Edoxaban versus enoxaparin for the prevention of venous thromboembolism after total knee or hip arthroplasty: pooled analysis of coagulation biomarkers and primary efficacy and safety endpoints from two phase 3 trials

Abstract

Background: The objective of this analysis was to assess the effects of edoxaban compared with enoxaparin on key coagulation biomarkers and present pooled primary efficacy and safety results from phase 3 STARS E-3 and STARS J-V trials for prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) or total hip arthroplasty (THA).

Methods: In the randomized, double-blind, double-dummy, multicenter, STARS E-3 and STARS J-V trials, patients received edoxaban 30 mg or enoxaparin 2000 IU (20 mg) twice daily for 11 to 14 days. The studies were conducted in Japan and Taiwan; enoxaparin dosing was based on Japanese label recommendations. The primary efficacy endpoint was incidence of VTE; the safety endpoint was major or clinically relevant nonmajor (CRNM) bleeding. Blood samples were taken at presurgical evaluation, pretreatment (postsurgery), predose on day 7, predose on completion of treatment, and at a follow-up examination 25 to 35 days after the last dose of study drug for D-dimer, prothrombin fragment 1 + 2 (F₁₊₂), and soluble fibrin monomer complex (SFMC) measurement.

Results: A total of 716 patients enrolled in STARS E-3 and 610 patients enrolled in STARS J-V; 1326 patients overall. This analysis included 657 patients who received edoxaban 30 mg QD and 650 patients who received enoxaparin 20 mg BID. Incidence of VTE was 5.1 and 10.7% for edoxaban and enoxaparin, respectively (P <0.001). Incidence of combined major and CRNM bleeding was 4.6 and 3.7% for edoxaban and enoxaparin, respectively (P = 0.427). On day 7, mean D-dimer (4.4 vs 5.5 μg/mL), F₁₊₂ (363 vs 463 pmol/L), and SFMC (5.7 vs 6.8 μg/mL) were lower in edoxaban-treated patients relative to enoxaparin-treated patients, respectively (P <0.0001 for all). At end of treatment, mean D-dimer (5.4 vs 6.2 μg/mL), F₁₊₂ (292 vs 380 pmol/L), and SFMC (6.2 vs 7.2 μg/mL) were lower in edoxaban-treated patients relative to enoxaparin-treated patients (P <0.0001 for all).

Conclusions: Edoxaban was superior to enoxaparin in prevention of VTE following TKA and THA, with comparable rates of bleeding events. Relative to enoxaparin, edoxaban significantly reduced D-dimer, F₁₊₂, and SFMC.

Trial registration: Clintrials.gov NCT01181102 and NCT01181167. Both registered 8/12/2010.

Keywords: Biomarker; DOAC; Total hip arthroplasty; Total knee arthroplasty; VTE prophylaxis.

Fig. 1

Distribution of patients in the pooled data analyses. ^aThe safety analysis set included all enrolled patients who received study drug, had posttreatment safety data, and did not have significant GCP violations. ^bThe full analysis set included all patients receiving ≥1 dose of study drug and excluded patients with significant GCP violations or with inadequate venography. ^cMultiple answers were allowed; patients falling under multiple categories were counted once for each category. ^dThe per-protocol set included patients in the FAS and excluded patients with violations of inclusion or exclusion criteria, violation of rules for prohibited concomitant drugs/treatment, or <80% compliance with study drug. GCP = good clinical practice; FAS = full analysis set; THA = total hip arthroplasty; TKA = total knee arthroplasty

Fig. 2

Primary efficacy endpoint – incidence of VTE. ^aChi square test. VTE = venous thromboembolism

Fig. 3

Levels of coagulation biomarkers. a D-dimer; b Prothrombin fragments 1 + 2 (F₁₊₂); c Soluble fibrin monomer complex (SFMC). Open circles mark mean; horizontal lines indicate median; boxes represent 25–75%; capped lines represent 10 and 90%; ^* = P <0.001 (Wilcoxon test)

Fig. 4

Incidence of major and CRNM bleeding events. ^aChi square test; CI = confidence interval; CRNM = clinically relevant nonmajor