Methods

The design of the ENVISAGE-TAVI AF (NCT02943785) trial was previously published. ^, Briefly, ENVISAGE-TAVI AF was a global, prospective, randomized, controlled, open-label, adjudicator-masked trial comparing the efficacy and safety of edoxaban with those of VKA. Patients with prevalent or incident AF were eligible if they were aged ≥18 years and had undergone a successful TAVI (defined as the implantation of a bioprosthetic aortic valve without unresolved periprocedural complications) for severe aortic stenosis. Patients were excluded if deemed to be at a great risk of bleeding because of coexisting conditions (e.g., active peptic ulcer with upper gastrointestinal bleeding within the 90 days before randomization, malignancy, recent brain or spinal surgery, or arteriovenous malformations). In addition, an exclusion criterion was the indication for dual antiplatelet therapy for >3 months.

The trial was conducted in accordance with the International Council for Harmonisation and the Declaration of Helsinki. All patients signed informed consent before enrollment. An independent data and safety monitoring board reviewed all serious adverse events to ensure patients’ safety.

Patients were randomly assigned 1:1 to receive either edoxaban or VKA within 12 hours to 7 days after successful TAVI. Stratification was performed by means of an interactive Webresponse system. Patients in the experimental arm received edoxaban 60 mg once daily. The edoxaban dose was reduced to 30 mg once daily if patients had any of the following dose adjustment criteria: (1) body weight ≤60 kg (not used as a dose criterion in patients from the United States), (2) moderate renal impairment defined as a creatinine clearance of 15 to ≤50 ml/min, or (3) use of certain P-glycoprotein inhibitors (i.e., systemic use of erythromycin, clarithromycin, ketoconazole, and itraconazole; not used as a dose criterion in patients from the United States). In patients randomized to the VKA arm, the target international normalized ratio (INR) was 2.0 to 3.0, adjusted to 1.6 to 2.6 for patients aged ≥70 years in Japan. Prescription of antiplatelet therapy in addition to edoxaban or VKA was at the discretion of each treating physician.

This post hoc analysis focused on IS events. Stroke was defined as an acute-onset focal neurologic deficit of vascular etiology persisting for >24 hours. Patients were followed up 3 months after randomization and every 6 months thereafter (minimum of 6 months and up to 36 months). During the follow-up period, an independent clinical events committee, whose members were masked to the drug assignment, adjudicated all major adverse events.

This on-treatment analysis comprised the patients from the ITT population who received ≥1 dose of the study drug (safety cohort). Baseline patient demographics and clinical characteristics were stratified by IS incidence. Categorical variables were presented as frequencies and percentages; continuous variables were presented as means with standard deviation (SD). Categorical variables were compared using Fisher’s exact tests, and continuous variables were compared using a 1-way analysis of variance, with statistical significance set at p <0.05 for both. Blood pressure was recorded at each visit and considered a continuous variable. Hypertension was defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg or the use of an antihypertensive medication.

A temporal trend analysis evaluated the incidence of IS after TAVI over the duration of the study; the time points examined included 7 days, 14 days, 30 days, 60 days, 90 days, 180 days, and every 6 months thereafter. The event rates for IS were calculated as the number of patients who experienced an event divided by the sum of the time duration of exposure across all persons at risk. The time duration of exposure was defined as the time frame during which the patient was on treatment; any time during which the patient was not actively taking the drug was not added to the exposure time.

Cox regression determined patient characteristics associated with the first IS event. The model was built using the stepwise selection method, with candidate variables listed in Supplementary Table 1 . The individual components of the CHA ₂ DS ₂ -VASc (Congestive heart failure, Hypertension, Age ≥75 [doubled], Diabetes, Stroke [doubled], Vascular disease, Age 65 to 74, and Sex Category [female]) score were included in the candidate variables rather than the score itself. HRs with 95% CIs were calculated. A significance level of p <0.05 was required for the inclusion of a variable in the model and for a variable to remain in the model.

All analyses were performed using SAS software version 9.2 or newer (SAS Institute, Cary, NC).

Results

Of the 1,426 patients enrolled in the ENVISAGE-TAVI AF trial, 50 (3.5%) had an IS. There were 10 patients with IS in the ITT population not included in the on-treatment analysis because the patients were not receiving the study medication when the IS occurred ( Supplementary Table 2 ). In this on-treatment analysis, 1,377 patients were included, of whom 41 (3.0%) experienced an IS and 1,336 (97%) did not ( Figure 1 ). The total exposure time to edoxaban versus VKA was 931.6 versus 828.0 days. The baseline demographics and clinical characteristics were well balanced between patients with and those without IS ( Table 1 ), with no significant difference in mean ± SD CHA ₂ DS ₂ -VASc (4.4 ± 1.5 vs 4.5 ± 1.3, p = 0.9) score. Similarly, there were no significant differences in mean ± SD HAS-BLED ([Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly] 1.5 ± 0.6 vs 1.6 ± 0.8, p = 0.5), or Society of Thoracic Surgeons (4.4 ± 3.5 vs 4.9 ± 3.8, p = 0.5) scores.

Patient disposition.

Table 1

Demographics and baseline characteristics

	Patients with IS n = 41	Patients without IS n = 1,336	p -value
Age at enrollment, year, mean ± SD	81.7 ± 4.4	82.1 ± 5.5	0.7
Sex, male	16 (39.0%)	703 (52.6%)	0.1
BMI, kg/m 2 , mean ± SD	29.3 ± 7.2	27.6 ± 5.5	0.06
History of stroke/TIA	8 (19.5%)	225 (16.8%)	0.7
Hypertension	37 (90.2%)	1,221 (91.4%)	0.8
Diabetes mellitus	14 (34.1%)	492 (36.8%)	0.9
Non-CNS systemic embolic event	6 (14.6%)	64 (4.8%)	0.02
Congestive heart failure	33 (80.5%)	1,130 (84.6%)	0.5
Myocardial infarction	1 (2.4%)	190 (14.2%)	0.04
History of major bleeding or predisposition to bleeding	4 (9.8%)	115 (8.6%)	0.8
Creatinine clearance, mL/min, mean ± SD	61.0 ± 18.4	58.2 ± 24.3	0.5
STS score, mean ± SD	4.4 ± 3.5	4.9 ± 3.8	0.5
CHA 2 DS 2 -VASc score, mean ± SD	4.4 ± 1.5	4.5 ± 1.3	0.9
EuroScore I, mean ± SD	10.6 ± 7.4	13.0 ± 9.9	0.1
EuroScore II, mean ± SD	3.6 ± 2.9	4.6 ± 5.6	0.3
Pre-TAVI use of VKA	27 (65.9%)	606 (45.4%)	0.01
Pre-TAVI use of NOAC	6 (14.6%)	378 (28.3%)	0.08
No pre-TAVI use of VKA or NOAC	8 (19.5%)	352 (26.3%)	0.4
Treatment arm, edoxaban	19 (46.3%)	673 (50.4%)	0.6
Treatment arm, VKA	22 (53.7%)	663 (49.6%)	0.6

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