Comparison of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and an Aortic Bioprosthetic Valve

Abstract

Background: Current guidelines equally recommend direct oral anticoagulants (DOACs) and warfarin for atrial fibrillation (AF) patients with a bioprosthetic valve (BPV); however, there are limited data comparing DOACs and warfarin in AF patients with an aortic BPV.

Methods and Results: This post-hoc subgroup analysis of a multicenter, prospective, observational registry (BPV-AF Registry) aimed to compare DOACs and warfarin in AF patients with an aortic BPV. The primary outcome was a composite of stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or BPV reoperation. The analysis included 479 patients (warfarin group, n=258; DOAC group, n=221). Surgical aortic valve replacement was performed in 74.4% and 36.7% of patients in the warfarin and DOAC groups, respectively. During a mean follow up of 15.5 months, the primary outcome occurred in 45 (17.4%) and 32 (14.5%) patients in the warfarin and DOAC groups, respectively. No significant difference was found in the primary outcome between the 2 groups (adjusted hazard ratio: 0.88, 95% confidence interval: 0.51–1.50). No significant multiplicative interaction was observed between the anticoagulant effects and type of aortic valve procedure (P=0.577).

Conclusions: Among AF patients with an aortic BPV, no significant difference was observed in the composite outcome of adverse clinical events between patients treated with warfarin and those treated with DOACs, suggesting that DOACs can be used as alternatives to warfarin in these patients.

With an aging population, the number of patients undergoing aortic valve replacement with bioprosthetic valves (BPV) is increasing,^1,2 as is the number of patients with atrial fibrillation (AF).^3,4 Although surgical aortic valve replacement (SAVR) is an established procedure for aortic valve disease, transcatheter aortic valve implantation (TAVI) has enabled treating high-risk patients with aortic stenosis who are ineligible for SAVR, and has become a standard procedure for aortic stenosis in the elderly.^5,6 In addition to mitral valve disease, aortic valve disease is also commonly observed in clinical practice for AF patients;⁷ therefore, the number of patients with both AF and an aortic BPV is expected to increase, and an optimal anticoagulation strategy for these patients needs to be established.

Editorial p 1708

In patients with non-valvular AF, the non-inferiority of direct oral anticoagulants (DOACs) over warfarin has already been demonstrated;^8,9 therefore, DOACs are widely used in daily clinical practice because they do not require routine anticoagulation monitoring or dose adjustment.^10,11 DOACs have also demonstrated efficacy as an alternative to warfarin in AF patients with valvular heart disease.¹² Current guidelines recommend DOACs as first-line therapy in AF patients with a BPV, as well as warfarin;^13,14 however, these guidelines are based on large-scale randomized clinical trials in which 70–90% of the enrolled patients had mitral valve disease as the underlying valvular heart disease.^15–18 There are limited reports on the efficacy and safety of DOACs in AF patients with an aortic BPV.

The present study aimed to compare the clinical outcomes between AF patients with an aortic BPV treated with warfarin and those treated with DOACs. As an exploratory objective, the study also investigated whether the treatment effect of oral anticoagulants differed according to the type of aortic valve procedure.

Methods

Study Population

This was a post-hoc subgroup analysis of a multicenter, prospective, observational registry (BPV-AF Registry). Details of the main study design have been published previously.^19,20 In brief, patients from 16 hospitals in Japan were enrolled during the period from September 2018 to October 2019. The follow-up period ended in October 2020. The key inclusion criteria for the main study were as follows: (1) at least 3 months have passed after aortic or mitral valve replacement using a BPV (surgery or TAVI); (2) a definitive diagnosis of AF; and (3) ability to provide written informed consent. The key exclusion criteria for the main study were as follows: patients who were participating or scheduled to participate in interventional studies; those with moderate to severe mitral stenosis or mechanical valves, who are at particularly high risk of thromboembolism²¹ and for whom warfarin is the only anticoagulant recommended for use in current guidelines;^13,14 and those deemed ineligible for enrollment by the research director or co-investigators.

In this subgroup analysis, data on patients with an aortic BPV who received anticoagulant therapy were extracted from the database of the main study. These patients were divided into 2 groups according to their anticoagulant therapy (warfarin or DOACs). Baseline characteristics and clinical outcomes of the warfarin and DOAC groups were compared. In addition, comparisons of clinical outcomes between the warfarin and DOAC groups were conducted separately for patients who underwent SAVR and those who underwent TAVI.

Data Collection

Baseline clinical data, antithrombotic therapy status, and information regarding valve procedures were collected from medical records. Data available per routine clinical practice were collected every 6 months during the follow-up period. The prothrombin time with international normalized ratio of the patients receiving warfarin was recorded. Information regarding any invasive procedures and adverse clinical events were collected throughout the follow-up period.

Outcomes

The primary outcome of this subgroup analysis was defined as a composite of stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or BPV reoperation. These events were selected to assess the net clinical benefit.²² The secondary outcomes were stroke/systemic embolism and major bleeding. The detailed definitions of each event have been published previously.^19,20

Statistical Analysis

Continuous variables are presented as median (interquartile range [IQR]) or mean±standard deviation and compared using the t-test or Wilcoxon rank sum test based on their distributions. Categorical variables were presented as number (%) and compared using the chi-squared test or Fisher’s exact test. For patients who underwent two or more aortic valve replacements, the most recent one was used for analysis. For the primary outcome, incidence rates (per 100 patient-years [PY]) and 95% confidence intervals (CIs) were calculated. The Kaplan-Meier method was used to calculate the cumulative incidence rate of the primary outcome, and differences between the 2 groups were assessed using the log-rank test. We used multivariate Cox proportional hazards regression models to estimate hazard ratios (HRs) and their 95% CIs for the association between anticoagulant therapy (warfarin vs. DOAC) and outcomes. Cox proportional hazards regression models included adjustments for each component of the CHA₂DS₂-VASc score (heart failure, left ventricular ejection fraction, hypertension, age, diabetes mellitus, stroke/transient ischemic attack, vascular disease, and sex), body weight, antiplatelet use, estimated glomerular filtration rate, AF type, and type of aortic valve procedure (SAVR vs. TAVI). To clarify whether the therapeutic effect of anticoagulants differed between patients who underwent SAVR and those who underwent TAVI, we assessed the statistical multiplicative interaction using the likelihood ratio test, which compares models with and without interaction terms. Cox proportional hazards regression models were also used to assess the relationships between treatment subgroup and outcomes stratified by the type of aortic valve procedure. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). All reported P values were 2-tailed, and P values <0.05 were considered statistically significant.

Results

Study Population and Patient Characteristics

A total of 894 consecutive AF patients with a BPV were enrolled in the main study (Figure 1). Of these patients, 588 had only an aortic BPV, and 109 patients were excluded because they did not receive any anticoagulants. Thus, 479 patients were finally included in this subgroup analysis, with 258 patients (53.9%) in the warfarin group and 221 patients (46.1%) in the DOAC group. The median interval between the dates of the aortic valve procedure and study enrollment was 1.9 years (IQR: 0.9–4.5). Numbers of patients stratified by the type of anticoagulant and the type and era of aortic valve procedure are shown in Table 1.

Figure 1.

Study flow chart. DOAC, direct oral anticoagulant.

Table 1. Numbers of Patients Stratified by the Type of Anticoagulant and Type and Era of Aortic Valve Procedure

	Before 2008	2008–2011	2012–2015		2016–2019
	SAVR	SAVR	SAVR	TAVI	SAVR	TAVI
All (warfarin+DOAC)	21	47	78	10	123	196
Warfarin	13	30	58	6	89	60
DOAC	8	17	20	4	34	136

DOAC, direct oral anticoagulant; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation.

Patients’ baseline demographic and clinical characteristics are shown in Table 2. The patients in the DOAC group were older, predominantly female, and had a lower body weight, better renal function, more paroxysmal AF, higher CHADS₂ and CHA₂DS₂-VASc scores, and lower HAS-BLED scores than those in the warfarin group. No significant differences in comorbidities were observed between the 2 groups. The DOAC group had more patients after TAVI than the warfarin group.

Table 2. Baseline Demographic and Clinical Characteristics

Characteristic	All (N=479)	Warfarin group (n=258)	DOAC group (n=221)	P value
Male	224 (46.8)	137 (53.1)	87 (39.4)	0.003
Age (years)	81.8±6.5	80.6±6.3	83.1±6.4	<0.001
Weight (kg)	54.7±11.9	56.0±11.7	53.2±11.9	0.012
CHADS2 score	2.7±1.2	2.6±1.2	2.8±1.2	0.112
≥2.0	378 (85.5)	191 (82.0)	187 (89.5)	0.025
CHA2DS2-VASc score	4.4±1.5	4.2±1.5	4.6±1.5	0.006
≥3.0	411 (92.2)	207 (88.5)	204 (96.2)	0.002
HAS-BLED score	2.6±1.1	2.7±1.1	2.5±1.1	0.092
≥3.0	218 (49.4)	129 (55.4)	89 (42.8)	0.008
eGFR (mL/min/1.73 m2)	44.8±17.1	42.3±18.8	47.6±14.4	<0.001
Observation period (months)	15.5±4.0	15.5±4.2	15.4±3.8	0.705
Type of atrial fibrillation				<0.001
Paroxysmal	190 (39.7)	80 (31.0)	110 (49.8)
Persistent	176 (36.7)	115 (44.6)	61 (27.6)
Permanent	113 (23.6)	63 (24.4)	50 (22.6)
Previous history
Ischemic stroke	74 (15.5)	33 (12.8)	41 (18.6)	0.082
Hemorrhagic stroke	12 (2.5)	7 (2.7)	5 (2.3)	0.753
Major bleeding	19 (4.0)	11 (4.3)	8 (3.6)	0.719
Intracranial hemorrhage	12 (2.5)	5 (1.9)	7 (3.2)	0.391
Systemic embolism	6 (1.3)	4 (1.6)	2 (0.9)	0.691
Left ventricular ejection fraction				0.002
<50%	54 (12.1)	40 (16.7)	14 (6.8)
≥50%	391 (87.9)	200 (83.3)	191 (93.2)
Operative characteristics
Reasons for operation
Stenosis	368 (76.8)	184 (71.3)	184 (83.3)	0.010
Regurgitation	91 (19.0)	61 (23.6)	30 (13.6)
Infective Endocarditis	9 (1.9)	7 (2.7)	2 (0.9)
Type of aortic valve procedure				<0.001
SAVR	273 (57.0)	192 (74.4)	81 (36.7)
TAVI	206 (43.0)	66 (25.6)	140 (63.4)
History of replacement				0.078
First replacement	455 (95.0)	240 (93.0)	215 (97.3)
Re-replacement	22 (4.6)	17 (6.6)	5 (2.3)
Comorbidities
Hypertension	404 (84.3)	216 (83.7)	188 (85.1)	0.686
Heart failure	274 (57.2)	145 (56.2)	129 (58.4)	0.632
Dyslipidemia	263 (54.9)	142 (55.0)	121 (54.8)	0.950
Hyperuricemia	122 (25.5)	73 (28.3)	49 (22.2)	0.125
Diabetes mellitus	104 (21.7)	59 (22.9)	45 (20.4)	0.507
Chronic respiratory disease	49 (10.2)	22 (8.5)	27 (12.2)	0.184
Malignant tumor	43 (9.0)	19 (7.4)	24 (10.9)	0.182
Myocardial infarction	19 (4.0)	13 (5.0)	6 (2.7)	0.194
Dementia	27 (5.6)	13 (5.0)	14 (6.3)	0.540
Peripheral arterial disease	23 (4.8)	11 (4.3)	12 (5.4)	0.552
Liver dysfunction	12 (2.5)	5 (1.9)	7 (3.2)	0.391

Data are presented as number (%) or mean±standard deviation. eGFR, estimated glomerular filtration rate. Other abbreviations as in Table 1.

Details of status of antithrombotic therapy are shown in Table 3. Antiplatelet drugs, in addition to anticoagulants, were administered to 147 patients (30.7%). In the warfarin group, the median percentage of time in the therapeutic range was 85.8%. Data on the type and dose of DOACs used in the DOAC group are shown in Table 3.

Table 3. Status of Antithrombotic Therapy

	Warfarin group (N=258)	DOAC group (N=221)	P value
Antiplatelet therapy
No antiplatelet drug	175 (67.8)	157 (71.0)	0.448
With aspirin	70 (27.1)	46 (20.8)	0.108
With P2Y12 receptor inhibitor	11 (4.3)	16 (7.2)	0.159
With other antiplatelet drug	2 (0.8)	2 (0.9)	1.000
With DAPT	0	0	–
Warfarin monitoring
Time in therapeutic range*, %		–	–
Mean±SD	69.5±35.6	–	–
Median (IQR)	85.8 (42.8–100)	–	–
PT–INR*		–	–
<1.6	61 (26.2)	–	–
1.6–2.6	160 (68.7)	–	–
>2.6	12 (5.2)	–	–
DOAC type and dose
Edoxaban	–	85 (38.5)	–
15 mg	–	4 (1.8)	–
30 mg	–	74 (33.5)	–
60 mg	–	7 (3.2)	–
Apixaban	–	82 (37.1)	–
5 mg	–	67 (30.3)	–
10 mg	–	15 (6.8)	–
Rivaroxaban	–	46 (20.8)	–
10 mg	–	36 (16.3)	–
15 mg	–	10 (4.5)	–
Dabigatran	–	8 (3.6)	–
150 mg	–	1 (0.5)	–
220 mg	–	7 (3.2)	–

Data are presented as number (%) unless otherwise stated. *Data are available for 233 patients. DAPT, dual antiplatelet therapy; IQR, interquartile range; PT–INR, prothrombin time–international normalized ratio; SD, standard deviation.

Outcomes

During the mean follow-up period of 15.5±4.0 months, the composite outcome occurred in 45 patients (17.4%) in the warfarin group and 32 patients (14.5%) in the DOAC group; of them, stroke occurred in 8 and 3 patients, major bleeding in 8 and 7 patients, heart failure requiring hospitalization in 25 and 15 patients, all-cause death in 12 and 11 patients, and BPV reoperation in 4 patients and 1 patient in the warfarin and DOAC groups, respectively. No systemic embolism was observed in either group (Table 4).

Table 4. Summary of Clinical Outcomes

Outcomes	All (N=479)			Warfarin group (n=258)			DOAC group (n=221)
	n (%)	Per 100 PY	95% CI	n (%)	Per 100 PY	95% CI	n (%)	Per 100 PY	95% CI
Composite outcome*	77 (16.1)	13.29	(10.63–16.61)	45 (17.4)	14.37	(10.73–19.25)	32 (14.5)	12.01	(8.50–16.99)
Stroke	11 (2.3)	1.81	(1.00–3.26)	8 (3.1)	2.44	(1.22–4.88)	3 (1.4)	1.07	(0.34–3.32)
Systemic embolism	0 (0.0)	0.00	–	0 (0.0)	0.00	–	0 (0.0)	0.00	–
Major bleeding	15 (3.1)	2.47	(1.49–4.10)	8 (3.1)	2.44	(1.22–4.87)	7 (3.2)	2.52	(1.20–5.28)
Heart failure requiring hospitalization	40 (8.4)	6.70	(4.92–9.14)	25 (9.7)	7.74	(5.23–11.45)	15 (6.8)	5.48	(3.31–9.10)
All-cause death	23 (4.8)	3.73	(2.48–5.61)	12 (4.7)	3.60	(2.04–6.33)	11 (5.0)	3.88	(2.15–7.01)
BPV reoperation	5 (1.0)	0.81	(0.34–1.96)	4 (1.6)	1.21	(0.45–3.22)	1 (0.5)	0.35	(0.05–2.51)

*Composite outcome: stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or BPV reoperation. BPV, bioprosthetic valve; CI, confidence interval; DOAC, direct oral anticoagulant; PY, patient-years.

The Kaplan-Meier curve of the cumulative incidence of the composite outcome is shown in Figure 2. The difference between the 2 groups was not significant (log-rank P=0.452). The incidence of the composite outcome was 13.3/100 PY in all patients, 14.4/100 PY in the warfarin group, and 12.0/100 PY in the DOAC group (Table 4). The Cox proportional hazards regression models for the composite outcome showed no significant difference between the 2 groups (unadjusted HR: 0.84, 95% CI: 0.53–1.32, P=0.452; adjusted HR: 0.88, 95% CI: 0.51–1.50, P=0.631) (Table 5).

Figure 2.

Kaplan-Meier curves for the composite outcome according to oral anticoagulant. DOAC, direct oral anticoagulant.

Table 5. Cox Proportional Hazards Regression Models for Each Event

	Group	Number of events	Unadjusted model			Adjusted model*
			HR	95% CI	P value	HR	95% CI	P value
All (n=479)
Composite outcome	Warfarin	45	Ref.			Ref.
	DOAC	32	0.84	(0.53–1.32)	0.452	0.88	(0.51–1.50)	0.631
Stroke/systemic embolism	Warfarin	8	Ref.			Ref.
	DOAC	3	0.44	(0.12–1.66)	0.225	0.45	(0.10–2.01)	0.295
Major bleeding	Warfarin	8	Ref.			Ref.
	DOAC	7	1.02	(0.37–2.82)	0.964	0.99	(0.28–3.51)	0.990
	Group	Number of events	Unadjusted model			Adjusted model**
			HR	95% CI	P value	HR	95% CI	P value
SAVR (n=273)
Composite outcome	Warfarin	34	Ref.			Ref.
	DOAC	11	0.74	(0.37–1.46)	0.383	0.65	(0.30–1.38)	0.257
Stroke/systemic embolism	Warfarin	6	Ref.			Ref.
	DOAC	0	–	–	0.995	–	–	0.996
Major bleeding	Warfarin	5	Ref.			Ref.
	DOAC	5	2.35	(0.68–8.12)	0.177	2.76	(0.54–13.98)	0.221
TAVI (n=206)
Composite outcome	Warfarin	11	Ref.			Ref.
	DOAC	21	0.98	(0.47–2.04)	0.956	2.68	(0.91–7.87)	0.073
Stroke/systemic embolism	Warfarin	2	Ref.			Ref.
	DOAC	3	0.74	(0.12–4.43)	0.740	1.18	(0.09–14.83)	0.899
Major bleeding	Warfarin	3	Ref.			Ref.
	DOAC	2	0.33	(0.06–2.00)	0.230	1.02	(0.06–16.94)	0.991

*Adjusted for heart failure, left ventricular ejection fraction, hypertension, age, diabetes mellitus, stroke/transient ischemic attack, vascular disease, sex, body weight, antiplatelet use, eGFR, type of atrial fibrillation, and type of aortic valve procedure. **Adjusted for heart failure, left ventricular ejection fraction, hypertension, age, diabetes mellitus, stroke/transient ischemic attack, vascular disease, sex, body weight, antiplatelet use, eGFR, and type of atrial fibrillation. HR, hazard ratio. Other abbreviations as in Tables 1,2,4.

SAVR vs. TAVI

Baseline characteristics of the subgroup of patients after SAVR and those after TAVI are shown in Supplementary Tables 1,2, respectively. The cumulative incidence of the composite outcome was not significantly different between the warfarin and DOAC group in either subgroup (log-rank P=0.381 for patients after SAVR, log-rank P=0.956 for patients after TAVI, Figure 3). In either subgroup, there were some differences in baseline characteristics between the warfarin and DOAC group; however, even after adjustment for confounders, there was no significant difference in the clinical outcomes between the 2 groups (Table 5). We observed no significant multiplicative interaction between the type of oral anticoagulant (warfarin vs. DOACs) and type of aortic valve procedure (SAVR vs. TAVI) on the composite outcome (a likelihood ratio test, P=0.577).

Figure 3.

Kaplan-Meier curves for the composite outcome according to oral anticoagulant in (A) patients after SAVR and (B) patients after TAVI. DOAC, direct oral anticoagulant; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation.

Discussion

This is the first prospective analysis to compare the efficacy and safety of DOACs and warfarin in Japanese AF patients with an aortic BPV. This study revealed that: (1) the cumulative incidence of the composite outcome did not differ significantly between the warfarin and DOAC groups; and (2) no significant difference was observed between the groups even when the patients were stratified by the type of aortic valve procedure.

In this study, a majority of the patients after TAVI were treated with DOACs, whereas a majority of the patients after SAVR were treated with warfarin. Recently, DOACs have been selected more often than warfarin for the treatment of AF;^11,23 thus, cardiologists have become more experienced and familiar with the use of DOACs. Unlike in surgical valve replacement, many cardiologists such as interventional cardiologists and echocardiologists are involved in TAVI, which appears to explain the more frequent use of DOACs over warfarin in patients after TAVI in our study. In contrast, warfarin has historically been administered in the postoperative period following various cardiovascular surgeries. Thus, cardiovascular surgeons are accustomed to administering warfarin. In patients after SAVR, because of the longer interval between SAVR and study enrollment, we speculate that many attending cardiovascular surgeons would have continued warfarin use unless there was a specific reason to change to DOACs.

According to interaction analysis results, the effect of oral anticoagulants did not differ between patients after SAVR and those after TAVI. In the subgroup of patients after SAVR, no significant difference was observed in the composite outcome between the warfarin and DOAC groups. A randomized controlled trial (the RIVER trial) showed non-inferiority of rivaroxaban to warfarin by conducting a similar composite outcome analysis in AF patients with a mitral BPV;²² however, no studies have ever compared DOACs and warfarin in AF patients with an aortic BPV after SAVR. Our results provide additional evidence to support the current guidelines, which recommend DOACs for AF patients with a surgically implanted BPV, regardless of the position of the BPV. Nevertheless, the effects of the position of the surgically implanted BPV on clinical outcomes have not been fully investigated. We previously evaluated the impact of mitral BPV position vs. aortic BPV position on the clinical outcomes of AF patients after surgical valve replacement with a BPV and reported that thromboembolic risk did not differ according to valve position.²⁴ Bleeding risk was higher in patients with a mitral BPV than in those with an aortic BPV, although valve position itself might not be an independent predictor of bleeding.²⁴ However, that retrospective study involved a small sample size, and further research is needed.

With regard to the subgroup of patients after TAVI, no significant difference was observed in the composite outcome between the warfarin and DOAC groups. This result is consistent with a previous randomized controlled trial (the ENVISAGE-AF trial) involving AF patients after TAVI, in which edoxaban was found to be non-inferior to warfarin on a composite outcome of adverse clinical events.²⁵ The rate of composite outcome occurrence in patients after TAVI in the DOAC group of the present study was similar to that in the edoxaban group of the ENVISAGE-AF trial (12.8/100 and 17.3/100 PY, respectively). A lower tendency for major bleeding was observed in patients after TAVI in the DOAC group compared with those in the warfarin group in our study (1.4% vs. 4.5%). In comparison, a higher tendency for major bleeding was observed in the edoxaban group compared with the warfarin group in the ENVISAGE-AF trial (9.7/100 PY vs. 7.0/100 PY). However, these differences in major bleeding risk did not reach statistical significance in either study. Both the results of our study and those of the ENVISAGE-AF trial indicate that DOACs can be used as alternatives to warfarin in AF patients after TAVI.

Study Limitations

This study has some limitations. First, this study was a prospective observational cohort study, and the antithrombotic treatment strategy was decided by the attending cardiologist or cardiovascular surgeon. Because patients were not randomized to the warfarin group or the DOAC group, selection bias cannot be eliminated. Although we conducted multivariate analysis to adjust for potential confounders, the presence of unmeasured confounders is possible. Second, both BPV and AF are risk factors for thromboembolism; however, the timing and mechanism of thromboembolism are different between these 2 conditions. Thromboembolic risk is especially high within 3 months after aortic or mitral valve replacement using a BPV, but thromboembolic events can also occur later than 3 months after the surgery.²⁶ In addition, the temporal relationship between onset of AF and stroke varies according to studies;^27,28 therefore, it is difficult to clearly distinguish which thromboembolic events were associated with a BPV and which were associated with AF. This study cannot determine the extent to which each condition contributed to the outcomes. Third, this study showed only mid-term outcomes. Thus, it remains unclear whether similar findings will be observed over long periods of time. Finally, a low event rate for each adverse clinical event may have resulted in low statistical power in this study. To confirm the long-term efficacy and safety of DOACs in AF patients with a BPV, further long-term randomized controlled trials are warranted.

Conclusions

Among AF patients with an aortic BPV, there was no significant difference in the composite outcome of adverse clinical events between the warfarin and DOAC groups. The results suggest that DOACs are effective alternatives to warfarin for use in AF patients with an aortic BPV.

Acknowledgments

The authors gratefully acknowledge Kanako Takahashi and Riyo Masumoto of Tenri Hospital for their assistance. The authors also thank Michelle Belanger, MD, and Scott Wysong, BA, ELS, of Edanz for English editing support, which was funded by Tenri Hospital and Daiichi Sankyo Co., Ltd. in accordance with Good Publication Practice (GPP3) guidelines. In addition, the authors thank Daisuke Chiba of Daiichi Sankyo Co., Ltd. for helping with the 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

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., A.T. are employees of Daiichi Sankyo Co., Ltd. T.T. has received remuneration from Daiichi Sankyo Co., Ltd and Bayer Yakuhin 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. has received remuneration and research funding from Daiichi Sankyo Co., Ltd.

Ta. Kimura, C.I. are members of Circulation Journal’s Editorial Team.

M.M., M.T., Y.O., M.A., T. Kitai, T.F., T. Koyama, T. Komiya, H.K., K.E., K.Y., R.N., Y. Shibata, T.F., A.I. have no disclosures to report.

IRB Information

The main study was conducted in accordance with the Declaration of Helsinki; Ethical Guidelines for Medical and Health Research Involving Human Subjects issued by the Ministry of Health, Labour and Welfare of Japan; and all other applicable regulatory and legal requirements. The study protocol and informed consent document were reviewed and approved by the ethics committee of the National Cerebral and Cardiovascular Center (M30-068; September 26, 2018) and each participating hospital. The main study was registered in the UMIN Clinical Trials Registry under identifier number UMIN000034485.

Data Availability

The deidentified participant data that underlie the results reported in this article will be shared on a request basis immediately after publication until 36 months after publication of this article. The study protocol will also be available. 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. The data will be available to achieve aims in the approved proposal. Please directly contact the corresponding author to request data sharing. The data requestors will need to sign a data access agreement.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-22-0226

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