A 48-week course of edoxaban was non-inferior to warfarin in patients with chronic thromboembolic pulmonary hypertension (CTEPH) as treatment to prevent pulmonary vascular resistance, new trial results show. Kazuya Hosokawa, MD, of Kyushu University, Fukuoka, Japan, reported these results as featured science Monday at the American Heart Association Scientific Sessions 2023 in Philadelphia. Hosokawa and colleagues also reported the findings in a manuscript simultaneously published online in Circulation. For individuals diagnosed with CTEPH, experts recommend lifelong anticoagulation with vitamin K antagonists to prevent the recurrence of pulmonary embolism and deterioration of CTEPH. However, there is a notable absence of data from randomized controlled trials regarding the use of direct oral anticoagulants for CTEPH. Edoxaban, an approved oral factor Xa inhibitor for deep vein thrombosis, pulmonary embolism, and atrial fibrillation, had not previously been studied for potential use in CTEPH The KABUKI trial, a phase 3 investigator-initiated study, was a multicenter, single-blind, randomized, warfarin-controlled, noninferiority trial designed to assess the efficacy and safety of edoxaban in individuals with CTEPH. Conducted across 11 Japanese institutions, the study included eligible patients with CTEPH, World Health Organization (WHO) functional class I–III, who had been on warfarin for a minimum of 3 months before enrollment. Eligibility criteria also included patients who had undergone reperfusion therapy (such as pulmonary endarterectomy and balloon pulmonary angioplasty) or who were being treated with pulmonary vasodilators. In this trial, the prescribed target range for international normalized ratio (INR) adjustments with warfarin was 1.5–2.5, in accordance with Japanese guidelines. The daily dosage of edoxaban (60 mg for individuals weighing ≥60 kg, and 30 mg for those weighing <60 kg) was consistent with the regimen employed for venous thromboembolism prevention. The primary outcome measured the ratio of PVR at week 48 to the baseline PVR. Secondary outcomes included clinical deterioration of CTEPH, including events such as death, CTEPH-related hospitalization, rescue reperfusion treatment, initiation or dose escalation of pulmonary vasodilator, and a ≥15% reduction in the 6-minute walk distance with worsening WHO functional class. Additionally, N-terminal pro–B-type natriuretic peptide and D-dimer level were assessed. The safety outcome focused on clinically relevant bleeding, including major bleeding. Out of 80 individuals screened, 74 patients (mean age 63.6 ± 12.3 years, 62.2% females) were randomly assigned in a 1:1 ratio to receive either edoxaban or warfarin. In the per-protocol analysis, which was the primary analysis for the study, all patients, 36 in each group, had undergone reperfusion treatment prior to enrollment. The mean ratio of PVR at 48 weeks to baseline was 0.93 (95% confidence interval [CI]: 0.86 to 1.01) in the edoxaban group and 1.01 (95% CI: 0.93 to 1.10) in the warfarin group. The treatment effect, as indicated by the ratio of means, was 0.920 (95% CI: 0.820 to 1.032; P < 0.0001 for non-inferiority). All predefined secondary endpoints and exploratory outcomes demonstrated minimal changes in both groups, with no significant differences observed between them. There were no instances of clinical deterioration events in CTEPH, and no symptomatic venous thromboembolism were reported in either of the two groups. In the safety analysis, clinically relevant non-major bleeding was documented in one patient (2.7%) in the edoxaban group and one patient (2.7%) in the warfarin group. Serious adverse events occurred in one patient in the edoxaban group (2.7%) and in three patients (8.1%) in the warfarin group. No patients died during the trial. Hosokawa and colleagues said in the manuscript that caution should be exercised when interpreting the trial results due to several limitations. First, the trial was not structured to draw definitive conclusions regarding the effects of edoxaban on outcomes; rather, its purpose was to establish evidence of non-inferiority to warfarin. Second, all participants in the trial had previously undergone reperfusion therapy and had stable, mild disease. Lastly, the sample size was relatively small. The authors concluded that in patients with CTEPH who had undergone reperfusion treatment and were on stable warfarin therapy, edoxaban demonstrated noninferiority to warfarin in preventing deterioration of pulmonary hemodynamics over the 48-week treatment. They also found that the incidence of symptomatic venous thromboembolism and clinically relevant bleeding events for patients treated with edoxaban was comparable to that of patients treated with warfarin. However, Hosokawa and colleagues emphasized the need for a large-scale, multinational, longer-term study to robustly establish the safety and efficacy of edoxaban for anticoagulation in CTEPH patients. The study was funded by Japan Agency for Medical Research and Development and Daiichi-Sankyo Co. Ltd., the manufacturer of edoxaban. Source: Hosokawa K, Watanabe H, Taniguchi Y, et al. A Multicenter, Single-Blind, Randomized, Warfarin-Controlled Trial of Edoxaban in Patients with Chronic Thromboembolic Pulmonary Hypertension: KABUKI Trial. Circulation. 2023 Nov 13 (Article in press). Photo Credit: Jason Wermers/CRTonline.org Photo Caption: Kazuya Hosokawa, MD, discusses the KABUKI trial during a Featured Science session at the American Heart Association Scientific Sessions 2023 in Philadelphia.