Abstract
Background
Mitral transcatheter edge-to-edge repair (MTEER) and guideline-directed medical therapy (GDMT) may be used to treat functional mitral regurgitation (FMR) with heart failure (HF). The optimal management of FMR is unclear.
Methods
We performed a contemporary systematic review and meta-analysis comparing MTEER vs GDMT. PubMed, Embase, and Cochrane Central were systematically searched for randomized controlled trials and propensity score matched studies comparing outcomes of MTEER plus GDMT vs GDMT alone in FMR with HF. Odds ratios and risk ratios (RRs) with 95% CI were estimated using random-effects models.
Results
Three randomized controlled trials and 5 propensity score matched studies were identified (n = 2588) comparing MTEER (52.2%) vs GDMT alone (47.8%) for FMR with HF. MTEER was associated with lower risks of 12-month all-cause mortality (RR, 0.74; 95% CI, 0.58-0.95; P = .02), cardiovascular mortality (RR, 0.59; 95% CI, 0.38-0.93; P = .02), and HF hospitalization (RR, 0.64; 95% CI, 0.48-0.86; P < .001) compared with GDMT alone. Additionally, the MTEER group was more likely to achieve New York Heart Association class I/II at 12 months (odds ratio, 2.11; 95% CI, 1.48-2.99; P < .01) than the GDMT group. In contrast, the GDMT group had a significantly lower risk of mitral regurgitation recurrence than the MTEER group (RR, 2.20; 95% CI, 1.79-2.71; P < .01). There was no statistically significant difference in the risk of myocardial infarction or stroke between the groups.
Conclusion
MTEER reduced all-cause cardiovascular mortality and HF hospitalization in patients with FMR and HF compared with GDMT alone. Additionally, MTEER resulted in a significant improvement in functional status in these patients.
Keywords: heart failure, mitral transcatheter edge-to-edge repair, mitral valve, transcatheter
Introduction
Functional mitral regurgitation (FMR) is common among patients with heart failure (HF) and is associated with a poor prognosis.1 Mitral regurgitation (MR) is described as ‘functional’ or ‘secondary’ when the etiology of valve dysfunction is related to abnormalities in the morphology of the left atrium, left ventricle (LV), or mitral valve annulus.2 Higher grades of FMR are associated with worsening New York Heart Association (NYHA) functional class, larger LV and left atrium, and lower LV ejection fraction, resulting in greater mortality.3,4 Surgical treatment is not indicated for isolated FMR.5 Mitral transcatheter edge-to-edge repair (MTEER) was originally indicated for degenerative or primary MR but offers a promising therapy for FMR.6 However, conflicting evidence exists regarding the efficacy of MTEER plus guideline-directed medical therapy (GDMT) vs GDMT alone.1,7
Recently, 3 large, randomized controlled trials (RCTs) explored the role of MTEER as a first-line therapy for FMR in patients with HF. The MITRA-FR trial reported that MTEER did not decrease the rate of death from any cause or hospitalization for HF.8 In contrast, the COAPT and the RESHAPE-HF2 trials reported that MTEER led to both a lower rate of death from any cause and fewer hospitalizations for HF.1,9 In light of the inconsistent findings from these RCTs regarding the efficacy of MTEER for FMR, we sought additional information from nonrandomized studies that utilized propensity score matching (PSM) to increase statistical power while keeping confounding to a minimum.
Previous meta-analyses evaluating the efficacy of MTEER in patients with FMR and HF have included a smaller number of patients, disregarded PSM studies, and were published before RESHAPE-HF2.1,10, 11, 12 Given residual uncertainty about the outcomes of MTEER for FMR and the additional data available, we conducted a systematic review and updated meta-analysis assessing the clinical outcomes of these 2 approaches in patients with FMR and concomitant HF.
Methods
This systematic review and meta-analysis was performed following the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines (Supplemental Tables S1 and S2).13,14 The study protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024618251).
Search strategy and data extraction
PubMed, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception through September 15, 2024, with the search terms presented in Supplemental Table S3. Titles and abstracts were reviewed. Studies that did not meet the inclusion criteria were excluded, and all abstracts deemed potentially eligible were subjected to full text review by 2 authors (L.B. and A.N.). Two authors (L.B. and A.F.) independently extracted and organized data using standardized tables for predefined data elements and quality assessment metrics. Disagreements were resolved by consensus in consultation with a third author.
Eligibility criteria
Included studies needed to fulfill the following eligibility criteria: (1) RCT or PSM studies published in the indexed databases; (2) studies comparing with MTEER plus GDMT vs GDMT; (3) studies involving patients with FMR with HF; and (4) studies reporting at least one of the outcomes of interest. Studies were excluded based on the following criteria: (1) lack of a control group; (2) overlapping patient populations; (3) studies not involving patients with FMR with HF; (4) observational studies without PSM; and (5) meeting abstracts and case reports. There were no limitations on study language.
End points, subgroups, and sensitivity analysis
Outcomes of interest included 12- and 24-month all-cause mortality, cardiovascular mortality, HF hospitalization, NYHA functional class I/II at 12 months, 2+ or higher MR recurrence, myocardial infarction (MI), and stroke.
Two prespecified subgroup analyses were performed: (1) data stratified by type of study (RCT, PSM); and (2) data stratified by duration of follow-up (12 months, 24 months).
Additionally, 3 prespecified sensitivity analyses were performed: (1) pooled hazard ratios (HR) for the primary end point; (2) data limited to 12- or 24-month follow-up when applicable; and (3) leave-one-out sensitivity analyses, which analyze the effect of each individual study on the overall effect size to ensure that the result is not heavily influenced by study weight. Heterogeneity was assessed using R2 statistics, and a 2-tailed P value < .05 indicated statistical significance. Furthermore, a scatter plot figure was plotted to correlate potential baseline echocardiographic parameters (LV ejection fraction, end-diastolic dimensions, end-diastolic and systolic volume) that may contribute to overall effect size.
Quality assessment
Quality assessment was performed using the Cochrane Collaboration tool for assessing the risk of bias in randomized trials (RoB-2) and nonrandomized studies (ROBINS-I). Studies were scored as high, low, or unclear risk of bias in 5 domains for RCT: selection, performance, detection, attrition, and reporting biases. Nonrandomized studies were scored as having no information, critical, serious, moderate, and low risk in 7 domains: confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported result.15,16 Bias risk assessment was conducted independently by 2 authors (C.P. and E.B.). Discrepancies were resolved in consultation with a third author.
Statistical analysis
Binary end point data were aggregated using Mantel-Haenszel random-effects models to generate risk ratio (RR) and 95% CI. The DerSimonian and Laird method was used to calculate heterogeneity variance, tau.2 Heterogeneity was assessed with I2 statistics. I2 values of 0%, ≤25%, ≤50%, and >50% were assigned the descriptors of no observed, low, moderate, and substantial heterogeneity, respectively.17 Single-armed meta-analysis was performed using the inverse variance method with the arcsine or logit transformation, and proportions were reported as measures of prevalence. R version 4.3.2 (R Foundation for Statistical Computing) and the extension packages ‘meta’ and ‘dmetar’ were used for all calculations and graphics.18,19
Results
Study selection and characteristics
The systematic review identified 3 RCT1,8,9 and 5 PSM studies20, 21, 22, 23, 24 for meta-analysis (Figure 1, Central Illustration), including a total of 2588 patients, of whom 1351 received MTEER plus GDMT and 1237 received GDMT alone. Three studies reported a 24-month follow-up, whereas 5 reported a 12-month follow-up. The mean age was 71.8 ± 10.7 years, and the percentage of male participants was 68.9%. A total of 34.2% of patients had diabetes mellitus, and 47.5% of patients had a history of atrial fibrillation or atrial flutter. The mean LV ejection fraction of the patients was 34.3 ± 11.4%. GDMT requirements were defined by the individual studies but frequently included beta blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers, mineralocorticoid receptor antagonists, and diuretics. Sodium-glucose cotransporter 2 inhibitors were not widely used, as they were not approved for most of the enrollment period of these studies, limiting their availability and inclusion in the data. Detailed baseline characteristics of the included studies are presented in Table 1.
Figure 1.
PRISMA flow diagram of study screening and selection.
Central Illustration.
Summary of outcomes comparing MTEER plus GDMT vs GDMT alone in patients with FMR and HF across 3 RCTs and 5 propensity-matched studies (n = 2588). MTEER was associated with reduced mortality and HF hospitalization, improved NYHA class, but a higher rate of residual mitral regurgitation ≥2+. FMR, functional mitral regurgitation; GDMT, guideline-directed medical therapy; HF, heart failure; MTEER, mitral transcatheter edge-to-edge repair; NYHA, New York Heart Association; PSM, propensity score matched; RCT, randomized controlled trial; RR, risk ratio.
Table 1.
Baseline characteristics
| Studies | RESHAPE-HF21 | COAPT trial8 | MITRA-FR9 | Giannini et al20 | Asgar et al21 | Armeni et al22 | Velazquez et al23 | Swaans et al24 | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Groups | MTEER | GDMT | MTEER | GDMT | MTEER | GDMT | MTEER | GDMT | MTEER | GDMT | MTEER | GDMT | MTEER | GDMT | MTEER | GDMT |
| Type of study | RCT | RCT | RCT | PSM | PSM | PSM | PSM | PSM | ||||||||
| Follow-up | 24 mo | 24 mo | 12 mo | 12 mo | 12 mo | 12 mo | 12 mo | 12 mo | ||||||||
| Number of patients | 250 | 255 | 302 | 312 | 152 | 152 | 60 | 60 | 50 | 42 | 232 | 151 | 198/239a | 217/239a | 107/139a | 48/59a |
| Age, y | 70.0 ± 10.4 | 69.4 ± 10.7 | 71.7 ± 11.8 | 72.8 ± 10.5 | 70.1 ± 10.1 | 70.6 ± 9.9 | 74 ± 8 | 76 ± 8 | 75.4 ± 9.1 | 68.2 ± 15.5 | 71 ± 10 | 71 ± 11 | 73.7 ± 10.5 | 73.7 ± 11.0 | 74.6 ± 9.4 | 71.7 ± 9.6 |
| Male | 195 (78.0) | 211 (82.8) | 201 (66.6) | 192 (61.5) | 120 (78.9) | 107 (70.4) | 42 (70) | 38 (63) | 37 (74) | 33 (77) | 171 (73) | 112 (74) | 143 (59.8) | 130 (54.4) | 94 (67.6) | 32 (54.2) |
| Body mass index | 27.0 ± 4.3 | 26.7 ± 4.3 | 27.0 ± 5.8 | 27.1 ± 5.9 | — | — | 25 ± 4 | 26 ± 3 | — | — | 26 ± 4 | 25 ± 5 | 27.3 ± 13.3 | 27.0 ± 5.48 | 25.9 ± 4.7 | 26.5 ± 4.5 |
| History of hypertension | 141 (56.4) | 127 (49.8) | 243 (80.5) | 251 (80.4) | — | — | 39 (65) | 32 (53) | 29 (58) | 24 (57) | 191 (82) | 74 (49) | 210 (87.9) | 195 (81.6) | 74 (53.2) | 25 (42.4) |
| History of diabetes mellitus | 91 (36.4) | 85 (33.3) | 106 (35.1) | 123 (39.4) | 50 (32.9) | 39 (25.7) | 17 (28) | 18 (30) | 21 (42) | 13 (31) | 67 (30) | 44 (29) | 94 (39.5) | 105 (43.9) | 32 (23) | 17 (28.8) |
| History of hyperlipidemia | — | — | 166 (55.0) | 163 (52.2) | — | — | — | — | — | — | 140 (61) | 43 (28) | — | — | — | — |
| History of stroke or TIA | 29 (11.6) | 30 (11.8) | 56 (18.5) | 49 (15.7) | — | — | 1 (1.6) | 0 (0) | — | — | 19 (8) | 12 (8) | 34 (14.2) | 36 (15.1) | — | — |
| Previous chronic obstructive pulmonary disease | — | — | 72 (23.5) | 71 (23.1) | — | — | 15 (25) | 12 (20) | — | — | 58 (25) | 31 (21) | 22 (9.2) | 23 (9.6) | 31 (22.3) | 19 (32.2) |
| History of coronary artery disease | — | — | — | — | — | — | 27 (45) | 35 (58) | 39 (78) | 30 (71) | — | — | — | — | 89 (64.0) | 45 (76.3) |
| Prior myocardial infarction | 144 (57.6) | 135 (52.9) | 156 (51.7) | 160 (51.3) | 75 (49.3) | 52 (34.2) | 22 (37) | 23 (38) | — | — | 105 (45) | 75 (50) | 124 (52.1) | 109 (45.6) | 72 (51.1) | 25 (42.4) |
| Prior coronary revascularization | — | — | — | — | 71 (46.7) | 64 (42.1) | — | — | — | — | 51 (22) | 77 (50) | — | — | — | — |
| Prior percutaneous coronary intervention | 118 (47.2) | 125 (49.0) | 130 (43.0) | 153 (49.0) | — | — | 17 (28) | 21 (35) | 20 (40) | 14 (33) | — | — | — | — | 41 (29.5) | 9 (15.3) |
| History of atrial fibrillation/atrial flutter | 118 (47.2) | 125 (49.0) | 173 (57.3) | 166 (53.2) | 49 (32.2) | 48 (31.6) | 21 (35) | 23 (46) | 29 (58) | 27 (64) | 77 (33) | 50 (33) | 137 (64.9) | 139 (58.2) | 74 (53.2) | 24 (40.7) |
| History of ischemic cardiomyopathy | 162 (64.8) | 167 (65.5) | 184 (60.9) | 189 (60.6) | 95 (62.5) | 85 (55.9) | — | — | — | — | — | — | — | — | — | — |
| History of non-ischemic cardiomyopathy | 88 (35.2) | 88 (34.5) | 118 (39.1) | 123 (39.4) | 57 (37.5) | 66 (43.4) | — | — | — | — | — | — | — | — | — | — |
| ACEi | — | — | — | — | 111 (73.0) | 113 (74.3) | 42 (70) | 35 (58) | 22 (44) | 18 (43) | 125 (54) | 106 (70) | — | — | — | — |
| Beta-blockers | — | — | — | — | 134 (88.2) | 138 (90.8) | 40 (67) | 41 (68) | 43 (86) | 35 (83) | 158 (68) | 128 (85) | — | — | — | — |
| Aldosterone antagonists | — | — | — | — | 86 (56.6) | 80 (52.6) | 35 (58) | 27 (45) | 25 (50) | 26 (62) | 153 (66) | 98 (65) | — | — | — | — |
| Diuretics | — | — | — | — | 151 (99.3) | 149 (98.0) | 56 (93) | 52 (87) | 44 (88) | 36 (86) | — | — | — | — | — | — |
| History of cardiac resynchronization therapy | 77 (30.8) | 68 (26.7) | 115 (38.1) | 109 (34.9) | 46 (30.2) | 35 (23.0) | 24 (40) | 18 (30) | 10 (20) | 6 (14) | 47 (21) | 24 (16) | — | — | 30 (21.6) | 2 (3.4) |
| LV ejection fraction (%) | 31.6 ± 8.2 | 31.0 ± 8.9 | 31.3 ± 9.1 | 31.3 ± 9.6 | 33.3 ± 6.5 | 32.9 ± 6.7 | 36.2 ± 17.5 | 34.0 ± 10.6 | 38.3 ± 15.8 | 31.8 ± 13.6 | 34 ± 13 | 32 ± 10 | 41.5 ± 12.0 | 42.0 ± 10.7 | 36.8 ± 15.3 | 34.5 ± 16.5 |
| LV end-diastolic dimension (cm) | — | — | 6.2 ± 0.7 | 6.2 ± 0.8 | — | — | 6.4 ± 1.1 | 6.4 ± 7 | — | — | — | — | — | — | — | — |
| LV end-systolic volume (mL) | — | — | 135.5 ± 56.1 | 134.3 ± 60.3 | — | — | 187 ± 70 | 178 ± 54 | — | — | — | — | — | — | — | — |
| LV end-diastolic volume (mL) | 200.7 ± 71.6 | 204.6 ± 68.6 | 194.4 ± 69.2 | 191.0 ± 72.9 | 136.2 ± 37.4 ↟ | 134.5 ± 33.1↟ | 106.9 ± 63.0 | 115.1 ± 52.4 | — | — | — | — | — | — | — | — |
| NYHA class III | 150 (60.0) | 153 (60.0) | 154 (51.0) | 168 (54.0) | 82 (53.9) | 96 (63.2) | 36 (60) | 39 (66) | 16 (32) | 9 (21.4) | — | — | 187 (78.2) | 190 (79.8) | 91 (65.5) | 35 (59.3) |
| NYHA class IV | 41 (16.4) | 36 (14.1) | 18 (6.0) | 33 (10.6) | 14 (9.2) | 12 (7.9) | 8 (13) | 6 (10) | 33 (66) | 0 (0) | — | — | 32 (23.0) | 16 (27.1) | ||
| 3+ MR | 141 (56.4) | 141 (55.3) | 148 (49.0) | 172 (55.3) | — | — | 27 (45) | 30 (53) | 29 (58) | 32 (76) | — | — | — | — | — | — |
| 4+ MR | 109 (43.6) | 114 (44.7) | 154 (51.0) | 139 (44.6) | — | — | 33 (55) | 21 (37) | 21 (42) | 10 (24) | — | — | — | — | — | — |
Data are expressed as mean ± SD, median (IQR), or absolute numbers (%).
ACEi, angiotensin converting enzyme inhibitors; LV, left ventricular; MR, mitral regurgitation; MT, medical therapy; MTEER, mitral transcatheter edge-to-edge repair; NYHA, New York Heart Association; TIA, transient ischemic attack.
Functional mitral regurgitation patients/total population of study.
Pooled analysis
MTEER plus GDMT was associated with a lower risk of all-cause mortality at 12 months (RR, 0.74; 95% CI, 0.58-0.95; P = .02; I2 = 53%; Figure 2A) but there were no significant differences at 24 months (RR, 0.80; 95% CI, 0.63-1.02; P = .07; I2 = 0%; Figure 2B) compared with GDMT alone. The risk of cardiovascular mortality was lower in the MTEER group (RR, 0.59; 95% CI, 0.38-0.93; P = .02; I2 = 84%; Figure 3). Additionally, the risk of HF hospitalization was lower in the MTEER group (RR, 0.64; 95% CI, 0.48-0.86; P < .01; I2 = 88%; Figure 4). MTEER treatment was associated with a higher likelihood of achieving NYHA functional class I/II at 12 months (odds ratio, 2.11; 95% CI, 1.48-2.99; P < .01; I2 = 34%; Figure 5). However, MTEER was associated with a substantial proportion of MR recurrence with MR severity grade ≥2+ at 12 months (90.94%; 95% CI, 85.1-95.5; P = .01; I2 = 73%; Figure 6A), with a higher risk of MR grade ≥2+ at 12 months than the GDMT group (RR, 2.20; 95% CI, 1.79-2.71; P < .01; I2 = 52%; Figure 6B). There were no significant differences between groups in terms of MI (Figure 7A) or stroke (Figure 7B).
Figure 2.
MTEER plus GDMT reduced all-cause mortality in patients with mitral regurgitation with heart failure compared with GDMT alone at 12 months (A), but there were no significant differences at 24 months (B). GDMT, guideline-directed medical therapy; IV, inverse variance; MTEER, mitral transcatheter edge-to-edge repair; PSM, propensity score matched; RCT, randomized controlled trial; RR, risk ratio.
Figure 3.
MTEER plus GDMT reduced cardiovascular mortality in patients with mitral regurgitation with heart failure compared with GDMT alone. GDMT, guideline-directed medical therapy; IV, inverse variance; MTEER, mitral transcatheter edge-to-edge repair; PSM, propensity score matched; RCT, randomized controlled trial; RR, risk ratio.
Figure 4.
MTEER plus GDMT reduced overall heart-failure hospitalization in patients with mitral regurgitation with heart failure compared with GDMT alone. GDMT, guideline-directed medical therapy; IV, inverse variance; MTEER, mitral transcatheter edge-to-edge repair; PSM, propensity score matched; RCT, randomized controlled trial; RR, risk ratio.
Figure 5.
MTEER plus GDMT was associated with a higher likelihood of achieving NYHA functional class I/II at 12 months than GDMT alone. GDMT, guideline-directed medical therapy; IV, inverse variance; MTEER, mitral transcatheter edge-to-edge repair; NYHA, New York Heart Association; OR, odds ratio.
Figure 6.
MTEER plus GDMT was associated with a higher risk at 12 months than GDMT alone (A) and with a substantial proportion of class 2 or greater mitral regurgitation recurrence at 12 months (B). GDMT, guideline-directed medical therapy; IV, inverse variance; MTEER, mitral transcatheter edge-to-edge repair; RR, risk ratio.
Figure 7.
There were no significant differences between the 2 groups in terms of myocardial infarction (A) or stroke (B). GDMT, guideline-directed medical therapy; IV, inverse variance; MTEER, mitral transcatheter edge-to-edge repair; RR, risk ratio.
Subgroups
Randomized controlled trials
In a subgroup analysis including only RCT, MTEER demonstrated no significant difference in risk of either all-cause mortality at 12 months (RR, 0.93; 95% CI, 0.75-1.14; P = .48; I2= 0%; Figure 2A) or cardiovascular mortality (RR, 0.82; 95% CI, 0.61-1.10; P = .19; I2 = 51%; Figure 3). However, MTEER patients had a decreased risk of HF hospitalization (RR, 0.71; 95% CI, 0.53-0.95; P = .02; I2 = 89%; Figure 4) compared with patients who received GDMT alone.
12-month follow-up
In the patient cohort with 12-month follow-up, there was no statistically significant difference in cardiovascular mortality (RR, 0.49; 95% CI, 0.21-1.14; P = .10; I2 = 90%; Supplemental Figure S1A) or HF hospitalization (RR, 0.56; 95% CI, 0.15-2.04; P = .38; I2 = 92%; Supplemental Figure S1A).
24-month follow-up
In the patient cohort with 24-month follow-up, there was no statistically significant difference in cardiovascular mortality but a strong trend toward significance (RR, 0.74; 95% CI, 0.55-1.00; P = .05; I2 = 42%; Supplemental Figure S1B). MTEER was associated with a reduced risk of HF hospitalization at 24 months (RR, 0.60; 95% CI, 0.55-0.66; P < .02; I2 = 0%; Supplemental Figure S1B) compared with GDMT alone.
Sensitivity analyses
In a sensitivity analysis of precalculated HR, results were similar to the primary analysis showing reduced all-cause mortality at 12 months (HR, 0.69; 95% CI, 0.50-0.95; P = .02; I2 = 53%; Supplemental Figure S2A) and 24 months (HR, 0.66; 95% CI, 0.53-0.83; P < .01; I2 = 0%; Supplemental Figure S2B) among patients in the MTEER plus GDMT group compared with GDMT alone.
Results of the leave-one-out sensitivity analysis are reported in Supplemental Figure S3.
Scatter plot representation of the relationship between baseline echocardiographic parameters with the overall effect sizes for all-cause mortality and HF hospitalization is shown in Supplemental Figure S4. Steeper horizontal lines across the x-axis denote a suspected strong relationship between the baseline variable and the overall effect size.
Quality assessment
The individual assessment of RCT and observational studies is reported in Supplemental Figures S5 and S6. All 3 RCTs were classified as having concerns due to the nature of the intervention, which made it impossible to blind both the providers and the patients, despite efforts to mitigate the overall risk of bias in the studies. In the assessment of observational studies, 3 studies were classified as having some concerns, 1 as serious and 1 as critical, related to patient selection for the studies.
Discussion
In this systematic review and meta-analysis of 3 RCTs and 5 PSM studies including 2588 patients, we compared the efficacy of MTEER plus GDMT vs GDMT alone in patients with FMR with HF. The main findings from the pooled analysis were: (1) MTEER was associated with a reduced risk of all-cause mortality at 12 months, cardiovascular mortality, and HF hospitalization; (2) the MTEER group demonstrated a higher likelihood of achieving NYHA functional class I/II at 12 months; (3) a greater proportion of patients who underwent MTEER showed MR severity grade ≥2+ compared with the control group; and (4) there was no significant difference between groups in the risk of MI or stroke.
Reduced mortality and HF hospitalization
The analysis of all-cause mortality and cardiovascular mortality in our meta-analysis demonstrated that MTEER combined with GDMT resulted in a significant reduction in the risk of all-cause mortality at 12 months (P = .02) but not at 24 months (P = .07) compared with GDMT alone. Additionally, the risk of cardiovascular mortality was also significantly reduced (P = .02). These results are consistent with a meta-analysis analyzing RCT and PSM studies that found a significant reduction in all-cause mortality, although an analysis of RCT alone showed no statistical significance in this outcome.25,26 The results observed in individual trials such as COAPT9 and MITRA-FR8 suggest that the clinical benefits may vary depending on disease severity and the nature of the studied population. The COAPT study, for example, showed that the combination of transcatheter repair with GDMT was associated with a significant reduction in all-cause mortality at 24 months. Moreover, the reduction in mortality was observed regardless of the degree of MR or LV function. These findings indicate that mitral repair may be more effective in patients with severe HF who are at high risk of death due to LV overload.
In contrast, the MITRA-FR study did not find a significant reduction in all-cause mortality with MTEER, suggesting that the severity of HF and the presence of comorbidities, such as underlying cardiomyopathy, may influence clinical outcomes.27,28 Indeed, all-cause mortality was high in the MITRA-FR control group (29.6% at 2 years), though much lower than that observed in COAPT (46.1% in the control group), which may reflect a population of patients with less disease severity. This finding highlights the importance of identifying subgroups of patients who may benefit most from MTEER, such as those with severe HF and secondary MR that are difficult to control with GDMT alone. Another relevant point is that the optimized GDMT approach was highly effective in the control group, particularly with the use of angiotensin-neprilysin receptor inhibitors, which became available during some trials. This may have attenuated the potential additional benefits of transcatheter repair in certain clinical scenarios, as observed in MITRA-FR. The high quality of GDMT, with adherence to current guidelines, may have influenced the smaller difference between the treatment groups, as suggested by the study’s results.
Two previous meta-analyses found a 37% reduction in the risk of hospitalization for HF in patients undergoing MTEER compared with GDMT.25, 26 This result is consistent with our analysis, which found a 36% reduction in risk. A physiologically based analysis that examined hemodynamic changes immediately after MTEER demonstrated that despite the acute increase in LV afterload, the reduction in hemodynamic parameters of ventricular wall stress outweighed this increase, resulting in significant increases in cardiac index and reductions in pulmonary pressures. The increase in cardiac index contributes to the reduction of multiorgan failure resulting from hypoperfusion, improving the prognosis of these patients by reducing hospitalizations due to acute decompensations, which are associated with unfavorable outcomes in these patients.29,30
Improved functional status
Furthermore, our study found a significantly higher likelihood of achieving NYHA functional class I/II in patients undergoing MTEER, which is consistent with the COAPT trial and RESHAPE-HF but was not observed in MITRA-FR. As previously observed, increased cardiac index is associated with favorable medium-term clinical and echocardiographic outcomes.29
Residual MR
In our analysis, patients undergoing MTEER demonstrated a higher proportion of recurrence of MR severity grade ≥2+, associated with an increased risk compared with the control group. A recent meta-analysis comparing MTEER with surgical treatment for this same population demonstrated that patients undergoing MTEER had a higher frequency of residual moderate-to-severe MR and a higher need for reintervention.31,32 Consequently, such a result can be explained by previous studies having found a low success rate of the MTEER procedure6; however, with the accumulation of experience in performing the procedure, current success rates exceed 90%.33 Durability and recurrent MR have direct clinical implications. Observational studies indicate that residual or recurrent MR grade ≥2+ after transcatheter edge-to-edge repair predicts worse long-term survival, emphasizing the need to target MR grade ≤1+ at discharge and over follow-up. Predictors of recurrence include residual MR grade 2+ (both primary and secondary MR), flail leaflet in primary MR, and larger left atrial volume in secondary MR; recurrence correlates with higher HF hospitalization and greater need for reintervention. These data support careful anatomic selection and procedural strategies aimed at durable MR reduction.34,35
MI and stroke
A recent meta-analysis found an increased risk of MI in patients undergoing MTEER compared with surgical treatment; however, there was no significant difference concerning stroke.32 Our analysis did not detect a significant difference between the MTEER and GDMT groups regarding the outcomes of MI and stroke. Nevertheless, due to these findings in the literature, a comprehensive analysis of the criteria for submitting such patients to this procedure is warranted.
Differences between study populations
In light of the present findings, differences in the individual studies’ results are particularly noteworthy; the individual study populations may suggest which patients are most likely to benefit from MTEER. Baseline differences in the study populations particularly in LV ejection fraction, LV end-diastolic dimension, LV diastolic volume, and LV systolic volume may affect the overall success of intervention with MTEER, particularly in the outcomes of all-cause mortality and HF hospitalization. Despite efforts to demonstrate a possible correlation between certain variables, particularly LV diastolic volume, and the overall effect size, our representation lacks statistical power to provide a firm conclusion. Further research with adequately powered subgroups is necessary to determine which FMR patients may benefit from MTEER.
Although not eligible for inclusion in our pooled analysis due to its single-arm, noncomparative design, the EXPAND G4 registry36 provides valuable real-world insight into MTEER outcomes in both primary and secondary MR. These data reinforce the safety and effectiveness of contemporary MitraClip systems in routine practice and complement evidence from randomized trials and PSM studies. Future studies integrating real-world registries with comparative data may help clarify appropriate patient selection and the durability of MTEER.
Future directions
The results of our meta-analysis reinforce the effectiveness of percutaneous mitral valve repair in reducing all-cause and cardiovascular mortality but also highlight that the timing of the intervention, the severity of HF, and the quality of GDMT are crucial factors in maximizing the benefits of this approach. Although MTEER appears promising for improving survival in patients with HF and secondary MR, it is important to consider each patient’s clinical profile and the timing of the intervention to optimize long-term outcomes. Future studies focusing on timing as well as different clinical profiles are crucial to confirm the role of MTEER in patients with FMR. Finally, although 5-year follow-up data are available from the COAPT trial,37 these were not included in the present analysis because comparable long-term outcomes were not reported in the remaining RCT and PSM studies; hence, future meta-analyses incorporating longer follow-up when possible are warranted.
Limitations and strengths
The present study has several important limitations. First, the sample size of our study may be underpowered. Nonetheless, this meta-analysis has, to our knowledge, the largest number of patients on the subject to date. Additionally, for the outcomes of all-cause mortality and cardiovascular mortality, significant heterogeneity was obtained, and we observed a significant difference in the data only when PSM studies were added to the analysis, which compromised our conclusions. Due to the absence of data on the number of patients hospitalized for the first time due to HF in several studies, it was not feasible to perform a specific analysis of this outcome. Accordingly, the investigation was confined to the assessment of overall HF hospitalizations. Finally, due to the lack of randomized or high-quality evidence, a meta-regression analysis was not feasible (n < 10) to statistically assess whether certain baseline characteristics led to a significant contribution to the overall effect size or overall heterogeneity. However, a scatter plot demonstration for visual correlation between baseline echocardiographic parameters and the overall effect size was implemented to highlight the importance of well-powered subgroups in future investigations.
Nonetheless, this study is considered the most comprehensive and up-to-date analysis of the population in question that includes high-quality evidence to improve understanding of MTEER outcomes compared with those of GDMT. The use of PSM studies enhances statistical power despite possessing some remnant confounding. However, the utilization of HRs, leave-one-out sensitivity analysis, study design, and length of follow-up subgroups that demonstrated similar results to the initial findings while eliminating follow-up-dependent responses enhances the robustness of these results.
Conclusion
MTEER plus GDMT is associated with lower all-cause mortality at 12 months, cardiovascular mortality, and HF hospitalization, and with a higher likelihood of achieving NYHA functional class I/II compared with GDMT alone. However, MTEER plus GDMT was also associated with a higher proportion of MR grade ≥2+ recurrence than GDMT alone. No significant difference was observed in the outcomes of MI and stroke. More RCT powered for subgroup analyses are needed to confirm which patients with FMR benefit from adding MTEER to GDMT.
Acknowledgments
All authors extend their gratitude to Rhanderson Cardoso, of Meta-Analysis Academy, for imparting the essential knowledge that made this work possible.
Peer review statement
Associate Editor Andrew M. Goldsweig had no involvement in the peer review of this article and have no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Editor-in-Chief Alexandra J. Lansky.
Declaration of competing interest
Amit N. Vora reports consulting for Medtronic and Edwards Lifesciences. Andrew M. Goldsweig reports speaking for Philips and consulting for Philips and Conformal Medical, which are unrelated to the present research. All other authors report no relationships that could be construed as a conflict of interest. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Funding sources
This work was not supported by funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement and patient consent
This article does not report on patients or patient data. Ethical approval and patient consent were not required.
Footnotes
To access the supplementary material accompanying this article, visit the online version of the Journal of the Society for Cardiovascular Angiography & Interventions at 10.1016/j.jscai.2025.104165.
Supplementary Material
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