Two-Year Clinical Outcome of MitraClip Transcatheter Edge-to-Edge Repair From the J-MITRA Registry Data

Abstract

Background: The introduction of transcatheter edge-to-edge repair for moderate-to-severe or severe mitral regurgitation (MR) utilizing the MitraClip system became reimbursed and clinically accessible in Japan in April 2018. This study presents the 2-year clinical outcomes of all consecutively treated patients who underwent MitraClip implantation in Japan and were prospectively enrolled in the Japanese Circulation Society-oriented J-MITRA registry.

Methods and Results: Analysis encompassed 2,739 consecutive patients enrolled in the J-MITRA registry with informed consent (mean age: 78.3±9.6 years, 1,550 males, STS risk score 11.7±8.9), comprising 1,999 cases of functional MR, 644 of degenerative MR and 96 in a mixed group (DMR and FMR). The acute procedure success rate was 88.9%. After MitraClip implantation, >80% exhibited an MR grade ≤2+ and the trend was sustained over the 2 years. Within this observation period, the mortality rate was 19.3% and the rate of heart failure readmissions was 20.6%. The primary composite endpoint, inclusive of cardiovascular death and heart failure readmission, was significantly higher in patients with functional MR than in with degenerative MR (32.0% vs. 17.5%, P<0.001).

Conclusions: The 2-year clinical outcomes after MitraClip implantation were deduced from comprehensive data within an all-Japan registry.

Advanced mitral regurgitation (MR), resulting from mitral valve degeneration (degenerative MR [DMR]) or cardiac remodeling (functional MR [FMR]), refractory to guideline-directed medical therapy, is an indication for valvular intervention.^1,2 Nonetheless, surgical intervention can be challenging in cases of advanced heart failure (HF) and/or multiple comorbidities. As a minimally invasive valvular intervention option, particularly for cohorts at high surgical risk,³ transcatheter edge-to-edge mitral valve repair using the MitraClip system (Abbott Vascular, Santa Clara, CA, USA) was developed and introduced clinically over the past decade.⁴

The initial clinical application of MitraClip implantation dates back to 2003, with the system receiving CE mark approval in 2008.⁵ Subsequently, the MitraClip system garnered approval from the US Food and Drug Administration for DMR in 2013, extending to FMR in 2019. In Japan, following the acceptable results of the AVJ-514 trial,⁶ reimbursement for the 2nd-generation MitraClip NT system was granted for both DMR and FMR in 2018.⁷

Although numerous large-scale registry studies and randomized controlled trials from the USA and Europe have highlighted acceptable clinical outcomes post-MitraClip implantation,^8–11 few studies have been conducted in the Asia-Pacific region.¹² Asian patients present relatively unique clinical profiles, such as smaller physical characteristics, potentially challenging the direct applicability of findings from Western cohorts and vice versa.

In Japan, apart from the limited-scale AVJ-514 trial,⁶ moderate-size registry studies have reported 1-year clinical outcomes following MitraClip implantation,^13,14 leaving the longer-term and broader clinical trajectory uncertain. The Japanese Circulation Society commenced prospective enrollment of all consecutively treated patients who underwent MitraClip implantation upon its reimbursement in April 2018, documented within the J-MITRA registry. In this study, we report the 2-year clinical outcomes after MitraClip implantation using data from the comprehensive all-Japan J-MITRA registry.

Methods

Data Source

We used the J-MITRA registry database to study the 2-year outcomes in patients with HF who underwent MitraClip in Japan. The J-MITRA registry is a prospective nationwide multicenter registry performed by the Japanese Circulation Society in collaboration with the National Cerebral and Cardiovascular Center since April 2018, when MitraClip was reimbursed in Japan. Participation in J-MITRA is mandatory for MitraClip facilities accredited by the Japanese Circulation Society, and all consecutive patients receiving MitraClip implantation in Japan have been registered. Patients included in post-marketing use surveillance from October 2017 to May 2018 have been also included.¹⁵

Study Design and Patient Selection

We conducted a retrospective analysis using the prospectively constructed J-MITRA database. All registered patients with MitraClip implantation in Japan from April 2018 to December 2020 were identified and confirmed for the 2-year follow-up in April 2023 (Figure 1). The study was conducted in accordance with the Declaration of Helsinki, and approved by the review board of the Japanese Circulation Society, together with the institutional review boards of all participating institutions. All participants provided informed consent and were free to withdraw their participation at any time.

Figure 1.

Study flowchart. DMR, degenerative mitral regurgitation (MR); FMR, functional MR; HF, heart failure; J-MITRA, Japanese-MitraClip Registry.

Study Outcomes

We examined the patients’ characteristics, their detailed treatment, and clinical outcomes during the 2 years. The study’s primary outcome was a composite of cardiovascular death and first HF hospitalization after MitraClip implantation. Other outcomes such as all-cause death and the total number of HF hospitalizations were assessed during the 2-year observation period.

The progression of New York Heart Association (NYHA) functional class and MR grade were assessed. Acute procedural success was defined as successful device implantation with resulting MR ≤2+ at discharge. Adverse events, including single leaflet device attachment and leaflet damage/injury, through the 2 years were based on site reporting.

Statistical Analysis

Data are expressed as mean±standard deviation for continuous variables and number (%) for categorical variables after confirmation of their distribution. With the primary outcome of a composite of the first occurrence of cardiovascular death or HF hospitalization, the univariable and multivariable survival models with competing risk of noncardiovascular death were conducted with adjustment of significant variables from the univariable analysis and age/sex as forced variables in the model. Kaplan-Meier analysis was performed with the composite outcome, cardiovascular death, and HF hospitalization. Cumulative HF hospitalizations were counted and the annualized rate of all hospitalizations for HF within the 2 years was calculated. Hazard ratios (HR) and 2-sided 95% confidence intervals (CI) were calculated. All statistical analyses were performed with STATA18 (College Station, TX, USA).

Results

Study Flowchart

A total of 2,793 patients who underwent MitraClip implantation in Japan between April 2018 and December 2020 were identified (Figure 1) and of them, 54 were excluded for not giving consent. Subsequently, 2,739 eligible patients were enrolled, comprising 644 in the DMR group, 1999 in the FMR group, and 96 in the mixed group (DMR and FMR).

Baseline Characteristics (Table 1)

Table 1.

Baseline Clinical Characteristics of the Patients With Mitral Regurgitation

	Total	DMR group	FMR group	P value
n	2,739	644	1,999
Age, years	78.3±9.6	82.6±8.3	76.8±9.5	<0.001
Male sex	1,550 (56.6)	289 (44.9)	1,204 (60.2)	<0.001
Body mass index, kg/m2	21.2±3.4	20.9±3.6	21.2±3.4	0.055
Hypertension	1,542 (56.3)	392 (60.9)	1,091 (54.6)	0.018
Diabetes	796 (29.1)	94 (14.6)	682 (34.1)	<0.001
Previous myocardial infarction	733 (26.8)	50 (7.8)	659 (33.0)	<0.001
Previous PCI	834 (30.4)	93 (14.4)	717 (35.9)	<0.001
Previous cardiac surgeries	425 (15.5)	69 (10.7)	336 (16.8)	<0.001
Previous stroke or transient ischemic attack	444 (17.0)	94 (14.6)	334 (16.7)	0.22
Peripheral vascular disease	260 (9.5)	40 (6.2)	212 (10.6)	0.004
Chronic pulmonary disease	433 (15.8)	105 (16.3)	305 (15.3)	0.74
History of atrial fibrillation	1,689 (61.7)	370 (57.5)	1,244 (62.2)	<0.001
Renal failure	1,315 (48.0)	226 (35.1)	1,040 (52.0)	<0.001
eGFR
Mean, mL/min/1.73 m2	38.9±19.5	44.2±18.4	37.2±19.6	<0.001
≤60 mL/min/1.73 m2	2,390 (87.3)	534 (82.9)	1,774 (88.7)	<0.001
STS risk score
Mean	11.7±8.9	10.4±7.6	12.0±9.0	0.001
≥8%	1,678 (61.3)	386 (59.9)	1,227 (61.4)	0.51
NYHA functional class
III/IV	1,374/357 (64.3)	306/47 (54.8)	1,020/326 (67.3)	<0.001
Etiology of cardiomyopathy
Ischemic	761 (27.8)	–	739 (37.0)
Nonischemic	1,334 (48.7)	–	1,260 (63.0)
Hospitalization for HF within previous 1 year	2,021 (73.8)	396 (61.5)	1,551 (77.6)	<0.001
Previous cardiac resynchronization therapy	374 (13.7)	8 (1.2)	358 (17.9)	<0.001
BNP level, pg/mL	606.8±803.5	308.2±346.1	700.2±870.8	<0.001
N-terminal pro-BNP level, pg/mL	6,341.0±18,128.9	2,808.1±4,526.0	7,343.8±20,323.6	0.001
β-blockers	2,033 (74.2)	351 (54.5)	1,612 (80.6)	<0.001
ACE inhibitors or ARBs	1,652 (60.3)	368 (57.1)	1,224 (61.2)	0.065
MRAs	1,307 (47.7)	230 (35.7)	1,035 (51.8)	<0.001
Diuretic agents	2,391 (87.3)	517 (80.3)	1,787 (89.4)	<0.001
Severity of MR
Grade 3+	888 (32.4)	113 (17.5)	744 (37.2)	<0.001
Grade 4+	1,735 (63.3)	522 (81.1)	1,150 (57.5)
Effective regurgitant orifice area, cm2	0.40±0.24	0.51±0.24	0.36±0.23	<0.001
LV end-systolic dimension, cm	44.8±13.3	32.6±7.4	49.0±12.4	<0.001
LV end-diastolic dimension, cm	57.5±10.3	50.4±7.6	59.9±10.0	<0.001
LV end-systolic volume, mL	91.5±62.7	43.9±25.6	107.7±63.5	<0.001
LV end-diastolic volume, mL	152.2±71.7	111.7±41.5	166.5±74.4	<0.001
LVEF
Mean, %	45.2±16.1	62.7±9.8	39.2±13.4	<0.001
≤40%	1,302 (47.5)	24 (3.7)	1,255 (62.8)	<0.001
Tricuspid regurgitation
Grade 3+/4+	744/222 (35.3)	179/49 (35.4)	532/164 (34.8)	0.79

Data are n (%) or mean±standard deviation. P values are between DMR and FMR groups. ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor antagonist; BNP, B-type natriuretic peptide; DMR, degenerative mitral regurgitation (MR); eGFR, estimated glomerular filtration rate; FMR, functional MR; HF, heart failure; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid-receptor antagonist; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; STS, Society of Thoracic Surgeons.

Mean age was 78.3±9.6 years, with 1,550 males (56.6%). The STS risk score averaged 11.7±8.9%, and 1,678 patients (61.3%) had a score ≥8%. Roughly two-thirds of patients (64.3%) presented with NYHA functional class III–IV. Within the preceding year, 2,021 individuals (73.8%) had been admitted for HF. Notably, 888 patients (32.4%) were classified as grade 3 MR, and 1,735 (63.3%) had grade 4 MR. The mean effective regurgitant orifice area measured 0.40±0.24 cm², the mean left ventricular ejection fraction (LVEF) was 45.2±16.1%, and the mean LV end-diastolic dimension was 57.5±10.3 mm.

Comparison of Baseline Characteristics of DMR and FMR Patients

Of the total cohort, 644 patients were classified as having DMR, and 1,999 presented with FMR. Distinct differences in several baseline characteristics were observed between groups (Table 1). Specifically, the FMR group were younger (P<0.001) and there was a greater prevalence of NYHA class III–IV (P<0.001). MR severity was less in the FMR group than in the DMR group (P<0.001).

Clinical Outcomes

Throughout the 2-year observation period, the incidence of the primary outcome was 28.8% within the total cohort (Figure 2A). Significantly, the cumulative incidence of the primary outcome was higher in the FMR group compared with the DMR group (32.0% vs. 17.5%, P<0.001; Figure 2B).

Figure 2.

Kaplan-Meier curves for the clinical outcomes. Cumulative incidence of cardiovascular death or HF hospitalization (A,B) and the total number of HF hospitalizations (C,D) in the total (A,C) and DMR/FMR groups (B,D). DMR, degenerative mitral regurgitation (MR); FMR, functional MR; HF, heart failure.

The procedural outcomes are detailed in Table 2. Acute procedural success (APS) was achieved in 2,434 patients (88.9%). Among those who survived over 30 days (265 non-APS patients vs. 2,416 APS patients), the STS score was higher and valvular disease was more advanced in patients with non-APS (P<0.05). The device implantation time was longer and the incidences of single leaflet device attachment, leaflet injury, and iatrogenic atrial septal defect requiring intervention were higher in patients with non-APS.

Table 2.

Procedural and Clinical Outcomes at 2 Years

	Total	DMR group	FMR group	P value
Procedural outcome
APS	2,434 (88.9)	565 (87.7)	1,782 (89.1)	0.32
Device implantation time, min	84.5±50.0	85.3±48.6	83.9±50.3	0.59
SLDA
~Discharge	31 (1.1)	5 (0.8)	24 (1.2)	0.37
~30 days	18 (0.7)	3 (0.5)	14 (0.7)	0.53
~1 year	6 (0.2)	2 (0.3)	4 (0.2)	0.61
~2 years	3 (0.1)	0 (0)	3 (0.2)	0.32
Leaflet injury	22 (0.8)	5 (0.8)	16 (0.8)	0.95
Iatrogenic atrial septal defect requiring intervention	20 (0.7)	3 (0.5)	15 (0.8)	0.45
2-year clinical outcome
All-cause death	529 (19.3)	94 (14.6)	415 (20.8)	<0.001
CV death	315 (11.5)	50 (7.8)	256 (12.8)	0.001
Non-CV death	214 (7.8)	44 (6.8)	159 (8.0)
HF hospitalization	564 (20.6)	75 (11.6)	464 (23.2)	<0.001
Stroke or transient ischemic attack	42 (1.5)	9 (1.4)	32 (1.6)	0.72
Myocardial infarction	9 (0.3)	3 (0.5)	6 (0.3)	0.53
Revascularization (PCI or CABG)	4 (0.1)	1 (0.2)	2 (0.1)	0.72
Unplanned mitral valve intervention (MitraClip implantation or mitral valve surgery)	84 (3.1)	22 (3.4)	60 (3.0)	0.60

Data are n (%) or mean±standard deviation. P values are between DMR and FMR groups. APS, acute procedural success; CABG, coronary artery bypass grafting; CV, cardiovascular; SLDA, single leaflet device attachment. Other abbreviations as in Table 1.

The mean procedural duration was 84.5±50.0 min and overall procedure-related complications remained notably low. Instances of single leaflet device attachment were recorded in <1% of cases throughout the 2-year observation period. Leaflet injury was noted in 22 patients (0.8%), and iatrogenic atrial septal defect necessitating intervention occurred in 20 patients (0.7%). No statistically significant differences were observed in procedural outcomes between the 2 groups.

The 2-year clinical outcomes are summarized in Table 2. The all-cause mortality rate was 19.3%, with a cardiovascular mortality rate of 11.5%. The rate of HF hospitalizations reached 20.6%. Incidence of other cardiovascular outcomes remained relatively low (<5% for all).

The cumulative total count of HF hospitalizations amounted to 850 within the entire cohort (Figure 2C). The annualized rate of total count of HF hospitalizations was significantly greater in the FMR group than in the DMR group (23.2% vs. 9.0%, P<0.001; Figure 2D).

The cumulative incidence of all-cause death was significantly different between groups (22.1% vs. 15.6%, P<0.001; Figure 3A,B), and HF hospitalization incidence was notably higher in the FMR group compared with the DMR group (26.5% vs. 13.3%, P<0.001; Figure 3C,D).

Figure 3.

Kaplan-Meier curves for the clinical outcomes. Cumulative incidence of all-cause death (A,B) and HF hospitalization (C,D) in the total (A,C) and DMR/FMR groups (B,D). DMR, degenerative mitral regurgitation (MR); FMR, functional MR; HF, heart failure.

Progression of Functional Status and MR Severity

The baseline functional status predominantly reflected NYHA class III–IV among the majority of patients (Figure 4A). Following MitraClip implantation, a substantial shift towards NYHA functional class I–II was observed, maintaining this trend over the 2-year observational period, regardless of MR etiology (P=0.069 for class II and P=0.745 for class I in the DMR group; P=0.872 for class II and P=0.416 for class I in the FMR group).

Figure 4.

Changes in NYHA functional class (A) and MR grade (B) in the total cohort and DMR/FMR groups. DMR, degenerative mitral regurgitation (MR); FMR, functional MR; NYHA, New York Heart Association.

The trajectory of MR grade is depicted in Figure 4B. Initially, the majority of patients presented with grade 3 or 4 MR, and after MitraClip implantation, most patients exhibited an improvement to grade 1 or 2 MR, sustaining this trend over the 2-year observation period, irrespective of MR etiology (P=0.682 for MR2+ and P=0.148 for MR1+ in the DMR group; P=0.981 for MR2+ and P=0.602 for MR2+ in the FMR group).

Prognostic Effect of Baseline Characteristics

FMR had a significant prognostic effect on the 2-year primary outcome compared with DMR (HR 1.97, 95% CI: 1.59–2.43, P<0.001). Several other baseline characteristics also exhibited significance (P<0.05 for all; Table 3). The prognostic effect of FMR remained statistically significant even after adjusting for variables that showed significance in the univariable analyses (adjusted HR 1.43, 95% CI: 1.08–1.90, P=0.013; Table 3).

Table 3.

Predictors of 2-Year Composite Outcome (CV Death or HF Hospitalization)

	Univariable		Multivariable
	HR (95% CI)	P value	HR (95% CI)	P value
Age, years	1.01 (0.99, 1.02)	0.069	1.01 (1.00, 1.02)	0.011
Male sex	1.24 (1.06, 1.44)	0.006	1.21 (1.02, 1.42)	0.025
Body mass index, kg/m2	0.96 (0.94, 0.98)	<0.001	0.97 (0.95, 0.99)	0.027
eGFR, per 10 mL/min/1.73 m2	0.87 (0.83, 0.91)	<0.001	0.92 (0.88, 0.96)	<0.001
STS score	1.03 (1.02, 1.04)	<0.001	1.01 (1.00, 1.02)	0.006
Hypertension	0.89 (0.77, 1.03)	0.127
Diabetes	1.14 (0.98, 1.34)	0.096
Previous myocardial infarction	1.08 (0.92, 1.27)	0.319
Previous PCI	1.10 (0.94, 1.29)	0.221
Previous cardiac surgery	1.19 (0.98, 1.45)	0.079
Previous stroke or transient ischemic attack	1.00 (0.82, 1.23)	0.960
Peripheral vascular disease	1.38 (1.10, 1.73)	0.005	1.12 (0.89, 1.42)	0.339
Chronic pulmonary disease	1.18 (0.97, 1.43)	0.102
Atrial fibrillation	0.88 (0.69, 1.13)	0.316
Renal failure	1.39 (1.20, 1.61)	<0.001
Hospitalization for HF within previous 1 year	2.15 (1.76, 2.63)	<0.001	1.82 (1.46, 2.26)	<0.001
NYHA functional class III/IV	1.44 (1.23, 1.71)	<0.001	1.13 (0.95, 1.36)	0.167
Ischemic cardiomyopathy	0.87 (0.73, 1.02)	0.093
Baseline MR 4+	1.05 (0.90, 1.23)	0.505
LVEF, per 10%	0.85 (0.81, 0.89)	<0.001	0.90 (0.84, 0.97)	0.004
FMR	1.97 (1.59, 2.43)	<0.001	1.43 (1.08, 1.90)	0.013

CI, confidence interval; HR, hazard ratio. Other abbreviations as in Tables 1,2.

The prognostic effects of baseline characteristics were evaluated in each etiology group separately. In the DMR group (N=644), hospitalization for HF within the previous year and LVEF per 10% were independently associated with the primary endpoint (P<0.05 for both; Supplementary Table 1). In the FMR group (N=1,999), age, male sex, estimated glomerular filtration rate, STS score, hospitalization for HF within the past year, baseline severe MR, and LVEFR per 10% were independently associated with the primary endpoint (P<0.05 for all; Supplementary Table 2).

Subgroup Analysis of FMR Cohort Stratified by LVEF

Among the 1,999 patients with FMR, 457 had LVEF ≥50% and 1,538 had LVEF <50%. The 2-year cumulative incidence of the primary endpoint was not significantly stratified by LVEF (29.11% for ≥50% vs. 32.84% for <50%, P=0.133; Supplementary Figure). LVEF ≥50% was consistently not significantly associated with the primary endpoint with HR 0.84 (95% CI: 0.68–1.03, P=0.096) adjusted for age and sex.

Among the 1,538 patients with FMR and LVEF <50%, almost all patients (96.6%) received any HF medications at index discharge (Table 4). Major HF medications such as β-blockers, renin-angiotensin system inhibitors, and mineralocorticoid-receptor antagonists were associated with the primary endpoint (P<0.05 for all). The incremental number of HF medications was associated with a lower incidence of the primary endpoint with HR 0.75 (95% CI: 0.68–0.84, P<0.001). In contrast, incremental HF medications on admission was not significantly associated with the primary endpoint among the same cohort (P>0.05).

Table 4.

Prognostic Effect of HF Medications at Index Discharge Among Patients With FMR and LVEF <50%

	N	HR (95% CI)	P value
Any HF medications	1,486 (96.6%)	0.51 (0.26, 0.99)	0.047
Renin-angiotensin system inhibitor	999 (65.0%)	0.74 (0.62, 0.90)	0.002
Mineralocorticoid-receptor antagonist	836 (54.4%)	0.78 (0.65, 0.94)	0.009
β-blocker	1,292 (84.0%)	0.56 (0.45, 0.69)	<0.001
SGLT2 inhibitor	33 (2.1%)	0.64 (0.30, 1.34)	0.236
Diuretic	1,357 (88.2%)	0.78 (0.59, 1.03)	0.08
Digoxin	72 (4.7%)	1.10 (0.72, 1.68)	0.648
No. of HF medications		0.75 (0.68, 0.84)	<0.001
0	87 (5.7%)	Ref.
1	303 (19.7%)	0.60 (0.40, 0.89)	0.011
2	599 (38.9%)	0.48 (0.33, 0.70)	<0.001
3	537 (34.9%)	0.38 (0.26, 0.56)	<0.001
4	12 (0.8%)	0.22 (0.06, 0.90)	0.035

Cox proportional HR regression analysis was performed for the 2-year composite endpoint. SGLT2, sodium-glucose co-transporter 2. Other abbreviations as in Tables 1,3.

Discussion

We present a comprehensive analysis of the 2-year clinical outcomes following percutaneous transcatheter edge-to-edge mitral valve repair using MitraClip across all Japanese institutions enrolled in the J-MITRA registry. To the best of our knowledge, there are 2 medium-sized studies regarding the MitraClip procedure in Japan: Japanese PMS study¹³ and OCEAN-Mitral registry.¹⁴ However, they reported only 1-year clinical outcomes after MitraClip procedure and furthermore, had a selection bias. In contrast, we used J-MITRA registry data, which included all consecutive MitraClip candidates in Japan based on the formal command from the Japanese Circulation Society to assess the feasibility of MitraClip procedure, and have reported longer clinical outcomes.

Between April 2018 and December 2020, 2,793 patients underwent MitraClip implantation in Japan and were enrolled in the J-MITRA registry: 75% had FMR and 25% had DMR. Notably, the FMR group demonstrated more advanced HF with a higher STS risk score, whereas the DMR group exhibited more severe MR grade.

The APS rate was 88.9%, with low rates of procedure-related complications. Following MitraClip implantation, improvements were observed in HF symptoms and MR grade, both of which persisted over the 2-year observation period regardless of MR etiology. Overall, the 2-year all-cause mortality rate reached 19.3%, with a cardiovascular mortality rate of 11.5%, and HF hospitalization rate of 20.6%. The incidence of the primary composite outcome, comprising cardiovascular death and HF hospitalization, was significantly higher in the FMR group compared with the DMR group, a trend that persisted even after adjusting for potential confounders.

The AVJ-514 trial⁶ conducted in Japan before commercial availability reported that both the APS rate and MR grade improvement were comparable to the Asian MARS registry.¹² In the present study, these acute feasibility outcomes remained similarly acceptable despite the inclusion of all MitraClip candidates as real-world data. Over the 2-year period, sustained MR improvement, low rates of single leaflet device attachment, and preserved freedom from HF symptoms were observed.

The 1-year mortality rates following MitraClip implantation have demonstrated variability across several significant studies. Early 2010 studies, such as the German TRAMI registry,⁸ TVT registry,⁹ and COAPT trial,¹⁰ reported approximately 20% mortality rates within the first year post-implantation. Notably, the EXPAND study,¹¹ incorporating the 3rd-generation NTR/XTR system implanted between 2018 and 2019, depicted a relatively improved 1-year mortality rate of 14.9%.

In alignment with these trends, the J-MITRA study presented a favorable 1-year mortality rate of 11.8%, reflecting comparability with results from other smaller-scale Japanese studies, including the Japan PMS¹³ and OCEAN¹⁴ studies, which reported rates of 14.9% and 12.3%, respectively. The J-MITRA study revealed a lower 2-year mortality rate of 19.3% compared with the 29.1% rate observed in the COAPT trial.¹⁰

The 1-year incidence of HF hospitalization has also exhibited variability across different studies, ranging approximately between 20% and 30%.^9–11 This variability might stem from varying indications for HF admission among the studies. In the case of the J-MITRA study, the incidence was 13.9% at 1 year and 20.6% at 2 years, surpassing the previous Japan PMS study’s rates.¹³

Recent advancements in patient selection, an improved learning curve, and the implementation of HF medication strategies¹⁵ likely contributed to mitigating HF readmissions in this study. Notably, although the MitraClip indication was expanded from LVEF ≥30% to LVEF ≥20% in May 2020,¹⁶ resulting in the inclusion of sicker patients in the J-MITRA study, these strategies may have aided in preventing HF readmissions.

In concordance with various interventions including the MitraClip procedure,^17–20 numerous noncardiac factors (e.g., age, sarcopenia, and renal impairment) were identified as risk contributors for the primary outcome after MitraClip implantation in this study. The incidence of the primary outcome was notably higher in the FMR cohort than in the DMR cohort, which resonates with the ongoing discussion prompted by the COAPT trial vs. the MITRA-FR trial,²¹ both of which involved FMR cases. It poses a challenge to achieve favorable clinical outcomes solely through MitraClip intervention when the severity of HF surpasses the expectations dictated by the degree of MR. We would like to emphasize the importance of concomitant HF medications based on their favorable prognostic effect in this study.

Cardiac replacement therapies such as heart transplantation and durable LV assist devices are potential alternatives to MitraClip in cases of severely advanced HF and concomitant FMR. Notably, mechanical unloading through these therapies can potentially ameliorate FMR by facilitating reverse remodeling.²² However, heart transplantation might not be a feasible option for the majority of MitraClip candidates due to their advanced age. Similarly, durable LV assist devices might not be suitable for most MitraClip candidates, again owing to their multiple comorbidities and higher surgical risks.

Although surgical valvular intervention remains the primary approach for DMR, MitraClip is a favorable alternative, especially in cases where patients have an elevated surgical risk but have anatomical features suitable for the MitraClip procedure. Therefore, MitraClip is a viable option with promising clinical outcomes under specific circumstances, even in the context of DMR.²³

Study Limitations

We used data from the J-MITRA registry, encompassing all candidates for MitraClip therapy in Japan. However, due to the registry’s multi-institute nature, details of certain clinical parameters, such as right heart catheterization data, were not included. Additionally, the absence of medication dosages and prescription details, notably regarding SGLT2 inhibitors, which are recognized pivotal agents in HF management, limits a comprehensive understanding of the effect of medication on outcomes. Instead, we performed a subanalysis to evaluate the prognostic effect of the type and number of HF medications in patients with FMR and LVEF <50%, and confirmed the prognostic implication of multiple HF medications.

Another limitation pertains to the inclusion of atrial etiology within the FMR category. Discrepancies in clinical outcomes might exist between ventricular FMR and atrial FMR,²⁴ which were not differentiated in this study given the complexity of the diagnostic procedure. The etiology and severity of MR were site-reported and not assessed by a core laboratory. Instead, we performed a subanalysis to compare clinical outcomes between the FMR cohort with LVEF <50% and those with LVEF ≥50%, which did not reach statistical significance. Further studies are warranted to compare clinical outcomes between atrial FMR and ventricular FMR based on accurate diagnostic procedure.

Furthermore, the inability to perform a subanalysis for the MitraClip G4 system due to the small sample size since its introduction in September 2020 represents another constraint. The indication of the MitraClip procedure was expanded in May 2020 from those with LVEF ≥30% to those with LVEF ≥20%. Further studies with a robust database are warranted to validate the efficacy and feasibility of the MitraClip procedure in patients with extremely low LVEF.

Conclusions

The usefulness of assessing 2-year clinical outcomes following MitraClip implantation was evident in this study based on comprehensive data from an all-Japan registry. However, areas of future concern and exploration include evaluating the clinical outcomes associated with the new-generation MitraClip G4 system and examining the effect of the MitraClip procedure in patients with severely impaired cardiac function. These are crucial areas for further investigation and understanding within the realm of MitraClip interventions.

Acknowledgments / Conflicts of Interest

None.

Disclosure

K.K. received speakers’ bureau/honoraria from Otsuka Pharmaceutical, Daiichi Sankyo, Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., AstraZeneca Co., Nipro Medical Co., Abiomed Co., Abbott, Medtronic Japan Co., Ltd., Bayer’s Pharmaceuticals Co., Ltd., and Alnylam Pharmaceuticals Inc.; received manuscript fee from Otsuka Pharmaceutical; received advisory fees from Otsuka Pharmaceutical, Abiomed Co., Medtronic Japan Co., Novartis Pharma K.K., Boehringer Ingelheim Japan Co., Ltd., Abbott, and Bayer’s Pharmaceuticals Co., Ltd.; received research funds from Ono Pharmaceutical Co., Ltd., Kowa Co., Boehringer Ingelheim Japan Co., Ltd., Abbott, Boston Scientific Co., received scholarship donations from Otsuka Pharmaceutical Co., Ltd., Abbott, Japan Lifeline Co. K.Y. received speakers’ bureau/honoraria from Otsuka Pharmaceutical, Daiichi Sankyo, Novartis Pharma K.K.; and research funds from Abbott, Otsuka Pharmaceutical, Biotronik Japan, Japan Lifeline, Fukuda Denshi. T.A. received research grants from Daiichi Sankyo Co., Ltd. and Bristol-Myers Squibb Co., Ltd., scholarship funds from Biotronik Japan Co., Ltd., Medtronic Japan Co., Ltd., Terumo Co., Ltd, Win International Co., Ltd., Medical System Network Co., Ltd., and Hokuyaku Takeyama Holdings, Inc., and honoraria from Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan Co., Ltd., and Bayer’s Pharmaceuticals Co., Ltd. G.M. received research funds from Otsuka Pharmaceutical, Medtronic, Terumo, Century Medical. K. Hayashida, Y.M., Y. Seo, Y. Saiki, T.A., K.Y., K. Hirata, and K.K. are members of Circulation Journal’s Editorial Team.

IRB Information

The present study was approved by the Japanese Circulation Society (registration number 6, May 7 2019).

Appendix

J-MITRA Registry Investigators

Department of Cardiology, Keio University School of Medicine (Keiichi Fukuda); Department of Cardiology, Toyohashi Heart Center (Masanori Yamamoto); Department of Cardiology, Nagoya Heart Center (Yutaka Koyama); Division of Cardiology, Kokura Memorial Hospital (Kenji Ando); Department of Cardiology, Teikyo University School of Medicine (Ken Kozuma); Department of Cardiology, New Tokyo Hospital (Toru Naganuma); Department of Cardiology, Saiseikai Yokohama City Eastern Hospital (Yoshiaki Ito); Department of Cardiology, Sendai Kosei Hospital (Tatsushi Otomo); Department of Cardiology, Shonan Kamakura General Hospital (Shigeru Saito); Second Department of Internal Medicine, Toyama University Hospital (Koichiro Kinugawa); Department of Cardiology, Tokai University School of Medicine (Yuji Ikari); Division of Cardiology, Department of Internal Medicine, Iwate Medical University (Yoshifumi Nakajima); Division of Cardiology, St. Marianna University School of Medicine Hospital (Yoshihiro Akashi); Department of Cardiology, Sapporo Higashi Tokushukai Hospital (Seiji Yamazaki); Division of Cardiology, Saiseikai Kumamoto Hospital Cardiovascular Center (Tomohiro Sakamoto); Department of Cardiology Tokyo Woman’s Medical University (Nobuhisa Hagiwara); Department of Cardiology, Kurashiki Central Hospital (Kazushige Kadota); Department of Cardiology, National Cerebral and Cardiovascular Center (Chisato Izumi); Division of Cardiology, Mitsui Memorial Hospital (Kengo Tanabe); Department of Cardiology, Sakakibara Heart Institute (Itaru Takamizawa); Division of Cardiovascular Medicine, Hyogo Prefectural Himeji Cardiovascular Center (Yoshinori Yasaka); Department of Cardiology, Sakakibara Heart Institute of Okayama (Takao Morikawa); Division of Cardiology, Saitama Cardiovascular Respiratory Center (Takashi Miyamoto); Department of Cardiology, Kishiwada Tokushukai Hospital (Yoshiaki Yokoi); Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (Satoaki Matoba); Department of Cardiovascular Medicine, Osaka Metropolitan University Graduate School of Medicine (Daiju Fukuda); Department of Cardiovascular Medicine and Endocrinology and Metabolism, Tottori University (Kazuhiro Yamamoto); Division of Cardiology, Nephrology, Respiratory, and Neurology, Department of Internal Medicine, Asahikawa Medical University (Naoyuki Hasebe); Department of Cardiology, Tokushima Red Cross Hospital (Shinobu Hosokawa); Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine (Isamu Mizote, Yashushi Sakata); Department of Cardiology, Shizuoka General Hospital (Hiroki Sakamoto); Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University (Toshihisa Anzai); Department of Cardiology, Ehime Prefectural Central Hospital (Hideki Okayama); Department of Cardiology, Tokyo Bay Urayasu Ichikawa Medical Center (Kotaro Obunai); Department of Cardiology, Teine Keijinkai Hospital (Mitsugu Hirokami); Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine (Tetsuji Miura); Department of Cardiology, Sapporo Higashi Tokushukai Hospital, Sapporo (Seiji Yamazaki); Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine (Shinya Okazaki); Division of Cardiovascular Medicine, Toho University Ohashi Medical Center (Masato Nakamura); Department of Cardiovascular Medicine, Kitasato University School of Medicine (Junya Ako); Division of Cardiology, Yokohama City University Medical Center (Kazuo Kimura); Department of Cardiovascular Surgery, Chiba University Hospital (Goro Matsumiya); Department of Cardiology, Institute of Medicine, University of Tsukuba (Tomoya Hoshi); Department of Cardiovascular Medicine, Dokkyo Medical University (Teruo Inoue); Department of Cardiology, Dokkyo Medical University Saitama Medical Center (Isao Taguchi); Pediatric Cardiac Surgery, Saitama Medical University International Medical Center (Takaaki Suzuki); Department of Cardiology, Fujita Health University (Yukio Ozaki); Department of Cardiology, Gifu Prefectural General Medical Center (Toshiyuki Noda); Division of Cardiology, Osaka General Medical Center (Takahisa Yamada); Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine (Takeshi Kimura); Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital (Natsuhiko Ehara); Department of Cardiology, Hyogo Prefectural Amagasaki General Medical Center (Yukihito Sato); Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University (Yasuki Kihara); Division of Cardiology, Kochi Health Sciences Center (Yoshikazu Ohara); Department of Cardiovascular Surgery, Kyushu University Graduate School of Medicine (Akira Shiose); Department of Cardiology, Miyazaki Medical Association Hospital (Yoshisato Shibata); Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences (Tohru Minamino); Department of Cardiovascular Medicine, Sapporo Cardio Vascular Clinic (Daisuke Hachinohe); Department of Cardiovascular Surgery, Showa University Koto Toyosu Hospital (Hiroki Yamaguchi).

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0924

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