The number of patients with valvular heart diseases has been increasing, and the prevalence of bioprosthetic valve has also been increasing with aging society [1]. The incidence of embolic events has been reported to be high early after bioprosthetic valve replacement [2-6], thus anticoagulant therapy with vitamin K antagonists is recommended within 3 to 6 months after bioprosthetic valve replacement for preventing thromboembolic events [7-9].
On the other hand, efficacy and safety of direct oral anticoagulants (DOACs) were proven by randomized clinical trials for patients with nonvalvular atrial fibrillation (AF) [10-12], and DOACs have been widely used because of no need of routine monitoring of anticoagulation activity and low risk of interaction to other drugs and food. Evidence supporting the use of DOACs in AF patients who have undergone bioprosthetic valve replacement has been provided by subgroup analysis of randomized clinical trials [13-15] and some observational studies [16-18]. In addition, randomized trial comparing rivaroxaban and warfarin in patients with AF and bioprosthetic mitral valve [19] was performed and non-inferiority of rivaroxaban to warfarin was shown in this study population. However, this randomized trial included small number of patients early after bioprosthetic valve replacement (within 3 months). Data is limited about whether DOACs can be an alternative to warfarin in patients undergoing bioprosthetic valve replacement within 3 to 6 months, including patients with sinus rhythm [20]. Database analysis from the United States showed the growing use of DOAC at discharge after bioprosthetic valve replacement since 2011 in the real-world clinical practice [21].
Efficacy and safety of EdoxabaN in anticoagulant therapy after surgical Bioprosthetic vALVe replacement (ENBALV) trial is a randomized trial that will compare the efficacy and safety of edoxaban versus warfarin early after bioprosthetic valve replacement.
Objective and study design
ENBALV trial is an investigator-initiated, phase 3, randomized, open-label, multicenter study. The primary objective of ENBALV trial is to evaluate the efficacy and safety of edoxaban compared with warfarin in patients early (within 3 months) after bioprosthetic valve replacement.
Patient population, eligibility, and randomization
The subjects are patients undergoing bioprosthetic valve replacement at aortic and/or mitral position between 18 and 85 years of age. The inclusion and exclusion criteria of the ENBALV trial are shown in Table 1.
Patients are randomized 1:1 to receive either edoxaban or warfarin using a minimization method with prosthetic valve position, the presence of atrial fibrillation, and administration of antiplatelet drugs.
Trial treatment and follow-up
The study flow diagram is shown in Figure 1. Bioprosthetic valve replacement should be performed within eight weeks after randomization. Edoxaban or warfarin is started after bioprosthetic replacement as soon as surgeons determine that anticoagulant therapy can be started. Edoxaban is administered at the dose of 60 mg orally once daily, or 30mg once daily when creatine clearance is 30–50 mL/min (calculated using the Cockcroft-Gault equation) or body weight is ≦60kg or in patients receiving concomitant treatment with P-glycoprotein inhibitors.
Warfarin is administered with dose adjustment to maintain the prothrombin time-international normalized ratio (PT-INR) between 2.0 to 2.5.
Administration of edoxaban or warfarin is to be continued for 12 weeks after surgery if patients meet no discontinuance criteria. Their administration can be continued until 24 weeks according to judgements by surgeons.
Patients undergo clinical assessment and laboratory testing at 1 and 7 days after staring administration of edoxaban or warfarin, and at discharge. After discharge, patients are scheduled to visit an outpatient clinic at 4, 8, and 12 weeks after surgical intervention. Clinical assessment including symptoms suggestive of clinical thromboembolic or bleeding events and laboratory testing are performed at visits of outpatient clinic.
Imaging studies
Patients undergo a 12-leads electrocardiogram and transthoracic echocardiogram during screening and eligibility assessment prior to randomization, at discharge and at 12 weeks after surgical intervention. Brain MRI or CT scan was performed during screening and eligibility assessment prior to randomization, and at 12 weeks after surgical intervention.
Outcome measures
The primary outcome is the occurrence rate of stroke or systemic embolism at 12 weeks after surgical intervention. This primary endpoint is the standard efficacy endpoint which has been used in clinical studies elucidating the efficacy of anticoagulants in patients with non-valvular AF. The net clinical outcome is a composite of stroke, systemic embolism, or major bleeding, which is included in the secondary outcomes. The secondary outcomes are listed in Table 2. List of clinical events is shown in Table 3.
Statistical consideration
Sample Size
The event rates for the primary endpoints in the study and control treatment groups were assumed to be 1%–3% based on historical reports [2-5]. The difference in event rates between the control and study treatment groups was not expected to be very large. Furthermore, the number of patients that could be included within a reasonable study period was estimated to be approximately 450, and it was judged that it is not reasonable to conduct a non-inferiority trial on this scale to test the hypothesis. Therefore, to examine whether the study drug was not significantly inferior to the control drug, we decided to evaluate whether the difference in point estimates of event rates for the primary endpoint was below a certain threshold. A previous study [2] that included data from a no-treatment group estimated that the event rate within 3 months after surgery without treatment was more than 7%. On this basis, the experts in our study group determined that 2% is a clinically acceptable and reasonable threshold for the difference in event rates between the treatment and control groups. Given the 450 enrolled patients, 1:1 allocation, and a dropout rate of approximately 10%, the primary endpoint is expected to be assessed in 202 patients in each of the two groups. The event rates p and q for the treatment and control groups are assumed to follow a uniform distribution with the interval [0.01, 0.03], and the occurrence of events in the treatment and control groups are assumed to follow a Bernoulli distribution with occurrence probabilities p and q, respectively. Under these conditions, the probability that the point estimate of the p-q is less than 2% was evaluated by simulation study and estimated to be approximately 90%. Based on the above considerations, the target number of patients to be enrolled in this clinical trial was set at 450.
Statistical analysis
The primary analysis of this trial will be performed in a Full Analysis Set (FAS) based on Intention-to-Treat principles. The FAS will be composed of all assigned study participants, excluding all subjects who did not meet the primary enrollment criteria, who never received any study treatment, who did not have any post-assignment data, and who withdrew consent for use of all data. A point estimates of event rates for the primary endpoint will be calculated for each of the study and control treatment groups to assess whether the difference in event rates is less than or equal to 2%. For additional analysis, a similar evaluation will be performed on the per protocol set, a population of FAS that excludes subjects who were found to have violations or deviations from the study protocol that would affect the evaluation of the primary endpoint. Other endpoints will be summarized and compared by groups, with subpopulation analyses conducted as necessary.
Current status
The first patient was enrolled in April 2022. We recruited 24 hospitals and we have enrolled 385 patients as of December 2023.