Antithrombotic Therapy for Patients With Atrial Fibrillation and Bioprosthetic Valves　― Real-World Data From the Multicenter, Prospective, Observational BPV-AF Registry ―

Abstract

Background: Although bioprosthetic valve (BPV) replacements are becoming more common within our aging society, there are limited prospective data on the appropriate antithrombotic therapy for East Asian patients with atrial fibrillation (AF) and BPV replacement. Antithrombotic therapy and thrombotic and hemorrhagic event rates in Japanese patients with AF and BPV replacement are investigated.

Methods and Results: This multicenter, prospective, observational study enrolled patients with BPV replacement and AF. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding. Of the 894 patients analyzed, 54.7%, 29.4%, and 9.6%, were treated with warfarin-based therapy, direct oral anticoagulant (DOAC)-based therapy, or antiplatelet therapy without anticoagulants, respectively; 6.3% did not receive any antithrombotic drugs. The mean observation period was 15.3±4.0 months. The event rates for stroke or systemic embolism and major bleeding were 1.95%/year and 1.86%/year, respectively. The multivariate adjusted hazard ratios for DOAC vs. warfarin were 1.02 (95% confidence intervals [CI], 0.30–3.41 [P=0.979]) for systemic embolic events and 0.96 (95% CI, 0.29–3.16 [P=0.945]) for major bleeding.

Conclusions: Approximately 30% of patients with AF and BPV replacement were treated with DOAC. The risks of major bleeding and stroke or systemic embolism were similar between warfarin- and DOAC-treated patients with AF who had BPV replacement. Treatment with DOACs could be an alternative to warfarin in this population.

In recent years, the prevalence of valvular heart disease, which is age related, has been increasing in developed countries.^1,2 As a treatment for valvular heart disease in Japan, approximately 12,500 aortic valve operations and 11,000 mitral valve operations were performed in 2016, according to the annual report by the Japanese Association for Thoracic Surgery.³ With the aging demographic in Japan, bioprosthetic valve (BPV) replacements are becoming more common; the number of BPVs implanted in 2016 was 81.9% in the aortic and 65.2% in the mitral positions.³ A growing number of patients have atrial fibrillation (AF),⁴ thus the number of patients having both BPV replacement and AF is also increasing; however, data on antithrombotic therapy for patients with AF and BPV replacement are currently limited.

Until recently, there were regional discrepancies in AF treatment guidelines for patients receiving BPVs. In the US and Europe, patients with AF undergoing BPV replacement are classified as having non-valvular AF, and treatment with direct oral anticoagulants (DOACs) is recommended.^5,6 Japanese guidelines, published in 2013, defined patients with AF and BPV replacement as having valvular AF and recommended treatment with warfarin.⁷ Recent revision of the Japanese AF guidelines, in 2020, changed the classification of those with BPV replacement from valvular AF to non-valvular AF, and added the recommendation to use DOACs in this patient population.^8,9 However, although the guidelines recommend use of DOACs, they also state that the available data on their use in this patient population are insufficient. As patients with both BPV replacement and AF may have a high risk of embolic events, it is important to determine whether DOACs can be used as a treatment in this population.

Evidence supporting the use of DOACs for AF patients who have undergone BPV replacement has been provided by subgroup analysis of data from the ENGAGE AF-TIMI 48 and ARISTOTLE clinical trials.^10,11 The results showed that the efficacy and safety of DOACs were similar to those of warfarin, a finding consistent with the main analyses.^12,13 However, these subgroup analyses included only a low number of East Asians with AF and BPV replacement, and it is known that bleeding and embolism risk differ between East Asian and Western populations.¹⁴ Furthermore, there are reports that the plasma concentrations of DOACs may also differ between Asians and non-Asians.¹⁵ Therefore, data on antithrombotic therapy for East Asians with AF and BPV replacement are needed.

For this reason, we previously conducted a retrospective study to better understand the status of antithrombotic therapy in Japanese patients with AF and BPV replacement, and to examine the risk of thrombosis and bleeding.¹⁶ However, the study population was enrolled between 2011 and 2018, most patients were treated with warfarin, and only 7.5% received DOACs, and consequently, the findings of our previous study may not reflect current real-world clinical practice in Japan. Notably, our data indicated that the number of patients treated with DOACs started increasing after 2013,¹⁶ highlighting the need for more contemporary data.

The BPV-AF Registry study was a prospective observational study conducted to understand real-world clinical practice regarding antithrombotic therapy for Japanese AF patients after BPV replacement. Some baseline results have already been published; it was found that approximately 30% of patients were receiving DOAC-based therapy at baseline.¹⁷ Herein, the 1-year follow-up results are reported.

Methods

Study Design

Full details of the registry design have been published previously.¹⁷ In brief, this was a multicenter, prospective, observational study; the enrollment period was from September 2018 to October 2019, with a minimum of 1 year of follow up (until October 2020). The study was registered with the University Hospital Medical Information Network (identification code UMIN000034485). A full list of study personnel and institutions is provided in Supplementary Table 1.

As this was an observational study, there were no mandated study interventions, and patients with BPV replacement and AF were managed according to the discretion of the treating physician. Data collected at baseline and every 6 months (if available per routine clinical practice) included information on the administration status of antithrombotic drugs and other medications, blood clotting data (prothrombin time-international normalized ratio [PT-INR]) for patients receiving warfarin, information on the clinical course of the disease, and laboratory test results. Echocardiography data were collected at baseline and at 12 months. In addition, patient characteristics were collected at baseline, and details of any invasive procedures were collected during the follow-up period. The occurrence of adverse events (AEs; including incidence of stroke, systemic embolism, hemorrhagic event, heart failure requiring hospitalization, and reoperation of the bioprosthetic valve) was recorded throughout, using the Japanese Medical Dictionary for Regulatory Activities, version 23.0.

The study was conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable regulatory and legal requirements. The protocol and the informed consent document were reviewed and approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (M30-068; 26 September 2018; Clinical Trial Registration: University Hospital Medical Information Network UMIN000034485 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039323).

Study Population

Patients were eligible if they had undergone BPV replacement at least 3 months prior to enrollment and had a definite diagnosis of AF. The site of BPV replacement could be the aortic valve and/or the mitral valve, and the procedure could have been either surgical or transcatheter aortic valve implantation (TAVI). AF could have been paroxysmal, persistent, or permanent; however, patients with transient postoperative AF were excluded. Other exclusion criteria included mechanical valve replacement, and moderate or severe mitral stenosis. All patients provided written informed consent for participation prior to study entry.

Outcomes

The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding (based on the International Society on Thrombosis and Haemostasis criteria¹⁸) during the observation period.

Secondary outcomes were stroke, systemic embolism, ischemic stroke, hemorrhagic stroke, intracranial hemorrhage, cardiovascular events (including myocardial infarction, stroke, systemic embolism, and death from bleeding), and bleeding events (including clinically significant bleeding and minor bleeding). Exploratory outcomes were heart failure requiring hospitalization, death from cardiovascular disease, all-cause mortality, and reoperation of the bioprosthetic valve.

Statistical Analysis

The sample size calculations have been published elsewhere.¹⁷ After a mean observation period of 1 year, assuming that the event rate for stroke or systemic embolism was 3% per year in 1,000 patients, the 95% confidence interval (CI) for the data was calculated to be ±1.1%. We used median and interquartile range or mean and standard deviation (SD) to describe continuous variables, and n (%) for categorical variables. Differences between groups of patients receiving warfarin and DOACs in terms of baseline characteristics were compared using analysis of variance, the Kruskal-Wallis test for continuous variables, and the chi-squared test or Fisher’s exact test for categorical variables, as appropriate. In addition, we compared patients receiving warfarin-based treatment and DOAC-based treatment using the t-test and the Wilcoxon rank-sum test for continuous variables.

For the primary efficacy and safety outcomes, event rates in percentage/year and their 95% CIs were calculated using a Poisson distribution. Cumulative incidence rates of primary outcomes were calculated and expressed using Kaplan-Meier curves, and differences were assessed by using the log-rank test. Univariable Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs for primary outcomes. A model adjusted for sex and age was used, and multivariable Cox regression models were further adjusted by CHA₂DS₂-VASc score (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, previous stroke or transient ischemic attack - vascular disease, age 65 to 74 years, sex category), antiplatelet drug use, estimated glomerular filtration rate, type of AF, having undergone TAVI, malignancy, and valve position (mitral, aortic, or both) as potential confounders. Cumulative incidence rates for DOAC- and warfarin-based groups, excluding those who received DOACs at off-label dosages, were calculated. The level of significance was set as P<0.05. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Overall Patient Characteristics

In total, 928 patients were enrolled, of whom 34 were excluded (33 did not meet the criteria and 1 withdrew). Thus, 894 patients were included in the final data analysis set (data locked on 28 January 2021). Patient characteristics for the overall study population are shown in Table 1. The mean±SD observation period was 15.3±4.0 months. The mean age of patients was 80.4 years, and 45.9% (410/894) were male. The type of AF was paroxysmal in 37.1% (332/894), persistent in 34.7% (310/894), and permanent in 28.2% (252/894). The mean±SD risk of stroke, evaluated using the CHADS₂ and CHA₂DS₂-VASc measures, was 2.5±1.2 and 4.1±1.5, respectively; the mean±SD risk of bleeding, evaluated using the HAS-BLED score, was 2.5±1.1. More than three-quarters of patients (76.3%; 682/894) had hypertension, and more than half (55.0%; 492/894) had heart failure. The prosthesis position was the aortic valve in 65.8% (588/894), the mitral valve in 21.8% (195/894), and both in 12.4% (111/894). Of the patients who had the prosthesis positioned at the aortic valve, 59.9% (352/588) had the valve implanted surgically and 40.1% (236/588) by means of TAVI (Table 2).

Table 1. Patient Demographic and Clinical Characteristics at Baseline

Characteristic	All (N=894, 100%)	Warfarin-based therapy (n=489, 54.7%)	DOAC-based therapy (n=263, 29.4%)	Antiplatelet therapy (n=86, 9.6%)	No antithrombotic drugs (n=56, 6.3%)	P value
Male	410 (45.9)	231 (47.2)	105 (39.9)	46 (53.5)	28 (50.0)	0.089
Age (years)	80.4±7.0	79.5±6.7	82.3±6.6	79.9±7.9	79.5±8.2	<0.001
Weight (kg)	53.8±11.4	54.0±11.2	53.5±11.5	54.5±12.2	53.9±11.5	0.911
BMI (kg/m2)	22.2±3.7	22.0±3.4	22.5±4.2	22.5±3.3	21.9±4.0	0.459
CHADS2 score	2.5±1.2	2.4±1.2	2.7±1.2	2.5±1.2	2.2±1.1	0.002
≥2.0	673 (80.9)	357 (78.3)	218 (87.2)	63 (81.8)	35 (71.4)	0.010
CHA2DS2-VASc score*	4.1±1.5	4.0±1.4	4.5±1.5	3.8±1.5	3.6±1.5	<0.001
≥3.0	733 (87.7)	392 (85.8)	241 (95.3)	60 (77.9)	40 (81.6)	<0.001
HAS-BLED score	2.5±1.1	2.5±1.1	2.4±1.1	3.0±1.1	2.1±1.1	<0.001
≥3.0	374 (45.2)	210 (46.4)	100 (40.2)	48 (62.3)	16 (32.7)	0.002
eGFR (mL/min/1.73 m2)	46.7±17.7	45.5±18.5	48.3±14.6	47.9±20.8	47.5±18.3	0.205
CCr (mL/min)	40.5±18.3	40.2±18.6	41.1±16.5	38.8±21.2	42.0±21.0	0.767
Type of AF						<0.001
Paroxysmal	332 (37.1)	119 (24.3)	126 (47.9)	55 (64.0)	32 (57.1)
Persistent	310 (34.7)	196 (40.1)	75 (28.5)	24 (27.9)	15 (26.8)
Permanent	252 (28.2)	174 (35.6)	62 (23.6)	7 (8.1)	9 (16.1)
Left atrial plication, LAA occlusion/excision	103 (11.6)	74 (15.2)	17 (6.5)	9 (10.5)	3 (5.4)	0.002
Previous history of CVD
Ischemic stroke	123 (13.8)	57 (11.7)	49 (18.6)	15 (17.4)	2 (3.6)	0.005
Hemorrhagic stroke	21 (2.4)	11 (2.3)	6 (2.3)	3 (3.5)	1 (1.8)	0.907
Intracranial hemorrhage	30 (3.4)	13 (2.7)	11 (4.2)	4 (4.7)	2 (3.6)	0.512
Systemic embolism	11 (1.2)	7 (1.4)	3 (1.1)	1 (1.2)	0 (0.0)	1.000
Major bleeding	47 (5.3)	26 (5.3)	9 (3.4)	7 (8.1)	5 (8.9)	0.152
Comorbidities
Hypertension	682 (76.3)	353 (72.2)	215 (81.8)	73 (84.9)	41 (73.2)	0.005
Heart failure	492 (55.0)	273 (55.8)	145 (55.1)	46 (53.5)	28 (50.0)	0.854
Dyslipidemia	443 (49.6)	239 (48.9)	135 (51.3)	48 (55.8)	21 (37.5)	0.170
Diabetes mellitus	189 (21.1)	108 (22.1)	56 (21.3)	19 (22.1)	6 (10.7)	0.265
Renal dysfunction	84 (9.4)	50 (10.2)	14 (5.3)	13 (15.1)	7 (12.5)	0.024
Chronic respiratory disease	86 (9.6)	45 (9.2)	31 (11.8)	6 (7.0)	4 (7.1)	0.457
Malignant tumor	68 (7.6)	32 (6.5)	27 (10.3)	6 (7.0)	3 (5.4)	0.274
Myocardial infarction	45 (5.0)	23 (4.7)	7 (2.7)	13 (15.1)	2 (3.6)	0.001
Peripheral arterial disease	33 (3.7)	15 (3.1)	12 (4.6)	1 (1.2)	5 (8.9)	0.081
Thrombosis and embolism	28 (3.1)	13 (2.7)	13 (4.9)	2 (2.3)	0 (0.0)	0.201
LVEF (%)						0.002
<40	56 (6.7)	43 (9.5)	6 (2.4)	4 (5.0)	3 (5.8)
40–49	73 (8.8)	50 (11.0)	14 (5.7)	5 (6.3)	4 (7.7)
≥50	704 (84.5)	362 (79.6)	226 (91.9)	71 (88.8)	45 (86.5)

Data are presented as number (percentage) or mean±SD. *CHA₂DS₂-VASc score is defined according to congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, previous stroke or transient ischemic attack - vascular disease, age 65 to 74 years, sex category. AF, atrial fibrillation; BMI, body mass index; CCr, creatinine clearance; CVD, cardiovascular disease; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; LAA, left atrial appendage; LVEF, left ventricular ejection fraction; SD, standard deviation.

Table 2. Operative Characteristics Describing the Prosthesis Position, and Details of the Aortic and Mitral Valves

Characteristic	All (N=894)	Warfarin-based therapy (n=489)	DOAC-based therapy (n=263)	Antiplatelet therapy (n=86)	No antithrombotic drugs (n=56)	P value
Prosthesis position						<0.001
Aortic valve	588 (65.8)	258 (52.8)	221 (84.0)	69 (80.2)	40 (71.4)
Mitral valve	195 (21.8)	144 (29.5)	31 (11.8)	9 (10.5)	11 (19.6)
Both valves	111 (12.4)	87 (17.8)	11 (4.2)	8 (9.3)	5 (8.9)
Aortic valve	n=588	n=258	n=221	n=69	n=40
VHD subtype						0.021
Stenosis	445 (75.7)	184 (71.3)	184 (83.3)	50 (72.5)	27 (67.5)
Regurgitation	114 (19.4)	61 (23.6)	30 (13.6)	14 (20.3)	9 (22.5)
Others	10 (1.7)	7 (2.7)	2 (0.9)	1 (1.4)	0 (0.0)
Operation type						<0.001
Surgery	352 (59.9)	192 (74.4)	81 (36.7)	48 (69.6)	31 (77.5)
TAVI	236 (40.1)	66 (25.6)	140 (63.4)	21 (30.4)	9 (22.5)
History of replacement						0.283
First replacement	561 (95.4)	240 (93.0)	215 (97.3)	67 (97.1)	39 (97.5)
Re-replacement	25 (4.3)	17 (6.6)	5 (2.3)	2 (2.9)	1 (2.5)
Mitral valve	n=195	n=144	n=31	n=9	n=11
VHD subtype						0.240
Stenosis	81 (41.5)	63 (43.8)	12 (38.7)	3 (33.3)	3 (27.3)
Regurgitation	95 (48.7)	67 (46.5)	18 (58.1)	4 (44.4)	6 (54.6)
Others	9 (4.6)	7 (4.9)	0 (0.0)	0 (0.0)	2 (18.2)
Operation type
Surgery	195 (100)	144 (100)	31 (100)	9 (100)	11 (100)
History of replacement						0.437
First replacement	171 (87.7)	124 (86.1)	29 (93.6)	9 (100)	9 (81.8)
Re-replacement	24 (12.3)	20 (13.9)	2 (6.5)	0 (0.0)	2 (18.2)

Data are presented as number (percentage). TAVI, transcatheter aortic valve implantation; VHD, valvular heart disease. Other abbreviations as in Table 1.

Antithrombotic Therapy and Patient Clinical Characteristics

Data presented according to postoperative antithrombotic therapy are shown in Tables 1–3. Warfarin-based therapy was received by 54.7% (489/894), and DOAC-based therapy by 29.4% (263/894). The percentage of patients using a combination of antiplatelet drugs was 28.0% (137/489) for those receiving warfarin-based therapy and 28.1% (74/263) for those receiving DOAC-based therapy. In warfarin-treated patients, the median time in the therapeutic range (TTR) was 85.8% (Table 3). Antiplatelet therapy without oral anticoagulants was received by 9.6% of the population (86/894), and 6.3% (56/894) did not receive any antithrombotic drugs.

Table 3. Administration Status of Antithrombotic Agents (Anticoagulant and Antiplatelet)

Treatment, N=894 (100%)	n (%)
Warfarin-based therapy, n=489 (54.7%)
No antiplatelet drug	352 (72.0)
With antiplatelet drug	137 (28.0)
With aspirin	120 (24.5)
With P2Y12 inhibitor	12 (2.5)
With DAPT	0 (0.0)
With others	5 (1.0)
DOAC-based therapy, n=263 (29.4%)
No antiplatelet drug	189 (71.9)
With antiplatelet drug	74 (28.1)
With aspirin	55 (20.9)
With P2Y12 inhibitor	16 (6.1)
With DAPT	0 (0.0)
With others	3 (1.1)
Antiplatelet therapy, n=86 (9.6%)
Aspirin	67 (77.9)
P2Y12 inhibitor	11 (12.8)
DAPT	4 (4.7)
With others	4 (4.7)
No antithrombotic drugs, n=56 (6.3%)
TTR and PT-INR (patients receiving warfarin-based therapy; n=489)
TTR (%), mean±SD	70.5±35.1
Median (IQR)	85.8 (45.6–100)
PT-INR
Age, <70 years
<2.0	13 (52.0)
2.0–3.0	12 (48.0)
>3.0	0 (0.0)
Age, ≥70 years
<1.6	89 (21.4)
1.6–2.6	290 (69.7)
>2.6	37 (8.9)

Data are presented as number (percentage) unless otherwise specified. DAPT, dual antiplatelet therapy; IQR, interquartile range; PT-INR, prothrombin time-international normalized ratio; TTR, time in the therapeutic range. Other abbreviations as in Table 1.

Compared with warfarin-treated patients, DOAC-treated patients were older, had higher CHADS₂ and CHA₂DS₂-VASc scores, and were more likely to have undergone TAVI (P<0.001 for each; Supplementary Table 2 and Supplementary Table 3). Compared with DOAC-treated patients, warfarin-treated patients were more likely to have undergone mitral valve replacement, had persistent or permanent AF (P<0.001) and to have undergone left atrial plication, left atrial appendage occlusion or excision (P<0.001) (Supplementary Table 2 and Supplementary Table 3). Antiplatelet-treated patients who did not take oral anticoagulants had a higher HAS-BLED score than the other 3 groups (Table 1).

Operative characteristics for BPV replacement are shown in Table 2.

Primary Outcomes

In all patients, event rates for stroke or systemic embolism (the primary efficacy outcome) and major bleeding (the primary safety outcome) were 1.95%/year (95% CI, 1.29–2.97) and 1.86%/year (95% CI, 1.21–2.85), respectively (Table 4). Kaplan-Meier curves are shown in Figure A,B. Primary outcomes for patient subgroups according to treatment are shown in Table 4 and Supplementary Table 4.

Table 4. Summary of Primary and Secondary Outcomes

Outcome	All (N=894)		Warfarin-based therapy (n=489)		DOAC-based therapy (n=263)
	n (%)	%/year (95% CI)	n (%)	%/year (95% CI)	n (%)	%/year (95% CI)
Primary
Stroke or systemic embolism (efficacy)	22 (2.5)	1.95 (1.29–2.97)	13 (2.7)	2.10 (1.22–3.61)	5 (1.9)	1.48 (0.62–3.55)
Major bleeding (safety)	21 (2.4)	1.86 (1.21–2.85)	11 (2.3)	1.77 (0.98–3.20)	7 (2.7)	2.08 (0.99–4.36)
Secondary
Stroke	18 (2.0)	1.59 (1.00–2.53)	12 (2.5)	1.93 (1.10–3.41)	4 (1.5)	1.18 (0.44–3.14)
Ischemic stroke	14 (1.6)	1.24 (0.73–2.09)	9 (1.8)	1.45 (0.75–2.78)	4 (1.5)	1.18 (0.44–3.14)
Hemorrhagic stroke	4 (0.5)	0.35 (0.13–0.94)	3 (0.6)	0.48 (0.15–1.49)	0 (0.0)	0.00
Systemic embolism	4 (0.5)	0.35 (0.13–0.94)	1 (0.2)	0.16 (0.02–1.13)	1 (0.4)	0.29 (0.44–3.14)
Intracranial hemorrhage	6 (0.7)	0.53 (0.24–1.18)	3 (0.6)	0.48 (0.15–1.49)	3 (1.1)	0.88 (0.28–2.73)
Cardiovascular events*	25 (2.8)	2.22 (1.50–3.29)	14 (2.9)	2.26 (1.34–3.81)	6 (2.3)	1.77 (0.80–3.95)
Clinically relevant non-major bleeding and/or minor† bleeding	43 (4.8)	3.88 (2.88–5.23)	25 (5.1)	4.10 (2.77–6.06)	14 (5.3)	4.25 (2.52–7.18)
Other
Heart failure requiring hospitalization	64 (7.2)	5.77 (4.51–7.37)	43 (8.8)	7.05 (5.23–9.51)	18 (6.8)	5.43 (3.42–8.62)
Cardiovascular death‡	10 (1.1)	0.88 (0.47–1.63)	6 (1.2)	0.96 (0.43–2.13)	4 (1.5)	1.17 (0.44–3.11)
All-cause death	47 (5.3)	4.12 (3.10–5.49)	24 (4.9)	3.83 (2.57–5.71)	11 (4.2)	3.21 (1.78–5.81)
Reoperation of the bioprosthetic valve	7 (0.8)	0.62 (0.29–1.29)	5 (1.0)	0.80 (0.33–1.93)	2 (0.8)	0.59 (0.15–2.34)
Myocardial infarction	2 (0.2)	0.18 (0.04–0.70)	0 (0.0)	0.00	0 (0.0)	0.00
Bleeding-related death	3 (0.3)	0.26 (0.08–0.82)	1 (0.2)	0.16 (0.02–1.13)	1 (0.4)	0.29 (0.04–2.07)
Major bleeding, clinically relevant bleeding, minor† bleeding	62 (6.9)	5.65 (4.40–7.24)	35 (7.2)	5.79 (4.16–8.06)	20 (7.6)	6.16 (3.97–9.54)

*Myocardial infarction, stroke, systemic embolism, death from hemorrhage. ^†Not clinically relevant. ^‡Death in which the involvement of cardiovascular factors cannot be ruled out. CI, confidence interval. Other abbreviations as in Table 1.

Figure.

Kaplan-Meier curves for (A) stroke or systemic embolism and (B) major bleeding events in all patients, and Kaplan-Meier curves for (C) stroke or systemic embolism and (D) major bleeding events in DOAC- and warfarin-based therapeutic subgroups. DOAC, direct oral anticoagulant.

A considerable number of patients were treated with warfarin or DOACs, thus we compared the outcomes between the 2 groups. The event rate for stroke or systemic embolism was 2.10%/year (95% CI, 1.22–3.61) in warfarin-treated patients and 1.48%/year (95% CI, 0.62–3.55) in DOAC-treated patients. The event rate for major bleeding was 1.77%/year (95% CI, 0.98–3.20) in warfarin-treated patients and 2.08%/year (95% CI, 0.99–4.36) in DOAC-treated patients (Table 4). There were no significant differences in stroke or systemic embolism or major bleeding event rates between warfarin- and DOAC-treated patients (log-rank P=0.500 and P=0.746, respectively) (Figure C,D).

Compared with the group receiving warfarin, the respective unadjusted HR and the HR adjusted for sex and age for stroke or systemic embolic events in the group receiving DOAC were 0.70 (95% CI, 0.25–1.97 [P=0.502]) and 0.69 (95% CI, 0.25–1.96 [P=0.489]). The respective unadjusted HR and the HR adjusted for sex and age for major bleeding were 1.17 (95% CI, 0.45–3.02 [P=0.747]) and 1.18 (95% CI, 0.45–3.07 [P=0.737]). After adjusting for possible confounders, the results remained consistent; the multivariable-adjusted HRs for systemic embolic events and major bleeding were 1.02 (95% CI, 0.30–3.41 [P=0.979]) and 0.96 (95% CI, 0.29–3.16 [P=0.945]), respectively (Table 5).

Table 5. Cox Regression Analyses for Efficacy and Safety Endpoints

	Univariate HR (95% CI); P value	Age- and sex-adjusted model HR (95% CI); P value	Multivariate adjusted model* HR (95% CI); P value
Stroke or systemic embolism (efficacy)
Warfarin-based therapy	Ref.	Ref.	Ref.
DOAC-based therapy	0.70 (0.25–1.97); P=0.502	0.69 (0.25–1.96); P=0.489	1.02 (0.30–3.41); P=0.979
Major bleeding (safety)
Warfarin-based therapy	Ref.	Ref.	Ref.
DOAC-based therapy	1.17 (0.45–3.02); P=0.747	1.18 (0.45–3.07); P=0.737	0.96 (0.29–3.16); P=0.945

*Adjusted for CHA₂DS₂-VASc score, antiplatelet use, eGFR, type of AF, transcatheter aortic valve implantation, malignancy, and valve position (mitral, aortic, or both). HR, hazard ratio. Other abbreviations as in Tables 1,4.

The event rates and Kaplan-Meier curves for each outcome, excluding patients who received DOACs at off-label dosages (n=6), are shown in Supplementary Table 5 and Supplementary Figure, respectively; these data were similar to those for the overall analysis set.

Secondary Outcomes

Overall, event rates for ischemic stroke, hemorrhagic stroke, and systemic embolism were 1.24%/year (95% CI, 0.73–2.09), 0.35%/year (95% CI, 0.13–0.94), and 0.35%/year (95% CI, 0.13–0.94), respectively. The event rate for intracranial hemorrhage was 0.53%/year (95% CI, 0.24–1.18). Secondary outcomes according to treatment subgroup are shown in Table 4 and Supplementary Table 4.

Discussion

The BPV-AF Registry study was the first large-scale, prospective study evaluating antithrombotic therapy in patients with AF and BPV replacement in East Asia, making these data clinically important. Our study results revealed that: (1) approximately 30% of patients enrolled in the BPV-AF Registry study received DOACs in current Japanese real-world practice; (2) the event rates for stroke or systemic embolism and major bleeding were 1.95%/year and 1.86%/year, respectively; and (3) no differences in these event rates were observed between the warfarin- and DOAC-treated patients.

Increasing Trend Toward DOAC Administration

The percentage of DOAC-treated patients was higher in the present study than in our previous retrospective study (29.4% vs. 7.5%).¹⁶ There are several possible reasons for this difference. The first is the timing of the 2 studies, as the retrospective study utilized data from 2011 to 2018, and this study was conducted between September 2018 and October 2020. At the start of the retrospective analysis, the first DOAC had just been approved in Japan, and the uptake may have been slow. In contrast, by the time the present study was conducted, almost 10 years had passed since the first DOAC approval; therefore, the number of DOAC-treated patients had increased. The second reason may be the response to guidelines published in the US and Europe in 2014 and 2016, respectively.^5,6 In these guidelines, AF patients with BPV are considered as having non-valvular AF, and DOACs are recommended for treatment. Compared with the previous retrospective study,¹⁶ the findings of the present study better reflect the current clinical setting, in which there is an increasing proportion of DOAC-treated patients. Furthermore, a greater percentage of patients who had undergone TAVI were enrolled in this study than in the previous retrospective study (40.1% vs. 8.6%).¹⁶ In general, patients who have undergone TAVI are older and at higher risk of bleeding. DOAC has been reported to reduce the risk of bleeding in older patients compared to warfarin, so DOACs are more commonly used in this population.¹⁹

Event Rates in Warfarin-Treated vs. DOAC-Treated Patients

Regarding the primary outcome in patients treated with warfarin (54.7%) or DOAC (29.4%), who represented most of the patients included in this study, the respective event rates for stroke or systemic embolism and major bleeding were not different between these treatment groups (stroke or systemic embolism, 2.10%/year and 1.48%/year; major bleeding, 1.77%/year and 2.08%/year). The adjusted cumulative incidence of stroke or systemic embolism and major bleeding events in each treatment subgroup was also similar.

Comparing our findings with those of the valvular heart disease subgroup analysis of the ENGAGE AF-TIMI 48 trial, which included patients with AF and BPV replacement,¹¹ the primary efficacy event rates were similar (BPV-AF Registry overall population, 1.95%/year and ENGAGE AF-TIMI 48 subpopulation, 1.79%/year). However, the event rate for the safety endpoint was lower in our study (1.86%/year vs. 3.16%/year, respectively). In our current analysis, the event rate for major bleeding in warfarin-treated patients was very low compared with that in previous studies. Although the major bleeding event rate in warfarin-treated patients was not reported in the ENGAGE AF-TIMI 48 subgroup analysis,¹¹ observation of the Kaplan-Meier curves suggests it was approximately three-fold higher than that of the present study.

The results of another randomized controlled trial (RIVER) of DOAC vs. warfarin treatment in patients with AF and BPV replacement, conducted in Brazil, have recently been published.²⁰ The authors concluded that DOAC was not inferior to warfarin in terms of mean time to death, major cardiovascular events, or major bleeding at 12 months. Stroke and major bleeding event rates in DOAC-treated patients were higher in our study than in the RIVER trial (1.18%/year and 2.08%/year, respectively, vs. 0.62%/year and 1.46%/year, respectively). This may be because the patients in our study were at higher risk of these events than those in the RIVER trial (due to being older, with higher CHA₂DS₂-VASc and HAS-BLED scores). However, regardless of the higher risk in our overall study population, stroke and major bleeding event rates in the warfarin-treated patients in our study were lower than those found in the RIVER trial (1.93%/year and 1.77%/year, respectively, vs. 2.50%/year and 2.72%/year, respectively).

One reason for the low bleeding event rates in the warfarin-treated patients in our study could be that warfarin was generally well-controlled in the BPV-AF study population (median TTR, 85.8%). This may be because, in the 10 years since DOACs became available in Japan, many patients for whom warfarin control was difficult may have been already switched to DOAC-based therapy, leaving only the proportion with well-controlled warfarin. A similar therapeutic switch in patients with AF has been observed across the globe.²¹ In addition, the target PT-INR differs between geographic regions; the recommended PT-INR for Japanese patients aged ≥70 years with AF is 1.6–2.6,²² which is lower than that recommended in Europe and the US. Furthermore, in Japanese clinical practice, patients taking warfarin are instructed to visit their physician on a regular basis, making it easier to monitor and adjust the PT-INR. Notably, in the ENGAGE-AF TIMI 48 trial, the Japanese TTR value was high compared with that found in other participating countries.²³ Therefore, in our study, the efficacy and safety of DOACs were similar to that observed in patients with very well-controlled warfarin.

Our study is the first prospective study conducted in East Asia to suggest that DOACs may be a good alternative to warfarin, with no difference in efficacy or safety. We believe that our results provide valuable evidence that supports the recommendation of DOAC administration for patients with AF and BPV replacement endorsed in the current Japanese Circulatory Society guidelines.^8,9

The main limitations of this study are related to the registry design, which means that the availability of data was dependent on the information supplied by the treating physicians. As our study population was selected to include patients at high risk for embolic events; that is, those who had both BPV replacement and AF with common risk factors for stroke or systemic embolism, we cannot evaluate the extent of the contribution of specific risk factors to the primary efficacy outcomes independently of BPV replacement or AF. However, because there is a lack of data from this high-risk group, we believe that our data are clinically useful for physicians. The sample size was set considering feasibility, not for hypothesis verification. Finally, all patients included in this study were Japanese, so we are unable to speculate on any ethnicity-based differences that may be observed within the global AF population. Randomized controlled trials of DOAC vs. warfarin treatment including patients with AF and BPV replacement from East Asia are warranted in the future.

Conclusions

This prospective, observational study revealed the current usage of anticoagulant therapy in Japanese patients with AF and BPV replacement, and the data demonstrated that approximately 30% of study patients received DOAC treatment. In addition, efficacy and safety results were similar between patients treated with warfarin and DOAC. These findings suggest that DOACs may be a reasonable alternative to warfarin treatment in patients with AF and BPV replacement.

Acknowledgments

The authors thank Michelle Belanger, MD, of Edanz Pharma, for providing medical writing support, which was funded by Daiichi Sankyo Co., Ltd. in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). In addition, the authors thank Jun Hosokawa, of Daiichi Sankyo Co., Ltd., for supporting preparation of the manuscript.

Sources of Funding

This study was supported by Daiichi Sankyo Co., Ltd. (Tokyo, Japan) in collaboration with the National Cerebral and Cardiovascular Center.

Disclosures

C.I. has received remuneration and research funding from Daiichi Sankyo Co., Ltd. H.T. has received consultancy fees from AstraZeneca PLC and Ono Pharmaceutical Co., Ltd. K.A. has received remuneration from Japan Lifeline Co., Ltd., Terumo Corporation, and Medtronic Japan Co., Ltd. M.I. has received consultancy fees from Abbott Medical Japan LLC, and remuneration from Edwards Lifesciences Corporation. Ta. Kimura has received remuneration from Abbott Medical Japan LLC; research funding from Research Institute for Production Development, EP-CRSU Co., Ltd., Edwards Lifesciences Corporation, and Kowa Pharmaceutical Co., Ltd.; and scholarship funds or donations from Nippon Boehringer Ingelheim Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited., Bayer Yakuhin Ltd., and Research Institute for Production Development. T.S. has received remuneration from Medtronic Japan Co., Ltd. K.M. has received scholarship funds or donations from Edwards Lifesciences Corporation, Terumo Co., Ltd., and Japan Lifeline Co., Ltd. K.T. has received remuneration from Amgen K.K., Bayer Yakuhin Ltd., Daiichi Sankyo Co., Ltd., Kowa Pharmaceutical Co. Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., and Pfizer Japan Inc; research funding from AMI Co., Ltd., Bayer Yakuhin Ltd., Bristol-Myers Squibb K.K., EA Pharma Co., Ltd., and Mochida Pharmaceutical Co., Ltd.; scholarship funding from AMI Co., Ltd., Bayer Yakuhin Ltd., Nippon Boehringer Ingelheim Co., Ltd, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Edwards Lifesciences Corporation, Johnson & Johnson K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; and is affiliated with the endowed department sponsored by Abbott Japan Co., Ltd., Boston Scientific Japan K.K., Fides-one Inc., GM Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Co., Ltd., Nipro Corporation, Terumo Co., Ltd., Abbott Medical Co., Ltd., Cardinal Health Japan LLC., Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., Medical Appliance Co., Ltd., and Medtronic Japan Co., Ltd. Y. Sakata has received remuneration from Daiichi Sankyo Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd.; and scholarship funding from Nippon Boehringer Ingelheim Co., Ltd., Bayer Yakuhin Ltd., and Daiichi Sankyo Co., Ltd. Te. Kimura, K.S., and A.T. are employees of Daiichi Sankyo Co., Ltd. K.N. has received research funding from Philips Japan Ltd., Terumo Co., Ltd., TEPCO Power Grid Inc., and Asahi Kasei Pharma Co. Y.F. has received remuneration from Daiichi Sankyo Co., Ltd., Bayer Yakuhin Ltd., Ono Pharmaceutical Co., Ltd., and Novartis Pharma K.K. C.I., Ta. Kimura, K.T., and Y. Sakata are members of Circulation Journal’s Editorial Team. M.M., T. Fujita, T. Koyama, T. Komiya, H.K., K.E., K.Y., R.N., Y. Shibata, T. Fukui, and M.T. have no disclosures to report.

IRB Information

The protocol and the informed consent document were reviewed and approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (M30-068; September 26, 2018).

Data Availability

The deidentified participant data and the study protocol will be shared on a request basis for up to 36 months after the publication of this article. Researchers who make the request should include a methodologically sound proposal on how the data will be used; the proposal may be reviewed by the responsible personnel at Daiichi Sankyo Co. Ltd., and the data requestors will need to sign a data access agreement. Please directly contact the corresponding author to request data sharing.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0564

References

• 1.   Hollenberg SM. Valvular heart disease in adults: Etiologies, classification, and diagnosis. FP Essent 2017; 457: 11–16.
• 2.   Ray S. Changing epidemiology and natural history of valvular heart disease. Clin Med (Lond) 2010; 10: 168–171.
• 3.   Committee for Scientific Affairs, The Japanese Association for Thoracic Surgery, Shimizu H, Endo S, Natsugoe S, Doki Y, Hirata Y, Kobayashi J, et al. Thoracic and cardiovascular surgery in Japan in 2016: Annual report by the Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg 2019; 67: 377–411.
• 4.   Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, et al. Prevalence of atrial fibrillation in the general population of Japan: An analysis based on periodic health examination. Int J Cardiol 2009; 137: 102–107.
• 5.   January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. Circulation 2019; 140: e125–e151.
• 6.   Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37: 2893–2962.
• 7.   JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013): Digest version. Circ J 2014; 78: 1997–2021.
• 8.   Ono K, Iwasaki Y, Shimizu W, Akao M, Ikeda T, Ishii K, et al. JCS/JHRS 2020 Guideline on pharmacotherapy of cardiac arrhythmias. The Japanese Circulation Society / Japanese Heart Rhythm Society Joint Guidelines [in Japanese]. http://www.j-circ.or.jp/guideline/pdf/JCS2020_Ono.pdf (accessed June 22, 2021).
• 9.   Izumi C, Eishi K, Ashihara K, Arita T, Otsuji Y, Kunihara T, et al; on behalf of the Japanese Circulation Society Joint Working Group. JCS/JSCS/JATS/JSVS 2020 guideline on the management of valvular heart disease. Circ J 2020; 84: 2037–2119.
• 10.   Guimarães PO, Pokorney SD, Lopes RD, Wojdyla DM, Gersh BJ, Giczewska A, et al. Efficacy and safety of apixaban vs warfarin in patients with atrial fibrillation and prior bioprosthetic valve replacement or valve repair: Insights from the ARISTOTLE trial. Clin Cardiol 2019; 42: 568–571.
• 11.   Carnicelli AP, De Caterina R, Halperin JL, Renda G, Ruff CT, Trevisan M, et al. Edoxaban for the prevention of thromboembolism in patients with atrial fibrillation and bioprosthetic valves. Circulation 2017; 135: 1273–1275.
• 12.   Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981–992.
• 13.   Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093–2104.
• 14.   Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 2007; 50: 309–315.
• 15.   Chao TF, Chen SA, Ruff CT, Hamershock RA, Mercuri MF, Antman EM, et al. Clinical outcomes, edoxaban concentration, and anti-factor Xa activity of Asian patients with atrial fibrillation compared with non-Asians in the ENGAGE AF-TIMI 48 trial. Eur Heart J 2019; 40: 1518–1527.
• 16.   Izumi C, Miyake M, Amano M, Kitai T, Obayashi Y, Takegami M, et al. Registry of antithrombotic therapy in atrial fibrillation patients with bioprosthetic valves: A retrospective observational study. J Cardiol 2020; 76: 44–50.
• 17.   Furukawa Y, Miyake M, Fujita T, Koyama T, Takegami M, Kimura T, et al. Rationale, design, and baseline characteristics of the bioprosthetic valves with atrial fibrillation (BPV-AF) study. Cardiovasc Drugs Ther 2020; 34: 689–696.
• 18.   Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific Standardization Committee of the International Society on Thrombosis Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692–694.
• 19.   Kato ET, Giugliano RP, Ruff CT, Koretsune Y, Yamashita T, Kiss RG, et al. Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF–TIMI 48 Trial. J Am Heart Assoc 2016; 5: e003432.
• 20.   Guimarães HP, Lopes RD, de Barros E Silva PGM, Liporace IL, Sampaio RO, Tarasoutchi F, et al. Rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve. N Engl J Med 2020; 383: 2117–2126.
• 21.   Kozieł M, Teutsch C, Bayer V, Lu S, Gurusamy VK, Halperin JL, et al. Changes in anticoagulant prescription patterns over time for patients with atrial fibrillation around the world. J Arrhythm 2021; 37: 990–1006.
• 22.   Omae T, Inada E. New-onset atrial fibrillation: An update. J Anesth 2018; 32: 414–424.
• 23.   Shimada YJ, Yamashita T, Koretsune Y, Kimura T, Abe K, Sasaki S, et al. Effects of regional differences in Asia on efficacy and safety of edoxaban compared with warfarin: Insights from the ENGAGE AF-TIMI 48 trial. Circ J 2015; 79: 2569–2567.