Concomitant Mitral Regurgitation in Severe Aortic Stenosis　― Insights From the CURRENT AS Registry-2 ―

Abstract

Background: Data on concomitant mitral regurgitation (MR) in patients with severe aortic stenosis (AS) are scarce.

Methods and Results: We investigated the risk of concomitant MR in patients with severe AS in the CURRENT AS Registry-2 according to initial treatment strategy (transcatheter aortic valve implantation [TAVI], surgical aortic valve replacement [SAVR], or conservative). Among 3,365 patients with severe AS, 384 (11.4%) had moderate/severe MR (TAVI: n=126/1,148; SAVR: n=68/591; conservative: n=190/1,626). The cumulative 3-year incidence for death or heart failure (HF) hospitalization was significantly higher in the moderate/severe than no/mild MR group in the entire population (54.6% vs. 34.3%, respectively; P<0.001) and for each treatment strategy (TAVI: 45.0% vs. 31.8% [P=0.006]; SAVR: 31.9% vs. 18.7% [P<0.001]; conservative: 67.8% vs. 41.6% [P<0.001]). The higher adjusted risk of moderate/severe MR relative to no/mild MR for death or HF hospitalization was not significant in the entire population (hazard ratio [HR] 1.15; 95% confidence interval [CI] 0.95–1.39; P=0.15); however, the risk was significant in the SAVR (HR 1.92; 95% CI 1.04–3.56; P=0.04) and conservative (HR 1.30; 95% CI 1.02–1.67; P=0.04) groups, but not in the TAVI group (HR 1.03; 95% CI 0.70–1.52; P=0.86), despite no significant interaction (P_interaction=0.37).

Conclusions: Moderate/severe MR was associated with a higher risk for death or HF hospitalization in the initial SAVR and conservative strategies, while the association was less pronounced in the initial TAVI strategy.

Aortic stenosis (AS) with mitral regurgitation (MR) is one of the most common combined valvular heart diseases. Approximately 10–35% of patients with severe AS were reported to have significant MR, the presence of which was associated with an increased risk of cardiovascular events.^1,2

Managing concomitant MR in severe AS remains challenging because the treatment options for severe AS with significant MR involve complex decision making, taking into account procedural risk and mitral valve anatomy.^3,4 Although transcatheter aortic valve implantation (TAVI) intrinsically does not treat MR itself, surgical aortic valve replacement (SAVR) has the option of concurrent mitral valve surgery. However, concomitant MR is sometimes left untreated even during SAVR due to concerns regarding increased perioperative risk as a result of additional mitral valve procedures and the prospect of an improvement in MR even if it is left untreated, particularly in case of functional MR.⁵ Indeed, in a certain proportion of patients, concomitant MR improves in the early phase after TAVI or isolated SAVR, along with a decrease in left ventricular pressure.^6–8

Because of the different strategies used and dynamic changes in MR, studies comparing TAVI and SAVR in patients with severe AS and significant MR in real-world clinical practice are limited. Furthermore, factors such as the study population, definitions of significant MR, and the timing of MR evaluation vary significantly across studies.^6–8 Because patients with concomitant MR are less likely to undergo interventions for severe AS due to their higher perioperative risk,⁹ a detailed evaluation of patients managed conservatively is needed. Therefore, the aim of the present study was to comprehensively investigate the impact of concomitant MR in patients with severe AS according to the initial treatment strategy, namely TAVI, SAVR, and conservative management.

Methods

Study Population

The Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis (CURRENT AS) Registry-2 is a prospective physician-initiated multicenter registry that enrolled consecutive patients with severe AS between April 2018 and December 2020 from 21 participating centers in Japan (Supplementary Appendix 1). This study was performed in accordance with the Declaration of Helsinki and the study protocol was approved by the institutional review boards in all 21 participating centers. Written informed consent was obtained from each patient at 19 centers, whereas the opt-out strategy, which waived the requirement for written informed consent, was used with permission from the institutional review boards in the remaining 2 centers.

A detailed study protocol and in-hospital outcomes after TAVI and SAVR have been published previously.^10,11 Briefly, patients with severe AS were defined as those who met at least 1 of 3 echocardiographic criteria (i.e., peak aortic jet velocity [V_max] >4.0 m/s, mean aortic pressure gradient >40 mmHg, or aortic valve area <1.0 cm²) for the first time during the enrollment period. The study population was divided into 3 groups according to the initial treatment strategy (TAVI, SAVR, or conservative) at the index echocardiography. Initial treatment strategies were determined by discussion between the attending physicians and patients, and occasionally involved heart team consultation. The follow-up period started on the day of the index echocardiography.

Of the 3,369 patients enrolled in the CURRENT AS Registry-2, 4 patients for whom MR severity at the index echocardiography was not available were excluded, leaving 3,365 patients with severe AS for analysis in the present study. MR severity was assessed by expert sonographers or cardiologists at each participating center and classified comprehensively according to the current guideline into 4 grades: none, mild, moderate, and severe.¹² The etiology of MR graded moderate or severe was also assessed and categorized as degenerative, functional, mixed, or unknown. The entire population and each of the treatment groups (based on initial treatment strategy) were further subdivided into 2 groups: those with no/mild MR and those with moderate/severe MR. Furthermore, in the SAVR group, patients with moderate/severe MR were divided into 2 groups according to whether they underwent concurrent mitral valve surgery during SAVR (Figure 1). In addition, patients with moderate/severe MR in the TAVI and SAVR treatment groups were evaluated for changes in MR severity from the index echocardiography to echocardiography at discharge after TAVI/SAVR.

Figure 1.

Study flow chart. AS, aortic stenosis; CURRENT AS Registry-2, Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis Registry-2; MR, mitral regurgitation; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation.

Clinical Outcomes and Definitions

The primary outcome of this study was a composite of all-cause death or hospitalization for heart failure. Hospitalization for heart failure was defined as hospitalization due to worsening heart failure requiring intravenous drug therapy. Other secondary outcomes included all-cause death, cardiovascular death, non-cardiovascular death, aortic valve-related death, sudden death, hospitalization for heart failure, stroke, and disabling stroke. The definitions of secondary outcomes are provided in Supplementary Appendix 2. A clinical event committee adjudicated the causes of death and stroke according to the Valve Academic Research Consortium-3 criteria (Supplementary Appendix 3).¹³ Information on cardiac surgeries during the follow-up period, including mitral transcatheter edge-to-edge repair (TEER), was also collected.

Statistical Analysis

Categorical variables are presented as numbers and percentages and were compared using the Chi-squared test or Fisher’s exact test. Continuous variables are presented as the mean±SD or median with interquartile range (IQR) and were compared using Student’s t-test or the Wilcoxon rank-sum test, depending on their distribution. The cumulative incidence of clinical outcomes was estimated by the Kaplan-Meier method and the significance of differences was assessed using log-rank tests. The risks of the moderate/severe MR group relative to the no/mild MR group for the outcomes are expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), as determined by the Cox proportional hazard model. The multivariable Cox proportional hazard models incorporated 22 clinically relevant risk-adjusting variables (Table 1), as well as the centers as a stratification variable. Proportional hazard assumptions for the risk-adjusting variables were assessed on plots of log(time) vs. log[−log(survival)] stratified by the variables. The assumptions were acceptable for all variables. We also estimated interactions between the initial treatment strategy and the effects of MR on the primary outcome, all-cause death, and hospitalization for heart failure. All P values are 2-sided and P<0.05 was considered statistically significant. All analyses were performed using R version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria).

Table 1.

Baseline and Echocardiographic Characteristics in the Entire Population

	Moderate/severe MR (n=384)	No/mild MR (n=2,981)	P value
Clinical characteristics
AgeA (years)	83.0±8.5	81.4±8.4	<0.001
Age ≥80 years	281 (73.2)	1,942 (65.1)	0.002
Male sexA	142 (37.0)	1,187 (39.8)	0.28
BMI (kg/m2)	21.7±3.6	22.7±3.7	<0.001
BMI <22.0 kg/m2 A	223 (58.1)	1,336 (44.8)	<0.001
HypertensionA	311 (81.0)	2,438 (81.8)	0.70
Dyslipidemia	197 (51.3)	1,593 (53.4)	0.43
Diabetes	100 (26.0)	892 (29.9)	0.12
On insulin therapyA	13 (3.4)	154 (5.2)	0.13
Current smokerA	8 (2.1)	123 (4.1)	0.051
Prior MIA	51 (13.3)	198 (6.6)	<0.001
Prior PCI	85 (22.1)	506 (17.0)	0.01
Prior CABG	31 (8.1)	99 (3.3)	<0.001
Coronary artery diseaseA	166 (43.2)	1,043 (35.0)	0.002
Prior open heart surgery	36 (9.4)	154 (5.2)	0.001
Prior HF hospitalization	121 (31.5)	411 (13.8)	<0.001
Prior symptomatic strokeA	59 (15.4)	427 (14.3)	0.58
Atrial fibrillation or flutterA	159 (41.4)	606 (20.3)	<0.001
Aortic and/or peripheral vascular diseaseA	31 (8.1)	225 (7.5)	0.71
Serum creatinine (mg/dL)	1.1 [0.8–1.6]	0.9 [0.7–1.2]	<0.001
Creatinine >2 mg/dL not on hemodialysisA	25 (6.5)	91 (3.1)	<0.001
eGFR (mL/min/1.73 m2)	42.3±22.7	50.5±22.6	<0.001
eGFR <30 mL/min/1.73 m2 not on hemodialysis	64 (16.7)	274 (9.2)	<0.001
HemodialysisA	46 (12.0)	235 (7.9)	0.006
Hemoglobin (g/dL)	11.4±1.9	11.9±1.8	<0.001
AnemiaA,B	258 (67.2)	1,532 (51.4)	<0.001
Chronic lung disease	72 (18.8)	692 (23.2)	0.049
Moderate or severeA	25 (6.5)	167 (5.6)	0.47
Malignancy	66 (17.2)	594 (19.9)	0.20
Currently under treatmentA	20 (5.2)	172 (5.8)	0.66
Chest wall irradiation	4 (1.0)	27 (0.9)	0.78
Liver cirrhosis (Child B or C)A	5 (1.3)	23 (0.8)	0.24
BNP (pg/mL)	437.8 [205.4–836.5]	146.7 [62.5–371.5]	<0.001
NT-proBNP (pg/mL)	2,871 [1,113–5,841]	753 [272–2,377]	<0.001
Clinical Frailty Scale score ≤4A	247 (64.3)	2,284 (76.6)	<0.001
STS PROM (%)	5.8 [3.6–8.5]	4.1 [2.7–6.0]	<0.001
EuroSCORE II (%)	4.6 [3.3–8.0]	3.1 [1.9–4.6]	<0.001
Logistic EuroSCORE (%)	15.1 [9.5–25.5]	11.1 [7.5–17.3]	<0.001
Any symptoms probably related to AS	304 (79.2)	1,705 (57.2)	<0.001
Chest pain	44 (14.5)	268 (15.7)	0.58
Syncope	17 (5.6)	177 (10.4)	0.009
Heart failure	286 (94.1)	1,472 (86.3)	<0.001
NYHA class			<0.001
II	130 (45.5)	975 (66.2)
III	110 (38.5)	348 (23.6)
IV	46 (16.1)	149 (10.1)
HF hospitalization at index echocardiographyA	93 (30.6)	243 (14.3)	<0.001
Medications
Antiplatelet therapy
Aspirin	107 (27.9)	803 (27.0)	0.71
Thienopyridine
Clopidogrel	46 (12.0)	350 (11.8)	0.90
Prasugrel	7 (1.8)	32 (1.1)	0.20
Ticlopidine	2 (0.5)	7 (0.2)	0.28
Warfarin	52 (13.5)	222 (7.5)	<0.001
DOAC	87 (22.7)	366 (12.3)	<0.001
β-blockers	146 (38.0)	799 (26.8)	<0.001
ACE-i or ARB	172 (44.8)	1,483 (49.8)	0.07
Calcium channel blockers	174 (45.3)	1,616 (54.3)	0.001
Diuretics	234 (60.9)	1,051 (35.3)	<0.001
Proton pump inhibitors	183 (47.7)	1,269 (42.6)	0.06
H2 receptor blockers	28 (7.3)	221 (7.4)	0.93
Echocardiography
LV end-diastolic diameter (mm)	47.5±7.6	44.3±6.2	<0.001
LV end-systolic diameter (mm)	33.0±9.0	29.2±6.5	<0.001
LVEF (%)	55.7±14.5	61.3±10.5	<0.001
<40%	61 (15.9)	158 (5.3)	<0.001
<50%	108 (28.1)	384 (12.9)	<0.001
<60%A	197 (51.3)	912 (30.6)	<0.001
TR PG (mmHg)	35.4±11.8	27.6±10.2	<0.001
≥40 mmHg	114 (29.7)	235 (7.9)	<0.001
Stroke volume index (mL/m2)	41.6±12.7	46.1±11.9	<0.001
≤35 mL/m2	118 (31.1)	502 (16.9)	<0.001
AVA (cm2)	0.7±0.2	0.8±0.2	<0.001
Vmax (m/s)	4.0±0.9	4.2±0.8	<0.001
>4 m/sA	187 (48.7)	1,710 (57.4)	0.001
>4.5 m/s	88 (22.9)	881 (29.6)	0.007
>5 m/s	43 (11.2)	424 (14.2)	0.11
Mean aortic PG (mmHg)	38.3±18.4	41.5±17.3	0.001
>40 mmHg	155 (40.4)	1,402 (47.1)	0.01
Any concomitant moderate/severe valvular heart diseases other than MRA	189 (49.2)	496 (16.6)	<0.001
AR	95 (24.7)	253 (8.5)	<0.001
MS	24 (6.2)	76 (2.5)	<0.001
TR	121 (31.5)	217 (7.3)	<0.001
MR (moderate/severe only)
Etiology
Degenerative	124 (32.3)	–	–
Functional	167 (43.5)	–	–
Mixed	35 (9.1)	–	–
Unknown	58 (15.1)	–	–
Vena contracta width (cm)	0.7±0.2	–	–
Regurgitant volume (mL)	44.5±17.8	–	–
Regurgitant fraction (%)	47.7±8.5	–	–
Effective regurgitant orifice area (cm2)	0.3±0.1	–	–

Categorical variables are presented as n (%); continuous variables are presented as the mean±SD or median [interquartile range]. ^ARisk-adjusting variables selected for the Cox proportional hazard models. ^BAnemia was defined as serum hemoglobin <12 g/dL for women or <13 g/dL for men. Missing values include: body mass index (BMI) in 14 patients; hemoglobin, serum creatinine, and estimated glomerular filtration rate (eGFR) levels in 296 patients; B-type natriuretic peptide (BNP) levels in 805 patients; N-terminal pro B-type natriuretic peptide (NT-proBNP) levels in 2,971 patients; medications in 3 patients; left ventricular (LV) end-diastolic diameter in 2 patients; LV end-systolic diameter in 25 patients; left ventricular ejection fraction (LVEF) in 1 patient; tricuspid regurgitation (TR) pressure gradient (PG) in 582 patients; stroke volume index in 23 patients; aortic valve area (AVA) in 7 patients; mean aortic PG in 7 patients; vena contracta width in 327 patients; regurgitant volume in 309 patients; regurgitant fraction in 365 patients; and effective regurgitant orifice area in 304 patients. ACE-i, angiotensin-converting enzyme inhibitor; AR, aortic regurgitation; ARB, angiotensin receptor blocker; AS, aortic stenosis; CABG, coronary artery bypass grafting; DOAC, direct oral anticoagulant; HF, heart failure; MI, myocardial infarction; MR, mitral regurgitation; MS, mitral stenosis; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; STS PROM, Society of Thoracic Surgeons – Predicted Risk of Mortality; V_max, peak aortic jet velocity.

Results

Baseline Characteristics

Among the 3,365 patients in the entire population, 1,018 patients had no MR (30.3%). Mild, moderate, and severe MR were observed in 1963 (58.3%), 334 (9.9%), and 50 (1.5%) patients, respectively, resulting in 384 patients with moderate/severe MR (11.4%). There were 1,148 patients in the initial TAVI group (34.1%), 591 patients in the initial SAVR group (17.6%), and 1,626 patients in the conservative group (48.3%). The prevalence of moderate/severe MR was similar regardless of the initial treatment strategy: 126 (11.0%) patients in the TAVI group, 68 (11.5%) in the SAVR group, and 190 (11.7%) in the conservative group (Figure 1).

As indicated in Table 1, in the entire population, patients with moderate/severe MR were older and were more likely to have a low (<22.0 kg/m²) body mass index than those with no/mild MR. In addition, compared with patients with no/mild MR, patients with moderate/severe MR more often had comorbidities, including prior myocardial infarction, prior heart failure, atrial fibrillation or flutter, and impaired renal function. Reflecting these comorbidities, patients with moderate/severe MR had higher surgical risk scores, as well as higher Clinical Frailty Scale scores. Regarding medications, patients with moderate/severe MR more often received anticoagulants, β-blockers, and diuretics than patients with no/mild MR (Table 1). With regard to echocardiographic parameters, patients with moderate/severe MR had a larger left ventricle, a higher tricuspid regurgitation pressure gradient, and a higher prevalence of concomitant significant valvular heart diseases, but lower left ventricular ejection fraction, stroke volume index, V_max, and mean aortic pressure gradient, than patients with no/mild MR (Table 1). These characteristics of patients with moderate/severe MR vs. those with no/mild MR were consistent across the 3 initial treatment strategy groups (Supplementary Tables 1–3).

Clinical Outcomes

The median follow-up period was 2.1 years (IQR 1.2–2.9 years). In the entire population, the cumulative 3-year incidence of the primary outcome was significantly higher in the moderate/severe than no/mild MR group (54.6% vs. 34.3% [log-rank P<0.001]; HR 1.99, 95% CI 1.68–2.36, P<0.001; Table 2; Figure 2A). After adjusting for confounders, the higher adjusted risk of the moderate/severe MR group relative to the no/mild MR group was not significant for the primary outcome (HR 1.15; 95% CI 0.95–1.39; P=0.15; Table 2; Figure 3). However, the increased adjusted risk of cardiovascular death in the moderate/severe MR group remained significant (HR 1.35; 95% CI 1.03–1.77; P=0.03; Table 2).

Table 2.

Clinical Outcomes According to the Severity of MR for the Entire Study Population and According to the Initial Treatment

	Moderate/severe MR		No/mild MR		Unadjusted HR (95% CI)	P value	Adjusted HR (95% CI)	P value
	No. patients with events	Cumulative 3-year incidence (%)	No. patients with events	Cumulative 3-year incidence (%)
Entire population	n=384		n=2,981
All-cause death or hospitalization for HF	163	54.6	822	34.3	1.99 (1.68–2.36)	<0.001	1.15 (0.95–1.39)	0.15
All-cause death	124	42.4	612	26.3	1.94 (1.60–2.35)	<0.001	1.09 (0.88–1.36)	0.43
Cardiovascular death	87	31.0	298	13.4	2.73 (2.15–3.47)	<0.001	1.35 (1.03–1.77)	0.03
Non-cardiovascular death	37	16.5	314	14.9	1.16 (0.82–1.63)	0.40	0.73 (0.50–1.06)	0.10
Aortic valve-related death	58	21.0	168	7.5	3.12 (2.32–4.21)	<0.001	1.26 (0.89–1.77)	0.19
Sudden death	18	7.9	71	3.4	2.41 (1.43–4.05)	<0.001	1.38 (0.75–2.53)	0.30
Hospitalization for HF	83	29.9	364	16.2	2.22 (1.75–2.82)	<0.001	1.20 (0.92–1.57)	0.19
Stroke	19	8.7	165	7.4	1.04 (0.65–1.67)	0.88	0.93 (0.56–1.55)	0.79
Disabling stroke	11	5.5	104	4.5	0.96 (0.52–1.79)	0.90	0.97 (0.50–1.86)	0.92
Initial TAVI group	n=126		n=1,022
All-cause death or hospitalization for HF	42	45.0	243	31.8	1.58 (1.14–2.20)	0.006	1.03 (0.70–1.52)	0.86
All-cause death	29	32.9	182	24.3	1.33 (0.90–1.97)	0.15	0.88 (0.56–1.37)	0.56
Cardiovascular death	14	15.9	63	8.8	1.86 (1.04–3.31)	0.04	1.29 (0.65–2.53)	0.46
Non-cardiovascular death	15	20.1	119	16.9	1.05 (0.62–1.80)	0.85	0.67 (0.36–1.26)	0.21
Aortic valve-related death	2	1.9	13	1.4	1.27 (0.29–5.61)	0.76	1.75 (0.38–7.95)	0.47
Sudden death	4	2.6	14	2.3	2.55 (0.84–7.76)	0.10	1.43 (0.36–5.75)	0.61
Hospitalization for HF	23	23.2	98	13.0	2.10 (1.33–3.30)	0.001	1.45 (0.88–2.38)	0.14
Stroke	9	9.7	62	7.9	1.22 (0.60–2.45)	0.58	0.96 (0.44–2.06)	0.91
Disabling stroke	6	7.1	42	5.2	1.20 (0.51–2.83)	0.67	1.03 (0.40–2.67)	0.94
Initial SAVR group	n=68		n=523
All-cause death or hospitalization for HF	19	31.9	75	18.7	2.51 (1.51–4.15)	<0.001	1.92 (1.04–3.56)	0.04
All-cause death	14	24.4	45	12.3	3.03 (1.66–5.53)	<0.001	2.16 (0.95–4.93)	0.07
Cardiovascular death	13	23.2	19	4.5	6.24 (3.08–12.7)	<0.001	3.42 (1.14–10.3)	0.03
Non-cardiovascular death	1	1.6	26	8.2	0.41 (0.05–2.99)	0.38	0.38 (0.04–3.97)	0.42
Aortic valve-related death	9	17.3	8	1.7	9.42 (3.63–24.5)	<0.001	3.09 (0.47–20.5)	0.24
Sudden death	3	10.2	4	0.9	7.15 (1.60–32.0)	0.01	–	–
Hospitalization for HF	8	13.5	35	8.2	2.09 (0.97–4.51)	0.06	2.11 (0.87–5.09)	0.10
Stroke	1	6.2	31	7.0	0.27 (0.04–1.97)	0.20	0.15 (0.02–1.31)	0.09
Disabling stroke	0	0.0	19	4.5	–	–	–	–
Conservative group	n=190		n=1,436
All-cause death or hospitalization for HF	102	67.8	504	41.6	2.16 (1.74–2.67)	<0.001	1.30 (1.02–1.67)	0.04
All-cause death	81	54.5	385	32.5	2.17 (1.71–2.76)	<0.001	1.29 (0.98–1.72)	0.07
Cardiovascular death	60	44.5	216	19.7	2.79 (2.10–3.72)	<0.001	1.49 (1.06–2.10)	0.02
Non-cardiovascular death	21	18.0	169	16.0	1.33 (0.84–2.10)	0.22	0.91 (0.53–1.56)	0.74
Aortic valve-related death	47	36.4	147	13.7	3.15 (2.26–4.38)	<0.001	1.42 (0.96–2.11)	0.08
Sudden death	11	12.1	53	5.1	2.09 (1.09–4.00)	0.03	1.48 (0.67–3.29)	0.33
Hospitalization for HF	52	41.6	231	21.5	2.37 (1.75–3.21)	<0.001	1.29 (0.91–1.82)	0.15
Stroke	9	9.2	72	7.1	1.27 (0.63–2.55)	0.50	1.23 (0.56–2.67)	0.61
Disabling stroke	5	6.5	43	4.1	1.23 (0.48–3.11)	0.67	1.49 (0.52–4.24)	0.45

CI, confidence interval; HF, heart failure; HR, hazard ratio; MR, mitral regurgitation; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation.

Figure 2.

Time-to-event curves for the primary outcome (composite of all-cause death or hospitalization for heart failure) according to the severity of mitral regurgitation (MR) in (A) the entire study population and separate groups according to initial treatment strategy: (B) transcatheter aortic valve implantation (TAVI); (C) surgical aortic valve replacement (SAVR); and (D) conservative treatment.

Figure 3.

Interactions between the initial treatment strategy and the effects of mitral regurgitation (MR). CI, confidence interval; HR, hazard ratio; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation.

In the initial TAVI group, the cumulative 3-year incidence of the primary outcome was significantly higher in the moderate/severe than no/mild MR group (45.0% vs. 31.8%, respectively [log-rank P=0.006]; HR 1.58, 95% CI 1.14–2.20, P=0.006; Table 2; Figure 2B). However, after adjusting for confounders, the higher risk of the moderate/severe MR relative to the no/mild MR group was no longer significant for the primary outcome (HR 1.03; 95% CI 0.70–1.52; P=0.86) or all other outcomes (Table 2; Figure 3).

In the initial SAVR group, the cumulative 3-year incidence of the primary outcome was significantly higher in the moderate/severe than no/mild MR group (31.9% vs. 18.7%, respectively [log-rank P<0.001]; HR 2.51, 95% CI 1.51–4.15, P<0.001; Table 2; Figure 2C). Even after adjusting for confounders, the higher risk of the moderate/severe relative to no/mild MR group remained significant for the primary outcome (HR 1.92; 95% CI 1.04–3.56; P=0.04; Table 2; Figure 3). The higher risk of the moderate/severe MR group relative to the no/mild MR group also remained significant for cardiovascular death (HR 3.42; 95% CI 1.14–10.3; P=0.03; Table 2).

In the conservative group, the cumulative 3-year incidence of the primary outcome was also significantly higher in the moderate/severe than no/mild MR group (67.8% vs. 41.6%, respectively [log-rank P<0.001]; HR 2.16, 95% CI 1.74–2.67, P<0.001; Table 2; Figure 2D). Even after adjusting for confounders, the higher risk of the moderate/severe MR group relative to the no/mild MR group remained significant for the primary outcome (HR 1.30; 95% CI 1.02–1.67; P=0.04; Table 2; Figure 3). For the secondary outcomes, the higher adjusted risks of the moderate/severe MR group relative to the no/mild MR group remained significant for cardiovascular death (HR 1.49; 95% CI 1.06–2.10; P=0.02; Table 2).

There was no significant interaction between the initial treatment strategy and the effects of moderate/severe MR for the primary outcome, all-cause death, and hospitalization for heart failure (Figure 3).

Changes in Moderate/Severe MR After TAVI/SAVR

The prevalence of degenerative and functional MR in moderate or severe MR was similar across the TAVI, SAVR, and conservative treatment strategies (degenerative: 30.2%, 25.0%, and 36.3%, respectively; functional: 45.2%, 51.5%, and 39.5%, respectively; Supplementary Tables 1–3).

Of the 126 patients with moderate/severe MR in the initial TAVI group, 124 patients actually underwent TAVI and MR severity at discharge was available for 119. Among these 119 patients, MR severity improved to mild or less at discharge in 57 (47.9%), despite the absence of any mitral valve interventions except in the case of 1 patient who underwent mitral TEER the day after TAVI (Figure 4A). Even in 35 patients with degenerative MR, moderate/severe MR improved at discharge in 13 (37.1%) patients, although the percentage of patients in whom MR improved was higher for patients with functional MR (29/54 [53.7%]; Figure 4B). The cumulative 3-year incidence of the primary outcome was numerically lower in the group with improved MR than in the group with residual MR, but the difference was not statistically significant (36.0% vs. 52.6%, respectively; log-rank P=0.11; Supplementary Figure 1A). During the follow-up period after TAVI, 6 patients underwent mitral TEER, including 1 redo procedure.

Figure 4.

Changes in mitral regurgitation (MR) severity after transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR). Changes in MR severity are shown from the index echocardiography to discharge after TAVI or SAVR in patients who underwent TAVI or SAVR and for whom MR severity at discharge was available. (A) Changes in the TAVI and the SAVR groups; (B) changes according to the etiology of MR in the TAVI group; and (C) changes according to concomitant mitral valve surgery in the SAVR group.

Of the 68 patients with moderate/severe MR in the initial SAVR group, 27 (40.9%) underwent SAVR with concurrent mitral valve procedures and 39 (59.1%) underwent SAVR without mitral valve procedures (Figure 1). The baseline and, echocardiographic characteristics, as well as details of surgery, were comparable between the 2 groups, except for a higher prevalence of degenerative MR, concomitant tricuspid valve surgery, and Maze procedure in the mitral valve surgery group (Supplementary Table 4). There was no significant difference in the cumulative 3-year incidence of the primary outcome between the groups with and without concurrent mitral valve surgery (22.2% vs. 39.1%, respectively; log-rank P=0.66; Supplementary Figure 2). Of the 59 patients for whom MR severity at discharge was available, moderate/severe MR in 50 patients (84.7%) improved to mild or less MR (Figure 4A). The vast majority of cases of moderate/severe MR improved in patients with mitral valve surgery (96.0%), whereas 76.5% of cases of moderate/severe MR improved in patients without mitral valve surgery (Figure 4C). No surgical or transcatheter intervention for MR was performed during the follow-up period.

Discussion

The main findings of the present study, which enrolled patients with severe AS undergoing different types of initial treatment, are as follows: (1) regardless of the initial treatment strategy, the prevalence of moderate/severe MR was 11–12%, with degenerative etiology accounting for one-third of cases; (2) the adjusted risk of all-cause death or hospitalization for heart failure was comparable between patients with moderate/severe and no/mild MR in the initial TAVI group, but was significantly higher for patients with moderate/severe MR in the initial SAVR and conservative treatment groups; and 3) moderate/severe MR improved at discharge in half the patients who underwent TAVI, compared with 85% of patients who underwent SAVR, although only 40% of these patients underwent concurrent mitral valve procedures.

The prevalence of moderate or severe MR in the present study (11.4%) is within the range reported in previous studies (8.5–36.8%), including landmark randomized trials comparing TAVI with SAVR,^14,15 large TAVI registries,^6,7 and registries that enrolled patients with severe AS managed conservatively.^2,9 However, the was a considerable discrepancy in the prevalence of moderate/severe MR between the CURRENT AS Registry-1 and CURRENT AS Registry-2 studies (20.0% vs. 11.4%, respectively), even though both studies involved patients who were managed conservatively at similar core hospitals in Japan.² This discrepancy may be due, in part, to the difference in enrollment periods. During the CURRENT AS Registry-1 study period (2003–2011), because TAVI was not available in Japan, patients with severe AS who were at high surgical risk tended to be managed conservatively at local family clinics. In contrast, during the enrollment period for the CURRENT AS Registry-2 (2018–2020), TAVI had become widely used in Japan, and patients with severe AS were more often referred to core hospitals for TAVI. In addition, in the present study, we encouraged all enrolling hospitals to use multiple acoustic windows to obtain the greatest peak velocity. As a result, patients with earlier-stage severe AS, lower left ventricular pressure, and milder MR severity may have been enrolled in this study.

Obviously, the most important advantage of TAVI lies in its minimal invasiveness; however, TAVI does not directly address concomitant MR. Despite this inherent disadvantage, the present study revealed that 47.9% of patients with concomitant moderate/severe MR experienced an improvement in MR after TAVI. The rate of MR improvement was consistent with the previous study from a large TAVI registry reported by Witberg et al (55.9%).⁶ Furthermore, previous studies demonstrated that MR improvement after TAVI was associated with more favorable outcomes.^6,7,16,17 These findings could explain the non-significant association in the TAVI group in the present study between moderate/severe MR and the composite endpoint after adjustment. Notably, even among patients with degenerative MR, 37.8% of patients with moderate/severe MR showed MR improvement, similar to previous studies.^8,18 This is attributed, in part, to the reduction in left ventricular pressure and left ventricular reverse remodeling following TAVI, although the degree of improvement in degenerative MR was modest compared with that seen in patients with functional MR. The choice between TAVI and SAVR for patients with moderate/severe MR appeared to be primarily influenced by a patient’s risk profile rather than MR etiology, as indicated by differences in patient backgrounds and similarities in MR etiologies between the TAVI and SAVR groups. Therefore, attempting TAVI for higher-risk patients with severe AS and significant MR, even if the etiology is degenerative, could be a realistic approach. However, in the case of degenerative MR, MR induced by mitral valve prolapse would remain unchanged after TAVI and patients with significant MR that required interventions may be more likely to undergo SAVR, highlighting the need for discussions with the heart team when determining the best course of action for each patient. Further research is warranted to differentiate more detailed etiologies of MR, such as prolapse or calcification in degenerative MR, as well as atrial or ventricular origin in functional MR. In addition, even though moderate/severe MR was not independently associated with a higher adjusted risk of the composite endpoint in the TAVI group, we should pay attention to the numerically higher risk of moderate/severe MR relative to no/mild MR for the primary outcome. Patients with moderate/severe MR should receive comprehensive follow-up after TAVI and transcatheter intervention for residual MR should be considered at an appropriate time, if deemed necessary and anatomically feasible.¹⁹

The advantage of SAVR for patients with severe AS and concomitant MR is the potential for concurrent mitral valve procedures, treating both aortic and mitral valves, and correcting degenerative MR. However, this advantage is the trade-off for the increased risk of multiple procedures.²⁰ In the present study, despite only 40.9% of patients undergoing SAVR with concurrent mitral valve procedures, moderate/severe MR improved in most patients after SAVR, and there was no significant difference in the primary outcome between patients with and without concurrent mitral valve surgery. These results suggest that decisions regarding concurrent procedures for concomitant MR were generally appropriate based on patient risk and expectations for MR improvement, although the number of patients with moderate/severe MR in the SAVR group was limited and the reasons why isolated aortic valve replacement was chosen in patients with moderate/severe MR were not available. Nevertheless, the incidence of the primary outcome in patients with moderate/severe MR was notably higher than in those with no/mild MR, especially in the early phase, and there was a significant association between moderate/severe MR and the primary outcome. Due to the relatively limited duration of follow-up in this study, the results could be highlighting the higher risk posed by SAVR with additional procedures for degenerative MR compared with the less invasive TAVI. In addition, despite adjustments for confounders, some residual confounders, such as myocardial damage or remodeling due to MR, may remain in patients with moderate/severe MR. Attention should be paid not only to the degree of MR, but also the overall condition of patients, even after successful SAVR.

In the conservative group, it was not surprising that concomitant moderate/severe MR was independently associated with the composite outcome because MR was left untreated, both directly and indirectly. In addition, among all patients with moderate/severe MR, outcomes were worst for those in the conservative group compared with the TAVI and SAVR groups. Although the presence of significant MR may favor conservative management, particularly in the elderly population, it is necessary to consider the indications for TAVI to mitigate the burden of both severe AS and concomitant MR.⁹ Furthermore, patients with moderate/severe MR in the conservative group tended to present fewer symptoms related to AS and to have a lower V_max than those in the TAVI and SAVR groups. For such patients, exercise stress echocardiography would be useful in revealing latent symptoms and assessing the true severity and impact of both AS and MR.²¹

Study Limitations

This study has several limitations. First, the choice of the initial treatment strategy (TAVI, SAVR, conservative) was at the discretion of each participating center, with baseline characteristics between the initial TAVI and SAVR groups, in particular, differing substantially. In addition, the indication for concurrent mitral valve procedures with SAVR depended on the attending surgeons. Furthermore, some patients with residual MR who underwent TAVI initially subsequently underwent mitral TEER during the follow-up period if deemed necessary by heart team discussion; thus, the TAVI group could be regarded as a group that underwent TAVI with additional mitral TEER depending on the situation. Therefore, differences in clinical outcomes may be due to the inclusion of such patients in the TAVI group. Second, echocardiographic evaluation in the core laboratory was not performed. The severity and etiology of MR may vary among observers, despite evaluation by expert sonographers or cardiologists at each participating center following the current guideline.¹² Furthermore, detailed etiologies of MR were not differentiated, such as prolapse or calcification in degenerative MR, as well as atrial or ventricular origin in functional MR. Third, the follow-up period was relatively short because of the prospective nature of this study as opposed to our previous study.² Considering the higher rate of MR reduction in the SAVR group, it is possible that different results will be obtained with a longer follow-up period.

Conclusions

In patients with severe AS, moderate/severe MR was associated with a higher risk of all-cause death or heart failure hospitalization for those undergoing SAVR and conservative treatment as the initial strategy. This association was less pronounced in patients with the initial TAVI strategy. A substantial proportion of moderate/severe MR improved after SAVR with and without concurrent mitral valve procedures, as well as after TAVI.

Acknowledgments

The authors appreciate the support and collaboration of the coinvestigators participating in the CURRENT AS Registry-2 (Supplementary Appendix 1). During the preparation of this manuscript, the authors used ChatGPT 3.5 only for English language proofreading.

Sources of Funding

This work was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan).

Disclosures

K. Ono and K. Minatoya are members of Circulation Journal’s Editorial Team. S.S. reports clinical proctoring for Edwards Life Science, Medtronic, and Abbott Vascular. H.S. reports receiving personal fees from Abbott Vascular, Boston Scientific, and Daiichi Sankyo. T.M. reports receiving lecturer fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray and manuscript fees from Bristol-Myers Squibb and Kowa, as well as being on the advisory board for Sanofi. T. Kimura reports being on the advisory board for Abbott Vascular and receiving grants from Edwards Lifescience, Daiichi Sankyo, Takeda Pharmaceutical, Bayer, Otsuka Parmaceutical, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Sumitomo Dainippon Pharma, Kowa, Abiomed, Japan Academic Research Forum, NIPRO, W.L. Gore & Associates G.K., RPM Co., Ltd., CSL Behring, Pfizer R&D Japan G.K., and EP-CRSU Co., Ltd; and honoraria from MSD, Eisai, Edwards Lifescience, Ono Pharmaceutical, Tsumura, Medical Review, Kowa, Sanofi, Pharmaceuticals and Medical Devices Agency, Bristol-Myers Squibb, Boston Scientific, Lifescience, Toray, Astellas Amgen Biopharma, Astellas, AstraZeneca, OrbusNeich, MSD Life Science Foundation, Public Health Research Foundation, Chugai Pharmaceutical, Japan Society for the Promotion of Science, Interscience, Philips, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Terumo, Novartis Pharma, HeartFlow Japan G.K., and CROSSCO Co. The remaining authors have no conflicts of interest to disclose.

IRB Information

The present study was approved by Kyoto University Graduate School and the Faculty of Medicine Ethics Committee (Reference no. R1501).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0103

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