Concomitant Mitral Regurgitation in Severe Aortic Stenosis　― A Report From the CURRENT AS Registry ―

Abstract

Background: The clinical significance of concomitant mitral regurgitation (MR) has not been well addressed in patients with severe aortic stenosis (AS).

Methods and Results: We analyzed 3,815 patients from a retrospective multicenter registry of severe AS in Japan (CURRENT AS registry). We compared the clinical outcomes between patients with moderate/severe MR and with none/mild MR according to the initial treatment strategy (initial aortic valve replacement [AVR] or conservative strategy). The primary outcome measure was a composite of aortic valve-related death or heart failure hospitalization. At baseline, moderate/severe MR was present in 227/1,197 (19%) patients with initial AVR strategy and in 536/2,618 (20%) patients with a conservative strategy. The crude cumulative 5-year incidence of the primary outcome measure was significantly higher in patients with moderate/severe MR than in those with none/mild MR, regardless of the initial treatment strategy (25.2% vs. 14.4%, P<0.001 in the initial AVR strategy, and 63.3% vs. 40.7%, P<0.001 in the conservative strategy). After adjusting confounders, moderate/severe MR was not independently associated with higher risk for the primary outcome measure in the initial AVR strategy (hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.67–1.83, P=0.69), and in the conservative strategy (HR 1.13, 95% CI 0.93–1.37, P=0.22).

Conclusions: Concomitant moderate/severe MR was not independently associated with higher risk for the primary outcome measure regardless of the initial treatment strategy.

Mitral regurgitation (MR) often coexists with severe aortic stenosis (AS).^1,2 The prevalence of concomitant moderate or severe MR has been reported in 13%³ to 33%⁴ of patients undergoing surgical aortic valve replacement (SAVR) and in 20–30% of patients undergoing transcatheter aortic valve replacement (TAVR).² In the current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, concomitant mitral valve repair or replacement is recommended for patients with severe primary MR (Class I) and mitral valve repair is described as a reasonable option for patients with moderate primary MR (Class IIa) when undergoing other cardiac surgery.⁵ Concomitant moderate functional MR in patients with severe AS is thought to often improve after SAVR without mitral intervention,⁶ although MR with a rheumatic or degenerative etiology does not improve in most patients undergoing isolated SAVR.⁷ In patients who underwent isolated SAVR, moderate concomitant MR has been thought to be associated with worse survival rate after surgery.⁸ With regard to patients undergoing TAVR, concomitant MR is also thought to be associated with worse prognosis.^9,10 Nevertheless, the prognostic impact of coexisting MR in severe AS remains controversial.

Editorial p 438

The aim of this study was to describe the clinical characteristics and factors associated with moderate/severe MR in patients with severe AS and to evaluate the prognostic impact of concomitant moderate/severe MR in patients with severe AS who either underwent initial SAVR or were managed conservatively.

Methods

Study Population

The CURRENT AS (Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis) registry is a retrospective multicenter registry that enrolled 3,815 consecutive patients with severe AS from 27 centers in Japan between January 2003 and December 2011 (Supplementary Appendix). Institutional review boards at all participating centers approved the protocol, and this study followed the Declaration of Helsinki and the ethical standards of the responsible committees on human experimentation. The need to obtain informed consent was waived because of the retrospective nature of the study. The details of the study design and primary results of the registry have been previously published.¹¹ Of the 3,815 patients in the entire cohort, the study population was divided into 2 groups based on the initial treatment strategy after the index echocardiography (initial aortic valve replacement [AVR] group: n=1,197; conservative management group: n=2,618) (Figure 1). During the study period (2003–2011), only surgical AVR was available in Japan except for clinical trials usage. Follow-up data were collected from medical chart review in each participating center or through contact with patients, families and/or referring physicians by mail or telephone.

Figure 1.

Study flowchart. AS, aortic stenosis; AVR, aortic valve replacement; MR, mitral regurgitation; SAVR, surgical AVR.

Echocardiographic data were not assessed in a central core laboratory, but were assessed in each participating center. MR severity on index echocardiography was graded as none, mild, moderate, or severe according to the American Society of Echocardiography recommendations.^12,13 Because of the retrospective nature of the registry, the etiology (e.g., degenerative or functional) of MR was not collected. We also could not collect the multiple quantitative parameters for MR severity assessment. We subdivided the study population into 2 groups according to the semiquantitative measurement of MR severity (no/mild MR group and moderate/severe MR group). We analyzed the clinical impact of moderate/severe MR on prognosis in patients with severe AS stratified by the initial treatment strategy.

Study Outcomes

The primary outcome measure was a composite of aortic valve-related death or hospitalization for heart failure (HF). Aortic valve-related death consisted of aortic procedure-related death, sudden death, and death due to HF considered to be related to the aortic valve. Aortic procedure-related death was defined as any death during the hospitalization for AVR or transcatheter aortic valve implantation. Sudden death was defined as unexplained death in a previously stable patient. HF hospitalization was defined as hospitalization due to worsening HF requiring intravenous drug therapy. Other secondary outcome measures included all-cause death, cardiovascular death, sudden death, and noncardiovascular death. Death was regarded as cardiovascular in origin unless obvious noncardiovascular cause. The causes of death were retrospectively classified according to the Valve Academic Research Consortium definitions, and were adjudicated by a Clinical Event Committee (Supplementary Appendix).^14,15 Definitions of the clinical events are given in the Supplementary Appendix.

Statistical Analysis

Continuous variables are expressed as the mean and standard deviation or median and interquartile range. Categorical variables are expressed as numbers and percentages. We used a t-test or Wilcoxon’s rank sum test for continuous variables, and a Chi-square test or Fisher’s exact test for categorical variables. We conducted a multivariable logistic regression analysis to evaluate the clinical factors associated with concomitant moderate/severe MR, including 15 clinically relevant candidate variables. Survival analysis was performed by Kaplan-Meier, and differences between groups were assessed with a log-rank test. Multivariable Cox proportional hazards models were used to assess the risks of moderate/severe MR relative to none/mild MR for the clinical outcome measures, which were expressed as hazard ratios (HRs) and their 95% confidence intervals (CIs). Consistent with our previous report,¹¹ we incorporated 20 factors in the initial AVR stratum and 19 factors in the conservative stratum as risk-adjusting variables, and the centers were incorporated as the stratification variable in the multivariable Cox proportional hazard models. Continuous risk-adjusting variables were dichotomized using the median or clinically meaningful reference values except for age. Missing values of binary variables were considered to be null because the physicians did not record these variables if there were no pertinent findings. Missing values of continuous variables were not to be imputed and analyses were conducted for the observations without missing variables. Proportional hazard assumptions for the variable included in the Cox proportional hazard models were assessed on the plots of log (time) vs. log [-log (survival)] stratified by the variable. The assumptions were considered acceptable for all the variables. In all analyses, two-tailed P value <0.05 was considered statistically significant. Statistical analyses were performed by physicians (R.M. and T.T.) and a statistician (T. Morimoto) using JMP 11.2.1 (SAS Institute Inc., Cary, NC, USA), R software package version 3.5.2. or SAS version 9.4 (SAS Institute Inc.).

Results

Baseline Clinical Characteristics and Associated Factors of Moderate/Severe MR

Among the total of 3,815 patients, MR grades on index echocardiography were none (n=787), mild (n=2,265), moderate (n=643) and severe (n=120). Thus, 763 (20%) patients had moderate/severe MR and 3,052 (80%) patients had no/mild MR on index echocardiography. Baseline characteristics were significantly different between the 2 groups (Table 1). Patients with moderate/severe MR were older, and more often had prior myocardial infarction, history of HF, atrial fibrillation, anemia, and renal dysfunction. Regarding the echocardiographic parameters, patients with moderate/severe MR had larger LV end-diastolic and endsystolic diameters, and more often had LV dysfunction, moderate/severe tricuspid regurgitation (TR), and pulmonary hypertension. The clinical factors independently associated with moderate/severe MR were age, low body mass index, prior myocardial infarction, history of HF, history of atrial fibrillation, hemodialysis, and anemia in the multivariable logistic regression analysis (Table 2).

Table 1. Baseline Characteristics and Echocardiographic Findings in the Entire Study Population According to Significance of MR

	Moderate/severe MR (n=763)	No/mild MR (n=3,052)	P value
Clinical characteristics
Age, years*, mean±SD	80.1±9.3	77.2±9.8	<0.001
≥80 years, n (%)	424 (55.6)	1,305 (42.8)	<0.001
Men,* n (%)	254 (33.3)	1,189 (39.0)	0.004
BMI <22 kg/m2,* n (%)	549 (72.0)	1,777 (58.2)	<0.001
Hypertension,* n (%)	513 (67.2)	2,154 (70.6)	0.08
Dyslipidemia, n (%)	214 (28.0)	1,113 (36.5)	<0.001
On statin therapy, n (%)	155 (20.3)	815 (26.7)	<0.001
Diabetes, n (%)	155 (20.3)	742 (24.3)	0.02
On insulin therapy,* n (%)	28 (3.7)	160 (5.2)	0.09
Smoking history, n (%)	147 (19.3)	683 (22.4)	0.07
Current smoking,* n (%)	37 (4.8)	159 (5.2)	0.76
Prior MI,* n (%)	82 (10.7)	241 (7.9)	0.01
Prior open heart surgery, n (%)	48 (6.3)	268 (8.8)	0.03
History of HF, n (%)	217 (28.4)	428 (14.0)	<0.001
Prior symptomatic stroke,* n (%)	114 (14.9)	389 (12.7)	0.12
Atrial fibrillation or flutter,* n (%)	268 (35.1)	560 (18.3)	<0.001
Aortic/PVD,* n (%)	111 (14.5)	468 (15.3)	0.63
Serum creatinine, mg/dL, median [IQR]	1.00 [0.78, 1.55]	0.86 [0.70, 1.20]	<0.001
Serum creatinine level >0.83 mg/dL,* n (%)	478 (62.6)	1,418 (46.5)	<0.001
Hemodialysis,* n (%)	102 (13.4)	303 (9.9)	0.007
Anemia,*,† n (%)	514 (67.4)	1,603 (52.5)	<0.001
Liver cirrhosis (Child-Pugh B/C),* n (%)	8 (1.0)	30 (1.0)	1
Malignancy	96 (12.6)	421 (13.8)	0.42
Malignancy currently under treatment*	30 (3.9)	119 (3.9)	1
Chronic lung disease	85 (11.1)	315 (10.3)	0.55
Chronic lung disease (moderate or severe),* n (%)	24 (3.1)	88 (2.9)	0.79
STS score (PROM), median [IQR]	5.1 [2.9, 8.9]	3.5 [2.1, 5.9]	<0.001
Any symptoms at index echocardiography, n (%)	550 (72.1)	1,455 (47.7)	<0.001
HF symptoms at index echocardiography, n (%)	496 (65.0)	1,107 (36.3)	<0.001
NYHA functional class, n (%)			<0.001
II	202 (40.7)	644 (58.2)
III	136 (27.4)	225 (20.3)
IV	151 (30.4)	222 (20.1)
Unknown	7 (1.4)	16 (1.4)
Echocardiographic findings
Vmax, m/s mean±SD	4.1±1.0	4.1±0.9	0.24
Vmax ≥4.0 m/s,* n (%)	424 (55.6)	1,761 (57.7)	0.31
Mean aortic PG, mmHg mean±SD	39.7±21.5	41.1±19.2	0.10
AVA (equation of continuity), cm2 mean±SD	0.67±0.20	0.73±0.18	<0.001
LV end-diastolic diameter, mm mean±SD	49.0±7.8	45.2±6.6	<0.001
LV endsystolic dimeter, mm mean±SD	34.4±9.4	29.2±7.1	<0.001
LVEF, % mean±SD	56.8±15.7	64.3±12.4	<0.001
LVEF <40%, n (%)	125 (16.4)	168 (5.5)	<0.001
Any combined moderate or severe valvular disease other than MR,* n (%)	481 (63.0)	795 (26.0)	<0.001
AR, n (%)	277 (36.3)	514 (16.8)	<0.001
MS, n (%)	46 (6.0)	87 (2.9)	<0.001
TR, n (%)	321 (42.1)	307 (10.1)	<0.001
TR pressure gradient ≥40 mmHg, n (%)	266 (34.9)	340 (11.1)	<0.001

*Risk-adjusting variables selected for the Cox proportional hazard model. ^†Defined by the World Health Organization criteria (hemoglobin <12.0 g/dL in women and <13.0 g/dL in men). AR, aortic regurgitation; AVA, aortic valve area; AVR, aortic valve replacement; BMI, body mass index; HF, heart failure; IQR, interquartile range; LV, left ventricular; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MR, mitral regurgitation; MS, mitral stenosis; PG, pressure gradient; PROM, predicted risk of mortality; PVD, peripheral vascular disease; SD, standard deviation; STS, Society of Thoracic Surgeons; TR, tricuspid regurgitation; Vmax, peak aortic jet velocity.

Table 2. Logistic Regression Analysis for the Predictors of Moderate/Severe MR

Variables	Univariate			Multivariate
	OR	95% CI	P value	OR	95% CI	P value
Age ≥80 years	1.67	1.43–1.96	<0.001	1.41	1.17–1.68	<0.001
Male	0.78	0.66–0.92	0.004	0.84	0.70–1.01	0.06
BMI <22	1.84	1.54–2.19	<0.001	1.42	1.18–1.71	<0.001
Hypertension	0.85	0.72–1.01	0.07	0.90	0.75–1.08	0.27
Dyslipidemia	0.68	0.57–0.80	<0.001	0.81	0.67–0.98	0.03
Diabetes on insulin	0.69	0.46–1.04	0.07	0.68	0.45–1.05	0.08
Current smoking	0.93	0.64–1.34	0.69	1.39	0.94–2.05	0.10
Prior MI	1.40	1.08–1.83	0.01	1.36	1.02–1.82	0.04
Prior symptomatic stroke	1.20	0.96–1.51	0.11	0.97	0.77–1.24	0.82
Atrial fibrillation or flutter	2.41	2.02–2.87	<0.001	2.10	1.75–2.53	<0.001
Aortic/PVD	0.94	0.75–1.18	0.59	0.83	0.65–1.06	0.14
Hemodialysis	1.40	1.10–1.78	0.006	1.41	1.07–1.84	0.01
Anemia†	1.87	1.58–2.21	<0.001	1.53	1.28–1.83	<0.001
Chronic lung disease (moderate or severe)	1.09	0.69–1.73	0.70	0.96	0.59–1.55	0.85
History of HF admission	2.44	2.02–2.94	<0.001	1.84	1.51–2.25	<0.001

^†Defined by the World Health Organization criteria (hemoglobin <12.0 g/dL in women and <13.0 g/dL in men). BSA, body surface area; CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Baseline Clinical Characteristics According to the Initial Treatment Strategy

Moderate/severe MR was present in 227 patients (19%) of 1,197 in the initial AVR stratum, and in 536 patients (20%) of 2,618 in the conservative stratum. The differences of the baseline clinical characteristics between the moderate/severe MR and no/mild MR group in each treatment strategy were consistent with those in the overall population (Table 3). Among 1,174 patients who actually underwent SAVR in the initial AVR group, 143 (12%) underwent concomitant mitral valve surgery (61 in the no/mild MR group and 82 in the moderate/severe MR group) (Supplementary Table 1).

Table 3. Baseline Characteristics and Echocardiographic Findings in the Initial AVR and Conservative Treatment Strata According to Significance of MR

	Initial AVR stratum			Conservative stratum
	Moderate/severe MR (n=227)	No/mild MR (n=970)	P value	Moderate/Severe MR (n=536)	No/mild MR (n=2,082)	P value
Clinical characteristics
Age, years,* mean±SD	74.7±7.7	73.0±9.2	0.01	82.3±8.9	79.1±9.5	<0.001
Age ≥80 years, n (%)	68 (30.0)	231 (23.8)	0.07	356 (66.4)	1,074 (51.6)	<0.001
Men,* n (%)	94 (41.4)	413 (42.6)	0.81	160 (29.9)	776 (37.3)	0.002
BMI <22 kg/m2,* n (%)	139 (61.2)	483 (49.8)	0.002	410 (76.5)	1,294 (62.2)	<0.001
Hypertension,* n (%)	143 (63.0)	664 (68.5)	0.13	370 (69.0)	1,490 (71.6)	0.27
Dyslipidemia, n (%)	75 (33.0)	401 (41.3)	0.03	139 (25.9)	712 (34.2)	<0.001
On statin therapy, n (%)	52 (22.9)	287 (29.6)	0.054	103 (19.2)	528 (25.4)	0.004
Diabetes, n (%)	43 (18.9)	233 (24.0)	0.122	112 (20.9)	509 (24.4)	0.10
On insulin therapy,* n (%)	9 (4.0)	49 (5.1)	0.61	19 (3.5)	111 (5.3)	0.11
Smoking history, n (%)	51 (22.5)	263 (27.1)	0.18	96 (17.9)	420 (20.2)	0.27
Current smoking,* n (%)	12 (5.3)	71 (7.3)	0.35	25 (4.7)	88 (4.2)	0.75
Prior MI,* n (%)	16 (7.0)	35 (3.6)	0.03	66 (12.3)	206 (9.9)	0.12
Prior open heart surgery, n (%)	9 (4.0)	39 (4.0)	1	39 (7.3)	229 (11.0)	0.014
History of HF, n (%)	40 (17.6)	110 (11.3)	0.014	177 (33.0)	318 (15.3)	<0.001
Prior symptomatic stroke,* n (%)	24 (10.6)	83 (8.6)	0.41	90 (16.8)	306 (14.7)	0.26
Atrial fibrillation or flutter,* n (%)	70 (30.8)	137 (14.1)	<0.001	198 (36.9)	423 (20.3)	<0.001
Aortic/PVD,* n (%)	24 (10.6)	138 (14.2)	0.18	87 (16.2)	330 (15.9)	0.88
Serum creatinine, mg/dL, median [IQR]	0.98 [0.78, 1.43]	0.80 [0.66, 1.03]	<0.001	1.00 [0.78, 1.64]	0.90 [0.70, 1.30]	<0.001
Serum creatinine level >0.83 mg/dL,* n (%)	143 (63.0)	422 (43.5)	<0.001	335 (62.5)	996 (47.8)	<0.001
Serum creatinine level >2 mg/dL, n (%)	44 (19.5)	105 (11.0)	0.001	96 (20.1)	272 (15.5)	0.02
Hemodialysis,* n (%)	39 (17.2)	96 (9.9)	0.003	63 (11.8)	207 (9.9)	0.25
Anemia,*,† n (%)	140 (61.7)	489 (50.4)	0.003	374 (69.8)	1,114 (53.5)	<0.001
Liver cirrhosis (Child-Pugh B/C),* n (%)	2 (0.9)	4 (0.4)	0.705	6 (1.1)	26 (1.2)	0.98
Malignancy	25 (11.0)	106 (1.9)	1	71 (13.2)	315 (15.1)	0.30
Malignancy currently under treatment*	7 (3.1)	17 (1.8)	0.31	23 (4.3)	102 (4.9)	0.64
Chronic lung disease	33 (14.5)	108 (11.1)	0.19	52 (9.7)	207 (9.9)	0.93
Chronic lung disease (moderate or severe),* n (%)	4 (1.8)	15 (1.5)	1	20 (3.7)	73 (3.5)	0.90
STS score (PROM), median [IQR]	3.8 [2.2, 6.3]	2.6 [1.7, 4.4]	<0.001	5.8 [3.4, 9.9]	4.0 [2.4, 6.8]	<0.001
Any symptoms at index echocardiography, n (%)	201 (88.5)	704 (72.6)	<0.001	349 (65.1)	751 (36.1)	<0.001
HF symptoms at index echocardiography, n (%)	172 (75.8)	487 (50.2)	<0.001	324 (60.4)	620 (29.8)	<0.001
NYHA functional class, n (%)			<0.001			<0.001
II	75 (43.6)	322 (66.1)		127 (39.2)	322 (51.9)
III	57 (33.1)	77 (15.8)		79 (24.4)	148 (23.9)
IV	37 (21.5)	76 (15.6)		114 (35.2)	146 (23.5)
Unknown	3 (1.7)	12 (2.5)		4 (1.2)	4 (0.6)
Echocardiographic findings
Vmax, m/s mean±SD	4.6±1.0	4.7±0.8	0.159	3.9±1.0	3.9±0.8	0.95
Vmax ≥4.0 m/s,* n (%)	173 (76.2)	821 (84.6)	0.003	251 (46.8)	940 (45.1)	0.52
Mean aortic PG, mmHg mean±SD	50.8±20.5	54.4±19.2	0.03	35.0±20.1	35.3±16.2	0.68
AVA (equation of continuity), cm2 mean±SD	0.61±0.20	0.66±0.17	0.001	0.70±0.20	0.76±0.17	<0.001
LV end-diastolic diameter, mm mean±SD	51.1±8.0	46.2±6.6	<0.001	48.0±7.5	44.7±6.5	<0.001
LV endsystolic dimeter, mm mean±SD	36.5±9.9	29.8±7.7	<0.001	33.5±9.0	28.9±6.9	<0.001
LVEF, % mean±SD	55.8±16.0	64.4±13.0	<0.001	57.2±15.6	64.2±12.2	<0.001
LVEF <40%, n (%)	42 (18.5)	61 (6.3)	<0.001	83 (15.5)	107 (5.1)	<0.001
Any combined moderate/severe valvular disease except MR,* n (%)	149 (65.6)	252 (26)	<0.001	332 (61.9)	543 (26.1)	<0.001
AR, n (%)	101 (44.5)	193 (19.9)	<0.001	176 (32.8)	321 (15.4)	<0.001
MS, n (%)	18 (7.9)	33 (3.4)	0.004	28 (5.2)	54 (2.6)	0.003
TR, n (%)	85 (37.4)	62 (6.4)	<0.001	236 (44.0)	245 (11.8)	<0.001
TR pressure gradient ≥40 mmHg, n (%)	91 (40.1)	89 (9.2)	<0.001	175 (32.6)	251 (12.1)	<0.001

*Risk-adjusting variables selected for the Cox proportional hazard model. ^†Defined by the World Health Organization criteria (hemoglobin <12.0 g/dL in women and <13.0 g/dL in men). Abbreviations as in Table 1.

Clinical Outcomes in the Initial AVR Strategy: Moderate/Severe MR vs. No/Mild MR

Among 1,197 patients in the initial AVR group, the crude cumulative 5-year incidence of the primary outcome measure was significantly higher in the moderate/severe MR group than in the no/mild group (25.2% vs. 14.4%, P<0.001) (Figure 2). After adjusting for confounders, moderate/severe MR was no longer associated with excess risk for the primary outcomes measure (HR 1.11, 95% CI 0.67–1.83, P=0.69) or for the secondary outcome measures (Table 4).

Figure 2.

Kaplan-Meier curves for the composite endpoint of aortic valve-related death and heart failure hospitalization (primary outcome measure) in the initial AVR stratum (Left), and in the conservative stratum (Right). We estimated the adjusted hazard ratio for the primary outcome measure by multivariable Cox proportional hazard model. AVR, aortic valve replacement; MR, mitral regurgitation.

Table 4. Clinical Outcomes in the Initial AVR and Conservative Treatment Strata According to Significance of MR

Clinical outcomes	Initial AVR stratum					Conservative stratum
	Moderate/severe MR N of patients with event (Cumulative 5-year incidence) (n=227)	No/mild MR N of patients with event (Cumulative 5-year incidence) (n=970)	P value (log-rank)	Adjusted HR (95% CI)	P value	Moderate/severe MR N of patients with event (Cumulative 5-year incidence) (n=536)	No/mild MR N of patients with event (Cumulative 5-year incidence) (n=2,082)	P value (log-rank)	Adjusted HR (95% CI)	P value
Aortic valve-related death or HF hospitalization	47 (25.2%)	118 (14.4%)	<0.001	1.11 (0.67–1.83)	0.69	257 (63.3%)	650 (40.7%)	<0.001	1.13 (0.93–1.37)	0.22
Aortic valve-related death	22 (10.5%)	46 (5.1%)	0.002	1.14 (0.53–2.48)	0.74	176 (47.4%)	365 (23.6%)	<0.001	1.46 (1.13–1.88)	0.004
HF hospitalization	27 (17.6%)	75 (10.1%)	0.03	1.15 (0.60–2.23)	0.67	209 (58.6%)	501 (33.7%)	<0.001	1.16 (0.93–1.44)	0.18
All-cause death	58 (31.4%)	178 (21.1%)	0.01	0.884 (0.57–1.36)	0.58	338 (69.6%)	875 (47.2%)	<0.001	1.27 (1.07–1.50)	0.006
Cardiovascular death	45 (24.7%)	106 (12.7%)	<0.001	1.07 (0.62–1.83)	0.81	248 (58.2%)	553 (33.1%)	<0.001	1.38 (1.12–1.70)	0.002
Sudden death	10 (6.2%)	17 (2.8%)	0.02			41 (12.0%)	128 (8.5%)	0.01	1.22 (0.75–1.98)	0.42
Noncardiovascular death	13 (8.9%)	72 (9.6%)	0.43	0.50 (0.22–1.13)	0.096	90 (27.1%)	322 (21.0%)	0.008	1.02 (0.75–1.38)	0.91

N of patients with event was counted through the entire follow-up period. HR, hazard ratio. Other abbreviations as in Tables 1,2.

Among 227 patients with moderate/severe MR in the initial AVR group, 215 actually underwent SAVR and of them, mitral valve surgery was simultaneously performed in 82 patients (mitral valve replacement: 35 patients; mitral annuloplasty: 28 patients; mitral valve plasty: 17 patients; annuloplasty with mitral valve plasty: 2 patients). Patient who underwent a mitral valve procedure had severe MR more frequently than those who did not (28.0% vs. 7.5%, P<0.001). The 30-day mortality rate was numerically higher in patients with SAVR and concomitant mitral valve surgery than in those without a concomitant mitral valve procedure (2.4% [n=2/82] vs. 0% [n=0/133], P=0.28). Postoperative echocardiography showed that MR improved in all patients who underwent mitral valve surgery, whereas residual moderate/severe MR was present in 22% of patients without a concomitant mitral valve procedure (Table 5). The cumulative 5-year incidence of the primary outcome measure was not significantly different between the 2 groups of patients who underwent SAVR with and without mitral valve surgery (21.6% vs. 22.9%, P=0.86) (Supplementary Table 2).

Table 5. Baseline Characteristics, Echocardiographic Findings and Procedural Details, Postoperative Echocardiographic Findings and 30-Day Mortality After AVR in the Initial AVR Stratum According to Concomitant Mitral Valve Surgery

Variables	Patients with moderate/severe MR in the initial AVR stratum (n=215)		P value
	Mitral valve surgery (n=82)	No mitral valve surgery (n=133)
Clinical characteristics
Age, years, mean±SD	72.9±8.1	75.9±7.2	0.005
Age ≥80 years, n (%)	17 (20.7)	48 (36.1)	0.03
Men, n (%)	36 (43.9)	52 (39.1)	0.58
BMI <22 kg/m2, n (%)	55 (67.1)	76 (57.1)	0.19
Hypertension, n (%)	51 (62.2)	82 (61.7)	1
Dyslipidemia, n (%)	30 (36.6)	41 (30.8)	0.47
On statin therapy, n (%)	20 (24.4)	29 (21.8)	0.79
Diabetes, n (%)	17 (20.7)	22 (16.5)	0.55
On insulin therapy, n (%)	5 (6.1)	4 (3.0)	0.45
Smoking history, n (%)	20 (24.4)	29 (21.8)	0.79
Current smoking, n (%)	5 (6.1)	6 (4.5)	0.85
Prior MI, n (%)	7 (8.5)	5 (3.8)	0.24
Prior open heart surgery, n (%)	3 (3.7)	4 (3.0)	1
History of HF, n (%)	20 (24.4)	15 (11.3)	0.02
Prior symptomatic stroke, n (%)	10 (12.2)	12 (9.0)	0.61
Atrial fibrillation or flutter, n (%)	33 (40.2)	33 (24.8)	0.03
Aortic/PVD, n (%)	5 (6.1)	15 (11.3)	0.30
Serum creatinine, mg/dL, median [IQR]	0.96 [0.71, 1.23]	0.98 [0.80, 1.48]	0.55
Serum creatinine level >0.83 mg/dL, n (%)	50 (61.0)	84 (63.2)	0.86
Hemodialysis, n (%)	12 (14.6)	24 (18.0)	0.64
Anemia,† n (%)	48 (58.5)	83 (62.4)	0.67
Liver cirrhosis (Child-Pugh B/C), n (%)	1 (1.2)	1 (0.8)	1
Malignancy	5 (6.1)	19 (14.3)	0.10
Malignancy currently under treatment	0 (0.0)	7 (5.3)	0.09
Chronic lung disease	13 (15.9)	18 (13.5)	0.78
Chronic lung disease (moderate or severe), n (%)	2 (2.4)	2 (1.5)	1
STS score (PROM), median [IQR]	3.18 [2.10, 5.76]	3.83 [2.22, 6.38]	0.51
Any symptoms at index echocardiography, n (%)	72 (87.8)	117 (88.0)	1
HF symptoms at index echocardiography, n (%)	66 (80.5)	94 (70.7)	0.15
NYHA functional class, n (%)			0.28
II	34 (51.5)	38 (40.4)
III	22 (33.3)	30 (31.9)
IV	9 (13.6)	24 (25.5)
Unknown	1 (1.5)	2 (2.1)
Echocardiographic findings
Vmax, m/s mean±SD	4.5±1.0	4.8±0.9	0.02
Vmax ≥4.0 m/s, n (%)	56 (68.3)	109 (82.0)	0.03
Peak aortic PG, mmHg mean±SD	84.0±36.7	94.9±36.8	0.04
AVA (equation of continuity), cm2 mean±SD	0.65±0.19	0.59±0.20	0.05
LV end-diastolic diameter, mm mean±SD	52.1±7.6	50.2±8.2	0.10
LV endsystolic dimeter, mm mean±SD	37.7±9.7	35.2±9.7	0.07
LVEF, % mean±SD	52.2±15.2	59.3±15.1	0.001
LVEF <40%, n (%)	21 (25.6)	15 (11.3)	0.01
MR severity, moderate/severe, n (%)	59 (72.0)/23 (28.0)	123 (92.5)/10 (7.5)	<0.001
Any combined moderate or severe valvular disease other than MR, n (%)	54 (65.9)	84 (63.2)	0.80
AR, n (%)	32 (39.0)	61 (45.9)	0.40
MS, n (%)	15 (18.3)	3 (2.3)	<0.001
TR, n (%)	34 (41.5)	44 (33.1)	0.27
TR pressure gradient ≥40 mmHg, n (%)	43 (52.4)	43 (32.3)	0.005
Details of surgery
MVR, n (%)	35 (42.7)	0 (0.0)	<0.001
MVP or annuloplasty, n (%)	47 (57.3)	0 (0.0)	<0.001
MVP	19 (23.2)	0 (0.0)	<0.001
Annuloplasty	30 (36.6)	0 (0.0)	<0.001
Bioprosthetic valve, n (%)	58 (70.7)	102 (76.7)	0.42
Mechanical prosthetic valve, n (%)	24 (29.3)	30 (22.6)	0.35
Tricuspid valve surgery, n (%)	32 (39.0)	9 (6.8)	<0.001
CABG, n (%)	19 (23.2)	43 (32.3)	0.20
MAZE operation, n (%)	18 (22.0)	9 (6.8)	0.002
Perioperative IABP use, n (%)	8 (9.8)	3 (2.3)	0.04
Postoperative echocardiography	n=77	n=121
Echocardiographic assessment timing after surgery, days median (IQR)	14 (8–43)	14 (9–355)	0.25
MR measurement, n (%)	62/77 (80.5)	115/121 (95.0)
MR moderate-severe after index AVR (%)	1/62 (1.6)	25/115 (21.7)	<0.001
MR change after index AVR (%)			<0.001
Improved	62/62 (100)	93/115 (80.8)
No change or worsened	0/62 (0)	22/115 (19.1)
30-day mortality after AVR, n (%)	2 (2.4)	0 (0.0)	0.28

^†Defined by the World Health Organization criteria (hemoglobin <12.0 g/dL in women and <13.0 g/dL in men). CABG, coronary artery bypass grafting; IABP, intra-aortic balloon pumping; MVR, mitral valve replacement; MVP, mitral valve plasty. Other abbreviations as in Table 1.

Clinical Outcomes in the Conservative Strategy: Moderate/Severe MR vs. No/Mild MR

Among 2,618 patients in the conservative management group, 569 patients (69 [13%] of 536 patients in the moderate/severe MR group and 500 [24%] of 2,082 patients in the no/mild MR group) underwent SAVR (540 patients) or TAVR (29 patients) during the follow-up period. Among these 2618 patients, the crude cumulative 5-year incidence of the primary outcome measure was significantly higher in the moderate/severe MR group than in the no/mild MR group (63.3% vs. 40.7%, P<0.001) (Figure 2). However, after adjusting confounders, moderate/severe MR on index echocardiography was no longer independently associated with excess risk for the primary outcome measure (HR 1.13, 95% CI 0.93–1.37, P=0.22). The adjusted excess risk of moderate/severe MR relative to no/mild MR remained significant for aortic valve-related death, cardiovascular death and all-cause death (Table 4).

We also conducted a sensitivity analysis to reduce the therapeutic bias of the conservative management stratum. We assessed the excessive risk of concomitant MR in the population who censored at the time of undergoing AVR. In this analysis, moderate/severe MR did not show excess risk of the primary outcome measure (cumulative 5-year incidence 69.9% vs. 47.3%, adjusted HR 1.18, 95% CI 0.96–1.44, P=0.11).

Discussion

The main findings of this study evaluating the clinical features and outcomes of severe AS patients with concomitant MR were as follows. (1) The clinical factors associated with moderate/severe MR by multivariable logistic regression analysis included age, low body mass index, prior myocardial infarction, history of HF, history of atrial fibrillation, hemodialysis, and anemia. (2) Concomitant moderate/severe MR was not independently associated with higher risk for the composite endpoint of HF hospitalization and aortic valve-related death regardless of the initial treatment strategy. (3) Among patients with initial AVR strategy, MR improved in all patients who underwent mitral valve surgery, but residual moderate/severe MR was present in 22% of patients who underwent isolated SAVR. However, long-term clinical outcomes were not significantly different between the 2 groups of patients who underwent AVR with and without mitral valve surgery.

The incidence of moderate/severe MR (20%) in our cohort was consistent with previous studies reporting an incidence of 13–33% in patients undergoing SAVR or TAVR.^2,3,6 The clinical factors associated with moderate/severe MR by univariate analysis included age, low body mass index, prior myocardial infarction, history of HF, history of atrial fibrillation and renal impairment, which was consistent with our multivariable logistic regression results. Regarding the echocardiographic findings, impaired LV ejection fraction, combined aortic regurgitation, combined TR and higher TR pressure gradient were associated with concomitant moderate/severe MR, in line with the previous reports,^16,17 suggesting that the major etiology of concomitant MR was functional.

In the subanalysis of the PARTNER trial, moderate or severe MR coexisted in about 20% of symptomatic severe AS patients. Baseline moderate/severe MR significantly affected mortality at 2 years (HR 1.96, 95% CI 1.26–3.06; P<0.01) in the SAVR population, but baseline moderate/severe MR did not affect mortality at 2 years (HR 1.14, 95% CI 0.72–1.78, P=0.58) in the TAVR population.¹⁸ From another meta-analysis including 13 TAVR population studies, preoperative moderate or severe MR was associated with a worse survival rate after TAVR.⁹ In our study, preoperative moderate/severe MR was not independently associated with worse outcomes in the initial AVR population. In our cohort, 38% of significant MR patients in the initial AVR group underwent a concomitant mitral valve procedure. In contrast, only 5.8% of the PARTNER SAVR cohort underwent mitral valve surgery and residual moderate/severe MR was observed in 30% of that population. Consequently, these differences in therapeutic management might be one of the reasons for the difference between the 2 studies.

On the other hand, little is known about the natural history of severe AS complicated by moderate or severe MR. One retrospective cohort study that included 453 severe AS patients managed medically, reported that patients with concomitant significant (grade 3–4+) MR had worse prognosis, although the multivariate Cox-hazard model did not show a statistically significant difference in mortality.¹⁹ We did not find significant excess adjusted risk of moderate/severe MR relative to no/mild MR for the primary outcome measure (composite of aortic valve-related death or hospitalization for HF), suggesting that the worse crude outcomes in patients with moderate/severe MR were not related to the presence of MR per se, but were related to comorbidities associated with MR. The cumulative 5-year incidence of aortic valve-related death was as high as 47% in patients with concomitant moderate/severe MR.

As suggested in the new staging classification of AS, the stage of cardiac damage with extra-aortic valvular conditions strongly affects all-cause death or cardiac death.²⁰ In this classification, left atrial or mitral valve extension of disease is classified as “Cardiac damage stage 2”. A retrospective study showed that cardiac damage stage greater than stage 1 was associated with a significantly higher risk for adverse events (stage 0 vs. stage 2: HR 1.456, 95% CI 1.002–2.118, P=0.049) in symptomatic severe AS.²¹ Another study reported that cardiac damage stage greater than stage 1 was associated with higher risk for all-cause death (stage 0 vs. stage 2: HR 2.27, 95% CI 1.25–4.12, P=0.007) or for cardiovascular death (stage 0 vs. stage 3–4: HR 5.24, 95% CI 1.79–15.4, P=0.003) in asymptomatic patients with severe AS.²² The association of moderate/severe MR and aortic valve-related death or all-cause death in the present study seems to be in line with this new staging classification of AS severity.

The clinical benefit of routine intervention for the mitral valve at the time of SAVR is still controversial. The operative mortality of combined aortic and mitral valve surgery is about twice as high compared with isolated SAVR.²³ Therefore, careful consideration is important for the indications of concomitant mitral valve surgery. A meta-analysis including 17 studies reported that moderate/severe concomitant MR remaining after SAVR affected survival after surgery, but in about 60% of patients who underwent SAVR, untreated concomitant MR improved after isolated SAVR.²⁴ In this setting, residual significant MR might negatively affect patient outcomes. In our study, a relatively high proportion (80%) of patients in whom moderate/severe MR was left untreated had none–mild MR after SAVR without a mitral valve procedure. However, the surgeons in our study decided to perform mitral valve surgery for selected younger patients who had worse cardiac conditions. In addition, there was a relatively higher proportion of moderate MR cases in the moderate/severe MR group (72% in concomitant mitral valve surgery group and 92.5% in no mitral valve surgery group) in our study population. This might be one of the reasons why concomitant mitral valve surgery apparently did not show a significant impact on patients’ outcomes. In general, imaging assessment of the etiology of MR (primary or secondary), the hemodynamic effect of MR, and the patient’s and surgical risks are thought to be important factors in deciding the indication of mitral valve surgery.²⁵ To determine the indication of concomitant mitral valve surgery, the possibility of MR improvement after SAVR is important. In patients undergoing SAVR, degenerative severe MR, preserved LV function, presence of atrial fibrillation, and/or pulmonary hypertension also might be important determinants for concomitant mitral surgery.²⁶ The current study results might have implications for the indications of mitral valve surgery at time of SAVR in patients with severe AS and concomitant MR. This subgroup analysis included a small number of patients, and thus we could not make adjusted comparison between those with and without MV surgery. Moreover, patients who underwent MV surgery had more severe MR than those who did not undergo MV surgery, and the decision to perform MV surgery was left to the experienced cardiovascular surgeon. Therefore, we could not deny serious selection bias in the comparison of outcomes between those with and without MV surgery. Concomitant mitral valve surgery might be beneficial in a specific population that is still to be debated.

Study Limitations

First, due to the retrospective observational nature of this study, selection bias might have affected the choice of initial treatment strategy. Also, there were no formal criteria for surgical intervention for severe AS and concomitant MR, which was left to the discretion of the surgeons. Second, echocardiographic data were site reported, and we did not have a core echocardiography laboratory. Therefore, we cannot deny the possibility of measurement error and variations in the echocardiographic measurement of MR severity. However, echocardiographic measurements were performed according to guidelines by experienced cardiologists and/or ultrasonographers at each participating center. Moreover, the etiology of concomitant MR was not assessed in the present study. Third, serial echocardiographic data after the index assessment were not fully available, so changes in MR severity during the follow-up period were not considered in this study.

Conclusions

Concomitant moderate/severe MR was not independently associated with higher risk for a composite endpoint of HF hospitalization and aortic valve-related death regardless of the initial treatment strategy.

Disclosures

T. Kimura and S. Miyazaki are members of Circulation Journal’s Editorial Team. The other authors declare no related conflicts of interest.

Sources of Funding

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

IRB Information

This study was approved by the Ethics Committee, Kyoto University, Kyoto, Japan. ID: E1916.

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0054

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