Transcatheter Repair of Functional Mitral Regurgitation in Heart Failure Patients　― A Meta-Analysis of 23 Studies on MitraClip Implantation ―

Roberta De Rosa; Angelo Silverio; Cesare Baldi; Marco Di Maio; Costantina Prota; Ilaria Radano; Julia Rey; Eva Herrmann; Rodolfo Citro; Federico Piscione; Gennaro Galasso

doi:10.1253/circj.CJ-18-0571

Abstract

Background: The aim of this study was to investigate long-term survival, clinical status, and echocardiographic findings of patients with severe functional mitral regurgitation (FMR) undergoing MitraClip (MC) treatment and to explore the role of baseline features on outcome.

Methods and Results: Randomized and observational studies of FMR patients undergoing MC treatment were collected to evaluate the overall survival, New York Heart Association (NYHA) class and echocardiographic changes after MC treatment. Baseline parameters associated with mortality and echocardiographic changes were also investigated. Across 23 studies enrolling 3,253 patients, the inhospital death rate was 2.31%, whereas the mortality rate was 5.37% at 1 month, 11.87% at 6 months, 18.47% at 1 year and 31.08% at 2 years. Mitral regurgitation Grade <3+ was observed in 92.76% patients at discharge and in 83.36% patients at follow-up. At follow-up, 76.63% of patients NYHA Class I–II and there were significant improvements in left ventricular (LV) volume, ejection fraction, and pulmonary pressure. Atrial fibrillation (AF) had a significant negative effect on 1-year survival (β=0.18±0.06; P=0.0047) and on the reduction in LV end-diastolic and end-systolic volumes (β=−1.05±0.47 [P=0.0248] and β=−2.60±0.53 [P=0.0024], respectively).

Conclusions: MC results in durable reductions in mitral regurgitation associated with significant clinical and echocardiographic improvements in heart failure patients. AF negatively affects LV reverse remodeling and 1-year survival after MC treatment.

Functional mitral regurgitation (FMR) affects patients with a structurally normal mitral valve (MV) apparatus. Ischemic or non-ischemic left ventricular (LV) dysfunction, caused by an imbalance between the tethering and closing forces due to chamber dilatation, impairs MV continence.¹ For several years, FMR has been considered a surrogate of LV systolic pump failure, but only recently has it been identified as a strongly independent prognostic predictor of poor outcome.² Therefore, FMR has become a therapeutic target in patients with persistent symptomatic heart failure (HF) despite optimal medical therapy.¹ Surgical treatment has been the first interventional treatment for severe FMR, but its application is limited by the high percentage of patients deemed unsuitable for intervention and the results have not shown significant benefit in terms of functional clinical status and long-term survival.³^–⁵

In the past decade, transcatheter mitral valve repair (TMVr) by implantation of the MitraClip (MC; Abbott Laboratories, Lake Bluff, IL, USA) has emerged as an alternative strategy for the treatment of severe FMR in HF patients deemed unsuitable for surgery. However, the data available in the literature derive from multicenter registries or small retrospective and prospective studies. Large multicenter trials comparing transcatheter edge-to-edge MV repair to optimal medical therapy alone are currently underway but, due to the low recruitment rate and the need for long-term clinical follow-up, results are not expected for a few years.¹^,⁶

Thus, the evidence gap regarding the clinical performance of TMVr in FMR and the prognostic predictors of death remains in daily clinical practice. The aims of the present meta-analysis were to investigate long-term survival, clinical status, and echocardiographic findings of patients undergoing MC treatment, and to explore the prognostic effects of patients’ baseline characteristics on clinical and functional outcomes after the procedure.

Methods

Protocol

This study was designed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.⁷ The study protocol has been registered with PROSPERO (CRD42017081174).

Study Selection

A comprehensive search was conducted in the Medline, Cochrane, ISI Web of Sciences, and SCOPUS databases up to January 2017 of literature dealing with outcomes after MC in patients with severe or moderate-to-severe FMR. The following medical subject headings were used in the search, in different combinations: “mitral regurgitation” (MR), “mitral insufficiency”, “MC”, “TMVr”, “FMR”, “secondary MR”, “outcome”, “echocardiography” and “ventricular remodeling”. Citations were screened at the title and abstract level by two independent reviewers (A.S., C.P.), and reports that were potentially eligible for inclusion in the analysis were retrieved and the full text scrutinized. Differences in opinion were resolved by discussion and consultation with a third investigator (RDR). First, full-size articles published in English in peer-reviewed journals were considered for this meta-analysis. Second, were searched for abstracts from relevant scientific international meetings since 2014 to the present.

Randomized or observational matched studies were included in the analysis if they met the following criteria: (1) inclusion of patients with severe or moderate-to-severe FMR undergoing TMVr with MC; (2) reports of all-cause mortality after MC with a minimum of 30 days follow-up; and (3) availability of patient baseline data. Studies reporting only composite endpoints, but no specific data on all-cause mortality, and those with fewer 10 patients were excluded. For papers collecting overlapping data, those studies with the largest number of patients were selected for inclusion in the analysis.

Data Extraction

Three investigators (A.S., C.P., and R.D.R.) independently extracted data using an agreed predefined sheet reporting the first author, journal, year of publication, and the number of patients included. Disagreements were resolved by consensus among all investigators. The following baseline patient characteristics were collected from the selected studies: (1) demographic data, namely age and sex; (2) clinical data, such as New York Heart Association (NYHA) functional class, the presence of coronary artery disease (CAD), atrial fibrillation (AF), moderate-to-severe chronic kidney disease (CKD), diabetes, hypertension, and chronic obstructive pulmonary disease (COPD), logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) score, and the Society of Thoracic Surgeons (STS) score; and (3) echocardiographic features, such as LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF), and systolic pulmonary artery pressure (sPAP). MR grade at discharge was also reported.

Study Endpoints

The primary endpoint of this meta-analysis was all-cause mortality after MC at different time points after the procedure, namely in-hospital mortality and mortality after 30 days, 6 months, and 1 and 2 years.

Secondary endpoints were: (1) NYHA Class <III at a minimum of 6 months follow-up after MC implantation; (2) MR Grade 1+ or 2+ at discharge and at least at the 6-month follow-up; and (3) changes in LVEDV, LVESV, LVEF and sPAP from baseline to a minimum of 6 months follow-up.

Furthermore, among baseline demographic, clinical, and echocardiographic characteristics, parameters associated with overall mortality at different time points and with echocardiographic changes at follow-up were investigated.

Data Synthesis and Analysis

The meta-analysis was performed by estimating the mean survival rates over all studies at different time points using random effects models with a restricted maximum-likelihood estimator.⁸ This model accounts for the heterogeneity of studies in the analysis of mean survival rates. Studies with a larger sample size, and therefore a smaller standard error, received more weight when calculating the mean survival rates for the different time points. For studies with survival rates of 100%, the amplitude of the confidence interval (CI) was calculated as 3/(number of patients at risk). The survival rates of many studies were not given directly, but could be estimated from the survival curves. Standard errors (SEs) of some studies were estimated using Peto’s formula:⁹

SE=(survival rate×(1−survival rate)/no. patients at risk)^0.5

The individual study proportions of outcomes were converted using the Freeman-Tukey double arcsine transformation method before pooled analysis.¹⁰ The summarized proportions in the original scales were calculated as the back-transformation of the arcsine-transformed estimates. Furthermore, different meta-regressions were performed to analyze possible correlations at various time points between single study-level independent variables and survival rates.¹¹

Further random effects models were used to estimate the proportion of patients with an MR Grade ≤2+ at discharge and mid-term and an NYHA Class <III at follow-up, in addition to detect echocardiographic changes, in particular decreases in LVESV, LVEDV, and sPAP and increases in LVEF after the procedure. Then, meta-regression analyses were performed to identify possible clinical predictors of the echocardiographic changes.

The hypothesis of statistical heterogeneity was tested by means of Cochran Q statistic and I² values, with I² values <40%, 40–60% and >60% indicating low, moderate, and substantial heterogeneity, respectively.¹² A funnel plot of the survival rate was used to evaluate the presence of publication bias, heterogeneity of studies, or data irregularities. The significance of asymmetry was tested by a rank correlation test based on Kendall’s τ.¹³ Normally distributed continuous data are presented as the mean±SD, whereas skewed continuous data are presented as the median with interquartile range (IQR); categorical data are presented as percentages. All analyses were performed using R (R Foundation for Statistical Computing, Vienna, Austria), particularly the R package meta by G. Schwarzer (version 4.8-1) and the R package metafor by W. Viechtbauer (version 1.9-9).

Results

Of a total of 2,174 reports initially identified, 105 were retrieved for more detailed evaluation. Twenty-two published articles¹⁴^–³⁵ and 1 study presented at the EuroPCR 2015 conference,³⁶ enrolling a total of 3,253 patients with FMR undergoing TMVr with MC, were finally included in the analysis according to the prespecified selection criteria (Figure 1). The main demographic, clinical, and echocardiographic features of the studies are reported in Table.

Figure 1.

Flow diagram of the study selection process according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. FMR, functional mitral regurgitation; DMR, degenerative mitral regurgitation.

Table. Baseline Characteristics of the Study Population

Author	Journal	Year	Multicenter	Study design	No. patients	Age (years)	Male (%)	CAD (%)	AF (%)	Moderate- severe CKD (%)	DM (%)	COPD (%)	Log (EuroSCORE)	STS	LVEDV (mL)	LVESV (mL)	LVEF (%)	sPAP (mmHg)	NYHA III/IV at baseline (%)	MR 1+ or 2+ at discharge (%)
Auricchio et al¹⁴	J Am Coll Cardiol	2011	Yes	PERMIT-CARE registry	51	70.26±9.16	86	73	NA	70	22	29	29.7±19.4	13.9±14.6	238.7±72.2	174.5±61	27.1±8.7	44.6±11.7	98	84
Franzen et al¹⁵	Eur J Heart Fail	2011	Yes	Retrospective	50	70±11	76	56	NA	NA	NA	NA	34±21	NA	252±88	195±72	19±5	NA	100	91.7
Altiok et al¹⁶	Circ Cardiovasc Imaging	2012	No	Retrospective	39	73±9	61.5	66.7	61.5	NA	NA	NA	12±12	NA	205.1±105.3	NA	46±16	NA	100	97.4
Chan et al¹⁷	Circ J	2012	No	Prospective	12	71±14	75	NA	NA	NA	NA	NA	27±16	13±6	228±123	173±96	32±17	48±15	100	92
Conradi et al¹⁸	Eur J Cardiothorac Surg	2012	No	Retrospective	95	72.4±8.1	64.2	52.6	57.9	9.9	40	28.7	33.7±18.7	NA	NA	NA	36.2±12.5	NA	97.8	95.3
Perl et al¹⁹	Isr Med Assoc J	2013	No	Prospective	10	69.3±15.9	90	90	50	50	40	30	28.5±15.8	NA	NA	NA	36.5±9.4	56.8±18.9	100	NA
Rudolph et al²⁰	Eur J Heart Fail	2013	No	Prospective	140	73±9	71	73	61	63	37	23	27±20.74	5.3±3.33	212±86.7	132±8.9	37±13	NA	96	91.5
Aksu et al²¹	Türk Göğüs Kalp Dama	2014	No	Retrospective	15	60.8±13	80	73.3	NA	NA	33.3	NA	NA	NA	NA	NA	28.7±8.8	NA	100	97.4
Braun et al²²	Catheter Cardiovasc Interv	2014	No	Prospective	47	70.7±9.7	76.6	70.2	70.2	51.1	19.1	25.5	28±21.1	NA	192.6±73.5	125.2±63.5	35.2±12.9	NA	97.8	NA
Matsumoto et al²³	Am J Cardiol	2014	No	Retrospective	91	75.2±11.1	61.5	62.6	50.5	NA	33	18.7	NA	11.1±7.7	NA	NA	42.1±16.1	51.5±9.7	95.6	92.3
Melisurgo et al²⁴	Am J Cardiol	2014	No	Retrospective	75	69±9	84	NA	NA	NA	NA	NA	24±17	11±9	NA	NA	27±9	50±15	82	100
Nickening et al²⁵	J Am Coll Cardiol	2014	Yes	SENTINEL Registry	452	72.8±9.8	67.7	31.9	27.2	32.8	33.1	19.8	21.9±17.6	NA	171.1±90.2	116.3±71.3	37.1±13.6	44.2±13.2	88.5	98
Taramasso et al²⁶	EuroIntervention	2014	No	Retrospective	109	69±9	83.5	75	34	47	22	28	22±16.5	NA	202.3±63.8	NA	28±11	49±15	82	87
Capodanno et al²⁷	Am Heart J	2015	Yes	GRASP-IT Registry	240	71.1±6.8	68.3	60.8	41.7	57.1	37.9	21.7	NA	NA	189.6±85.1	132.9±75.3	32.6±11.4	48.1±13.4	17.9	91.25
Feldman et al³⁶	EuroIntervention	2015	Yes	EVEREST II REALISM	439	74±11	62	84	69	31	41	33	NA	10.4±6.9	162	NA	42±12	NA	86	NA
Schäefer et al²⁸	Am J Cardiol	2015	Yes	ACCESS-EU registry	388	73±8.9	67.9	68.2	69.3	48.1	34	20	24.8±18.9	NA	NA	NA	NA	NA	87.3	91.6
Schueler et al²⁹	EuroIntervention	2015	Yes	TRAMI registry	505	75±7.4	62.4	76	45.3	NA	31.3	22.3	20±14.07	6±5.2	NA	NA	NA	43±8.9	89.1	NA
Adamo et al³⁰	Eur J Heart Fail	2016	No	Retrospective	62	68.9±9.7	77.4	58.1	51.6	59.7	33.9	NA	20±14.6	NA	226.5±59.9	163±63.1	28.7±7.7	49.9±15	100	85.5
Azzalini et al³¹	Catheter Cardiovasc Interv	2016	No	Retrospective	77	71.4±10.3	77.9	81.8	53.2	NA	48.1	15.6	NA	NA	NA	NA	33±7	53.8±16.4	91	93.5
Giannini et al³²	Int J Cardiol	2016	No	Prospective	169	72.1±8.3	78	64	40	28	31.3	27	19.6±16.8	NA	NA	NA	31±9	50±13	77	92
Ondrus et al³³	Interact Cardiovasc Thorac Surg	2016	Yes	Retrospective	24	75±9	75	88	75	48	NA	NA	NA	NA	NA	NA	31±9	48±21	88	100
Tay et al³⁴	Catheter Cardiovasc Interv	2016	Yes	MARS Registry	88	70.4±10.1	68.2	71.6	47.7	28.3	37.5	12.5	19±14.4	8.8±9.3	NA	NA	36±12	45±19	78.4	95.5
Berardini et al³⁵	Int J Cardiol	2017	Yes	Prospective study	75	67±11	77	59	NA	66	39	19	23±18	13±11	229±79	166±69	30±9	50±14	100	84
Pooled population					3,253	72.5±9.3	68.8	65.6	50.7	41.5	34.6	23.4	23±17.2	8.7±7.1	187.3±72.7	134.7±66.5	35.3±11.8	46.6±13	83.7	91.3

Unless indicated otherwise, data are given as the mean±SD. AF, atrial fibrillation; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; EuroSCORE, European System for Cardiac Operative Risk Evaluation; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MR, mitral regurgitation; NYHA, New York Heart Association; sPAP, systolic pulmonary artery pressure; STS, Society of Thoracic Surgeons score.

Primary Endpoint

The mean rate of in-hospital death, calculated using data available from 15 studies, was 2.31% (95% CI 0.14–4.48). The percentage of all-cause death was 5.37 (95% CI 2.90–7.84; calculated on the basis of 16 studies) at 1 month, 11.87% (95% CI 8.60–15.30) at 6 months (13 studies), 18.47% (95% CI 15.59–21.35) at 1 year (16 studies), and 31.08% (95% CI 24.59–37.57) at 2 years (6 studies). There was no significant heterogeneity between the studies for all the time points considered (Figure 2).

Figure 2.

Forest plot for survival rates at different time points. Solid squares represent survival rates and their size is proportional to the sample size. The 95% confidence intervals (CI) for individual studies are denoted by lines, whereas those for the pooled survival rates are indicated by solid diamonds.

Secondary Endpoint

In the population analyzed, TMVr with MC effectively reduced MR in the vast majority of patients. Of 2252 patients who were candidates for MC implantation in 19 selected studies, 92.76% (95% CI 90.46–95.07) had Grade 1+ or 2+ residual MR at discharge. Furthermore, at a mean follow-up of 11.7±3.5 months (median 12.0 months; IQR 10.5–12.0 months), MR Grade <3+ was observed in 83.36% (95% CI 79.22–87.50) of patients (Figure 3). For the analysis of MR at discharge and at follow-up, there was no evidence of substantial heterogeneity among studies.

Figure 3.

Forest plot for mitral regurgitation (MR) Degree 1+ or 2+ at discharge and at follow-up. Solid squares represent survival rates and their size is proportional to the sample size. The 95% confidence intervals (CI) for individual studies are denoted by lines, whereas those for the pooled survival rates are indicated by solid diamonds.

Data referring to clinical status evaluated by NYHA class were extracted from 11 studies. After a mean follow-up of 11.5±5.0 months (median 12.0 months; IQR 7.5–12.0 months), 76.63% (95% CI 71.57–81.69) of patients were in NYHA Class I or II (Figure 4), with moderate heterogeneity between studies (I²=42.9%; P=0.07). The analysis of echocardiographic parameters included 13 studies reporting both baseline and follow-up data in order to evaluate dynamic changes over time after the MC procedure (Figure 5, Table S1). Two studies²⁷^,³² used for primary endpoint analysis but not reporting echocardiographic data to follow-up were replaced by two papers addressing the same cohorts but with a smaller size.³⁷^,³⁸ At a mean follow-up of 12.4±4.8 months (median 12.0 months; IQR 12.0–12.3 months), significant reductions were observed in LVEDV and LVESV of 21.96±4.94 mL (P<0.0001) and 15.32±7.44 mL (P=0.0395), respectively, that were associated with a substantial improvement in LVEF but a high grade of heterogeneity (2.40±1.12; P=0.0315; I²=69.19%). Mean baseline sPAP of 48.85±3.65 mmHg suggested clinically relevant pulmonary hypertension; at follow-up, there was a marked reduction in sPAP of 7.85±1.10 mmHg (P<0.0001), although moderate grade heterogeneity was recorded among the studies analyzed (I²=49.31%; P=0.0699).

Figure 4.

Forest plot for New York Heart Association (NYHA) Class I–II at follow-up. Solid squares represent survival rates and their size is proportional to the sample size. The 95% confidence intervals (CI) for individual studies are denoted by lines, whereas those for the pooled survival rates are indicated by solid diamonds.

Figure 5.

Echocardiographic changes at follow-up. Bar graphs showing changes (delta) in echocardiographic parameters from baseline to follow-up. LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; sPAP, systolic pulmonary artery pressure.

Predictors of Outcome

The detailed results of meta-regression analysis are reported in Tables S2 and S3. Meta-regressions of clinical and echocardiographic baseline features associated with overall death revealed a significantly high incidence of in-hospital death in patients with worse LVEF evaluated by echocardiography (β=−0.17±0.08 [P=0.0241]; I²=0% [P=0.7777]; Figure S1) and a reduced 1-year survival for subjects with COPD (β=0.44±0.22 [P=0.0429]; I²=8.96% [P=0.4858]; Figure S2). Analysis of the 13 studies reporting both AF prevalence at baseline and mortality rate at 12 months revealed a significant negative effect of AF on the overall survival rate at 1-year (β=0.18±0.06 [P=0.0047]; I²=11.02% [P=0.6421]). Furthermore, AF emerged as a negative predictor of reverse LV remodeling, as demonstrated by the significant negative effect on reduction in LVEDV (β=−1.05±0.47 [P=0.0248]; I²=0% [P=0.8004]) and LVESV (β=−2.60±0.53 [P=0.0024]; I²=0% [P=0.8180]; Figure 6). Eventually, meta-regressions for echocardiographic changes revealed that male patients develop a significant reduction in LVESV at follow-up (β=−1.93±0.77 [P=0.0129]; I²=0% [P=0.4710]; Figure S3).

Figure 6.

Predictive role of atrial fibrillation (AF) on 1-year mortality and on left ventricular (LV) reverse remodeling in patients with functional mitral regurgitation undergoing MitraClip (MC) implantation. Scatter plots showing the effects of AF on (A) 12-month mortality and changes in (B) left ventricular end-diastolic volume (LVEDV) and (C) left ventricular end-systolic volume (LVESVC) at follow-up in the study population.

Publication Bias

There was no evidence of significant publication bias for the primary endpoint, according to the rank correlation test of Begg and Mazumdar (τ=0.2167, P=0.2650).

Discussion

The present study-level meta-analysis of a large population of 3253 patients supports the role of MC in the management of HF patients with severe FMR and increases knowledge of their natural history. The main findings of this analysis are: (1) TMVr with MC in patients with FMR is associated with an acceptable rate of in-hospital death and long-term survival; (2) MC implantation reduces the grade of MR and improves NYHA class at follow-up; (3) MC induces LV reverse remodeling and reduces pulmonary pressures; (4) patients with lower LVEF are at higher risk of in-hospital death; (5) AF is negatively associated with 12-month survival and reductions in LVEDV and LVESV at follow-up; and (6) COPD is correlated with high 12-month mortality.

Primary Endpoint

The results of this study suggest that performing MC in very high-risk patients with FMR is safe, as demonstrated by the low incidence of in-hospital deaths. Conversely, over a wider time frame, the results emphasize the unfavorable clinical evolution of patients with advanced pump failure and severe FMR, as suggested by the high rate of occurrence of fatal events at long-term follow-up (18.47% at 12 months, 31.08% at 24 months). These data seem to diverge from the results of the Endovascular Valve Edge-to-Edge Repair Study (EVEREST II; all-cause mortality 6% at 1 year, 17.4% at 4 years), but closely reflect the outcome reported by the main European registries.³⁹^–⁴¹ The apparent discrepancy can be explained by the baseline characteristics of the EVEREST II cohort, which had a lower risk profile compared with the real-world populations enrolled in the post-approval registries, with lower mean age (67.3±12.8 years), few patients with NYHA Class III or IV (51.1%), higher LVEF (60.0±10.1%), and a lower burden of comorbidity in the former. Notably, one of the most important differences is the etiological distribution of MR in patients enrolled in EVEREST II (27% of secondary forms) compared with the European registries (>70%).⁴¹

The question arises as to whether MC is associated with a survival benefit in patients with HF and FMR compared with medical treatment alone. The outcome of FMR patients undergoing MC treatment vs. conservative medical therapy has not yet been investigated in large studies using a propensity analysis strategy. Furthermore, dedicated trials comparing MC results with those of optimal medical therapy are still ongoing. In order to address this therapeutic conundrum, we compared our data with the results of available studies addressing the long-term outcomes of medically treated HF patients with FMR. In the prospective multicenter Italian Network on Heart Failure (IN-HF) outcome registry, the 1-year mortality of patients with worsening chronic HF was 27.7%.⁴² In 1421 consecutive HF patients with severely reduced LVEF (≤35%), those with severe MR had 1- and 3-year survival rates of 59.3±3.4% and 34.7±5.1%, respectively.⁴³ Furthermore, in an HF population with reduced EF (n=2057 patients), Trichon et al⁴⁴ reported that, in the subgroup with moderate-to-severe MR, the overall survival rates at 1, 3 and 5 years were 72.9%, 51.4%, and 39.9%, respectively. Although not negligible, the long-term mortality rates arising from the present meta-analysis are considerably lower, shedding light on the long-term survival benefit of MC implantation in patients with severe FMR.

Secondary Endpoints

In this study, MR Grade 2+ or less was reported in most patients at discharge. This rate is markedly higher than that reported in EVEREST II (79%),⁴⁵ suggesting a pivotal role for the good learning curve of surgeons in recent years. Furthermore, procedural success is confirmed at follow-up, reinforcing the efficacy of the MC system reducing the volume of MR with a low incidence of recurrent moderate-to-severe MR.

This analysis showed a significant reduction in LV volumes and an increase in LVEF. Echocardiographic improvement after MC treatment has already been reported in small cohorts.¹⁴^,³⁸^,⁴⁵ In a population of 379 FMR patients enrolled in the EVEREST II cohorts, Grayburn et al⁴⁶ reported a reduction in LVEDV from 166.5±51.8 to 150.7±49.4 mL and in LVESV from 95.6±41.0 to 87.4±40.6 mL. The LV reverse remodeling was significantly associated with the amount of MR reduction at 12 months and the balanced reduction of LV volumes did not result in a significant change in LVEF.⁴⁶ Although the results of the present analysis left some doubt about the possibility of obtaining reductions in LV volume even in patients with more severe LV dysfunction due to a mean LVEF of 44±11%, our analysis confirms the occurrence of LV reverse remodeling in a wide pooled population with markedly lower baseline systolic function (mean LVEF 35.2±11.8%).

AF as a Predictor of Outcome

In a post-hoc analysis of EVEREST II data, which primarily enrolled patients with degenerative MR, Herrmann et al⁴⁷ reported a substantially similar survival rate in patients with and without AF. Of note, AF patients had an older age and higher baseline prevalence of functional etiology, comorbidities, and NYHA Class III or IV than the non-AF subgroup. Conversely, in the transcatheter mitral valve interventions (TRAMI) registry, patients with pre-existing AF had significantly lower survival than patients in sinus rhythm (74.9% vs. 83.5% respectively; P<0.05).⁴⁸ In that cohort, AF was not associated with a different baseline clinical profile, but was an independent predictor of 1-year mortality. Moreover, an Italian study on 116 subjects undergoing TMVr reported a higher incidence of death and HF rehospitalization in AF patients at a median follow-up of 6 months.⁴⁹ These results were confirmed in a cohort of 75 high-risk subjects with LV dysfunction (LVEF ≤30%), showing significantly lower long-term survival in the AF group.⁵⁰ The discrepancies between these real-world results and EVEREST II data can be explained by the wide heterogeneity of the study cohorts. In the lower-clinical risk population of EVEREST II, AF seems to be a surrogate for a worse clinical status and a more advanced HF stage. Conversely, in the TRAMI registry, which enrolled a higher-risk population of patients who were not eligible for surgery, AF seems itself to stratify prognosis.

In a prospective Dutch multicenter registry enrolling 618 patients undergoing TMVr, Velu et al⁵¹ confirmed a higher mortality rate in AF vs. non-AF patients at the 5-year follow-up (34% vs 47%; P=0.006); however, that study failed to detect a significant difference in mortality at 1 year (82% vs 85%; P=0.30). Our analysis, based on a large pooled cohort of HF patients, supports the negative prognostic impact of prevalent AF on 1-year mortality in FMR patients undergoing MC treatment. In this population, AF was able to negatively predict LV reverse remodeling.

Transcatheter MV Repair for FMR: Unmet Need for Evidence From Randomized Studies

FMR represents the main target of TMVr with MC in the data of European registries (>70% of cases);⁴¹ conversely, the US Food and Drug Administration (FDA) has restricted the use of MC only to degenerative MR because of the absence of randomized trials on FMR patients demonstrating the superiority of MC over conservative medical therapy.

Although three large multicenter trials comparing MC with conservative medical therapy in FMR are currently underway, no results (even preliminary results), are available. In Europe, the Randomized Study of the MitraClip Device in Heart Failure Patients With Clinically Significant Functional Mitral Regurgitation (RESHAPE-HF) trail has been prematurely interrupted due to the low recruitment rate. In 2015, the RESHAPE-HF2 trial started recruitment, but results are not expected before 2019. The Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR) is a French, independent multicenter study designed for reimbursement by the public health insurance system.⁶ In the US, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) Phase 3 trial has been planned according to the FDA prescription to support the efficacy of MC in FMR.¹^,⁶ Despite several amendments of the study protocol, including an increase in the estimated number of patients to be enrolled, primary outcome measures will not be provided before July 2018.

In this scenario, the real-world data on clinical outcomes from prospective registries remain the only source available. A meta-analysis collecting published data from individual studies is the proper tool to describe the current state of the art and to direct the decision process in this difficult clinical area.

Study Limitations

Meta-analyses collect and combine data from numerous studies, and their value depends on the underlying limitations of the original individual studies. We have included one unpublished study³⁶ presented at an international congress and only one study had a randomized design.¹⁵ Therefore, the heterogeneity observed for some results, such as the reduction in LVEF at follow-up, may reflect differences between the study cohorts included in the meta-analysis. In order to improve the quality of the analysis, studies with less than 10 patients were excluded and only the more common clinical and echocardiographic variables available in most cases were collected and analyzed.

The correlation between AF and mortality at 1 year was not confirmed at 2 years, probably due to the lower number of studies (only 6) reporting the survival rate at 24 months. Moreover, the limited number of studies available for meta-regression analysis did not allow the use of a multivariate random effect model.

Conclusions

In patients with HF and severe FMR, TMVr with MC is safe and results in a durable MR reduction associated with significant clinical and echocardiographic improvement. Despite the need for confirmation by randomized studies, the results of this analysis suggest good performance of MC in terms of all-cause mortality in this particularly high-risk population.

Due to negative prognostic effects on LV reverse remodeling and 1-year survival, AF should be carefully considered in the selection of patients as candidates for MC and during follow-up.

Acknowledgement

This research did not receive any specific funding.

Conflict of Interest

None declared.

Supplementary Files

Supplementary File 1

Figure S1. Predictive role of left ventricular ejection fraction (LVEF) on in-hospital mortality in patients with functional mitral regurgitation (FMR) undergoing MitraClip (MC) implantation.

Figure S2. Predictive role of chronic obstructive pulmonary disease (COPD) on 12-month mortality in patients with functional mitral regurgitation (FMR) undergoing MitraClip (MC) implantation.

Figure S3. Predictive role of male sex on reductions in left ventricular end-systolic volume (LVESV) at the time of follow-up in patients with functional mitral regurgitation (FMR) undergoing MitraClip (MC) implantation.

Table S1. Changes in echocardiographic parameters from baseline to follow-up

Table S2. Correlations of clinical covariates and primary outcome at different follow-up times

Table S3. Correlations between clinical covariates and echocardiographic changes at follow-up

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-0571

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