deaths in the edoxaban 60 mg arm (769 patients, 11.0%) than in the warfarin arm (836 patients, 11.9%). In both arms, the bulk of the deaths were driven by cardiovascular causes (7.5% in the edoxaban 60 mg arm; 8.7% in the warfarin arm). Approximately one-third of the patients in the ENGAGE AF-TIMI 48 trial experienced a nonbleeding serious adverse event (SAE). In total, 2,315 patients (33.0%) experienced nonbleeding SAEs in the edoxaban 60 mg arm, and 2,516 patients (35.9%) experienced nonbleeding SAEs in the warfarin arm.

The reviewed IDCs suggest that edoxaban does result in fewer major bleeding events than does warfarin. However, the results of the IDC of edoxaban with other DOACs are mixed, with some showing statistically significance in favour of edoxaban and others not showing statistical significance. It is important to consider the results of the IDCs with considerable caution: There is no trial comparing DOACs head to head, only four trials are available to inform DOAC comparisons, there is clinical heterogeneity between these trials, and the fixed-effects model was used in all the reviewed IDCs. All these factors present a challenge in assessing the reliability and accuracy of the IDC results. As such, all results of the DOAC IDCs should be considered as exploratory in nature and in need of further hypothesis testing. However, given the currently available evidence, no better-quality IDC could have been produced.