AVJ-514 Trial　― Baseline Characteristics and 30-Day Outcomes Following MitraClip^® Treatment in a Japanese Cohort ―

Abstract

Background: The MitraClip^® system is a transcatheter-based therapeutic option for patients with chronic mitral regurgitation (MR) who are at high risk for surgery. A prospective, multicenter, single-arm study was initiated to confirm the transferability of this system to Japan.

Methods and Results: Patients with symptomatic chronic moderate-to-severe (3+) or severe (4+) functional or degenerative MR with a Society of Thoracic Surgery (STS) score ≥8%, or the presence of 1 predefined risk factor were enrolled. Patients with left ventricular (LV) ejection fraction (EF) <30% were excluded. MR severity and LV function were assessed by an independent echocardiography core lab. Primary outcome included major adverse events (MAE) at 30 days and acute procedural success (APS). A total of 30 patients (age: 80±7 years; STS score: 10.3%±6.6%) were treated with the MitraClip^®. At baseline, all patients had MR 3+/4+ with 53%/47% patients with degenerative/functional etiology with mean LVEF of 50.2±12.8%, and 37% of patients were NYHA class III/IV. APS was achieved in 86.7% with no occurrence of MAE. At 30 days, 86.7% of patients had MR ≤2+ and 96.7% were NYHA class I/II.

Conclusions: The MitraClip^® procedure resulted in clinically meaningful improvements in MR severity, function and quality of life measures, and low MAE rates. These early results suggest the transferability of this therapy to appropriately selected Japanese patients. (Trial Registration: clinicaltrials.gov Identifier NCT02520310.)

Primary (or degenerative) mitral regurgitation (MR) is caused by a structural or degenerative abnormality of the mitral valve (MV) involving the leaflets, chordae tendineae, papillary muscles, or mitral annulus. Secondary MR, also referred to as functional MR, occurs in the absence of primary MV disease, usually from left ventricular (LV) dysfunction. Contrary to degenerative MR, functional MR is associated with a worse prognosis, and the benefits of conventional MV surgery are uncertain.^1,2

In functional MR, optimal medical therapy, cardiac resynchronization, or revascularization may decrease MR severity if reverse remodeling of the LV occurs. There is limited evidence that medical therapy directly decreases MR severity or improves clinical outcomes in degenerative MR. Degenerative MR is therefore more amenable to surgical therapy. However, many patients are not offered MV surgery because of their high surgical risk status.

A percutaneous MV repair device (overseas brand name MitraClip^®, Abbott Vascular, Santa Clara, CA, USA) has shown promise in reducing MR severity and improving clinical and functional outcomes and quality of life (QOL) in patients with severe MR.^3–5

The MitraClip^® device, which simulates the Alfieri technique,⁶ grasps and coapts the MV leaflets, resulting in fixed approximation of the leaflets throughout the cardiac cycle. This percutaneous procedure is performed without the need for either arresting the heart or cardiopulmonary bypass.

The MitraClip^® device is commercially available in 51 countries, and over 40,000 patients worldwide have undergone the procedure. This report presents evidence of the safety and effectiveness of the MitraClip^® technology in Japanese patients who had been deemed difficult for MV surgery by the local sites’ heart teams.

Methods

Trial Design

The AVJ-514 trial is a prospective, multicenter, single-arm study to confirm the reproducibility of the safety and efficacy of the MitraClip^® technology in Japanese patients. The study was approved by the Pharmaceuticals and Medical Devices Agency (Japan) and all of the participating local institutional review boards. All patients gave written informed consent to participate in the trial.

Investigators (operators) were selected based on being skilled in the manipulation of catheter-based technology in structural heart disease, and having an understanding of the risks associated with such manipulations. A total of 6 Japanese sites enrolled 30 patients, representing the first patients to be treated with the MitraClip^® device in Japan.

Patient Population

The study included 30 patients treated in the AVJ-514 trial at 6 Japanese sites enrolled from September 2015 to June 2016.

For inclusion in the trial, patients were selected by the multidisciplinary local heart team. Each local heart team consisted of an interventional cardiologist, a cardiothoracic surgeon, and an echocardiologist. Patients were screened to ensure they met all inclusion criteria and none of the exclusion criteria. Patients are also assessed by the cardiothoracic surgeon investigator to assess for surgical risk from either Society of Thoracic Surgery (STS) surgical death risk for MV replacement ≥8% or the presence of one of the predefined surgical risk factors. Echocardiographic evaluation, by transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), was also performed to determine patient suitability and eligibility for the procedure and trial, and was confirmed by an independent echo core lab (ECL) (University of California, San Francisco, CA, USA).

Patients who qualified for the trial had symptomatic chronic moderate-to-severe (3+) or severe (4+) degenerative MR (DMR) or functional MR (FMR), LVEF ≥30%, MV area ≥4.0 cm², LV endsystolic dimension (LVESD) ≤60 mm, and deemed difficult for MV surgery by the local site’s heart team. Some key exclusion criteria were: leaflet anatomy that precluded correct positioning of the device on the leaflets or sufficient MR reduction; life expectancy <1 year; presence of intracardiac mass, thrombus or vegetation; and/or active endocarditis. An Independent Eligibility Committee provided final confirmation of a patient’s inclusion in the trial.

MitraClip^® System

The MitraClip^® System was developed as a percutaneous technology to provide a treatment option for patients with significant MR. The MitraClip^® System received Conformité Européenne approval in 2008, United States Food and Drug Administration (USFDA) approval in 2013,⁷ and is approved and commercially available in over 40 countries. The MitraClip^® System has 2 parts: (1) the clip delivery system (CDS) and (2) the steerable guide catheter (SGC). The SGC is inserted into the femoral vein and advanced across the transseptal puncture and then the CDS is introduced into the body through the catheter. The CDS is used to advance and manipulate the implantable MitraClip^® device for correct positioning and placement on the MV leaflets. Fluoroscopic and echocardiographic guidance was used during the procedure to visualize the device and the vasculature and cardiac anatomy. The complete procedure has been previously described.^8–12

Study Endpoints

The trial primary safety endpoint was freedom from major adverse events (MAE) at 30-days post procedure. MAE was a composite of death, stroke, myocardial infarction (MI), renal failure, and non-elective cardiovascular surgery for device- or procedure-related AEs occurring after femoral vein puncture for transseptal access. The primary efficacy endpoint was acute procedural success (APS), and successful implantation of the MitraClip^® device with resulting MR severity ≤2+ as determined by the ECL at discharge. Patients who died or underwent MV surgery before discharge were considered an APS failure (non-APS).

The total procedure time was defined as the time elapsed from the start of the transseptal procedure to the time the SGC was removed. The device time was defined as the time the SGC was placed in the intra-atrial septum until the time the CDS was retracted into the SGC.

Additional prespecified secondary endpoints included New York Heart Association¹³ (NYHA) heart failure (HF) functional class (FC) and QOL scores using the Kansas City Cardiomyopathy Questionnaire (KCCQ).¹⁴ KCCQ is a disease-specific measure for patients with HF. It is a 23-item self-administered questionnaire that covers the following domains: physical limitation, total symptoms (symptom frequency and burden), symptom stability, self-efficacy (whether or not a patient thinks that they have the knowledge and skills to manage their HF as an outpatient), QOL, and social limitations. The KCCQ is scored from 0 to 100, with higher scores indicating less symptom burden and better QOL.

Statistical Analysis

Descriptive analysis was performed to summarize baseline characteristics, APS, and the clinical and safety event data. Continuous data are summarized as mean±standard deviation (SD). P-values comparing baseline to follow-up were performed for descriptive purposes. Paired t-test was used to evaluate change over time in continuous variables (e.g., KCCQ as a continuous variable), while the Bowker test was used to evaluate a positive shift in the distribution of paired ordinal data, including MR severity and NYHA functional classification. For comparison between subgroups of interest (e.g., FMR vs. DMR), 2-sample t-test was applied for continuous outcome and Fisher’s exact test was applied for binary outcome. All statistical analyses were performed using SAS for Windows version 9.2 (SAS Institute, Cary, NC, USA).

Results

Patients

A total of 30 patients were consecutively enrolled and treated at 6 Japanese sites. Table 1 presents the baseline demographics and comorbidities of the MR patients enrolled and treated in the AVJ-514 trial. The overall cohort was elderly (80.4±7.0 years) with 80.0% of patients aged over 75 years and 76.7% were male. All patients had either moderate-to-severe (3+, 80%) or severe (4+, 20%) MR of either functional (46.7%) or degenerative (53.3%) etiology. The comorbidity profile of the patients included hypertension (70.0%), renal disease (66.7%), anemia (60.0%), hypercholesterolemia (53.3%), coronary artery disease (40.0%), prior MI (26.7%), prior stroke (23.3%), angina (20.0%), myocardial ischemia (20.0%), and diabetes (20.0%). A total of 20% of the patients had had prior cardiac surgery and 26.7% patients had had a prior percutaneous coronary intervention. The NYHA FC profile showed the majority of patients were class II (63.3%) and the remaining patients (36.6%) were NYHA III/IV. Mean distance for the 6-min walk test (6MWT) was 349.4±118.4 m. Mean EuroScore II was 5.6±3.7% and mean STS risk of death for replacement was 10.3±6.6%.

Table 1. Baseline Demographics and Comorbidities of Patients in AVJ-514 Trial of MitraClip^®

Characteristic	AVJ-514 (n=30)
Age (years)
Mean±SD (N)	80.4±7.0 (30)
>75 years, % (n/N)	80.0 (24/30)
Sex, % (n/N)
Male	76.7 (23/30)
Female	23.3 (7/30)
Body size
Mean height (cm)	157.0±9.0 (30)
Mean weight (kg)	54.4±13.1 (30)
Body mass index (kg/m2)	21.8±3.8 (30)
Comorbidity, % (n/N)
CAD	40.0 (12/30)
Hypertension	70.0 (21/30)
Hypercholesterolemia	53.3 (16/30)
Angina	20.0 (6/30)
Endocarditis	0.0 (0/30)
Rheumatic heart disease	0.0 (0/30)
Severe symptomatic carotid stenosis	0.0 (0/30)
Prior TIA	3.3 (1/30)
Prior stroke	23.3 (7/30)
Prior MI	26.7 (8/30)
Myocardial ischemia	20.0 (6/30)
COPD	16.7 (5/30)
Diabetes	20.0 (6/30)
Peripheral vascular disease	16.7 (5/30)
Deep vein thrombosis	0.0 (0/30)
Renal disease	66.7 (20/30)
History of anemia	60.0 (18/30)
History of major bleeds or bleeding disorder	3.3 (1/30)
Coagulopathy	0.0 (0/30)
Infections requiring current antibiotic therapy	0.0 (0/30)
Previous intervention, % (n/N)
Any cardiac surgery	20.0 (6/30)
PCI	26.7 (8/30)
CRT/CRT-D/ICD/permanent pacemaker	20.0 (6/30)
Ventricular arrhythmia history, % (n/N)
Ventricular fibrillation	0.0 (0/30)
Ventricular flutter	0.0 (0/30)
Ventricular tachycardia	40.0 (12/30)
Atrial arrhythmia history, % (n/N)
Atrial flutter	20.0 (6/30)
Atrial fibrillation	66.7 (20/30)
NYHA FC, % (n/N)
I	0.0 (0/30)
II	63.3 (19/30)
III	33.3 (10/30)
IV	3.3 (1/30)
STS score (risk of mortality for replacement) (mean±SD %, (N))	10.3±6.59 (30)
STS score (morbidity or mortality) (mean±SD %, (N))	41.9±13.55 (30)
EuroScore II (mean±SD, (N))	5.6±3.70 (30)
6-min walk test distance (mean±SD m, (N))	349.4±118.37 (30)
Echocardiographic findings
MR etiology, % (n/N)
Functional	46.7 (14/30)
Degenerative	53.3 (16/30)
MR, % (n/N)
0: none	0.0 (0/30)
1+: mild	0.0 (0/30)
2+: moderate	0.0 (0/30)
3+: moderate-to-severe	80.0 (24/30)
4+: severe	20.0 (6/30)
LVEDD (mean±SD cm, (N))	5.7±0.9 (30)
LVESD (mean±SD cm, (N))	4.1±1.18 (30)
LVEF (mean±SD %, (N))	50.2±12.8 (30)
MV area (cm2)	6.0±1.1 (30)

CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVESD, left ventricular end systolic dimension; MI, myocardial infarction; MR, mitral regurgitation; MV, mitral valve; NYHC FC, New York Heart Association functional class; STS, Society of Thoracic Surgeons; TIA, transient ischemia attack.

MitraClip^® Procedure

All patients were implanted with at least 1 MitraClip^® device, representing a 100% implant rate under general anesthesia with TEE guidance. Most of the patients (n=19, 63.3%) were implanted with 2 MitraClip^® devices, 9 patients (30.0%) received 1 MitraClip^® device, and 2 patients (6.7%) received 3 MitraClip^® devices.

Mean total procedure time was 284.6±90.67 min, mean device time was 126.6±79.57 min, and mean fluoroscopy duration was 62.5±31.11 min (Table 2). Post-procedural length of stay in the intensive care unit averaged 36.8±36.3 h and the mean duration of hospital stay excluding rehabilitation was 14.4±8.5 days. Most (96.7%) of the patients were discharged home after the procedure; 1 patient (3.3%) required admission to a rehabilitation facility.

Table 2. Procedure Time, Device Time, Fluoroscopy Duration, and Device Implantation in AVJ-514 Trial of MitraClip^®

Parameter	AVJ-514 (n=30)
Total procedure time (mean±SD min (N))	284.6±90.67 (30)
Device time (mean±SD min (N))	126.6±79.57 (30)
Fluoroscopy duration (mean±SD min (N))	62.5±31.11 (30)
No. of implanted study devices, % (n/N)
0	0
1	30.0 (9/30)
2	63.3 (19/30)
≥3	6.7 (2/30)
Implant rate % (n/N)	100.0 (30/30)
Acute procedural success % (n/N)	86.7 (26/30)
Major adverse events % (n/N)	0

Device-Related Complications

One patient received 1 clip and had an echo core lab-reported single leaflet device attachment (SLDA) not requiring non-elective cardiovascular surgery. The MR severity remained the same at discharge (MR 3+) and 30-day (MR 3+) post-implant as compared with baseline of MR 3+, as determined by the ECL. No further intervention or surgical procedure was performed, except for continued optimized medical therapy. There were no other reports of device-related complications (mitral stenosis, SLDA, device embolization, or iatrogenic atrial septal defect).

Adverse Events

A total of 3 patients were reported with major bleeding (Bleeding Academic Research Consortium (BARC)-Type 3) during the 30 days: 1 patient experienced bleeding from the right internal jugular vein, 1 patient was diagnosed with gastrointestinal bleeding secondary to dual antiplatelet therapy and anticoagulation therapy, and 1 patients was noted, post-procedurally, to have an atrial septal puncture resulting in pericardial effusion, which required transfusion of 8 units of packed red blood cells. No additional clinical intervention was reported for the third patient. Major bleeding in these 3 patients was resolved without sequela.

Neither conversion to MV surgery, additional MitraClip^® device intervention, nor non-elective cardiovascular surgery was required through the 30 days post-implantation.

There were no occurrences of MAE through the 30 days in the AVJ-514 trial.

Echocardiographic Outcomes

APS was defined as the primary efficacy endpoint of the AVJ-514 trial. The APS rate was 86.7%, whereby 26 of the 30 patients had MR ≤2+ at discharge (Table 2). At 30-days post-implantation, these 26 patients continued to have MR ≤2+. The majority of patients had MR severity of 1+ at discharge (70%; 21 patients) and 30 days (56.7%; 17 patients). There were no deaths or MV surgery before discharge (Figure 1).

Figure 1.

Mitral regurgitation severity grade assessed by echocardiography core laboratory at baseline, discharge, and 30 days.

There were 4 non-APS patients (3 with DMR, 1 with FMR) who received at least 1 clip implant, but were unable to achieve MR grade <3+ at discharge; 3 of the 4 patients had baseline MR severity of 3+ and maintained the same severity at discharge and 30 days post-implantation; 1 patient had an echo core lab-reported SLDA of the implanted device at 2 days post-implantation; however, MR severity did not worsen and was maintained at 3+. The NYHA FC of that patient improved from II at baseline to I at 30 days. Another of the 3 patients had a gradual improvement in MR severity from baseline 4+, discharge 3+, and 2+ at 30 days; however, discharge MR severity ≤2+ was predefined for APS. That patient’s NYHA FC did improve from II at baseline to I at 30 days. The remaining 2 patients underwent clip implantation with no improvement in MR severity from a baseline 3+, which was unchanged at discharge and 30-day follow-up. One them had an improvement in NYHA FC from III at baseline to II at 30 days, presumed related to improvement of MR, while the other patient maintained the NYHA FC of II at baseline and 30 days post-treatment. In summary, all 4 non-APS patients showed no worsening of MR severity or NYHA FC, but there were individual cases of some improvement in MR and/or NYHA.

Pre- and post-procedural TTE was performed. LV end-diastolic dimensions (LVEDD) were significantly reduced after the procedure (5.7±0.88 vs. 5.4±0.84, P<0.001), whereas LVESD were not (4.1±1.2 vs. 4.1±1.1, P=0.86). LVEF was slightly decreased after the procedure (50.2±12.8% vs. 45.0±11.8%, P=0.002). Although the mean MV pressure gradient was slightly increased after the procedure (2.4±0.75 vs. 3.6±2.0, P=0.008), the pulmonary arterial pressure was significantly decreased (39.4±10.9 vs. 35.1±5.5, P=0.02).

Clinical Outcomes

Improvement in NYHA FC was observed at 30-days post-implantation, as compared with baseline (Figure 2). Overall, patients experienced a significant improvement in NYHA at 30-days post-implantation. At baseline, the majority (63.3%) of patients were NYHA II, with the remaining (36.6%) patients NYHA III/IV. Most (70%) of the patients were NYHA I, 26.7% of patients were NYHA II, and 3.3% were NYHA III at 30 days.

Figure 2.

New York Heart Association functional class at baseline vs. 30-day follow-up. Paired data. Bowker method P-value.

Significant improvement in KCCQ scores was also observed at 30-days post-implantation, as compared with baseline (Figure 3).

Figure 3.

Mean Kansas City Cardiomyopathy Questionnaire score at baseline vs. 30-day follow-up. Error bars indicate 95% confidence interval. Paired data. Paired t-test P-value.

Outcomes by MR Etiology

Both functional and degenerative MR etiologies were represented in the AVJ-514 trial. Baseline characteristics as well as safety and effectiveness outcomes were evaluated by MR etiology (Table 3). DMR patients were older, on average, than FMR patients (by 5.5 years), had a larger proportion of female patients and a slightly higher incidence of diabetes at baseline. FMR patients were more likely to present with moderate-to-severe renal or to have had previous cardiovascular surgery. Despite these minor differences, safety outcomes were similar between the 2 groups, and both groups experienced improvements in efficacy measures.

Table 3. Safety and Effectiveness Outcomes in AVJ-514 Trial of MitraClip^® by Mitral Regurgitation Etiology (Degenerative or Functional)

	DMR (n=16)	FMR (n=14)	P value
Baseline characteristics % (n/N)
Age, years	82.9±5.8 (16)	77.4±7.3 (14)	0.0264
Female	37.5% (6/16)	7.1% (1/14)	0.0860
Diabetes	31.3% (5/16)	7.1% (1/14)	0.1755
MI	25.0% (4/16)	28.6% (4/14)	1.0000
Moderate-to-severe renal disease	56.3% (9/16)	78.6% (11/14)	0.2602
Stroke	18.8% (3/16)	28.6% (4/14)	0.6746
COPD	6.3% (1/16)	28.6% (4/14)	0.1571
Previous cardiovascular surgery	12.5% (2/16)	28.6% (4/14)	0.3778
NYHA FC III–IV heart failure	37.5% (6/16)	35.7% (5/14)	1.0000
LVEF	58.7±10.5 (16)	40.4±6.8 (14)	<0.0001
MR ≥3+	100% (16/16)	100% (14/14)	NA
Safety outcomes % (n/N)
30-day mortality	0.0% (16)	0.0% (14)	NA
30-day major adverse event	0.0% (16)	0.0% (14)	NA
Effectiveness measure
APS % (n/N)	87.5% (14/16)	85.7% (12/14)	1.0000
MR grade ≤2+ at discharge % (n/N)	81.3% (13/16)	92.9% (13/14)	0.6015
MR grade ≤2+ at 30 days % (n/N)	81.3% (13/16)	92.9% (13/14)	0.6015
Improvement in LVEDV at 30 days, mL (mean±SD min (N))	−18.6±33.4 (16)	−9.0±18.5 (14)	0.3398
Improvement in LVESV at 30 days, mL (mean±SD min (N))	−2.9±10.1 (16)	−8.3±16.5 (14)	0.2736
Improvement in KCCQ at 30 days, points (mean±SD min (N))	7.8±16.4 (16)	11.5±12.6 (14)	0.4912
NYHA FC III or IV from baseline → 30 days, %	37.5% → 6.3%	35.7% → 0.0%	NA

APS, acute procedural success; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end systolic volume. Other abbreviations as in Table 1.

Discussion

This is the first study to examine the safety and efficacy of the AVJ-514 System (MitraClip^® device) in Japan. In this prospective, multicenter study, the MitraClip^® device achieved a high implantation rate (100%) and APS (86.7%), with a low rate of serious complications, 30-day mortality, and subsequent MV surgery. Notably, MAEs were not noted in any patient. A large majority of these patients achieved reduction in MR severity to ≤2+ and this was associated with improvements in NYHA FC and QOL.

The MitraClip^® device was originally studied in surgical candidates. In the Endovascular Valve Edge-to-Edge Repair Study II randomized clinical trial (EVEREST II RCT), 279 patients with MR grade 3+ or 4+ were randomized 2:1 to the MitraClip^® procedure or to surgical repair/replacement.⁸ Long-term safety and durability of MR reduction in this population were recently reported through 5 years by Feldman et al.¹⁵

Whitlow et al described the initial experience with the MitraClip^® device in 78 high surgical risk patients enrolled in the EVEREST II High Risk Registry (HRR).³ Glower et al.⁵ subsequently reported the 12-month outcomes in an expanded cohort of 351 high surgical risk patients. These data were presented to the USFDA’s Circulatory System Devices Panel on March 20, 2013. The MitraClip^® device received USFDA approval for percutaneous reduction of significant symptomatic MR (≥3+) caused by a primary abnormality of the mitral apparatus (degenerative MR) in patients who have been determined to be at prohibitive risk for MV surgery by a heart team, which includes a cardiac surgeon experienced in MV surgery and a cardiologist experienced in MV disease, and in whom existing comorbidities would not preclude the expected benefit of reduction of MR severity. Lim et al. reported the outcomes for the MitraClip^® in patients with severe DMR at prohibitive surgical risk,⁴ and more recently reported midterm durability of MR repair in this same cohort of patients through 3 years.¹⁶

Whereas DMR etiology accounted for approximately 73% of patients randomized in the EVEREST II RCT, the EVEREST II HRR population comprised a majority (59%) of FMR patients. In Europe the MitraClip^® device has been available commercially since 2008 and has been predominantly used in high surgical risk FMR patients.^17–21

The current study results showed that Japanese patients deemed difficult for MV surgery because of either STS surgical mortality risk for MV replacement of ≥ 8% or the presence of protocol-defined surgical high-risk factors can be successfully treated with the MitraClip^® device. Compared with the EVEREST II high surgical risk patient population described by Glower et al,⁵ the present study enrolled slightly older patients (mean age: 80.4 vs. 75.7 years) with a higher proportion of male patients (77% vs. 61%). However, patients enrolled in the Japan trial were less symptomatic, with 36.6% in NYHA FC III or IV compared with 84.9% in the EVEREST II high-risk cohort. Japanese patients also had a higher incidence of prior stroke (23.3% vs. 12.8%) and renal disease (66.7% vs. 30.5%), but a lower incidence of prior MI (26.7% vs. 50.7%), diabetes (20.2% vs. 39.4%) and chronic obstructive pulmonary diseases (16.7% vs. 28.9%). Despite these differences, patients in the Japan trial were similarly high risk for surgery as supported by an STS score of 10.3±6.6%, compared with 11.3±7.7% in the EVEREST II high-risk cohort.

The present study represents the initial experience with the MitraClip^® device in Japan. As such, the total procedure time of 206.4±84.1 min was significantly longer than in the EVEREST II high-risk pooled cohort (156.6±71.9 min). Device time was 126.6±79.6 min in our study compared with 120.4±64.0 min in the EVEREST II high-risk cohort. In the initial EVEREST experience reported by Feldman et al in 107 patients, total procedure time was 231 min and device time 175 min.¹⁰ As with any new procedure, there is a procedural learning curve that is followed by a rapid reduction in the procedure and device times as operators gain more experience. Schillinger et al described an institutional learning curve that became evident in decreasing procedural times and safety events over time, accompanied with increased durability and completeness of MV repair over time.²²

APS was achieved in 86.7% of the present patients. Non-APS in 4 patients was related to MR >2+ at discharge. It is important to note that MR severity for non-APS patients remained the same or improved, that NYHA FC for non-APS patients remained the same or improved and finally, and most importantly, the MitraClip^® procedure and the device itself did not appear to have exacerbated the mitral insufficiency or clinical condition of the patients.

Procedural safety was demonstrated. There were no MAEs reported within 30 days and complications to date are primarily related to major bleeding events occurring during the MitraClip^® procedure. There was 1 case of SLDA in a patient with a degenerative flail of the anterior leaflet at P1 and presenting a large left atrium and dilated annulus. The SLDA was detected on the discharge echocardiogram. According to the echo core laboratory, the anterior leaflet was secured; however, the posterior leaflet was not appropriately inserted into the MitraClip^® device.

In the cases of non-APS (n=4) in this study, MR severity was either maintained or improved at 30 days post-treatment. The results indicated that failure to achieve APS did not exacerbate MR severity, thus suggesting the safety of the procedure and device. Additionally, the patients who did not achieve APS either maintained or improved their NYHA FC. Patients who may have had a partial (<1 grade) improvement in MR severity can potentially see clinical benefit such as improvement in NYHA FC.

Study Limitations

These data represent the early experience with MitraClip^® device in Japan and are thus limited by the learning curve of the individual operators. Longer-term follow-up will provide additional data to better understand the effect of the MitraClip^® device in the Japanese population. Yearly clinical and echocardiographic evaluations are planned for 5 years of follow-up. A recent publication of the EVEREST II RCT provides insights into the long-term durability of the MitraClip^® therapy through 5 years.¹⁵ These data also were limited by the lack of randomization or the presence of a parallel surgical or medical control group.

In this study, the sponsor (Abbott Vascular) established a rigorous education and training program centered on the Heart Team,^23,24 with the objective of improving patient screening and selection. Specifically, the program focused on patient selection and covered echocardiographic image acquisition before and during the procedure with a specific focus on proper assessment of valvular anatomy. Physicians were also provided with case planning techniques to help them mitigate procedural risks and achieve successful procedures.

The selection of experienced centers was an important factor in the introduction of this new structural heart treatment modality in Japan. Indeed, there were no cases of conversion to open chest surgery in this study and the safety of the device has already been demonstrated in other large studies and registries.^{3,5,8–21,25} Therefore, a hybrid operating room may not be necessary for this procedure.

The MitraClip^® procedure requires a highly sophisticated and interactive multidisciplinary heart team approach. Therefore, the maturity of the center’s heart team, as well as experience with other structural heart disease intervention modalities, are important criteria to consider when selecting MitraClip^® centers and likely contributed to the overall success of this initial introduction of the MitraClip^® therapy in Japan.

Conclusions

We describe here our preliminary experience using the MitraClip^® System technology in Japanese patients who were deemed difficult for MV surgery by the local sites’ heart teams. Despite the very early experience in Japan, the 30-day primary endpoint results of the MitraClip^® demonstrated the safety, efficacy and clinical benefit of the MitraClip^® device in this patient group. The results supported an overall favorable risk-to-benefit profile of the MitraClip^® device in this Japanese population and confirmed that the MitraClip^® technology can indeed be successfully transferred to Japanese patients.

Acknowledgments

All authors had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Design and conduct of the study: Abbott Vascular, Inc. Collection, management, analysis, and clinical events adjudication: Abbott Vascular, Inc. Interpretation of the data: K.H., A.Q., R.Y., M.T. Preparation, review, or approval of the manuscript: K.H., S.Y., T.M., M.A., S.M., T.T., K.J., T.O., J.Y., K.F., S.S., E.F., A.Q., R.Y., M.T.

Funding / Support

The trial was funded by Abbott Vascular, Inc.

Role of the Funder / Sponsor

The trial was designed, managed, and analyzed by Abbott Vascular in conjunction with external investigators. Abbott Vascular, as the trial sponsor, was directly involved in the design and conduct of the trial, collection, management, analysis, and interpretation of the data, and preparation and review of the manuscript.

Conflict of Interest Disclosures

Drs Foster and Qasim received funding support from Abbott Vascular and Medtronic. The other authors have no disclosures related to this study.

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