Abstract
Background: There are few studies evaluating the prognostic prediction method in atrial fibrillation (AF) patients after bioprosthetic valve (BPV) replacement. The R2-CHA2DS2-VASc score is increasingly used for the prediction of cardiovascular (CV) events in patients with AF, device implantation, and acute coronary syndrome. We aimed to evaluate the predictive value of the R2-CHA2DS2-VASc score for future CV events in AF patients after BPV replacement.
Methods and Results: The BPV-AF, an observational, multicenter, prospective registry, enrolled AF patients who underwent BPV replacement. The primary outcome measure was a composite of stroke, systemic embolism, CV events including heart failure requiring hospitalization, and cardiac death. A total of 766 patients was included in the analysis. The mean R2-CHA2DS2-VASc score was 5.7±1.8. Low (scores 0–1), moderate (scores 2–4), and high (scores 5–11) R2-CHA2DS2-VASc score groups consisted of 12 (1.6%), 178 (23.2%), and 576 (75.2%) patients, respectively. The median follow-up period was 491 (interquartile range 393–561) days. Kaplan-Meier analysis showed a higher incidence of the composite CV events in the high R2-CHA2DS2-VASc score group (log rank test; P<0.001). Multivariate Cox proportional hazards regression analysis revealed that the R2-CHA2DS2-VASc score as a continuous variable was an independent predictor of composite CV outcomes (hazard ratio 1.36; 95% confidence interval 1.18–1.55; P<0.001).
Conclusions: The R2-CHA2DS2-VASc score is useful for CV risk stratification in AF patients after BPV replacement.
The incidence of valvular heart disease is increasing in the aging society, and surgical valve replacement with bioprosthetic valve (BPV) is widely performed.1–3 Atrial fibrillation (AF) is also increasing and associated with cardiovascular (CV) events including thromboembolism, heart failure, and death.4–6 Various clinical features have been identified to stratify the CV risk. The CHADS2
and CHA2DS2-VASc scores are commonly used for thromboembolic risk stratification for patients with AF, and also predict mortality and other CV events.7–9 In addition to the components of the CHADS2
and CHA2DS2-VASc scores, chronic kidney disease (CKD) is known as an important CV risk factor in the general population and increases the risk of thromboembolism in AF patients independently of other risk factors.10,11 Thus, the R2-CHA2DS2-VASc score, which includes renal dysfunction in addition to the components of the CHA2DS2-VASc score, is increasingly being used for the prediction of CV events.12–19 The R2-CHA2DS2-VASc score has been reported to improve the predictive ability for morbidity and mortality risk in patients with AF.12 However, the predictive performance of the R2-CHA2DS2-VASc score in AF patients undergoing BPV replacement has not been assessed. The aim of the present study was to investigate the value of the R2-CHA2DS2-VASc score to the prognosis and risk stratification of AF patients after BPV replacement.
Methods
Study Population
The present study was a subgroup analysis of the registry investigating antithrombotic therapy in patients with AF after BPV replacement (BPV-AF Registry). Details of the main study design and primary results have been published previously.20,21 In brief, it was a multicenter, prospective, observational registry that enrolled 894 AF patients who had undergone BPV replacement in Japan between September 2018 and October 2019. The key inclusion criteria were as follows: BPV replacement at least 3 months prior to enrollment; definitive diagnosis of AF; availability of at least 1-year follow-up data during the observation period; and ability to provide written informed consent. The key exclusion criteria were as follows: transient postoperative AF; participation in interventional studies during the data collection period; moderate or severe mitral stenosis; and mechanical valve replacement.
From the 894 patients enrolled into the BPV-AF registry, 766 patients whose R2-CHA2DS2-VASc score had been obtained were included in the present subanalysis (Figure 1). The R2-CHA2DS2-VASc score was modified from the CHA2DS2-VASc score (congestive heart failure, hypertension, age >75 years, diabetes, stroke, vascular disease, age 65–74 years, female sex) by adding reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2). Patients were stratified into three risk groups according to their R2-CHA2DS2-VASc score as follows: low (scores 0–1); moderate (scores 2–4); and high (scores 5–11).13 Baseline characteristics and clinical outcomes were compared.
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 with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (ID: UMIN000034485).
Outcomes
The primary outcome of the present subgroup analysis was a composite of stroke, systemic embolism, CV events (including myocardial infarction, stroke, systemic embolism, and death from bleeding), heart failure requiring hospitalization, and CV death. The detailed definitions of each event have been published previously.20,21
The secondary outcomes were stroke, systemic embolism, major bleeding, CV events, heart failure requiring hospitalization, CV death, all-cause mortality, reoperation of the BPV, and bleeding events (including clinically relevant bleeding and minor bleeding).
Statistical Analysis
Categorical variables were expressed as numbers and percentages and compared with the Chi-square test or Fisher’s exact test variables, as appropriate. Continuous variables were expressed as median with interquartile range (IQR) or mean and standard deviation and were compared using the Wilcoxon rank-sum test or Student t test based on their distribution. For the primary outcome, incidence rates in percent and per 100 person-years and 95% confidence intervals (CIs) were calculated using a Poisson distribution. The cumulative incidences were estimated using the Kaplan-Meier method, and differences among each group were assessed using a log-rank test. We used the Cox proportional hazards regression model to estimate hazard ratios (HRs) and their 95% CIs for the primary outcome measure. The multivariable Cox proportional hazards assumptions were conducted for the primary outcome measure using the following covariates: antiplatelet use, type of AF, transcatheter aortic valve implantation (TAVI), malignancy, and valve position (mitral, aortic, or both) as potential confounders. All P values reported are 2-tailed, and P<0.05 was considered statistically significant. All statistical analyses were performed using SAS (version 9.4; SAS Institute Inc., Cary, NC, USA).
Results
Patient Characteristics
Among the 766 patients with BPV replacement and AF, low, moderate, and high R2-CHA2DS2-VASc score groups consisted of 12 (1.6%), 178 (23.2%), and 576 (75.2%) patients, respectively (Figure 1). The distribution of the R2-CHA2DS2-VASc score is shown in Figure 2. The mean R2-CHA2DS2-VASc score was 5.7±1.8. More than half of the patients were classified into the high-risk group. The baseline clinical characteristics of each group are summarized in Table 1. The mean age of patients was 80.3 years, and 54.7% were female. The median follow-up period was 491 (IQR 393–561) days. Operative characteristics are described in Table 2. Aortic stenosis and TAVI were more frequent in the high R2-CHA2DS2-VASc score group. Administration status of antithrombotic agents is shown in Table 3 and it was not significantly different among the three groups.
Table 1.
Baseline Patient Demographic and Clinical Characteristics
| |
All
(n=766) |
R2-CHA2DS2-VASc
0–1 (n=12) |
R2-CHA2DS2-VASc
2–4 (n=178) |
R2-CHA2DS2-VASc
5–11 (n=576) |
P value |
| Female |
419 (54.7) |
0 (0.0) |
67.0 (37.6) |
352 (61.1) |
<0.001 |
| Age (years) |
80.3±6.8 |
66.4±5.8 |
76.4±6.7 |
81.8±5.9 |
<0.001 |
| Weight (kg) |
53.8±11.3 |
62.9±8.4 |
55.8±11.4 |
53.0±11.2 |
<0.001 |
| BMI (kg/m2) |
22.2±3.7 |
22.7±3.4 |
21.9±3.1 |
22.3±3.9 |
0.531 |
| HAS-BLED score |
| Mean±SD |
2.4±1.0 |
1.1±0.7 |
2.0±0.8 |
2.6±1.0 |
<0.001 |
| ≥3.0 |
337 (44.5) |
0 (0.0) |
43 (24.3) |
294 (51.8) |
<0.001 |
| eGFR (mL/min/1.73 m2) |
47.1±17.5 |
68.9±5.6 |
61.5±17.6 |
42.1±14.7 |
<0.001 |
| CCr (mL/min) |
40.9±18.2 |
76.0±13.6 |
55.2±18.5 |
36.0±14.9 |
<0.001 |
| Type of AF |
|
|
|
|
0.277 |
| Paroxysmal |
288 (37.6) |
4 (33.3) |
65 (36.5) |
219 (38.0) |
|
| Persistent |
254 (33.2) |
6 (50.0) |
68 (38.2) |
180 (31.3) |
|
| Permanent |
224 (29.2) |
2 (16.7) |
45 (25.3) |
177 (30.7) |
|
Left atrial plication, LAA
occlusion/excision |
86 (11.2) |
1 (8.3) |
22 (12.4) |
63 (11) |
0.831 |
| Previous history of CVD |
| Ischemic stroke |
108 (14.1) |
0 (0.0) |
4 (2.3) |
104 (18.1) |
<0.001 |
| Hemorrhagic stroke |
19 (2.5) |
0 (0.0) |
2 (1.1) |
17 (3) |
0.463 |
| Intracranial hemorrhage |
26 (3.4) |
0 (0.0) |
6 (3.4) |
20 (3.5) |
0.806 |
| Systemic embolism |
11 (1.4) |
0 (0.0) |
1 (0.6) |
10 (1.7) |
0.558 |
| Major bleeding |
45 (5.9) |
1 (8.3) |
11 (6.2) |
33 (5.7) |
0.913 |
| Comorbidities |
| Hypertension |
575 (75.1) |
4 (33.3) |
104 (58.4) |
467 (81.1) |
<0.001 |
| Heart failure |
434 (56.7) |
5 (41.7) |
71 (39.9) |
358 (62.2) |
<0.001 |
| Dyslipidemia |
384 (50.1) |
2 (16.7) |
70 (39.3) |
312 (54.2) |
<0.001 |
| Diabetes |
160 (20.9) |
0 (0.0) |
22 (12.4) |
138 (24.0) |
<0.001 |
| Renal dysfunction |
70 (9.1) |
0 (0.0) |
6 (3.4) |
64 (11.1) |
0.004 |
| Chronic respiratory disease |
65 (8.5) |
0 (0.0) |
16 (9.0) |
49 (8.5) |
0.557 |
| Malignant tumour |
61 (8.0) |
1 (8.3) |
9 (5.1) |
51 (8.9) |
0.262 |
| Myocardial infarction |
39 (5.1) |
0 (0.0) |
5 (2.8) |
34 (5.9) |
0.188 |
| Peripheral arterial disease |
28 (3.7) |
0 (0.0) |
1 (0.6) |
27 (4.7) |
0.030 |
| Thrombosis and embolism |
24 (3.1) |
0 (0.0) |
1 (0.6) |
23 (4.0) |
0.059 |
| Liver dysfunction |
21 (2.7) |
1 (8.3) |
5 (2.8) |
15 (2.6) |
0.371 |
| Dementia |
37 (4.8) |
0 (0.0) |
3 (1.7) |
34 (5.9) |
0.053 |
| Left ventricular ejection fraction |
|
|
|
|
0.272 |
| <40% |
51 (7.1) |
1 (8.3) |
7 (4.2) |
43 (8.0) |
|
| 40–49% |
67 (9.4) |
1 (8.3) |
20 (12.0) |
46 (8.6) |
|
| ≥50% |
598 (83.5) |
10 (83.3) |
140 (83.8) |
448 (83.4) |
|
Data are presented as n (%) or mean±SD. AF, atrial fibrillation; BMI, body mass index; CCr, creatinine clearance; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; LAA, left atrial appendage.
Table 2.
Operative Characteristics Describing the Prosthesis Position, and Full Details of the Aortic and Mitral Valves
| |
All
(n=766) |
R2-CHA2DS2-VASc
0–1 (n=12) |
R2-CHA2DS2-VASc
2–4 (n=178) |
R2-CHA2DS2-VASc
5–11 (n=576) |
P value |
| Prosthesis position |
|
|
|
|
<0.001 |
| Aortic valve |
491 (64.1) |
8 (66.7) |
86 (48.3) |
397 (68.9) |
|
| Mitral valve |
176 (23) |
3 (25.0) |
61 (34.3) |
112 (19.4) |
|
| Both valves |
99 (12.9) |
1 (8.3) |
31 (17.4) |
67 (11.6) |
|
| Aortic valve |
(n=491) |
(n=8) |
(n=86) |
(n=397) |
|
| VHD subtype |
|
|
|
|
<0.001 |
| Stenosis |
364 (74.1) |
3 (37.5) |
50 (58.1) |
311 (78.3) |
|
| Regurgitation |
101 (20.6) |
3 (37.5) |
32 (37.2) |
66 (16.6) |
|
| Other |
9 (1.8) |
1 (12.5) |
2 (2.3) |
6 (1.5) |
|
| Operation type |
|
|
|
|
<0.001 |
| Surgery |
291 (59.3) |
8 (100) |
71 (82.6) |
212 (53.4) |
|
| TAVI |
200 (40.7) |
0 (0) |
15 (17.4) |
185 (46.6) |
|
| History of replacement |
|
|
|
|
0.147 |
| First replacement |
465 (94.7) |
6 (75.0) |
83 (96.5) |
376 (94.7) |
|
| Re-replacement |
24 (4.9) |
2 (25.0) |
3 (3.5) |
19 (4.8) |
|
| Mitral valve |
(n=176) |
(n=3) |
(n=61) |
(n=112) |
|
| VHD subtype |
|
|
|
|
0.040 |
| Stenosis |
72 (40.9) |
0 (0.0) |
29 (47.5) |
43 (38.4) |
|
| Regurgitation |
88 (50.0) |
2 (66.7) |
24 (39.3) |
62 (55.4) |
|
| Other |
9 (5.1) |
1 (33.3) |
3 (4.9) |
5 (4.5) |
|
| History of replacement |
|
|
|
|
0.311 |
| First replacement |
155 (88.1) |
2 (66.7) |
53 (86.9) |
100 (89.3) |
|
| Re-replacement |
21 (11.9) |
1 (33.3) |
8 (13.1) |
12 (10.7) |
|
Data are presented as n (%). TAVI, transcatheter aortic valve implantation; VHD, valvular heart disease.
Table 3.
Administration Status of Antithrombotic Agents (Anticoagulant and Antiplatelet Drugs)
| |
All
(n=766) |
R2-CHA2DS2-VASc
0–1 (n=12) |
R2-CHA2DS2-VASc
2–4 (n=178) |
R2-CHA2DS2-VASc
5–11 (n=576) |
P value |
| No antithrombotic drug |
38 (5.0) |
2 (16.7) |
12 (6.7) |
24 (4.2) |
|
| Warfarin-based therapy |
419 (54.7) |
5 (41.7) |
107 (60.1) |
307 (53.3) |
|
| No antiplatelet drug |
306 (73.0) |
5 (100.0) |
80 (74.8) |
221 (72.0) |
0.420 |
| With antiplatelet drug |
113 (27.0) |
0 (0.0) |
27 (25.2) |
86 (28.0) |
|
| With aspirin (monotherapy) |
97 (23.2) |
0 (0.0) |
26 (24.3) |
71 (23.1) |
0.682 |
| With P2Y12 (monotherapy) |
11 (2.6) |
0 (0.0) |
0 (0.0) |
11 (3.6) |
0.156 |
| With DAPT |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
– |
| With others |
5 (1.2) |
0 (0.0) |
1 (0.9) |
4 (1.3) |
1.000 |
| Warfarin monitoring |
| Time in therapeutic range (%) |
|
|
|
|
0.056 |
| Mean±SD |
70.4±35.0 |
68.1±47.2 |
78.1±31.1 |
67.8±35.8 |
|
| Median (IQR) |
85.2 (45.6–100.0) |
86.1 (36.1–100.0) |
99.1 (64.3–100.0) |
81.3 (39.2–100.0) |
|
| PT-INR |
| Age <70 years |
|
|
|
|
1.000 |
| <2.0 |
13 (54.2) |
1 (50.0) |
9 (56.3) |
3 (50.0) |
|
| 2.0–3.0 |
11 (45.8) |
1 (50.0) |
7 (43.8) |
3 (50.0) |
|
| >3.0 |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
|
| Age ≥70 years |
|
|
|
|
0.021 |
| <1.6 |
80 (21.0) |
1 (33.3) |
10 (11.5) |
69 (23.7) |
|
| 1.6–2.6 |
264 (69.3) |
2 (66.7) |
72 (82.8) |
190 (65.3) |
|
| >2.6 |
37 (9.7) |
0 (0.0) |
5 (5.8) |
32 (11) |
|
| DOAC-based therapy |
241 (31.5) |
3 (25.0) |
37 (20.8) |
201 (34.9) |
|
| No antiplatelet drug |
173 (71.8) |
2 (66.7) |
25 (67.6) |
146 (72.6) |
0.691 |
| With antiplatelet drug |
68 (28.2) |
1 (33.3) |
12 (32.4) |
55 (27.4) |
|
| With aspirin (monotherapy) |
50 (20.8) |
1 (33.3) |
10 (27.0) |
39 (19.4) |
0.312 |
| With P2Y12 (monotherapy) |
15 (6.2) |
0 (0.0) |
1 (2.7) |
14 (7.0) |
0.570 |
| With DAPT |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
– |
| With others |
3 (1.2) |
0 (0.0) |
1 (2.7) |
2 (1.0) |
0.421 |
Antiplatelet therapy
(without warfarin/DOAC) |
68 (8.9) |
2 (16.7) |
22 (12.4) |
44 (7.6) |
|
| Aspirin (monotherapy) |
54 (79.4) |
2 (100) |
19 (86.4) |
33 (75.0) |
0.594 |
| P2Y12 (monotherapy) |
9 (13.2) |
0 (0.0) |
3 (13.6) |
6 (13.6) |
1.000 |
| DAPT |
3 (4.4) |
0 (0.0) |
0 (0.0) |
3 (6.8) |
0.585 |
| With others |
2 (2.9) |
0 (0.0) |
0 (0.0) |
2 (4.6) |
0.575 |
Data are presented as n (%), unless indicated otherwise. DAPT, dual antiplatelet therapy; DOAC, direct oral anticoagulant; INR, international normalized ratio; PT, prothrombin time.
Association of R2-CHA2DS2-VASc Score and Clinical Outcome
During the follow-up period, the primary endpoint was recorded in 8.74%/years (95% CI 7.06–10.83) in total study population and 10.99%/years (95% CI 8.8–13.72) in the high R2-CHA2DS2-VASc score group (Table 4). The incidence of secondary outcomes is also shown in Table 4. The incidence of stroke or systemic embolism was 1.82%/years (95% CI 1.15–2.89).
Table 4.
Summary of Clinical Outcomes
| |
All
(n=766) |
R2-CHA2DS2-VASc 0–1
(n=12) |
R2-CHA2DS2-VASc 2–4
(n=178) |
R2-CHA2DS2-VASc 5–11
(n=576) |
| n (%) |
%/years
(95% CI) |
n (%) |
%/years
(95% CI) |
n (%) |
%/years
(95% CI) |
n (%) |
%/years
(95% CI) |
| Primary outcome |
Composite of stroke,
SE, cardiovascular
events*, HF requiring
hospitalization, and
cardiac death |
84 (11.0) |
8.74
(7.06–10.83) |
1 (8.3) |
6.47
(0.91–45.97) |
5 (2.8) |
2.12
(0.88–5.09) |
78 (13.5) |
10.99
(8.8–13.72) |
| Secondary outcomes |
| Stroke/SE |
18 (2.4) |
1.82
(1.15–2.89) |
1 (8.3) |
6.47
(0.91–45.97) |
0 (0.0) |
– |
17 (3.0) |
2.31
(1.44–3.72) |
| Major bleeding |
16 (2.1) |
1.62
(0.99–2.64) |
1 (8.3) |
6.78
(0.95–48.12) |
1 (0.6) |
0.42
(0.06–2.99) |
14 (2.4) |
1.90
(1.12–3.20) |
| Cardiovascular events* |
19 (2.5) |
1.92
(1.23–3.01) |
1 (8.3) |
6.47
(0.91–45.97) |
0 (0.0) |
– |
18 (3.1) |
2.45
(1.54–3.88) |
HF requiring
hospitalization |
58 (7.6) |
5.96
(4.61–7.71) |
0 (0.0) |
– |
5 (2.8) |
2.12
(0.88–5.09) |
53 (9.2) |
7.35
(5.61–9.61) |
| Cardiovascular death |
10 (1.3) |
1.00
(0.54–1.86) |
0 (0.0) |
– |
0 (0.0) |
– |
10 (1.7) |
1.34
(0.72–2.49) |
| All-cause death |
39 (5.1) |
3.90
(2.85–5.33) |
0 (0.0) |
– |
5 (2.8) |
2.12
(0.88–5.09) |
34 (5.9) |
4.55
(3.25–6.36) |
| Reoperation of the BPV |
6 (0.8) |
0.60
(0.27–1.34) |
1 (8.3) |
6.46
(0.91–45.86) |
1 (0.6) |
0.42
(0.06–2.99) |
4 (0.7) |
0.54
(0.2–1.43) |
Major bleeding, clinically
relevant bleeding, minor
bleeding |
54 (7.1) |
5.62
(4.30–7.33) |
1 (8.3) |
6.78
(0.95–48.12) |
9 (5.1) |
3.88
(2.02–7.45) |
44 (7.6) |
6.16
(4.58–8.28) |
*Cardiovascular events included myocardial infarction, stroke, SE, and death from bleeding. BPV, bioprosthetic valve; HF, heart failure; SE, systemic embolism.
Kaplan-Meier analysis showed a higher incidence of the composite CV outcome in the high R2-CHA2DS2-VASc score group (log rank test; P<0.001; Figure 3). Multivariate Cox proportional hazards regression analysis revealed that the R2-CHA2DS2-VASc score as a continuous variable was an independent predictor of composite CV outcome (HR 1.36; 95% CI 1.18–1.55; P<0.001), stroke and systemic embolism (HR 1.53; 95% CI 1.12–2.08; P=0.007), CV events (HR 1.47; 95% CI 1.10–1.98; P=0.010), heart failure requiring hospitalization (HR 1.29; 95% CI 1.10–1.52; P=0.002), and CV death (HR 1.67; 95% CI 1.10–2.53; P=0.016; Table 5).
Table 5.
Cox Proportional Hazards Regression Models for Each Event
| Variable |
R2-CHA2DS2-VASc score |
| Univariate model |
Multivariate model* |
| HR (95% CI) |
P value |
HR (95% CI) |
P value |
| Composite outcome |
1.33 (1.18–1.51) |
<0.001 |
1.36 (1.18–1.55) |
<0.001 |
| Stroke/systemic embolism |
1.48 (1.13–1.94) |
0.005 |
1.53 (1.12–2.08) |
0.007 |
| Major bleeding |
1.16 (0.88–1.54) |
0.282 |
1.16 (0.84–1.58) |
0.368 |
| Cardiovascular events† |
1.43 (1.10–1.86) |
0.008 |
1.47 (1.10–1.98) |
0.010 |
| Heart failure requiring hospitalization |
1.24 (1.07–1.44) |
0.004 |
1.29 (1.10–1.52) |
0.002 |
| Cardiovascular death |
1.73 (1.19–2.53) |
0.005 |
1.67 (1.10–2.53) |
0.016 |
| All-cause death |
1.14 (0.95–1.36) |
0.156 |
1.07 (0.88–1.30) |
0.484 |
| Reoperation of the BPV |
0.79 (0.52–1.22) |
0.290 |
0.78 (0.49–1.25) |
0.302 |
| Major bleeding, clinically relevant bleeding, minor bleeding |
1.07 (0.92–1.25) |
0.352 |
1.08 (0.92–1.28) |
0.340 |
*Adjusted for antiplatelet use, type of atrial fibrillation, transcatheter aortic valve implantation, malignancy, and valve position (mitral, aortic, or both). †Cardiovascular events included myocardial infarction, stroke, systemic embolism, and death from bleeding. BPV, bioprosthetic valve; CI, confidence interval; HR, hazard ratio.
Discussion
This is the first prospective analysis to evaluate the prognostic estimation value of the R2-CHA2DS2-VASc score in AF patients after BPV replacement. The major findings of the present study are as follows: (1) the R2-CHA2DS2-VASc score could stratify the CV risk of AF patients undergoing BPV replacement; and (2) more than half of the patients were at high risk of CV events as defined by the R2-CHA2DS2-VASc score ≥5.
Prevalences of AF and valvular heart disease are increasing and frequently coexist among aging populations. BPV replacement is a common, increasingly utilized treatment for valvular heart disease. Various adverse events after BPV replacement are associated with increased mortality and disability. The incidence of stroke varied between 1.4% and 2.4% of patients during the in-hospital stay, and between 6.1% and 13.8% during long-term follow-up.22 The short-term incidence of stroke and systemic embolism in the present study (1.82%/years; 95% CI 1.15–2.89) was comparable with previous reports. Marc et al reported that age >75 years, female gender, past and present cigarette smoking, coronary artery disease, AF, and advanced left ventricular dysfunction were risk factors for embolic stroke after surgical valve replacement.23 However, data regarding the prediction of prognosis after BPV replacement in AF patients remains limited.
The CHADS2
and CHA2DS2-VASc scores have been developed mainly for the assessment of thromboembolic risk in patients with nonvalvular AF.7,8 A growing body of evidence showed an association between the CHADS2
or CHA2DS2-VASc score and CV events regardless of the presence of AF.9 The CHA2DS2-VASc score has also been reported to be a predictor of mechanical prosthetic valve thrombosis.24 Piccini et al found that CKD is a strong and independent predictor of stroke in the AF population, and validated R2-CHA2DS2-VASc score in the risk stratification.11 It has been reported that the R2-CHA2DS2-VASc score is a better predictive method for CV morbidity and mortality than the CHADS2
and CHA2DS2-VASc scores.12 The R2-CHA2DS2-VASc score has been proposed as a tool for prediction of CV adverse events and prognosis in several different clinical settings, which include mortality in the high CV risk population,14 acute coronary syndrome (ACS) in patients with chest pain,15 no-reflow phenomenon in patients with ST-segment elevation myocardial infarction,16,17 prognosis of ACS,18,19 and atrial highrate episodes in pacemaker patients.13 In these studies, every 1-point increase in the R2-CHA2DS2-VASc score was associated with a 31–53% increase in the risk of CV events. In the present study, every 1-point increase in the R2-CHA2DS2-VASc score was associated with a 36% increase in the risk of composite CV outcome. Although the optimal cut-off value has not been definitively set yet, most studies defined a R2-CHA2DS2-VASc score of ≥4–5 as a high risk of adverse events. In the present study, an R2-CHA2DS2-VASc score ≥5 was defined as high risk in AF patients after BPV replacement, based on a previous report.13 The R2-CHA2DS2-VASc score is easily calculated by adding renal impairment to the CHA2DS2-VASc score, and will be useful in daily practice.
Study Limitations
Several limitations of this study should be acknowledged. First, this was an observational cohort study and the number of CV events were relatively small. A low incidence of each adverse clinical outcome measure might cause relatively low statistical power in this study. The clinical value of the R2-CHA2DS2-VASc score may need to be validated by future studies with a larger number of patients. Second, this study showed only mid-term outcomes. Therefore, studies with longer follow-up periods are needed.
Conclusions
The R2-CHA2DS2-VASc score is useful for CV risk stratification in AF patients after BPV replacement.
Acknowledgments
The authors thank the staff and participants of the BPV-AF Registry for their important contributions to this work.
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. 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.M. has received scholarship funds or donations from Edwards Lifesciences Corporation, Terumo Co., Ltd., and Japan Lifeline Co., Ltd. K.T. is a member of Circulation Reports’ Editorial Team, and 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 3 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. K.S. is an employee 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. C.I. has received remuneration and research funding from Daiichi Sankyo Co., Ltd. Y.F. has received remuneration from Daiichi Sankyo Co., Ltd, and Bayer Yakuhin Ltd. All other authors have no conflicts of interest to disclosure.
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) and institutional review boards at each participating center.
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 contact the corresponding author directly to request data sharing.
References
- 1.
Ray S. Changing epidemiology and natural history of valvular heart disease. Clin Med (Lond) 2010; 10: 168–171.
- 2.
Hollenberg SM. Valvular heart disease in adults: Etiologies, classification, and diagnosis. FP Essent 2017; 457: 11–16.
- 3.
Committee for Scientific Affairs, The Japanese Association for Thoracic Surgery; Yoshimura N, Sato Y, Takeuchi H, Abe T, Enco S, Hirata Y, et al. Thoracic and cardiovascular surgeries in Japan during 2021: Annual report by the Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg 2024; 72: 254–291.
- 4.
Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001; 285: 2370–2375.
- 5.
Doi K, Ogawa H, Ishigami K, Ikeda S, Aono Y, Hamatani Y, et al. Impact of valvular heart disease on mortality, thromboembolic and cardiac events in Japanese patients with atrial fibrillation: The Fushimi AF Registry. Circ J 2020; 84: 714–722.
- 6.
Ogawa H, Akao M. Is progression from paroxysmal to sustained atrial fibrillation bad news? Circ J 2022; 86: 176–181.
- 7.
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA 2001; 285: 2864–2870.
- 8.
Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The EURO Heart Survey on Atrial Fibrillation. Chest 2010; 137: 263–272.
- 9.
Horikoshi T, Nakamura T, Yoshizaki T, Nakamura J, Uematsu M, Kobayashi T, et al. Predictive value of CHADS2, CHA2DS2-VASc and R2-CHADS2 scores for short- and long-term major adverse cardiac events in non-ST-segment elevation myocardial infarction. Circ J 2023, doi:10.1253/circj.CJ-23-0733.
- 10.
Go AS, Fang MC, Udaltsova N, Chang Y, Pomernacki NK, Borowsky L. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Circulation 2009; 119: 1363–1369.
- 11.
Piccini JP, Stevens SR, Chang Y, Singer DE, Lokhnygina Y, Go AS, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: Validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation 2013; 127: 224–232.
- 12.
Fu S, Zhou S, Luo L, Ye P. R2(GFR)CHADS2 and R2(GFR)CHA2DS2VASc schemes improved the performance of CHADS2 and CHA2DS2VASc scores in death risk stratification of Chinese older patients with atrial fibrillation. Clin Interv Aging 2017; 12: 1233–1238.
- 13.
Li YP, Chen JY, Chen TW, Lu WD. Atrial high-rate episodes intensify R2CHA2DS2-VASc score for prognostic stratification in pacemaker patients. Sci Rep 2023; 13: 7640.
- 14.
D’Errico M, Piscitelli P, Mirijello A, Santoliquido M, Salvatori M, Vigna C, et al. CHA2DS2-VASc and R2CHA2DS2-VASc scores predict mortality in high cardiovascular risk population. Eur J Clin Invest 2022; 52: e13830.
- 15.
Topaz G, Ben-Zvi E, Pereg D, Kitay-Cohen Y, Benchetrit S, Zitman-Gal T, et al. Prediction of acute-coronary-syndrome using newly-defined R2-CHA2DS2-VASc score among patients with chest pain. J Cardiol 2021; 77: 370–374.
- 16.
Zhang Q, Hu M, Ma S, Niu T. New R2-CHA2DS2-VASc score predicts no-reflow phenomenon and long-term prognosis in patients with ST-segment elevation myocardial infarction after primary percutaneous coronary intervention. Front Cardiovasc Med 2022; 9: 899739.
- 17.
Zorlu Ç, Köseoğlu C. Comparison of RCHA2DS2-VASc score and CHA2DS2-VASc score prediction of no-reflow phenomenon in patients with ST-segment elevation myocardial infarction. Turk Kardiyol Dern Ars 2020; 48: 664–672.
- 18.
Węgiel M, Rakowski T, Dziewierz A, Wojtasik-Bakalarz J, Sorysz D, Bartuś S, et al. CHA2DS2-VASc and R2-CHA2DS2-VASc scores predict in-hospital and post-discharge outcome in patients with myocardial infarction. Postepy Kardiol Interwencyjnej 2018; 14: 391–398.
- 19.
Kiliszek M, Szpakowicz A, Filipiak KJ, Kołtowski Ł, Południewska D, Szymański F, et al. CHA2DS2-VASc and R2CHA2DS2-VASc scores have predictive value in patients with acute coronary syndromes. Pol Arch Med Wewn 2015; 125: 545–552.
- 20.
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.
- 21.
Izumi C, Miyake M, Fujita T, Koyama T, Tanaka H, Ando K, et al. Antithrombotic therapy for patients with atrial fibrillation and bioprosthetic valves: Real-world data from the multicenter, prospective, observational BPV-AF Registry. Circ J 2022; 86: 440–448.
- 22.
Lehto J, Malmberg M, Biancari F, Hartikainen J, Ihlberg L, Yannopoulos F, et al. Occurrence and classification of cerebrovascular events after isolated bioprosthetic surgical aortic valve replacement: A competing risk analysis of the CAREAVR study. Structural Heart 2018; 2: 157–163.
- 23.
Ruel M, Masters RG, Rubens FD, Bédard PJ, Pipe AL, Goldstein WG, et al. Late incidence and determinants of stroke after aortic and mitral valve replacement. Ann Thorac Surg 2004; 78: 77–84.
- 24.
Çınar T, Hayıroğlu MI, Tanık VO, Aruğaslan E, Keskin M, Uluganyan M, et al. The predictive value of the CHA2DS2-VASc score in patients with mechanical mitral valve thrombosis. J Thromb Thrombolysis 2018; 45: 571–577.
