Midterm outcomes for patients presenting with heart failure and functional mitral regurgitation (MR) treated with Mitraclip remain unclear. Pubmed, Medline, and Google Scholar were systematically searched for studies enrolling patients with severe-moderate MR who underwent Mitraclip implantation. All events after at least 6 months were the primary safety end point (including death, rehospitalization for heart failure, and reinterventions), whereas change in the ejection fraction, left ventricular volumes, arterial pulmonary pressure, and left atrial diameters were considered as secondary end points. Meta-regression analysis was performed to evaluate the effect of baseline clinical and echocardiographic parameters on efficacy outcomes: 875 patients were included in 9 studies; 1.48 clips (1.3 to 1.7) for patients were implanted, and after a median follow-up of 9 months (6 to 12), 409 patients (78% [75% to 83%]) were in class New York Heart Association I/II and 57 (11% [8% to 14%]) still had moderate-to-severe MR. Overall adverse events occurred in 137 (26% [20% to 31%]) of the patients and 78 (15% [1% to 17%]) of them died; 6-minute walk test improved by 100 m (83 to 111), whereas a significant reduction in left ventricular volumes and systolic pulmonary pressure was reported. At meta-regression analysis, an increase in left ventricle systolic volumes positively affected reduction of volumes after Mitraclip, whereas atrial fibrillation reduced the positive effect of the valve implantation on ejection fraction on end-diastolic and -systolic volumes. In conclusion, Mitraclip represents an efficacious strategy for patients with heart failure and severe MR. It offers a significant improvement in functional class and in cardiac remodeling, in patients with severely dilated hearts as well, although its efficacy remains limited in the presence of atrial fibrillation.
Recently, Mitraclip has emerged as a safe and efficacious treatment for patients with severe mitral regurgitation (MR), with good results in terms of reintervention-free survival and clinical benefit for the patients. Most of the available data report interventional experience on both patients with degenerative and functional mitral regurgitation (FMR). The latter affects patients with more severe co-morbidities and is associated with a higher interventional risk. In addition, these patients present with severely depressed left ventricular function and markedly remodeled cardiac ventricles, rendering the potential benefit of Mitraclip implantation unpredictable in terms of functional and echocardiographic outcomes. We performed a meta-analysis to explore the safety and efficacy of the Mitraclip procedure for patients with FMR.
Methods
The present research was elaborated according to current guidelines, including the recent Preferred Reporting Items for Systematic reviews and Meta-Analyses amendment to the Quality of Reporting of Meta-analyses statement and recommendations from The Cochrane Collaboration and Meta-analysis of Observational Studies in Epidemiology. No language restriction was applied.
Pertinent articles were searched in Pubmed, Medline, Cochrane Library, Biomed Central and Google Scholar in keeping with established methods with Mesh strategy and with terms ((outcomes)) AND ((Mitral clipping)) AND ((mitral regurge/OR regurgitation)) related to patients with FMR who underwent percutaneous valve implantation with Mitraclip. Three independent reviewers (DC, FC, and FDA) first screened retrieved citations at the title and/or abstract level, with divergences resolved after consensus. If potentially pertinent, they were then appraised as complete reports according to the following explicit selection criteria. Studies were included if (1) investigating patients presenting with heart failure and FMR, (2) treated with Mitraclip, and (3) reporting baseline and follow-up clinical and echocardiographic data (all of them had to be met for inclusion), whereas exclusion criteria were duplicate reporting (in which case the manuscript reporting the largest sample of patients was selected).
Two unblinded reviewers (DC and FD) abstracted data about baseline profile of the patients, on echocardiographic data and on risk score for surgery.
Every patient underwent a follow-up of at least 6 months. The primary safety end point was a composite of all-cause death, rehospitalization for heart failure, and reinterventions during follow-up. The primary efficacy end point was the change in 6-minute walk test (6MWT). Secondary efficacy end points were change in left ventricle ejection fraction (EF), left ventricle volumes, pulmonary arterial pressure, and left atrial volumes, whereas the secondary safety end points were the single components of the primary composite one, cardiac death, and acute kidney injury during index hospitalization. Meta-regression analysis was performed to evaluate the effect of baseline clinical and echocardiographic data on efficacy outcomes.
Unblinded independent reviewers (DC and FD) evaluated quality of included studies on prespecified forms. Modifying the MOOSE items to take into account the specific features of included studies, we separately abstracted and appraised study design, setting, and data source.
Continuous variables are reported as mean (SD) or median (range). Categorical variables are expressed as “n” or “n (%).” Statistical pooling was performed according to a random-effect model with generic inverse-variance weighting, computing risk estimates with 95% confidence intervals. Meta-regression analysis was performed with random-effects model, to test the influence of baseline clinical and echocardiographic features on improvements after Mitraclip. All computations were performed using RevMan 5 (The Cochrane Collaboration, The Nordic Cochrane Center, Copenhagen, Denmark) and Comprehensive Meta-analysis. Small study bias was appraised by graphical inspection of funnel plots. Standard hypothesis testing was set at the 2-tailed 0.05 level.
Results
Sixteen studies were appraised, of these we excluded 4 studies, which included degenerative MR, 2 because only short-term follow-up after Mitraclip was reported, and 1 because not evaluating Mitraclip but permanent percutaneous transvenous mitral annuloplasty. Nine were included in the final analysis (see Figure 1 ).
Overall, 875 patients were included, 95% (94% to 100%) had moderate-to-severe MR (see Table 1 ). Their median age was 71 years (69 to 73), 34% of them were women (23% to 38%), with ischemic origin of heart failure in 70% of the case (63% to 75%), and severely reduced performance at 6MWT; 72% (65% to 81%) had an implantable cardioverter defibrillator and/or a cardiac resynchronization therapy (CRT), whereas 51% (41% to 56%) presented with a history of atrial fibrillation (AF). New York Heart Association (NYHA) class was III/IV in 80% (88% to 98%) of them.
| 9 studies, 875 patients | |
|---|---|
| Age (years) | 71 (69-73) |
| women | 23-38 (34%) |
| Hypertension | 54-74 (70%) |
| Diabetes mellitus | 22-40 (33%) |
| Coronary heart disease | 63-75 (70%) |
| Previous myocardial infarction | 34-53 (43%) |
| Non ischemic heart disease | 25-37(30%) |
| Atrial fibrillation | 41-56 (51%) |
| Intracardiac defibrillator/Cardiac resynchronization therapy | 65-81 (72%) |
| Logistic Euroscore | 18-28 (24) |
| STS score | 8-14 (12) |
| NYHA class III/IV | 88-98 (90%) |
| Baseline 6 minute walk test (meters) | 220-262 (230) |
At echocardiography, median left ventricle EF was 34% (29% to 36%), with severely dilated left ventricle and atrial chambers (see Table 2 ). To perform percutaneous mitral valve repair, 1.5 clips per patient (1.3 to 1.7) were implanted. Inhospital rates of cardiac death were 0.9% (0% to 1.3%), whereas acute kidney injury occurred in 11.3% (7% to 16%).
| 9 studies, 875 patients | |
|---|---|
| Left ventricle ejection fraction (%) | 29- 36(34%) |
| Left ventricle end diastolic volume (ml) | 192-229 (212) |
| Left ventricle end systolic volume (ml) | 124-182 (152) |
| Systolic pulmonary artery pressure (mmHg) | 32-54 (33) |
| Left atrial volume (ml) | 118-129 (125) |
After a median follow-up of 9 months (6 to 12), 409 patients (78% [75% to 83%]) were in NYHA class I/II and 57 (11% [8% to 14%]) still had moderate-to-severe MR.
The primary safety end point occurred in 137 patients (26% [20% to 31%]), and 78 (15% [1% to 17%]) of them died, with a continuous increase according to the length of follow-up. Mean improvement in 6MWT was 100 m (83 to 111). A significant reduction in left ventricular volumes (>20 cm 3 ) and in systolic pulmonary pressure (12 mm Hg) was recorded. Only 0.5% (0.4% to 0.6%) needed a reintervention (see Figures 2 to 4 ).
Meta-regression analysis (see Table 3 , Figure 5 ) showed that increased left ventricular systolic volumes positively affected reduction of LVESV (B −1.1; p <0.001) and improvement of 6MWT (B −0.5; p = 0.03) after Mitraclip implantation. In contrast, AF reduced the positive effect of clip implantation on EF (B −0.2; p = 0.003), on left ventricular end diastolic volume (B 0.75; p = 0.004), and LVESV (B 4.15; p <0.001). Moreover, AF had a negative trend on improvement in NYHA class, but it did not reach statistical significance (B −0.5; p = 0.07).
| Age | Female gender | Ischemic heart disease | Previous MI | Atrial fibrillation | Baseline 6MWT | Baseline LVEF | Baseline EDV | Baseline ESV | |
|---|---|---|---|---|---|---|---|---|---|
| Improvement in NYHA class | -4.2 (-5.0 to 0.1) p = 0.42 | -0.07 (-0.09 to 0.11) p = 0.41 | 0.3 (-0.2 to 0.5) p = 0.39 | -0.2 (-0.5 to 0.45) p = 0.92 | -0.5 (-1.2 to 0.4) p = 0.07 | 0.45 (-0.31 to 0.67) p = 0.67 | -0.34 (-0.67 to 0.46) p = 0.93 | -1.1 (-2.3 to 3.4) p = 0.65 | -0.4 (-0.7 to 0.6) p = 0.88 |
| Improvement in 6MWT | -3.2 (-5 to 1.4) p = 0.34 | -1.3 (-4.5 to 0.5) p = 0.06 | 0.1 (-0.6 to 0.9) p = 0.56 | 0.45 (-0.3 to -0.98) p = 0.76 | -0.02 (-0.08 to 0.10) p = 0.75 | -0.2 (-0.5 to 01) p = 0.87 | 0.98 (-1.01 to 3.01) p = 0.67 | -0.18 (-0.64 to 0.27) p = 0.49 | -0.5 (-0.9 to -0.1) p = 0.03 |
| Improvement in LVEF | 0.36 (-0.35 to 1.10) p = 0.67 | 0.17 (-0.02 to 0.19) p = 0.056 | -0.007 (-0.011 to 0.41) p = 0.93 | 0.07 (-0.16 to 0.32) p = 0.87 | -0.2 (-0.34 to -0.1) p = 0.003 | 0.006 (-0.02 to 0.04) p = 0.96 | -0.14 (-0.4 to 0.18) p = 0.39 | -0.011 (-0.09 to 0.4) p = 0.67 | 0.004 (-0.11 to 0.45) p = 0.78 |
| Reduction in LVEDV | -0.2(-3.8 to 3.4) p = 0.71 | -0.62 (-1.77 to 0.5) p = 0.28 | -0.18 (-1.2 to 0.56) p = 0.76 | -0.8 (-0.92 to 0.45) p = 0.67 | 0.75 (0.12 to 1.38) p = 0.004 | -0.03 (-0.07 to 0.19) p = 0.94 | -0.13 (-1.7 to 1.4) p = 0.86 | -0.05 (-0.1 to 0.34) p = 0.56 | -0.14 (-0.21 to 0.35) p = 0.85 |
| Reduction in LVESV | 3.7 (-9.1 to 17.2) p = 0.98 | -1.13 (-2.14 to 0.98) p = 0.45 | -4.4 (-9.1 to 0.65) p = 0.93 | 0.21 (-0.98 to 1.43) p = 0.67 | 4.15 (1.7 to 6.2) p <0.001 | 0.45 (-0.67 to 1.23) p = 0.45 | -3.98 (-5.67 to 4.5) p = 0.45 | 0.8 (-0.5 to 2.2) p = 0.45 | -1.1 (1-.56 to -0.45) p<0.001 |
| Reduction in sPap (mmHg) | -0.3 (-1.1 to 0.45) p = 0.34 | -0.28 (-0.45 to 0.56) p = 0.45 | 0.08 (-0.14 to 0.91) p = 0.57 | 0.45 (-0.67 to 0.91) p = 0.91 | 0.45 (-0.38 to 4.5) p = 0.67 | -0.13 (-0.45 to 0.98) p = 0.36 | -0.18 (-0.81 to 0.44) p = 0.98 | -0.07 (-0.23 to 0.07) p = 0.67 | 0.0068 (-0.45 to 0.71) p = 0.67 |
