Abstract
Background
The Clinical Frailty Scale (CFS) is a useful frailty marker for predicting clinical outcomes in patients undergoing invasive therapy. However, the clinical impact of CFS after transcatheter edge‐to‐edge repair in patients with mitral regurgitation (MR) remains unclear. This study aimed to elucidate the association between the baseline frail status defined by the CFS and clinical outcomes with or without postprocedural MR ≥2+ (post‐MR ≥2+) after transcatheter edge‐to‐edge repair.
Methods and Results
Based on a Japanese multicenter registry (OCEAN [Optimized Catheter Valvular Intervention]‐Mitral), data from 2078 patients with MR who underwent transcatheter edge‐to‐edge repair were analyzed. The patients were classified into 5 groups: CFS 1 to 3, 4, 5, 6, and ≥7. The procedural and clinical outcomes and post‐MR ≥2+ were compared among the groups. All‐cause mortality for up to 2 years was explored using Cox proportional hazards regression analysis. Although the rates of acute procedural success and post‐MR ≥2+ were similar, all‐cause mortality at 2 years was significantly increased across the 5 CFS categories (15.5%, 23.8%, 27.7%, 34.6%, and 48.8%, respectively, P<0.001). The incremental CFS categories and post‐MR ≥2+ were independent predictive risk factors of all‐cause mortality (all P<0.05). Among the patients with 5 CFS categories, the incidence of all‐cause mortality was higher in those with post‐MR ≥2+ than in those without (all P<0.05).
Conclusions
Although prognosis was poor in patients with higher CFS grade after transcatheter edge‐to‐edge repair, minimizing modifiable factors of residual MR is warranted to improve the clinical outcomes.
Registration Information
URL: https://center6.umin.ac.jp/cgi‐open‐bin/ctr/ctr_view.cgi?recptno=R000027188;
Unique identifier: UMIN000023653.
Keywords: Clinical Frailty Scale, residual mitral regurgitation, risk stratification, transcatheter edge‐to‐edge repair
Subject Categories: Heart Failure, Valvular Heart Disease, Catheter-Based Coronary and Valvular Interventions, Treatment, Mortality/Survival
Nonstandard Abbreviations and Acronyms
- APS
acute procedural success
- CFS
Clinical Frailty Scale
- FMR
functional mitral regurgitation
- MR
mitral regurgitation
- OCEAN
Optimized Catheter Valvular Intervention
- TEER
transcatheter edge‐to‐edge repair
Clinical Perspective.
What Is New?
The transcatheter edge‐to‐edge repair procedure achieved a similar acute procedural success and mitral regurgitation reduction regardless of baseline Clinical Frailty Scale differences.
Both baseline Clinical Frailty Scale and post‐mitral regurgitation ≥2+ after transcatheter edge‐to‐edge repair could stratify the postprocedural risk of all‐cause mortality.
Although transcatheter edge‐to‐edge repair in frail patients is challenging, a survival benefit is observed even in frail patients with reduced mitral regurgitation after transcatheter edge‐to‐edge repair.
What Are the Clinical Implications?
Minimizing modifiable factors of residual mitral regurgitation is warranted to improve the clinical outcomes.
Transcatheter edge‐to‐edge repair (TEER) using the MitraClip (Abbott Vascular, Menlo Park, CA) has been established as an effective treatment for heart failure (HF) in patients with mitral regurgitation (MR). 1 Considering the indication of TEER for older patients with HF, careful baseline risk evaluations should be required before intervention. The number of frail patients has been increasing in recent decades, and frailty is well‐known as a syndrome characterized by a diminished physiological reserve, causing increased vulnerability to adverse events. 2 Thus, frailty assessment is useful for risk stratification in patients undergoing TEER. The Clinical Frailty Scale (CFS) is a simple tool to classify patient frailty status that is evaluated based on a physician's eyeball test. 3 , 4 Although CFS is a semiquantitative frailty marker that does not require a geriatric specialist assessment, numerous clinical investigations are consistent with similar conclusions that patients with a high CFS score are associated with worse prognoses and adverse events. 5 , 6 , 7 , 8 , 9
According to the recent data from our OCEAN (Optimized Catheter Valvular Intervention)‐Mitral Japanese multicenter registry, a residual MR ≥2+ (equal to or more than moderate) after TEER is one of the independent predictive factors with increased risk of mortality or HF readmission at 1 year. 10 The interventionists always make a conscious effort to minimize the residual MR during TEER, whereas postprocedural MR ≥2+ (post‐MR ≥2+) is considered the Achilles heel for this specific procedure. It is of paramount importance to estimate the procedural and postprocedural risks of residual MR in frail and nonfrail patients after TEER.
To date, no data exist on the relationship between CFS and late adverse events in older patients after TEER. There is also no information on the clinical impact of post‐MR ≥2+ in frail and nonfrail patients who have undergone TEER. Therefore, this study aimed to elucidate (1) the association between the baseline frail status defined by CFS and clinical outcomes after TEER and (2) the clinical outcomes of frail status stratified by post‐MR ≥2+ after TEER.
METHODS
The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.
Study Population
OCEAN‐Mitral is an ongoing, prospective, investigator‐initiated, multicenter registry to assess the safety and efficacy of TEER in patients with significant MR. 10 , 11 A total of 21 Japanese institutions participated in this registry. Between April 2018 and June 2021, 2150 consecutive symptomatic patients with MR underwent TEER. The CFS is a tool that provides a generally accepted clinical definition of frailty. 3 All baseline CFS grades were determined by an attending physician or medical staff, such as a physical therapist, in the individual centers. Based on the semiquantitative eyeball test, the CFS was graded from 1 (very fit) to 9 (terminally ill) by face‐to‐face assessments with patients. These evaluations were performed before TEER during hospitalization. If the patient condition was unstable with HF, the CFS was graded as per the status before hospital admission or could not be calculated. As a result, 72 patients had missing CFS grading in the entire cohort, and a total of 2078 patients were included in the study.
The CFS grade can be assessed by any health care professional in direct interaction with the patient or by reviewing the medical records. In this study, the CFS was determined using the available information at the first hospital visit. CFS was graded in patients with acute HF before hospital admission. We divided the patients into 5 groups as follows: nonfrail (CFS 1–3, n=918), vulnerable (CFS 4, n=627), mildly frail (CFS 5, n=287), moderately frail (CFS 6, n=138), and severely frail (CFS ≥7, n=138). The final flowchart of the study is shown in Figure 1. The University Hospital Medical Information Network Clinical Trials Registry has registered this study with the International Committee of Medical Journal Editors (UMIN000023653). All patients provided informed consent before the TEER procedure, and the study protocol was approved by the institutional review board of each institution. The study was conducted in accordance with the latest version of the Declaration of Helsinki and the guidelines for epidemiological studies issued by the Ministry of Health, Labor, and Welfare of Japan.
Figure 1. Patient flowchart of this study.
CFS indicates the Clinical Frailty Scale; OCEAN‐Mitral, Optimized Catheter Valvular Intervention)‐Mitral; and TEER, transcatheter edge‐to‐edge repair.
Detailed TEER Procedure
The MitraClip device (Abbott Vascular) is the only commercially available mitral transcatheter device in Japan. After introducing the MitraClip Generation (G)2 system, the latest version of the G4 system (without introducing the G3 system) was launched in September 2020. The MitraClip G4 system has 4 different size variations (NT, NTW, XT, and XTW) that aim to adapt to individual patients' different mitral valve morphologies. TEER is indicated in patients with moderate‐to‐severe MR, regardless of the MR cause. Baseline MR severity was assessed based on the guidelines of the American Society of Echocardiography 12 and after the TEER procedure was assessed as previously described. 13
MR severity was classified as 0+ (none/trivial), 1+ (mild), 2+ (moderate), 3+ (moderate to severe), and 4+ (severe). Individual heart team members considered the appropriateness of TEER based on patient background, including age, frailty, and operative risk of cardiac surgery. The detailed TEER procedure has been reported previously. 10 , 11 All TEER procedures were performed under general anesthesia under transesophageal echocardiography guidance. An acceptable MR reduction after clipping the mitral valve was defined as MR ≤2+ using perioperative transesophageal echocardiography findings. If further MR reduction was required, the physicians attempted to change the position of the first clip or implant a second or third clip, depending on the situation. The acute procedural success (APS) of TEER was determined as maintenance of procedural safety without life‐threatening complications and an adequate reduction of MR ≤2+ in transthoracic echocardiography (TTE) at discharge based on a previous formula and our data. 10 , 11 , 13 , 14 The residual MR was also evaluated by TTE before discharge. All TTE and transesophageal echocardiography parameters were calculated based on individual center decision according to the American Society of Echocardiography guidelines. 15
Clinical Outcome Measures and Definitions
Baseline characteristics, laboratory data, TTE findings, and transesophageal echocardiography findings were examined at each center. Clinical follow‐up was conducted at baseline and 1, 12, and 24 months after TEER. At each visit, patients were asked about their history of hospitalization for HF after TEER. According to the previous consensus statement, 16 HF hospitalization is defined as an event in which the patient is admitted to the hospital with a primary diagnosis of HF, and the length of hospital stay is ≥24 hours. If patients could not visit a hospital, clinical data, including mortality information, were collected through telephone interviews with the patients, their family members, or relatives. Baseline patient data, procedural variables, and clinical outcomes were compared among the CFS categories and subgroups of frail patients. The residual MR was currently applied to the post‐MR ≥2+ evaluated via TTE at discharge. In addition, the clinical outcomes were assessed between the baseline CFS and the presence or absence of post‐MR ≥2+ after TEER. The primary end point of this study was the event rate for all‐cause mortality, and the secondary end point of this study was all‐cause mortality and HF hospitalization up to 2 years after TEER. Annual changes in the frailty status were also checked during the study years. Thereafter, the annual trends of functional MR (FMR), APS, and in‐hospital mortality rates were calculated in each frailty subset.
Statistical Analysis
Data are presented as mean±SD or median for continuous variables and as frequencies (percentages) for categorical variables unless otherwise indicated. Data comparisons among the 5 groups were made using χ2 tests for categorical covariates and 1‐way ANOVA for continuous covariates. Statistical significance was set at P<0.05, and 95% CIs were reported as appropriate. To explore whether the association between all‐cause mortality or hospitalization for HF and baseline frailty status was linear, we first constructed Kaplan‐Meier survival curves for the primary end point, which were examined using the log‐rank test. To detect the predictors of the primary end point, clinical variables in the univariate analysis (P<0.05) were included in a Cox proportional hazards regression analysis with force entry procedures, and the results were presented as hazard ratios (HRs) and 95% CIs. A subsequent multivariate model that included all significant variables and HRs was constructed, and the 95% CI was estimated. The different clinical scenarios were used to clarify whether baseline frailty status or post‐MR ≥2+ after TEER affected the primary end point results. All statistical analyses were performed using JMP version 14.0.0 software (SAS Institute, Cary, NC).
RESULTS
Baseline Characteristics and Procedural Variables
The patient characteristics, laboratory parameters, medical therapy, and TTE data are summarized in Table 1. Among the 5 groups, numerous significant differences were observed for mean age, male sex, body characteristics, incidence of baseline comorbidities, and TTE findings (all P<0.05). The procedural variables are presented in Table 2. Higher APS rates were achieved regardless of the baseline CFS grade (CFS 1–3: 94.6%, CFS 4: 94.4%, CFS 5: 95.8%, CFS 6: 94.2%, and CFS ≥7: 94.4%, P=0.91). In addition to the similar incidence of non‐APS, the prevalence of post‐MR ≥2+ did not differ among the 5 groups (CFS 1–3: 23.3%, CFS 4: 23.1%, CFS 5: 22.0%, CFS 6: 28.3%, and CFS ≥7: 30.6%, P=0.30). The prevalence of clip distribution was similar among the 5 groups, with G2 NT being the most frequently used (approximately 70%). The length of hospital and intensive care unit stay differed significantly among the groups. The rates of procedural complications, including clip embolization, leaflet tear, access site, single leaflet detachment, and transesophageal echocardiography, were also similar among the 5 groups. The rates of in‐hospital mortality were also significantly different among the groups and were highest in the CFS 6 and CFS ≥7 groups (CFS 1–3: 1.2%, CFS 4: 1.8%, CFS 5: 1.4%, CFS 6: 4.4%, and CFS ≥7: 13.0%, P<0.001) (Table 2).
Table 1.
Baseline Characteristics of Study Participants
| Characteristic | Normal CFS 1–3 | Vulnerable CFS 4 | Mildly CFS 5 | Moderately CFS 6 | Severely CFS ≥7 | P value | P value for trend |
|---|---|---|---|---|---|---|---|
| Total patients, n (%) | 918 | 627 | 287 | 138 | 108 | ||
| Mean age, y | 75.5±9.6 | 80.0±8.6 | 81.2±8.9 | 82.3±8.5 | 79.8±11.4 | <0.001 | <0.001 |
| Men, n (%) | 605 (65.9) | 342 (54.6) | 125 (43.6) | 57 (41.3) | 40 (37.0) | <0.001 | <0.001 |
| Body mass index, kg/m2 | 21.9±3.4 | 21.2±3.2 | 23.4±3.8 | 22.7±3.7 | 22.7±3.7 | <0.001 | <0.001 |
| Body mass index <20 kg/m2, n (%) | 282 (30.7) | 222 (35.4) | 129 (45.1) | 68 (49.3) | 63 (58.3) | <0.001 | <0.001 |
| STS score for mitral valve repair, % | 6.6±5.9 | 8.7±6.7 | 9.0±6.4 | 10.5±7.8 | 12.7±11.1 | <0.001 | <0.001 |
| EuroSCORE II, % | 5.9±5.7 | 6.8±6.3 | 7.0±5.7 | 7.7±5.9 | 11.8±12.2 | <0.001 | <0.001 |
| NYHA class III/IV, n (%) | 473 (52.5) | 398 (63.5) | 229 (79.8) | 118 (85.5) | 102 (94.4) | <0.001 | <0.001 |
| Comorbidity, n (%) | |||||||
| Hypertension, n (%) | 637 (69.4) | 421 (67.2) | 203 (70.7) | 89 (64.5) | 68 (63.0) | 0.41 | 0.40 |
| Dyslipidemia, n (%) | 512 (55.8) | 314 (50.1) | 120 (41.8) | 70 (50.7) | 50 (46.3) | <0.001 | <0.001 |
| Diabetes, n (%) | 257 (28.0) | 165 (26.4) | 71 (24.7) | 33 (25.9) | 29 (26.9) | 0.51 | 0.74 |
| Chronic kidney disease, n (%) | 244 (60.6) | 241 (60.4) | 172 (62.6) | 186 (62.4) | 186 (62.4) | 0.90 | 0.90 |
| Dialysis dependent, n (%) | 49 (45.0) | 34 (5.4) | 18 (6.3) | 4 (2.9) | 4 (3.7) | 0.56 | 0.60 |
| Atrial fibrillation, n (%) | 538 (58.6) | 399 (63.6) | 201 (70.1) | 104 (75.4) | 79 (73.2) | <0.001 | <0.001 |
| Current smoking, n (%) | 75 (8.2) | 19 (6.2) | 19 (6.6) | 6 (4.4) | 4 (3.7) | <0.001 | <0.001 |
| Prior stroke, n (%) | 81 (8.8) | 73 (11.6) | 44 (15.3) | 21 (15.2) | 21 (19.4) | <0.001 | <0.001 |
| Liver cirrhosis, n (%) | 14 (1.5) | 6 (1.0) | 5 (1.7) | 3 (2.2) | 2 (1.9) | 0.74 | 0.75 |
| Pulmonary disease, n (%) | 95 (10.4) | 53 (8.5) | 32 (11.1) | 12 (8.7) | 8 (7.4) | 0.54 | 0.55 |
| Coronary artery disease, n (%) | 124 (13.5) | 80 (12.8) | 26 (9.1) | 22 (15.9) | 14 (13.0) | 0.16 | 0.17 |
| Peripheral artery disease, n (%) | 83 (39.7) | 65 (10.4) | 27 (9.4) | 15 (10.9) | 19 (17.6) | 0.13 | 0.09 |
| Prior cardiac surgery, n (%) | 119 (13.0) | 68 (10.9) | 31 (10.8) | 15 (10.9) | 5 (4.6) | 0.071 | 0.12 |
| Preprocedural laboratory data | |||||||
| Albumin, g/dL | 3.8±0.5 | 3.7±0.5 | 3.6±0.5 | 3.4±0.5 | 3.1±0.5 | <0.001 | <0.001 |
| eGFR, mg/min | 41.0±18.5 | 38.2±18.2 | 36.2±18.3 | 39.4±21.3 | 45.8±31.4 | <0.001 | 0.78 |
| Echocardiographic data | |||||||
| Ejection fraction | 43.8±16.5 | 45.5±16.1 | 49.6±15.4 | 48.5±16.1 | 43.1±16.5 | <0.001 | <0.001 |
| LV end‐diastolic diameter, cm | 59.3±10.2 | 56.7±10.1 | 54.8±9.5 | 53.3±10.2 | 53.5±10.4 | <0.001 | <0.001 |
| LV end‐systolic diameter, cm | 46.5±13.5 | 44.0±13.1 | 40.9±12.4 | 39.9±12.5 | 41.6±13.2 | <0.001 | <0.001 |
| LA volume index, cm3/m2 | 85.0±42.2 | 88.0±45.1 | 99.7±49.1 | 98.4±53.7 | 84.1±48.1 | <0.001 | <0.001 |
| Mitral regurgitation characteristics | |||||||
| Moderate–severe MR, n (%) | 903 (98.4) | 611 (97.5) | 285 (99.4) | 136 (98.5) | 106 (98.2) | 0.21 | 0.21 |
| Functional MR, n (%) | 725 (79.0) | 460 (73.4) | 202 (70.4) | 96 (69.6) | 77 (71.3) | 0.005 | 0.005 |
| MR PISA EROA, cm2 | 0.38±0.22 | 0.37±0.20 | 0.43±0.30 | 0.43±0.46 | 0.41±0.23 | 0.029 | 0.069 |
| MR regurgitation volume, mL | 57.0±26.0 | 55.8±26.3 | 58.8±26.8 | 56.2±27.2 | 52.4±23.7 | 0.26 | 0.40 |
| TMPG, mm Hg | 1.7±1.1 | 1.8±1.1 | 2.0±1.4 | 1.9±1.2 | 2.4±1.9 | <0.001 | <0.001 |
| Medication | |||||||
| ARNI, n (%) | 21 (2.3) | 11 (1.8) | 3 (1.1) | 1 (0.7) | 3 (2.8) | 0.43 | 0.49 |
| SGLT2 inhibitor, n (%) | 107 (11.7) | 52 (8.3) | 20 (7.0) | 13 (9.4) | 13 (12.0) | 0.074 | 0.079 |
| β‐Blocker, n (%) | 698 (76.0) | 455 (72.5) | 200 (69.6) | 105 (76.1) | 66 (61.0) | <0.001 | <0.001 |
| MRA, n (%) | 503 (54.7) | 333 (55.5) | 160 (55.7) | 70 (50.1) | 59 (54.5) | 0.093 | 0.14 |
ARNI indicates angiotensin receptor neprilysin inhibitor; CFS, Clinical Frailty Scale; eGFR, estimated glomerular filtration rate; EROA, effective regurgitant orifice area; EuroSCORE II, European System for Cardiac Operative Risk Evaluation II; LA, left arterial; LV, left ventricular; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; PISA, proximal isovelocity surface area; SGLT2, sodium‐glucose cotransporter 2; STS, Society of Thoracic Surgeons; and TMPG, transmitral mean pressure gradient.
Table 2.
Procedural Results and Early Clinical Outcomes
| Procedure | Normal CFS 1–3 | Vulnerable CFS 4 | Mildly CFS 5 | Moderately CFS 6 | Severely CFS ≥7 | P value | P value for trend |
|---|---|---|---|---|---|---|---|
| Total patients, n (%) | 918 | 627 | 287 | 138 | 108 | ||
| Achievement of APS, n (%) | 868 (94.6) | 592 (94.4) | 275 (95.8) | 130 (94.2) | 102 (94.4) | 0.91 | 0.92 |
| No. of implanted clips | 1.38±0.53 | 1.42±0.55 | 1.42±0.55 | 1.38±0.52 | 1.41±0.51 | 0.67 | 0.53 |
| Residual MR (≥2+), n (%) | 214 (23.3) | 145 (23.1) | 63 (22.0) | 39 (28.3) | 33 (30.6) | 0.30 | 0.27 |
| Procedural time, min | 99.2±52.9 | 98.0±48.9 | 95.6±41.8 | 96.0±49.2 | 96.8±53.9 | 0.85 | 0.31 |
| Device time, min | 69.8±45.7 | 67.9±40.6 | 66.4±37.6 | 67.2±40.9 | 69.7±45.4 | 0.82 | 0.48 |
| Fluoroscopy time, min | 31.4±21.7 | 31.8±21.5 | 27.5±17.6 | 29.9±19.4 | 32.9±21.7 | 0.038 | 0.35 |
| G2 NT, n (%) | 635 (69.2) | 453 (72.2) | 215 (74.9) | 103 (74.6) | 77 (71.3) | 0.11 | 0.04 |
| G4, n (%) | 275 (30.0) | 169 (27.0) | 71 (24.7) | 31 (22.5) | 31 (28.7) | ||
| G4 NT, n (%) | 113 (12.3) | 72 (11.5) | 40 (13.9) | 15 (10.9) | 11 (10.2) | ||
| G4 NTW, n (%) | 145 (15.8) | 81 (12.9) | 27 (9.4) | 13 (9.4) | 18 (16.7) | ||
| G4 XT, n (%) | 2 (0.2) | 3 (0.5) | 0 (0) | 3 (2.2) | 0 (0) | ||
| G4 XTW, n (%) | 15 (1.6) | 13 (2.1) | 4 (1.4) | 3 (2.2) | 2 (1.9) | ||
| Length of hospital stay, d | 18.2±19.1 | 20.6±19.6 | 23.9±25.9 | 27.3±23.5 | 49.8±62.7 | <0.001 | <0.001 |
| Length of ICU stay, d | 2.1±5.4 | 2.0±4.4 | 1.8±2.7 | 2.4±4.1 | 7.5±16.2 | <0.001 | <0.001 |
| Clip embolization, n (%) | 1 (0.1) | 2 (0.3) | 0 (0) | 0 (0) | 0 (0) | 0.62 | 0.70 |
| Leaflet tear, n (%) | 8 (0.9) | 8 (1.3) | 6 (2.1) | 1 (0.7) | 3 (2.8) | 0.35 | 0.28 |
| Access site related complications, n (%) | 22 (2.4) | 14 (2.2) | 4 (1.4) | 6 (4.4) | 1 (0.9) | 0.35 | 0.33 |
| Single leaflet detachment, n (%) | 16 (1.7) | 10 (1.6) | 6 (2.1) | 2 (1.5) | 2 (1.9) | 0.99 | 0.99 |
| TEE‐associated complications, n (%) | 3 (0.3) | 9 (1.4) | 4 (1.4) | 2 (1.5) | 2 (1.9) | 0.092 | 0.13 |
| Bleeding event, n (%) | 5 (0.5) | 2 (0.2) | 2 (0.7) | 3 (2.2) | 2 (1.9) | 0.19 | 0.08 |
| In‐hospital death, n (%) | 11 (1.2) | 11 (1.8) | 4 (1.4) | 6 (4.4) | 14 (13.0) | <0.001 | <0.001 |
APS indicates acute procedural success; CFS, Clinical Frailty Scale; G2, Generation 2; G4, Generation 4; ICU, intensive care unit; MR, mitral regurgitation; and TEE, transesophageal echocardiography.
Cumulative Event Rates of All‐Cause Mortality or All‐Cause Mortality and HF Hospitalization
Figure 2A presents the Kaplan‐Meier curve showing incremental all‐cause mortality rates at 2 years after TEER across the CFS grades (CFS 1–3: 15.5%, CFS 4: 23.8%, CFS 5: 27.7%, CFS 6: 34.6%, and CFS ≥7: 48.8%, P<0.001). Figure 2B also demonstrates the cumulative all‐cause mortality and HF hospitalization rates up to 2 years according to the CFS grade (CFS 1–3: 27.8%, CFS 4: 38.0%, CFS 5: 40.7%, CFS 6: 50.2%, and CFS ≥7: 57.6%, P<0.001). The cumulative incidences of all‐cause mortality after TEER in the patients with FMR and non‐FMR are shown in Figures 3A and 3B, respectively. A higher incidence of all‐cause mortality was observed among frail patients in both the FMR (15.8% versus 26.3% versus 29.9% versus 37.2% versus 46.6%, P<0.001) and non‐FMR (14.7% versus 16.5% versus 22.4% versus 26.3% versus 61.6%, P<0.001) categories. Table 3 presents the annual changes in the frail status and the annual trends in the FMR, APS, and in‐hospital mortality rates in each frail group. The distribution of nonfrailty gradually increased, and mild frailty decreased, whereas advanced frailty remained unchanged. The rate of patients with FMR also gradually increased in the nonfrail group. Among the frailty subgroups, APS and in‐hospital mortality rates remained unchanged over the study period.
Figure 2. Kaplan‐Meier curve of all‐cause mortality at 2 years in the CFS 1 to 3, 4, 5, 6, and ≥7 groups (A), and Kaplan‐Meier curve of all‐cause mortality and HF hospitalization at 2 years in the CFS 1 to 3, 4, 5, 6, and ≥7 groups (B).
CFS indicates the Clinical Frailty Scale; HF, heart failure; and TEER, transcatheter edge‐to‐edge repair.
Figure 3. Kaplan‐Meier curve of all‐cause mortality at 2 years according to frail status and MR cause.
CFS indicates the Clinical Frailty Scale; FMR, functional mitral regurgitation; MR, mitral regurgitation; and TEER, transcatheter edge‐to‐edge repair.
Table 3.
Annual Trends in Frailty Status and Association With Functional MR, APS, and In‐Hospital Mortality Rates
| Annual data | 2018 | 2019 | 2020 | 2021 |
|---|---|---|---|---|
| Frailty status | ||||
| CFS 1–3, n (%) | 151 (43.0%) | 234 (38.6%) | 361 (47.7%) | 172 (47.3%) |
| CFS 4, n (%) | 101 (28.8%) | 209 (34.5%) | 211 (27.9%) | 106 (29.1%) |
| CFS 5, n (%) | 55 (15.7%) | 93 (15.4%) | 94 (12.4%) | 45 (12.4%) |
| CFS 6, n (%) | 25 (7.1%) | 45 (12.4%) | 47 (6.2%) | 21 (5.8%) |
| CFS ≥7, n (%) | 19 (5.4%) | 25 (4.1%) | 44 (5.8%) | 20 (5.5%) |
| Rate of functional MR | ||||
| CFS 1–3, n (%) | 113 (74.8%) | 174 (74.4%) | 293 (81.2%) | 145 (84.3%) |
| CFS 4, n (%) | 79 (78.2%) | 144 (68.9%) | 158 (74.9%) | 79 (74.5%) |
| CFS 5, n (%) | 39 (70.9%) | 63 (70.0%) | 67 (71.3%) | 34 (75.6%) |
| CFS 6, n (%) | 18 (72.0%) | 31 (68.9%) | 31 (66.0%) | 17 (81.0%) |
| CFS ≥7, n (%) | 16 (84.2%) | 24 (96.0%) | 43 (97.7%) | 18 (90.0%) |
| Achievement of APS | ||||
| CFS 1–3, n (%) | 140 (92.7%) | 227 (97.0%) | 338 (93.6%) | 167 (97.1%) |
| CFS 4, n (%) | 97 (96.0%) | 199 (95.2%) | 198 (93.8%) | 98 (92.5%) |
| CFS 5, n (%) | 50 (90.9%) | 90 (96.8%) | 92 (97.9%) | 43 (95.6%) |
| CFS 6, n (%) | 24 (96.0%) | 43 (95.6%) | 45 (95.7%) | 18 (85.7%) |
| CFS ≥7, n (%) | 16 (84.2%) | 24 (96.0%) | 42 (95.5%) | 20 (100%) |
| In‐hospital death | ||||
| CFS 1–3, n (%) | 1 (0.66%) | 3 (1.3%) | 2 (0.55%) | 1 (0.58%) |
| CFS 4, n (%) | 0 (0%) | 4 (1.9%) | 2 (0.95%) | 5 (4.8%) |
| CFS 5, n (%) | 3 (5.5%) | 0 (0%) | 1 (1.1%) | 0 (0%) |
| CFS 6, n (%) | 1 (4.0%) | 2 (4.4%) | 3 (6.4%) | 0 (0%) |
| CFS ≥7, n (%) | 2 (10.5%) | 5 (20.0%) | 4 (6.8%) | 4 (20.0%) |
APS indicates acute procedural success; CFS, Clinical Frailty Scale; and MR, mitral regurgitation.
In the groups classified as CFS 5, the incidence of all‐cause mortality also increased with the presence of post‐MR ≥2+ after TEER compared with non–post‐MR ≥2+ (CFS 1–3: 10.9% versus 17.8%, CFS 4: 20.9% versus 25.5%, CFS 5: 20.5% versus 38.1%, CFS 6: 24.2% versus 43.6%, CFS ≥7: 37.5% versus 54.6%, respectively, all P<0.001). Some of these results are summarized in Figure 4.
Figure 4. Periprocedural results and in‐hospital mortality according to frailty status and the all‐cause mortality at 2 years in each group with or without post‐MR ≥2+.
APS indicates acute procedural success; CFS, Clinical Frailty Scale; MR, mitral regurgitation; and TEER, transcatheter edge‐to‐edge repair.
Risk Factors for Predicting All‐Cause Death or HF Hospitalization
A clinical scenario was used to investigate the independent association of all‐cause mortality between baseline frailty status or post‐MR ≥2+ after TEER. In multivariable analysis, using the nonfrail group (CFS 1–3) as a reference, the remaining 4 groups and residual MR (≥2+) after TEER were significantly associated with an increased risk of all‐cause mortality (all P<0.05) (Table 4).
Table 4.
Cox Proportional Hazards Regression Analysis for the Association Between All‐Cause Mortality and Clinical Findings
| All‐cause mortality | Univariable | Multivariable | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Factors | ||||||
| CFS 1–3 (reference) | ||||||
| CFS 4 | 1.83 | 1.24–2.71 | 0.003 | 1.50 | 1.12–2.00 | 0.006 |
| CFS 5 | 2.05 | 1.52–2.77 | <0.001 | 1.54 | 1.08–2.18 | 0.017 |
| CFS 6 | 2.53 | 1.70–3.74 | <0.001 | 2.44 | 1.63–3.67 | <0.001 |
| CFS ≥7 | 4.57 | 3.27–6.40 | <0.001 | 3.06 | 2.01–4.65 | <0.001 |
| Age (per 1‐y increase) | 1.02 | 1.01–1.03 | <0.001 | 1.02 | 1.01–1.04 | 0.0084 |
| Men | 1.44 | 1.18–1.76 | <0.001 | 1.77 | 1.39–2.27 | <0.001 |
| Body mass index <20 kg/m2 | 1.81 | 1.49–2.20 | <0.001 | 1.70 | 1.36–2.13 | <0.001 |
| NYHA III/IV | 1.77 | 1.49–2.11 | <0.001 | 1.40 | 10.7–1.83 | 0.013 |
| STS score | 1.06 | 1.05–1.07 | <0.001 | 1.02 | 1.01–1.04 | <0.001 |
| Hypertension | 1.14 | 0.93–1.40 | 0.19 | |||
| Diabetes | 1.33 | 1.08–1.63 | 0.008 | 1.20 | 0.93–1.54 | 0.15 |
| Arterial fibrillation | 1.32 | 1.08–1.63 | 0.009 | 1.33 | 1.04–1.70 | 0.023 |
| Coronary artery disease | 1.25 | 0.94–1.64 | 0.13 | |||
| Peripheral artery disease | 1.78 | 1.35–2.31 | <0.001 | 1.32 | 0.96–1.81 | 0.090 |
| Prior stroke | 1.42 | 1.08–1.84 | 0.014 | 1.46 | 1.08–1.97 | 0.013 |
| Pulmonary disease | 1.14 | 0.83–1.54 | 0.40 | |||
| FMR | 1.30 | 1.03–1.65 | 0.030 | 1.30 | 0.92–1.82 | 0.13 |
| Pre‐left ventricular EF (per 1.0% increase) | 0.99 | 0.98–0.99 | <0.001 | 0.98 | 0.97–0.99 | <0.001 |
| Hemoglobin <10 g/dL | 1.83 | 1.46–2.26 | <0.001 | 1.20 | 0.93–1.56 | 0.16 |
| eGFR (per 1 increase) | 0.99 | 0.98–0.99 | <0.001 | 0.99 | 0.98–0.99 | 0.006 |
| Residual MR (≥2+) | 1.70 | 1.38–2.09 | <0.001 | 1.42 | 1.11–1.81 | 0.005 |
CFS indicates Clinical Frailty Scale; EF, ejection fraction; eGFR, estimated glomerular filtration rate; FMR, functional mitral regurgitation; HR, hazard ratio; MR, mitral regurgitation: NYHA, New York Heart Association, and STS, Society of Thoracic Surgeons.
In Table 5, we presented the same clinical scenario to investigate all‐cause mortality and HF hospitalization for each CFS category. The incremental CFS category was also shown as an independent predictor of all‐cause mortality and HF hospitalization. Residual MR (≥2+) after TEER was significantly associated with increased risk of all‐cause mortality and HF hospitalization (HR, 1.40 [95% CI, 1.15–1.69]; P<0.001).
Table 5.
Cox Proportional Hazards Regression Analysis for the Association Between All‐Cause Mortality or Heart Failure Hospitalization and Clinical Findings
| All‐cause mortality | Univariable | Multivariable | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Factors | ||||||
| CFS 1–3 (reference) | ||||||
| CFS 4 | 1.48 | 1.10–2.00 | 0.013 | 1.53 | 1.09–2.15 | 0.017 |
| CFS 5 | 1.63 | 1.33–2.00 | <0.001 | 1.45 | 1.15–1.82 | 0.002 |
| CFS 6 | 2.30 | 1.77–3.00 | <0.001 | 1.79 | 1.33–2.43 | <0.001 |
| CFS ≥7 | 2.40 | 1.81–3.18 | <0.001 | 2.03 | 1.47–2.79 | <0.001 |
| Age (per 1‐y increase) | 1.01 | 1.00–1.02 | <0.001 | 1.01 | 1.00–1.02 | 0.16 |
| Men | 1.25 | 1.07–1.47 | <0.001 | 1.39 | 1.15–1.67 | <0.001 |
| Body mass index <20 kg/m2 | 1.41 | 1.21–1.65 | <0.001 | 1.33 | 1.11–1.59 | 0.002 |
| NYHA III/IV | 1.77 | 1.49–2.11 | <0.001 | 1.41 | 1.15–1.73 | <0.001 |
| STS score | 1.05 | 1.04–1.06 | <0.001 | 1.02 | 1.01–1.03 | <0.001 |
| Hypertension | 1.06 | 0.90–1.25 | 0.46 | |||
| Diabetes | 1.23 | 1.04–1.46 | 0.015 | 1.11 | 0.91–1.34 | 0.31 |
| Arterial fibrillation | 1.26 | 1.07–1.49 | 0.006 | 1.28 | 1.06–1.54 | 0.011 |
| Coronary artery disease | 1.03 | 0.80–1.29 | 0.84 | |||
| Peripheral artery disease | 1.52 | 1.20–1.89 | 0.006 | 1.17 | 0.89–1.51 | 0.25 |
| Prior stroke | 1.24 | 0.99–1.55 | 0.065 | |||
| Pulmonary disease | 1.17 | 0.86–1.56 | 0.32 | |||
| FMR | 1.53 | 1.26–1.86 | <0.001 | 1.02 | 0.78–1.33 | 0.91 |
| Pre‐left ventricular EF (per 1.0% increase) | 0.98 | 0.98–0.99 | <0.001 | 0.98 | 0.98–0.99 | <0.001 |
| Hemoglobin <10 g/dL | 1.79 | 1.50–2.14 | <0.001 | 1.30 | 1.06–1.59 | 0.012 |
| eGFR (per 1 increase) | 0.99 | 0.98–0.99 | <0.001 | 0.99 | 0.98–0.99 | <0.001 |
| Residual MR (≥2+) | 1.51 | 1.27–1.79 | <0.001 | 1.40 | 1.15–1.69 | <0.001 |
CFS indicates Clinical Frailty Scale; EF, ejection fraction; eGFR, estimated glomerular filtration rate; FMR, functional mitral regurgitation; HR, hazard ratio; MR, mitral regurgitation; NYHA, New York Heart Association; and STS, Society of Thoracic Surgeons.
DISCUSSION
There were 3 important findings in this study that should be noted. First, the TEER procedure could similarly provide acceptable rates of APS and post‐MR ≥2+ regardless of baseline differences in CFS grade, although increased in‐hospital deaths were observed in the groups with higher CFS scores. Second, both baseline CFS and post‐MR ≥2+ (ie, moderate grade or higher after TEER) could stratify the postprocedural risk of all‐cause mortality or HF hospitalization within a cohort of patients with MR who underwent TEER. The results of the current study revealed an independent association between the CFS grade and increased risk of all‐cause mortality or HF hospitalization after TEER, even after adjusting for many clinical variables, including traditional surgical risk score such as the Society of Thoracic Surgeons. Third, TEER in frail patients was clinically challenging because the rate of all‐cause mortality or HF hospitalization was according to the baseline CFS grading. In addition, the incremental rates of all‐cause mortality among the 5 frail subgroups were confirmed in both FMR and non‐FMR cohorts. The baseline CFS grade was an independent predictive factor of all‐cause mortality or HF hospitalization after TEER. However, baseline CFS was considered an unmodifiable factor, and the survival benefit of those without post‐MR ≥2+ compared with those with post‐MR ≥2+ was equal in all patients regardless of the baseline CFS grade. Although challenging, the advanced frailty status itself should not be a contraindication of TEER. Considering the negative impact of moderate or greater residual MR after TEER, physicians need to achieve an optimal procedure to minimize postprocedural MR in patients undergoing TEER.
TEER treatment for MR has changed the landscape of clinical practice. The procedure is a safe alternative to a high‐risk cohort of cardiac surgery and improvement of prognosis with reduced HF. 1 , 14 Decision‐making on invasive treatment indications should be determined based on clinical risk–benefit balance. Identifying appropriate candidates who are likely to gain survival benefits from TEER is an important clinical concern. Frailty is an important factor in decision‐making on the indications for invasive intervention among older patients. A previous study revealed that baseline frailty status was associated with an increased risk of in‐hospital mortality and higher hospitalization costs in patients who underwent TEER. 16 This study focused on the early outcomes after TEER; thus, further clinical data on frailty status are needed. Many assessment tools are available in the literature to evaluate the frailty status. The CFS is an established indicator of frailty that is widely used in various clinical fields. 5 , 6 , 7 , 8 , 9 Current data, derived from different countries and populations, demonstrate that advanced CFS grading significantly correlates with clinical adverse events and worse prognosis. 5 , 6 , 7 , 8 , 9 Consistent with previous studies, our data show the usefulness of CFS grading for the postprocedural risk stratification of patients with MR after TEER.
Notably, the incremental CFS grades at baseline are also related to increased procedural complications, low rates of procedural success, and higher early mortality in patients who underwent noncardiac surgery, cardiac surgery, and catheter‐related interventions. 6 , 7 , 8 Previous data also revealed increased procedural vascular complications, bleeding, and early mortality after transcatheter aortic valve implantation. 9 Consistent with the results of previous studies, our study revealed that the incidence of in‐hospital mortality after TEER was significantly higher in patients with CFS 6 (4.4%) and CFS ≥7 (13%) compared with the lower CFS groups ranging from 1.2% to 1.8%.
However, access‐related complications, bleedings, APS, and post‐MR ≥2+ did not differ in the different CFS categories in our study. Notably, the transvenous, less invasive TEER procedure does not increase procedural complications and achieves equivalent APS rates and MR reduction in frail patients.
Less‐invasive TEER is considered challenging for patients with progressive frailty. Baseline CFS assessment allowed us to optimize the patient's clinical pathway before TEER. One of the key roles in improving clinical outcomes is to mitigate the degree of residual MR after TEER. Our results suggested that reducing residual MR might improve prognosis even in patients with advanced frailty. The current study is consistent with the findings of previous studies establishing post‐MR ≥2+ as an independent predictor of all‐cause mortality or HF hospitalization after TEER. 10 Subanalysis of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial revealed that reduced MR at 30 days was associated with greater freedom from death or HF hospitalizations and improved quality of life through a 2‐year follow‐up. 17 This finding is consistent with the results of the present study. Of note, the incidence of post‐MR ≥2+ in the present study is comparable with that observed in the Endovascular Valve Edge‐to‐Edge Repair (EVEREST II) and COAPT trials. 1 , 14
Conversely, the EXPAND (A Contemporary, Prospective Study Evaluating Real‐world Experience of Performance and Safety for the Next Generation of MitraClip Devices) and EXPAND G4 registries using the recent version of MitraClip G3–G4 systems have shown that the rate of post‐MR ≥2+ decreased to 9.0% to 11.2%. 17 , 18 In the OCEAN‐Mitral registry, the MitraClip G2 system was mainly implanted, and G4 use was limited to only one‐fourth of the patients. 11 Thus, current data present limited evidence on the relationship between device differences and the rates of post‐MR ≥2+ after TEER. In addition to device‐specific differences, the risk reduction of residual MR following TEER will be achieved along with overcoming the operator learning curve and correct imaging modality knowledge shared with the heart team.
Study Limitations
Several important limitations are inherent to the current registry data. First, this was a retrospective, single Japanese cohort, nonrandomized, unblinded, observational study, which might introduce a traditional bias similar to previous cohort studies. Second, procedural and postprocedural MR severity was not assessed in the central core laboratory. However, we decided to use a consensus document based on the relevant guidelines and share it with the participating institutions to minimize the knowledge and technical gap before enrollment in the registry. Third, the multivariable analysis did not capture unpredictable factors, although considerably important clinical variables were included. Fourth, the relatively longer hospital stay in this study reflects the Japanese medical insurance system that broadly covers the cost during hospitalization. This specific situation may limit the application to other countries of the current early results on in‐hospital mortality. Fifth, the data mainly comprised the classical MitraClip G2 system and a limited number of the latest G4 devices, which could limit the translatability of the findings to contemporary clinical practice. Sixth, there is no control group as the noninvasive treatment arm because we used the registry data of patients who underwent TEER. Finally, only the CFS was evaluated as an indicator of frailty; other frailty indicators were not used in the current analysis. This study focused on the clinical relationship between CFS and residual MR findings following TEER. A comparative assessment of frailty markers is beyond the scope of this study. Thus, our findings do not comprehensively address these limitations. Therefore, additional large‐scale investigations using global data are required to validate our findings.
CONCLUSIONS
Our study is the first to demonstrate the impact of CFS and its relation to post‐MR ≥2+ on clinical outcomes after TEER. TEER can maintain an acceptable APS and similar rates of MR reduction regardless of the baseline CFS. However, the incremental CFS grade and post‐MR ≥2+ following TEER were related to the increased risk of all‐cause mortality or HF hospitalization. Although TEER in frail patients is challenging, a favorable result to mitigate residual MR is required in patients undergoing TEER.
Sources of Funding
The OCEAN‐Mitral registry, which is part of the OCEAN‐SHD (Optimized Catheter Valvular Intervention–Structural Heart Disease) registry, is supported by Edwards Lifesciences, Medtronic Japan, Boston Scientific, Abbott Medical Japan, and the Daiichi‐Sankyo Company.
Disclosures
Drs Yamamoto, Kubo, Saji, Izumo, Watanabe, Nakajima, Ohno, Enta, Shirai, Mizuno, Boda, and Amaki are clinical proctors of TEER for Abbott Medical and have received lecture/consultant fees from Abbott Medical. Drs Asami and Kodama have received speaker fees from Abbott Medical. Dr Yamaguchi is a clinical proctor of TEER for Abbott Medical and has received a lecture fee and a scholarship donation from Abbott Medical. The remaining authors have no disclosures to report.
Supporting information
Appendix S1
Acknowledgments
The authors thank all OCEAN‐Mitral investigators who participated in this registry.
T. Tokuda and M. Yamamoto contributed equally to this article.
This article was sent to Amgad Mentias, MD, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.124.035109
For Sources of Funding and Disclosures, see page 11.
Contributor Information
Takahiro Tokuda, Email: tkhrtkd@yahoo.co.jp.
Masanori Yamamoto, Email: masa-nori@nms.ac.jp.
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Associated Data
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Supplementary Materials
Appendix S1