This report describes the 12-month outcomes of the a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe (ACCESS-EU postapproval study of MitraClip therapy) with respect to preprocedural left ventricular ejection fraction (LVEF). Transcatheter deployment of the MitraClip device may be considered for patients who are not suitable for conventional surgery. A total of 567 patients with significant mitral regurgitation (MR) underwent MitraClip therapy. Of those, 393 had functional MR (FMR) and were subdivided by preprocedural LVEF (A: 10% to 20%, B: >20% to 30%, C: >30% to 40%, D: >40%). Procedural safety and efficacy and treatment outcomes including MR grade, New York Heart Association (NYHA) functional class, 6-minute walk test, and the Minnesota Living with Heart Failure Questionnaire were analyzed at baseline, 30 days, and 12 months. Baseline mean logistic EuroSCORE was 25 ± 19; 87% of patients were in NYHA classes III or IV (A: 96%, B: 83%, C: 90%, D: 86%). There was no incidence of death or stroke intraprocedurally. Eleven patients died within 30 days with no differences among subgroups. Kaplan–Meier survival at 12 months was 81.8% (A: 71%, B: 79%, C: 87%, D: 86%). There was a significant improvement in MR severity at 30 days and 12 months (p <0.0001). At 12 months, all subgroups experienced similar improvements in NYHA class, 6-minute walk test, and Minnesota Living with Heart Failure Questionnaire. This real-world registry reports promising results of MitraClip therapy in patients with FMR. In conclusion, the low rates of hospital mortality and adverse events in patients with FMR—even in patients with severely reduced LVEF—provide additional evidence of substantial benefits after MitraClip implantation.
Mitral regurgitation (MR) regardless of its cause portends a poor prognosis in patients with systolic heart failure, and mitral valve surgery (MVS) is the current gold standard in low-risk symptomatic patients with severe MR. However, MVS in high-risk surgical patients is associated with an increased operative mortality and does not seem to prolong life. Although several studies have reported reverse left ventricular (LV) remodeling and improvements in symptoms after MVS in patients with advanced LV dysfunction, operative mortality is elevated and may range between 8.8% and 21%. In addition, the recurrence rate of significant MR has been reported to approach >30% within 12 months after MVS. In this regard, the MitraClip (Abbott Vascular, Inc., Santa Clara, California) might be a promising, minimal invasive, percutaneous treatment technique, simulating the surgical treatment of the edge-to-edge technique. Recent European guidelines included the MitraClip as a treatment option in high-risk surgical patients with functional MR (FMR) as a class IIb indication (level of evidence C), indicating that there are still data warranted to make stronger recommendations. However, importantly, there are accumulating data demonstrating that the MitraClip appears to be safe and efficacious. The aim of the present data analysis was to describe the differential outcomes in patients after MitraClip implantation with respect to their preprocedural left ventricular ejection fraction (LVEF).
Methods
The ACCESS-EU phase I is a prospective, observational, multicenter, postapproval study of the MitraClip system for the treatment of MR in Europe ( ClinicalTrials.gov # NCT01288976 ). The study was designed to gain information regarding the use of the MitraClip system in the European Union with respect to health economics and clinical care and to provide further evidence of the safety and effectiveness of the MitraClip system in a real-world setting. Patient enrollment began in October 2008 and was completed in April 2011. Patients were assigned to MitraClip based on the current CE mark–approved labeling as outlined in the MitraClip system instructions for use and in accordance to local institutional practice. Patients were eligible for the ACCESS-EU phase I study if they had moderate to-severe (>3) or severe (>4) MR. Patients underwent transthoracic and transesophageal echocardiography at baseline to quantify MR and to assess morphologic suitability for MitraClip implantation. Before participation in the study, all patients provided written informed consent. The study protocol was reviewed and approved by the institutional review board and/or independent ethics committee of each participating site. The ACCESS-EU study complies with the Declaration of Helsinki.
The MitraClip device and percutaneous procedure have been described in detail previously. Echocardiographic and clinical assessments were performed as per routine practice at the institutions at baseline, discharge, 6 months, and 1 year after enrollment. The 6-minute walk test (6MWT) and Minnesota Living with Heart Failure (MLHFQ) were administered at baseline and 6 and 12 months. Periprocedural and postprocedural adverse events were site reported without prospective definition of event types and without adjudication by a clinical events committee. MR severity was evaluated by transthoracic echocardiography at each individual site at discharge and 6 and 12 months.
Results were analyzed for the entire FMR cohort and additionally stratified in a post hoc manner into subgroups of baseline LVEF based on the following categories: 10% to 20%, >20% to 30%, >30% to 40%, and >40%. Baseline LVEF was not available for 5 patients. Baseline and demographic qualitative variables were expressed as percentages, and quantitative variables were expressed as mean (±SD). MR severity was compared between baseline and 12 months using Bowker test. Changes in 6MWT distance and MLHFQ scores between baseline and 12 months were analyzed using paired t tests. Survival rates up to 12 months were presented as Kaplan–Meier curves. Differences were considered statistically significant at p values ≤0.05. The data were analyzed with SAS statistical software version 9.1.3 (SAS Institute, Inc., Cary, North Carolina).
Results
Patients
A total of 567 patients with significant MR were enrolled at 14 European sites (ACCESS-EU phase I centers and original investigators’ affiliation are listed in the Supplementary Table ) and received the MitraClip device. Of these, 393 (69.3%) were determined to have FMR. Forty-three patients withdrew consent before study completion, and 269 completed the 12-month follow-up visit (14 patients missed the 12-month follow-up visit). Table 1 provides baseline characteristics of patients with FMR stratified by LVEF. Patients with FMR were elderly with a mean age of 73 years. Patients with LVEF >40% were slightly older, whereas patients with FMR with an LVEF 10% to 20% were on average younger. In patients with an LVEF >40%, the nature of FMR was predominantly due to nonischemic cardiomyopathy, whereas there was a more even split between ischemic and nonischemic cardiomyopathies for the other LVEF subgroups. LV dilation was more pronounced in patients with an LVEF 10% to 20% than in patients with an LVEF >40% (LV internal dimension, systole 6.2 ± 1.3 vs 3.9 ± 0.8 cm).
| Characteristic ∗ | All FMR Patients (N=393) | Left Ventricular Ejection Fraction (%) | |||
|---|---|---|---|---|---|
| 10-20 (N=52) | 20-30 (N=120) | 30-40 (N=85) | >40 (N=131) | ||
| Age (years) | 73.0±8.9 | 68.3±10.2 | 71.1±8.0 | 73.6±7.7 | 76.1±8.8 |
| Patients > 75 years of age | 160 (41%) | 11 (21%) | 34 (28%) | 32 (38%) | 81 (62%) |
| Female | 126 (32%) | 10 (19%) | 33 (28%) | 22 (26%) | 59 (45%) |
| Male | 267 (68%) | 42 (81%) | 87 (73%) | 63 (74%) | 72 (55%) |
| Congestive Heart failure | 277 (71%) | 49 (94%) | 94 (78%) | 57 (68%) | 73 (56%) |
| Coronary artery disease | 267 (68%) | 36 (69%) | 86 (72%) | 65 (77%) | 77 (59%) |
| Myocardial infarction | 132 (35%) | 16 (33%) | 51 (44%) | 37 (46%) | 28 (22%) |
| Atrial fibrillation | 248 (69%) | 30 (68%) | 74 (71%) | 54 (68%) | 87 (70%) |
| Cerebrovascular disease | 54 (14%) | 7 (14%) | 14 (12%) | 13 (15%) | 18 (14%) |
| Cardiomyopathy | 212 (54%) | 47 (90%) | 87 (73%) | 52 (61%) | 23 (18%) |
| Hypertension | 298 (76%) | 35 (67%) | 90 (76%) | 67 (80%) | 102 (78%) |
| Diabetes mellitus | 134 (34%) | 24 (46%) | 46 (38%) | 26 (31%) | 37 (28%) |
| Moderate to severe renal disease | 189 (48%) | 33 (64%) | 70 (58%) | 41 (48%) | 43 (33%) |
| Peptic ulcer disease | 26 (7%) | 3 (6%) | 5 (4%) | 8 (10%) | 10 (8%) |
| Chronic pulmonary disease | 79 (20%) | 14 (27%) | 26 (22%) | 19 (23%) | 20 (16%) |
| Previous coronary artery bypass grafting | 131 (33%) | 12 (23%) | 43 (36%) | 36 (42%) | 37 (28%) |
| Previous percutaneous intervention | 156 (40%) | 21 (41%) | 52 (44%) | 39 (47%) | 43 (33%) |
| Cardiac Rhythm Device Implant | |||||
| Cardiac resynchronization therapy | 49 (13%) | 18 (35%) | 25 (21%) | 5 (6%) | 1 (1%) |
| Implantable cardiac defibrillator | 77 (20%) | 20 (39%) | 41 (35%) | 12 (15%) | 4 (3%) |
| Pacemaker | 50 (13%) | 1 (2%) | 8 (7%) | 15 (18%) | 25 (20%) |
| No devices | 206 (54%) | 12 (24%) | 43 (37%) | 50 (61%) | 97 (76%) |
| Logistic EuroSCORE | 24.8±18.9 | 29.1±23.1 | 27.7±19.9 | 26.0±16.5 | 19.8±16.2 |
| Logistic EuroSCORE ≥ 20% | 190 (48%) | 26 (50%) | 66 (55%) | 48 (57%) | 49 (37%) |
| NYHA Functional Class | |||||
| I | 1 (0.3%) | 0 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
| II | 47 (12%) | 2 (4%) | 20 (18%) | 7 (9%) | 18 (14%) |
| III | 268 (71%) | 32 (62%) | 75 (66%) | 63 (78%) | 96 (74%) |
| IV | 63 (17%) | 18 (35%) | 19 (17%) | 10 (12%) | 16 (12%) |
| Mitral Regurgitation Severity | |||||
| 2+: Moderate | 6 (2%) | 2 (4%) | 1 (1%) | 2 (2%) | 1 (1%) |
| 3+: Moderate-to-Severe | 155 (40%) | 13 (25%) | 44 (37%) | 33 (39%) | 62 (47%) |
| 4+: Severe | 232 (59%) | 37 (71%) | 75 (63%) | 50 (59%) | 68 (52%) |
| LV Internal Dimensions, systole (cm) | 5.1 ±1.4 | 6.2±1.3 | 5.6±1.1 | 5.0±1.4 | 3.9±0.8 |
| FMR Etiology | |||||
| Ischemic | 165 (42%) | 26 (50%) | 65 (54%) | 46 (54%) | 26 (20%) |
| Non-ischemic | 228 (58%) | 26 (50%) | 55 (46%) | 39 (46%) | 105 (80%) |
∗ Sample sizes smaller than 393 (All FMR), 52 (LVEF 10% to 20%), 120 (LVEF 20% to 30%), 85 (LVEF 30% to 40%) or 131 (LVEF >40%) reflect missing data.
Patients with FMR in the ACCESS-EU phase I study were deemed to have a high surgical mortality risk as demonstrated by a mean logistic EuroSCORE of 24.8 ± 18.9% and the presence of multiple co-morbidities. Patients with an LVEF 10% to 20% were more likely to present congestive heart failure, cardiomyopathy, and moderate to severe renal disease. Conversely, patients with an LVEF >40% had a lower incidence of congestive heart failure, coronary artery disease, previous myocardial infarction, and moderate to severe renal disease.
Most patients in the FMR cohort had an MR grade >3 or >4 at baseline, and most were symptomatic with New York Heart Association (NYHA) functional classes III or IV. The subgroup of patients with an LVEF 10% to 20% had the highest proportion of patients in NYHA class IV. At baseline, 46% of the FMR cohort was implanted with a cardiac rhythm management device, including 13% with cardiac resynchronization therapy (CRT), 20% with an implantable cardiac defibrillator, and 13% with a pacemaker. The subgroups of patients with an LVEF 10% to 20% and 20% to 30% had the highest rate of CRT device implants. Seventy-six percent of patients with an LVEF >40% had no cardiac rhythm device implanted. Two hundred twenty-seven patients with FMR (58%) were treated with 1 MitraClip device, 153 (39%) received 2 devices, and 13 (3%) received ≥3 devices during the index procedure. There was no difference in the number of devices implanted across the 4 LVEF subgroups. Procedure time, contrast volume, and fluoroscopy duration data are presented in Table 2 . Patients in the LVEF >40% subgroup had a slightly longer average procedure time, required more contrast volume, and were more likely to receive contrast compared to the other subgroups. Postprocedural intensive care unit duration was longer for patients with an LVEF 10% to 20% compared to patients with an LVEF >40% ( Table 3 ). Similarly, patients with an LVEF 10% to 20% tended to have a longer hospitalization course after index procedure on average compared to the overall FMR cohort. A majority of patients (79%) with FMR were discharged home after the procedure with no notable differences among the 4 LVEF subgroups ( Table 3 ).
| Mean ± SD (N) ∗ Median [Min, Max] | All FMR Patients (N=393) | Left Ventricular Ejection Fraction (%) | |||
|---|---|---|---|---|---|
| 10-20 (N=52) | 20-30 (N=120) | 30-40 (N=85) | >40 (N=131) | ||
| Procedure Time † (min) | 111.6 ± 66.9 (239) | 110.4 ± 54.8 (33) | 111.3 ± 67.7 (80) | 104.6 ± 58.4 (52) | 121.1 ± 76.7 (70) |
| 93.0 (20.0, 342) | 97.0 (20.0, 239.0) | 89.0 (20.0, 324.0) | 90.0 (28.0, 255.0) | 104.0 (23.0, 342.0) | |
| Contrast Volume (ml) | 18.2 ± 39.5 (386) | 7.1 ± 18.4 (51) | 16.5 ± 38.7 (118) | 18.8 ± 46.3 (83) | 24.0 ± 41.3 (129) |
| 0 (0, 308.8) | 0 (0, 96.0) | 0 (0, 300.0) | 0 (0, 308.0) | 0 (0, 180.0) | |
| Patients With No Contrast | 264 (68%) | 41 (80%) | 80 (68%) | 57 (69%) | 82 (64%) |
| Fluoroscopy Duration (min) | 30.4 ± 20.8 (330) | 27.9 ± 16.4 (46) | 29.7 ± 19.1 (97) | 28.1 ± 17.3 (65) | 33.5 ± 24.8 (117) |
| 26.0 (0.0, 152.0) | 26.0 (0.0, 75.0) | 24.0 (0.0, 96.0) | 24.0 (0.0, 79.0) | 28.0 (0.0, 152.0) | |
∗ Sample sizes smaller than 393 (All FMR), 52 (LVEF 10% to 20%), 120 (LVEF 20% to 30%), 85 (LVEF 30% to 40%) or 131 (LVEF >40%) reflect missing data.
† Procedure time is defined as the time from trans-septal puncture until removal of the guide catheter.
| All FMR Patients (N=393) | Left Ventricular Ejection Fraction (%) | ||||
|---|---|---|---|---|---|
| 10-20 (N=52) | 20-30 (N=120) | 30-40 (N=85) | >40 (N=131) | ||
| ICU and Hospital Stay | |||||
| Post-Procedure ICU Duration (days) | 2.8 ± 7.6 | 5.9 ± 18.4 | 2.6 ± 4.2 | 2.4 ± 3.6 | 1.9 ± 3.1 |
| Post-Procedure Hospital Stay (days) | 7.9 ± 9.1 | 11.6 ± 17.7 | 8.0 ± 8.4 | 7.1 ± 5.0 | 7.1 ± 6.2 |
| Discharge Status and Facility ∗ | |||||
| Death | 7 (2%) | 2 (4%) | 2 (2%) | 2 (2%) | 1 (1%) |
| Home | 310 (79%) | 38 (73%) | 99 (83%) | 65 (77%) | 104 (80%) |
| Nursing Home | 7 (2%) | 0 (0%) | 4 (3%) | 0 (0%) | 3 (2%) |
| Skilled Nursing Facility | 67 (17%) | 12 (23%) | 14 (12%) | 18 (21%) | 22 (17%) |
∗ Sample sizes smaller than 393 (All FMR), 52 (LVEF 10% to 20%), 120 (LVEF 20% to 30%), 85 (LVEF 30% to 40%) or 131 (LVEF >40%) reflect missing data.
There was no incidence of death, stroke, or respiratory failure intraprocedurally and in the immediate postoperative period after the MitraClip procedure. Table 4 provides selected site-reported adverse events within 30 days and 12 months. A total of 11 patients with FMR (2.8%) died within 30 days, 4 (36%) of whom from cardiac causes. At 12 months, 67 deaths (17.0%) were reported, 55% from cardiac causes. The Kaplan–Meier estimates of freedom from mortality at 12 months are 71%, 79%, 87%, and 86% for LVEF subgroups 10% to 20%, 20% to 30%, 30% to 40%, and >40%, respectively ( Figure 1 ). There were no device embolizations observed in the ACCESS-EU study. Eleven patients experienced a single leaflet device attachment (SLDA) during the study, 7 (64%) of whom had an LVEF >40%. In 4 patients, the SLDA was noted intraprocedurally: in 1 case, an additional device was immediately implanted at the time of the index procedure; a second patient underwent a second MitraClip device intervention 6 days after index procedure; and no additional intervention were required in the other 2 cases. Of the remaining 7 SLDA cases discovered postprocedurally, 4 patients underwent a second MitraClip device intervention; 2 required MVS, including 1 who had previously underwent a second device intervention; and 2 patients had no additional intervention. A total of 21 patients with FMR required MVS after index procedure including 2 instances as a result of an SLDA (mentioned previously). Most MVS (12 procedures) were performed in patients with an LVEF >40%; 4 MVS were performed in patients with an LVEF 30% to 40%, 2 each in the LVEF 20% to 30% and 10% to 20% subgroups, and 1 in a patient with an undocumented LVEF.
| Safety Outcomes | All FMR Patients (N=393) | Left Ventricular Ejection Fraction (%) | |||
|---|---|---|---|---|---|
| 10-20 (N=52) | 20-30 (N=120) | 30-40 (N=85) | >40 (N=131) | ||
| 30-Day Safety Outcomes | |||||
| Death | 11 (3%) | 2 (4%) | 3 (3%) | 4 (5%) | 2 (2%) |
| Stroke | 2 (0.5%) | 1 (2%) | 0 (0%) | 1 (1%) | 0 (0%) |
| Myocardial Infarction | 3 (1%) | 0 (0%) | 1 (1%) | 0 (0%) | 2 (2%) |
| Renal Failure | 20 (5%) | 4 (8%) | 9 (8%) | 0 (0%) | 6 (5%) |
| Respiratory Failure | 4 (1%) | 1 (2%) | 0 (0%) | 1 (1%) | 2 (2%) |
| Need for Resuscitation | 9 (2%) | 1 (2%) | 1 (1%) | 4 (5%) | 3 (2%) |
| Cardiac Tamponade | 4 (1%) | 1 (2%) | 1 (1%) | 0 (0%) | 2 (2%) |
| Bleeding Complications | 15 (4%) | 3 (6%) | 2 (2%) | 3 (4%) | 6 (5%) |
| 12-Month Safety Outcomes | |||||
| Death | 67 (17%) | 14 (27%) | 23 (19%) | 10 (12%) | 18 (14%) |
| Stroke | 4 (1%) | 1 (2%) | 1 (1%) | 1 (1%) | 1 (1%) |
| Myocardial Infarction | 7 (2%) | 2 (4%) | 2 (2%) | 1 (1%) | 2 (2%) |
| Renal Failure | 43 (11%) | 6 (12%) | 14 (12%) | 7 (8%) | 15 (12%) |
| Respiratory Failure | 4 (1%) | 1 (2%) | 0 (0%) | 1 (1%) | 2 (2%) |
| Need for Resuscitation | 11 (3%) | 1 (2%) | 1 (1%) | 6 (7%) | 3 (2%) |
| Cardiac Tamponade | 4 (1%) | 1 (2%) | 1 (1%) | 0 (0%) | 2 (2%) |
| Bleeding Complications | 18 (5%) | 3 (6%) | 3 (3%) | 3 (4%) | 8 (6%) |
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