Efficacy and Safety of Transcatheter Mitral Valve Repair (MitraClip) Compared to Medical Therapy and Surgery in Patients With Secondary Mitral Regurgitation: A Systematic Review & Pairwise Meta-analysis

Abstract

Background

Secondary mitral regurgitation (SMR) worsens outcomes in heart failure. Transcatheter mitral valve repair (MitraClip/TMVr) is an established alternative for patients who remain symptomatic on guideline-directed medical therapy (GDMT), but comparative efficacy versus GDMT and surgery has been debated.

Methods

We searched MEDLINE, Embase, and Cochrane through February 2025. To avoid double counting, quantitative syntheses used unique randomized controlled trials (RCTs) only; RCT substudies informed qualitative context. Pairwise random-effects meta-analyses compared MitraClip + GDMT vs GDMT and MitraClip vs surgery. Primary outcomes were all-cause mortality and heart-failure hospitalization (HFH). Secondary outcomes included quality of life (Kansas City Cardiomyopathy Questionnaire (KCCQ), MR ≤ 2+, stroke/MI, and major adverse events (MAE). Heterogeneity was explored with I²/τ², leave-one-out, and prespecified sensitivity analyses per Cochrane/JBI guidance.

Results

Nineteen studies were included, of which 5 unique Randomized Control Trials (RCTs) (n = 1912 randomized) contributed to pooling. Versus GDMT, MitraClip reduced mortality (RR 0.77, 95 % CI 0.63–0.95; I² = 73 %) and (Heart Failure Hospitalization) HFH (RR 0.76, 0.65–0.89; I² = 90 %), and improved KCCQ (MD + 13.7 points, 6.6–20.7). Including all available comparators across RCTs, mortality remained lower with MitraClip (RR 0.80, 0.65–1.00; p = 0.047; I² = 26 %). Versus surgery, MitraClip had fewer 30-day MAE (Major Adverse events) (RR 0.29, 0.21–0.40; I² = 0 %), with no difference in 1-year mortality and similar MR ≤ 2+ at ~1 year. Stroke/MI were comparable. Procedural success exceeded 96 %; partial clip detachment occurred in 1–2 %.

Conclusions

In contemporary RCTs, MitraClip on top of GDMT lowers mortality and HF hospitalizations and improves quality of life in SMR. Compared with surgery, TMVr offers a superior early safety profile with similar MR reduction at ~1 year. These results support Heart-Team use of MitraClip after optimized GDMT in anatomically suitable SMR, while reserving surgery for selected scenarios.

1. Introduction

Mitral regurgitation (MR) is one of the most common forms of valvular heart disease, affecting millions of patients worldwide, most commonly in the elderly population. Reports suggest that MR is observed in nearly 10 % of individuals older than 75 years of age, and its prevalence increases with age [1,2]. Mitral regurgitation occurs when the mitral valve does not close properly during systole, allowing blood to flow back into the left atrium. Consequently, this can lead to volume overload, left ventricular dysfunction, and possibly heart failure over time if not addressed [3]. MR can be broadly categorized as either primary (degenerative) MR, which is caused by structural abnormalities of the mitral valve apparatus, or secondary (functional) MR due to left ventricular remodeling due to ischemic or non-ischemic cardiomyopathy [4,5]. Secondary MR is associated with increased mortality, hospitalizations, and diminished quality of life in heart failure patients [6]. The implications of secondary MR are clinically significant. Patients with severe secondary MR frequently experience signs and symptoms, including dyspnea, fatigue, and decreased exercise tolerance, all of which may impose significant limitations on their quality of life [6,7]. Severe mitral valve disease, particularly mitral regurgitation, significantly increases the mortality risk. Reports show that those with secondary MR and a median follow-up of 3.1 years have an all-cause unadjusted mortality of 30.1 %. The risk of mortality is further increased in patients with a pre-existing condition of heart failure [8].

In a separate study, the one-year mortality rate for patients with secondary MR was as high as 20 %, and the five-year mortality rate was as high as 50 % among those receiving medical management alone [9]. This also places a significant burden on the healthcare system, with regular hospital admissions due to secondary MR, surgical interventions, and long-term medical management generating significant costs. Patients with secondary MR receiving medical management incurred average total charges of $23 575 for the year due to secondary MR, related to an additional $10 559 in charges the year because of their MR [10].

Over the previous several decades, the management of patients with secondary MR has advanced significantly and now includes a variety of treatment strategies, including medical management, surgical mitral valve repair or replacement (SMVR), and transcatheter mitral valve repair (TMVr), with MitraClip established as the most used TMVr device [11]. Unlike primary MR, secondary MR arises from left ventricular remodeling rather than intrinsic valve disease, and its optimal management remains debated particularly for those who are asymptomatic or have mild to moderate severity MR [12]. The essential objectives of medical management of secondary MR are to alleviate symptoms, minimize after load, and delay disease progression. Some of the more common medications employed in the medical management of secondary MR include diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). Although medical management can improve symptoms and delay MR progression, medications alone do not improve the underlying pathological process involving the valvular disease process and are typically limited to patients with more than moderate severity secondary MR [13].

The gold standard management for severe secondary MR continues to be surgical intervention, particularly in the setting of primary MR. SMVR (Secondary mitral valve replacement) involves either repairing the native valve or replacing it with either a mechanical valve or bioprosthesis. SMVR will typically be favored over replacement due to longer-term outcomes, including less thromboembolism and better preservation of the left ventricular function [14]. However, SMVR is associated with significant perioperative risks, including stroke, bleeding, and infection, and can lead to considerably longer recovery. Up to 50 % of patients with severe MR may be considered inoperable due to surgical risk, age, or comorbidities [3]. Although surgery holds a weaker Class IIb recommendation in current guidelines for isolated secondary MR, it remains a therapeutic consideration in selected patients, especially those undergoing multivalvular or revascularization procedures. Including surgical comparators allows for a more comprehensive synthesis of intervention options available in clinical practice [15–17]. MitraClip has emerged as a minimally invasive alternative to surgery in high-risk or inoperable patients. The MitraClip system is the TMVr device with the most clinical experience. This procedure involves percutaneous insertion of a clip that grasps and approximates the mitral valve leaflets and leads to decreased regurgitation [16]. TMVr has several advantages over surgery, including shorter length of stay, lower procedural mortality, and shorter recovery [17].

Current guidelines provide Class IIa recommendations for transcatheter mitral valve repair in symptomatic patients with secondary mitral regurgitation who remain symptomatic despite optimal guideline-directed medical therapy, meet anatomical criteria, and are considered high or prohibitive surgical risk. The 2021 ESC/EACTS guidelines support TMVr in this population based on growing trial evidence, particularly COAPT, while emphasizing the importance of a multidisciplinary heart team decision-making process [15]. Similarly, the 2020 ACC/AHA guidelines highlight TMVr as a reasonable option in appropriately selected patients with secondary MR [12]. However, comparative evidence between TMVr, surgery, and medical therapy across broader risk groups remains limited.

Yet, uncertainty remains about the true benefit of TMVr due to conflicting results from major trials. The COAPT trial demonstrated significant reductions in hospitalizations and mortality with TMVr + GDMT compared to GDMT alone, while the MITRA-FR trial found no significant benefit. These discrepancies may stem from differences in patient selection, timing of intervention, and disease severity, underscoring the need for comparative analyses across broader clinical scenarios. Moreover, prior studies often combine TMVr with GDMT, making it difficult to isolate the independent effects of TMVr versus surgery or medical therapy alone. Real-world data and updated systematic reviews suggest variable outcomes across risk groups, but comprehensive comparisons remain limited.

We aimed to quantitatively compare the efficacy and safety of TMVr (MitraClip) with medical therapy and surgery in adults with secondary MR. Outcomes of interest included mortality, heart-failure hospitalization, MR recurrence, quality of life, and procedural complications. By integrating recent randomized and comparative studies, this work seeks to provide contemporary evidence to guide clinical decision-making and identify residual gaps for future research.

2. Materials and methods

This systematic review and pairwise meta-analysis was conducted in accordance with PRISMA 2020 and Cochrane Handbook recommendations. The protocol was registered in PROSPERO (CRD420251016943). A comprehensive literature search was performed to identify randomized controlled trials evaluating TMVr versus surgical or medical therapy.

2.1. Search terms and keywords

The search strategy was structured according to the PICO framework to capture all relevant studies addressing the research question. The population included adult patients with secondary mitral regurgitation, most with underlying heart failure and left ventricular dysfunction. Eligible interventions comprised TMVr (MitraClip), either alone or in combination with GDMT. Comparators included GDMT alone or surgical mitral-valve repair/replacement (SMVR). The primary outcomes were MR reduction, mortality, heart-failure hospitalization, quality of life, and procedural safety.

Keywords were grouped under population, intervention, comparator, and outcome domains. Population: “mitral regurgitation,” “mitral valve disease,” “heart failure.” Intervention: “transcatheter mitral valve repair,” “MitraClip,” “TMVr,” “transcatheter edge-to-edge repair.” Comparator: “guideline-directed medical therapy,” “medical therapy,” “mitral valve surgery,” “surgical repair,” “valve replacement.” Outcomes: “mortality,” “heart failure hospitalization,” “efficacy,” “safety,” “adverse events,” “complications,” “quality of life.”

2.2. Boolean operators and search strategy

Boolean operators (“AND,” “OR”) were used to refine the search and retrieve all relevant studies. The final search string combined population, intervention, and comparator terms ((“mitral regurgitation” OR “MR”) AND (“MitraClip” OR “TMVr” OR “transcatheter mitral valve repair”) AND (“medical therapy” OR “mitral valve surgery”)).

Searches were conducted in MEDLINE (via PubMed), Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from database inception to Feb 2025. Reference lists of relevant reviews and included trials were hand-searched to identify additional eligible studies.

2.3. Inclusion and exclusion criteria

Inclusion and exclusion criteria were pre-specified and agreed upon by all reviewers.

2.3.1. Inclusion criteria

Randomized controlled trials (RCTs) and open-label RCT substudies evaluating TMVr (MitraClip). Adult patients (≥18 years) with secondary or mixed MR associated with heart failure. Studies comparing TMVr ± GDMT with either GDMT alone or surgical mitral-valve repair/replacement. Follow-up duration of ≥1 year, with studies reporting clinical or echocardiographic outcomes up to 5 years. Publications available in English (or translated versions with full-text access).

2.3.2. Exclusion criteria

Non-randomized studies (observational cohorts, case-control, registries without randomization). Studies exclusively involving primary/degenerative MR, endocarditis, or congenital mitral pathology. Interventions not involving the MitraClip system (Pascal or other transcatheter devices). Studies lacking efficacy/safety outcomes or with inadequate follow-up (<1 year). Duplicate publications or low-quality studies with high risk of bias.

2.4. Systematic search and article screening

Two authors (SY and SS) independently screened all titles and abstracts using the Rayyan software, following PRISMA 2020 methodology. Discrepancies were resolved by consensus with the senior author. The initial search identified 257 records, from which 66 duplicates were removed. The remaining 191 unique studies underwent title and abstract screening. After exclusion of irrelevant studies, 21 full-text articles were assessed for eligibility; 2 were excluded due to population mismatch, leaving 19 studies for inclusion (Fig. 1).

Fig. 1.

PRISMA flow diagram. The systematic search yielded 257 articles, with 66 duplicate titles removed.

2.5. Data extraction and quality appraisal

Data extraction was performed independently by two reviewers using a standardized form. Extracted variables included study design, sample size, patient demographics, baseline cardiac function, intervention details, comparators, and clinical outcomes. Demographic and clinical parameters included age, sex, NYHA class (New York Heart Association), LVEF (Left Ventricular Ejection Fraction), and MR severity (3+ or 4+). Intervention details comprised number of clips used, procedural success rates, and definitions of MR reduction (≤2+). Comparator data captured outcomes in GDMT-only or surgical arms.

Outcomes were categorized as follows. Efficacy: MR reduction, LV reverse remodeling, and improvement in NYHA class and 6-min walk distance. Quality of Life: changes in Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Clinical Endpoints: all-cause and cardiovascular mortality, HF hospitalizations, and composite events. Safety: major adverse events (MAE), stroke, myocardial infarction, device embolization, leaflet detachment, and reintervention rates. For synthesis purposes, trials were grouped. MitraClip + GDMT vs GDMT alone (n = 15). MitraClip vs surgical mitral-valve repair/replacement (n = 3). No study compared all three modalities simultaneously. Study characteristics and key outcomes are summarized in Tables 1–4.

Table 1.

Study characteristics of included RCTs and substudies.

Study ID	Study Design	Unique RCT or Substudy	Patient Population	Population Size (Intervention/Control)	Intervention	Comparison or Control	Comparator Type	Outcome measured	Follow-up
Baldus et al. [18]	RCT	Unique RCT	Patients with HF and significant SMR	208 patients (104 intervention/104 control)	Transcatheter edge-to-edge repair (MitraClip)	Surgical mitral-valve repair or replacement	Two arm	Death, HFH, reintervention, assist device, stroke	Median 1 yr
Feldman et al. [19]	RCT	Unique RCT (EVEREST II)	Patients with grade 3+ or 4+ chronic SMR + HF	279 (184 intervention/95 control)	Percutaneous mitral valve repair (MitraClip)	Conventional mitral valve surgery (repair or replacement)	Two-arm	Freedom from death, surgery for dysfunction, severe MR; safety: major adverse events at 30 days	1–2 years
Obadia et al. [20]	RCT	Unique RCT (MITRA-FR)	Patients with severe SMR, HF, and reduced LVEF (15–40 %)	304 patients (152 intervention/152 control)	Percutaneous mitral-valve repair using MitraClip + GDMT	GDMT	Two-arm	Death from any cause or unplanned hospitalization for heart failure at 12 months	1 year
Anker et al. [21]	RCT	Unique RCT (RESHAPE-HF2)	HF patients with moderate-to-severe or severe SMR	505 (250 intervention/255 control)	Transcatheter mitral-valve repair with MitraClip + GDMT	GDMT	Two-arm	First/recurrent hospitalization for HF or CV death at 24 months; first/recurrent HFH at 24 months; change in KCCQ-OS score at 12 months	Mean 18.8 ± 8.2 months
Stone et al. [22]	RCT	Unique RCT (COAPT)	Patients with HF and moderate to severe SMR	614 (302 intervention/312 control)	Transcatheter mitral-valve repair (MitraClip) + GDMT	GDMT	Two arm	Primary effectiveness: all HFH in 24 months; Primary safety: device-related complications at 12 months	Median 22.7 months
Arnold et al. [23]	RCT	COAPT substudy	Patients with HF and severe SMR	614 enrolled; 551 in analysis (279 intervention/272 control)	TMVr with MitraClip + GDMT	GDMT alone	Two-arm	Death or HFH	Median 2 years
Asch et al. [24]	RCT	COAPT substudy	Patients with HF and 3+ or 4+ SMR	614 (302 intervention/312 control)	Transcatheter mitral valve repair (TMVr) + GDMT	GDMT	Two-arm	Death or HFH	2 years
Ben-Yehuda et al. [25]	RCT	COAPT substudy	Patients with HF and moderate-to-severe or severe SMR	614 (302 intervention/312 control)	Transcatheter mitral valve repair (TMVr) with MitraClip + GDMT	GDMT	Two-arm	Composite of death or HFH, PASP reduction, and individual components	Median 2 years
Cox et al. [26]	RCT	COAPT substudy	Patients with HF and moderate-to-severe or SMR	606 (intervention 464/control 142)	GDMT + TMVr	GDMT alone	Two-arm	GDMT tolerability, dose levels, reasons and predictors of intolerance	Up to 5 years
Feldman et al. [27]	RCT	EVEREST II substudy	Patients with grade 3+ or 4+ chronic SMR	258 (178 intervention/80 control)	Percutaneous mitral valve repair with MitraClip	Conventional mitral valve surgery	Two arm	Freedom from death, surgery for mitral valve dysfunction, and grade 3+ or 4+ mitral regurgitation	5 years
Giustino et al. [28]	RCT	COAPT substudy	HF patients with moderate to severe SMR and NYHA Class II–IV symptoms	613 (intervention 302/control 311)	MitraClip + GDMT	GDMT	Two-arm	All-cause death or HFH at 2 years; plus other secondary outcomes (QOL, 6MWD, echocardiography)	24–60 months
Giustino et al. [29]	RCT	COAPT substudy	Patients with HF and severe SMR	614 (302 intervention/312 control)	TMVr + GDMT	GDMT alone	Two arm	Hospitalizations (fatal and nonfatal), mortality, days alive and out of hospital	2 years
Hahn et al. [30]	RCT	COAPT substudy	HF, LVEF 20–50 %, SMR 3+/4+, stratified by TR	614 total (255 MitraClip + GDMT, 246 GDMT; 44 MitraClip + GDMT, 54 GDMT with Mod TR)	GDMT alone MitraClip +	GDMT	Two arm	Death or HFH	2 years
Kar et al. [31]	RCT	COAPT substudy	Patients with HF and severe (3+/4+) SMR	614 (302 intervention, 314 control)	TMVr using MitraClip + GDMT	GDMTalone	Two-arm	Death, HFH, quality of life (KCCQ score)	2 years
Kong et al. [32]	RCT	COAPT substudy	Patients with HF (LVEF 20–50 %) and moderate-to-severe or severe SMR	614 (504 intervention/245 control)	Transcatheter Edge-to-Edge Repair (TMVr) with MitraClip + GDMT	GDMT alone	Two-arm	WRF at 30 days; all-cause death; HFH	2 years
Leurent et al. [33]	RCT	MITRA-FR substudy	Patients with SMR and HF	140 (67 intervention/73 control)	TMVR (MitraClip) + GDMT	GDMT alone	Two-arm	Cumulative HFH rate between 12 and 24 months	1–2 years
Mack et al. [34]	RCT	COAPT substudy	Patients with symptomatic HF and moderate-to-severe or severe SMR	614	MitraClip device + GDMT	GDMT alone	Two arm	Recurrent HFH (effectiveness); device-related complications	2 years
Mauri et al. [35]	RCT	EVEREST II substudy	Patients with grade 3+ or 4+ SMR who were candidates for surgery	279 (intervention 185/95 control)	MitraClip percutaneous repair	Surgical repair or replacement	Two arm	Freedom from death, surgery for mitral valve dysfunction, and grade 3+ or 4+ MR at 12 months	4 yrs
Shah et al. [36]	RCT	COAPT post hoc	Symptomatic HF patients with moderate-severe or severe SMR	614 (302 intervention/312 control)	MitraClip implantation + GDMT	GDMT alone	Two arm	2-year rate of death or HFH	2 yrs

Abbreviations: RCT: Randomized Controlled Trial; HF: Heart Failure; SMR: Secondary Mitral Regurgitation; LVEF: Left Ventricular Ejection Fraction; GDMT: Guideline-Directed Medical Therapy; CV: Cardiovascular; HFH: Heart Failure Hospitalization; TMVr: Transcatheter Mitral Valve Repair; MR: Mitral Regurgitation; QOL: Quality of Life; 6MWD: 6- Minute Walk Distance; KCCQ: Kansas City Cardiomyopathy Questionnaire; KCCQ-OS: Kansas City Cardiomyopathy Questionnaire – Overall Summary Score; PASP: Pulmonary Artery Systolic Pressure; TR: Tricuspid Regurgitation; Mod TR: Moderate Tricuspid Regurgitation; WRF: Worsening Renal Function; NYHA: New York Heart Association.

Table 2.

Patient characteristics and mitral regurgitation (MR) outcomes across included studies.

Study	Mean Age	Sex (M/F)	Key Comorbidities	NYHA Class (Before → After)	MR Severity (Before → After)
Baldus et al. [18]	70.5 ± 7.9	60.1 %/39.9 %	HTN: 83 %, DM: 26 %, CAD: 44 %, AF: 51 %, CKD: 35 %	III–IV: 86 %→23 % (TMVr), 18 % (Surg)	≥3+: 96 %, 4+: 38 % → ≤2+: 96 % (TMVr), 99 % (Surg)
Feldman et al. [19]	67.3 (TMVr), 65.7 (Surg)	62–66 %/34–38 %	CHF: 91 %, CAD: 47 %, AF: 34–39 %, DM: ~10 %	III–IV: 52 % → 2 % (TMVr), 13 % (Surg)	3+: 71 %, 4+: 25 % → ≤2+: 86 % (TMVr), 96 % (Surg)
Obadia et al. [20]	70.1 (TMVr), 70.6 (Ctrl)	79 %/21 % (TMVr)	Isch. CM: 63 %, MI: 49 %, AF: 35 %, DM: 33 %	III–IV: 63 % → Not stated	EROA: 31 mm2 → MR ≤ 2+: 92 % (TMVr), ≥3+: high at 1 yr
Anker et al. [21]	72.3 ± 8.4	72 %/28 %	CAD: 58 %, AF: 61 %, DM: 32 %, HTN: 83 %, CKD: 48 %	III–IV: 74 %→28 % (TMVr), 50 % (Ctrl)	3+/4+: 100 % → ≤2+: 90 % (TMVr), 36 % (Ctrl)
Stone et al. [22]	72.2 ± 11.2	~64 %/36 %	HTN: 81 %, CAD: 73 %, CKD: 73 %, DM: 37 %, AF: 55 %	III–IV: 61 % → I/II: 72 % (TMVr), 50 % (Ctrl)	3+: 52 %, 4+: 48 % → ≤2+: 95 % (TMVr), 47 % (Ctrl)
Arnold et al. [23]	71.9 ± 11.3	64 %/36 %	Isch. CM: 60 %, CAD: 72 %, MI: 51 %, AF: 53 %	Mod–sev HF → Improved KCCQ	SMR 3–4+ → Improved w/TMVr
Asch et al. [24]	71.9 ± 11.3	64 %/36 %	HFrEF (LVEF 31 %), CAD, TR ≥ mod: 16 %	Not reported	3+/4+ → 1-grade improvement
Ben-Yehuda et al. [25]	72.1 ± 11.5	63 %/37 %	DM: 43 %, CAD, AF: 55 %, CKD: ~50 %	NYHA III–IV: ~62 % → NA	3+: ~48 %, 4+: ~52 % → Improved
Cox et al. [26]	73 (IQR: 66–80)	65 %/35 %	CAD: 70 %, CKD: 54 %, AF: 53 %, HTN: 78 %	III–IV: ~60 % → NA	3+: 48 %, 4+: 52 % → NA
Feldman et al. [27]	67.0 (TMVr), 64.7 (Surg)	~35 %/65 %	CHF: 90 %, CAD: 47 %, AF: 33 %, DM: 8 %	III–IV: ~50 % → 8.6 % (TMVr), 2.5 % (Surg)	3+: ~71 %, 4+: ~24 %→≤2+: 88 % (TMVr), 98 % (Surg)
Giustino et al. [28]	~74 yrs	51–69 % M	HTN: 83 %, CKD: 72 %, AF: ~55 %, COPD: 43 %	III–IV: 61 % → Improved	3+/4+: 41–67 % → ↓ post- TMVr
Giustino et al. [29]	74 (IQR 67–81)	64 %/36 %	HTN: 81 %, DM: 39 %, CKD: 76 %, COPD: 25 %, AF: 60 %	III–IV: 63 % → Not detailed	3+: 49 %, 4+: 51 %→↓ post-TMVr
Hahn et al. [30]	~73 yrs	58–66 % M	CKD: 85 %, DM: 39 %, AF: 59 %	NYHA III–IV: 79 % (Mod-Sev TR) → NA	3+/4+: 100 % → MR ≤ 2+: ~95 %
Kar et al. [31]	~72 yrs	58–68 % M	DM: ~40 %, AF: ~55 %, CKD: ~75 %, COPD: ~25 %	NYHA III–IV: 52–67 % → NA	3+/4+: 100 % → MR ≤ 2+: 93 % (TMVr)
Kong et al. [32]	~72 yrs	58 %/42 %	HTN: 91 %, DM: 51 %, Renal: 72 %, CAD: 90 %	III–IV: ~62 % → NA	3+: 56 %, 4+: 44 % → NA
Leurent et al. [33]	69.0 ± 9.8	79 %/21 %	Isch. CM: ~67 %, AF: ~50 %, DM: ~40 %	NYHA III–IV: 55–63 % → NA	EROA: ~29 mm2 → ↓ to 11.5 mm2 (TMVr)
Mack et al. [34]	–	–	HFrEF, renal dysfxn, ↑BNP/NT-proBNP	NYHA II–IVa → Improved at 12 mo	3+/4+ → Target ≤2+ at 12 mo
Mauri et al. [35]	67.3 (TMVr), 65.7 (Surg)	~65 %/35 %	CHF: 91 %, CAD: 47 %, AF: 34 %, COPD: 15 %	III–IV: 51 %→5.7 % (TMVr), 6.3 % (Surg)	3+/4+: ~96 % → ≤2+: ~78 % (TMVr), 92 % (Surg)
Shah et al. [36]	72.2 ± 11.2	64 % M overall	HTN: 81 %, Isch. CM: 61 %, CAD: 73 %, CKD: 23 %, AF: 55 %	NYHA III–IV: 61 % → NA	All had ≥3+/4+ MR → Post: NA

Abbreviations: MR: Mitral Regurgitation; NYHA: New York Heart Association functional class; HTN: Hypertension; DM: Diabetes Mellitus; CAD: Coronary Artery Disease; AF: Atrial Fibrillation; CKD: Chronic Kidney Disease; CHF: Congestive Heart Failure; COPD: Chronic Obstructive Pulmonary Disease; Isch. CM: Ischemic Cardiomyopathy; TMVr: Transcatheter Mitral valve repair (MitraClip); Surg: Surgery group; Ctrl: Control group; EROA: Effective Regurgitant Orifice Area; RVol: Regurgitant Volume; HFrEF: Heart Failure with reduced Ejection Fraction; KCCQ: Kansas City Cardiomyopathy Questionnaire; TR: Tricuspid Regurgitation; BNP/NT-proBNP: B-type Natriuretic Peptide/N-terminal pro-BNP; Mod–sev: Moderate to severe; d/c: Discharge; NA: Not Available or Not Reported; ↓: Reduction observed.

Table 3.

MR reduction, functional status, QoL, and outcomes.

Study	MR Grade (Pre → Post)	NYHA Class (Pre → Post)	QoL Change	Hosp./Mortality
Baldus et al. [18]	≥3+: 96 %, 4+: 38 % → ≤2+: 96 % (TMVr), 99 % (Surg)	III–IV: 82–89 % → 23 % (TMVr), 18 % (Surg)	MLHFQ (Minnesota Living with Heart Failure Questionnaire) ↓10 (TMVr), ↓5 (Surg)	1-yr death/HFH: 16.7 % (TMVr), 22.5 % (Surg)
Feldman et al. [19]	3+/4+: 96 % → ≤2+: 86 % (TMVr), 96 % (Surg)	III–IV: 52 % → 2 % (TMVr), 13 % (Surg)	SF-36 ↑ in both, faster with TMVr	12-mo mortality: 6 %, 24-mo: 11 %; 20 % TMVr reintervention
Obadia et al. [20]	All severe → ≤2+: 92 % (at d/c)	III–IV: 63 % → unquantified	EQ-5D: minor ↑, no formal stats	12-mo death/HFH: ~54 −51 %, NS
Anker et al. [21]	All 3+/4+ → ≤2+: 90 % (TMVr), 36 % (GDMT)	III–IV: 74 % → 28 % (TMVr), 50 % (Ctrl)	KCCQ: ↑21.6 (TMVr), ↑8.0 (Ctrl), p < 0.001	Death/HFH ↓36 %, p = 0.002
Stone et al. [22]	3+: 52 %, 4+: 48 % → ≤2+: 95 % (TMVr), 47 % (Ctrl)	I/II at 12 mo: 72 % (TMVr), 50 % (Ctrl)	KCCQ: +12.5 (TMVr), −3.6 (Ctrl)	2-yr death: 29 % (TMVr), 46 % (Ctrl), p < 0.001
Arnold et al.[23]	All 3–4+ → ↓ MR w/ TMVr	–	KCCQ ↑16.9 pts (TMVr); risk ↓14 %/10-pt ↑	Adjusted HR death/HFH: 0.75
Asch et al. [24]	MR ≥ 3+ → ≤2+: 92.6 % at 30 d	–	–	↓ HFH + mortality at 2 yrs
Ben-Yehuda et al. [25]	All 3+/4+ → ↓ MR + PASP	–	–	2-yr death/HFH ↓ by PASP strata
Cox et al. [26]	All 3+/4+ → not analyzed	III–IV: ~61 %	KCCQ ~53, change NA	Mortality not analyzed
Feldman et al. (2015) [27]	All 3+/4+ → MR 3+/4+ at 5 yrs: 19 % (TMVr), 3 % (Surg)	III–IV ↓: 1 % (TMVr), 7.5 % (Surg)	SF-36 ↑ both arms	5-yr death: 21 % (TMVr), 27 % (Surg)
Giustino et al. [28]	3+: 50 %, 4+: 50 % → ↓ post-TMVr	NYHA III/IV improved most	KCCQ ↑ esp. NYHA III/IV	↓ HFH + mortality (TMVr)
Giustino et al. [29]	3+: 49 %, 4+: 51 % → ↓ post-TMVr	NYHA ↑, more days alive/out of hospital	KCCQ, 6MWT improved	↓ 2-yr HFH: 35 % (TMVr) vs 56 % (GDMT)
Hahn et al. [30]	All ≥3+ → ≤2+: ~94 %	III/IV: 57–79 % baseline	KCCQ lower w/Mod-Sev TR	2-yr death/HFH: ↓ w/TMVr across TR strata
Kar et al. [31]	All 3+/4+ → ≤2+: 93 % at 30 d (TMVr)	NYHA improved w/MR ≤ 2+	KCCQ ↑ only if MR ≤ 2+	2-yr death/HFH: 38 % (0/1+), 72 % (3+/4+)
Kong et al. [32]	3+: 56 %, 4+: 44 %	NYHA II–IV baseline	Not assessed	TMVr ↓ death even in WRF pts
Leurent et al. [33]	EROA ~29 mm2 → ↓ to 11.5 (TMVr), 24.5 (GDMT)	III/IV: ~55–63 % → not detailed	–	HFH: HR 0.45, composite: HR 0.55
Mack et al. [34]	All 3+/4+ confirmed	–	KCCQ ↑ at 12 mo	↓ HFH + mortality at 2 yrs
Mauri et al. [35]	3+: 71 %, 4+: 25 % → ≤2+: 78 % (TMVr), 92 % (Surg)	III/IV ↓ to 5.7 % (TMVr), 6.3 % (Surg)	–	4-yr survival: ~82 % both
Shah et al. [36]	All ≥3+/4+	III/IV: 61 % → NA	–	2-yr death/HFH: 44 % ((TMVr) vs 64 % (GDMT)

Abbreviations: MR: Mitral regurgitation; NYHA: New York Heart Association functional class; QoL: Quality of Life; HFH: Heart Failure Hospitalization; TMVr: Transcatheter mitral valve repair (MitraClip); Surg: Surgical repair/replacement; MLHFQ: Minnesota Living with Heart Failure Questionnaire; 6MWT: 6-Minute Walk Test; SF-36: Short Form-36 Health Survey; EROA: Effective Regurgitant Orifice Area; PASP: Pulmonary Artery Systolic Pressure; WRF: Worsening Renal Function; HR: Hazard Ratio; NS: Not Significant; d/c: Discharge.

Table 4.

Safety outcomes across studies.

Study	Device-Related Complications	Procedure-Related Complications	Mortality
Baldus et al. [18]	Clip detachment (1), chordae rupture (2)	Bleeding: 3.1 % (TMVr) vs 24.4 % (Surg); AF: 3.1 % vs 27.8 %	30 d: 2.0 % (TMVr), 4.3 % (Surg); 1 y: 8.3 % vs 10.3 %
Feldman et al. [19]	Chordal tear (7); 23 % post-TMVr MR ≥ 3+ → surgery	Major AE: 15 % (TMVr) vs 48 % (Surg); transf. ≥2U: 13 % vs 45 %	1 y: 6 %, 2 y: 11 % (both groups)
Obadia et al. [20]	Implant fail: 4.2 %; MR ≥ 2+ at 1 y in ≥48 pts	Peri-proc: 14.6 % (bleed: 3.5 %, septal defect: 2.8 %, shock: 2.8 %)	30 d: 3.3 % (TMVr), 2.6 % (Ctrl); 1 y: 24.3 % vs 22.4 %
Anker et al. [21]	Implant success: 96.9 %; clip detachment: 2 %	Comp: 5.6 % (bleed 2 %, stroke 0.4 %, re-op 0.4 %)	2 y: 22.3 % (TMVr) vs 29.6 % (GDMT); NS
Stone et al. [22]	Device-related AE: 3.4 % (SLDA, embolization, etc.)	No reop in 30 d; death 2.3 %, stroke 0.7 %	2 y: 29.1 % (TMVr), 46.1 % (Ctrl); p < 0.001
Arnold et al [23]	–	–	2 y: Lower in TMVr; HR 0.82 per 10-pt ↑ KCCQ
Asch et al. [24]	–	–	2 y: 29 % (TMVr), 46 % (GDMT)
Ben-Yehuda et al. [25]	–	–	2 y: TMVr < GDMT (PASP ≥50: 38 % vs 57 %)
Cox et al. [26]	–	–	–
Feldman et al. [27]	SLDA: 10 (9 early); 1 mitral stenosis	Device failure: 9.5 %	5 y: 20.8 % (TMVr), 26.8 % (Surg); NS
Giustino et al. [28]	SLDA (9), embolization (1)	Stroke/TIA: 4.2 % (TMVr), 7.2 % (Surg)	2 y: 20.8 % (TMVr), 26.8 % (Surg)
Giustino et al. [29]	–	–	Lower mortality rate (TMVr)
Hahn et al. [30]	–	In-hosp death: 5.1 % (Mod-Sev TR), 0.8 % (Mild TR)	2 y: 50.4 % (Mod-Sev TR), 33.3 % (Mild TR)
Kar et al. [31]	–	–	2 y: MR 0/1+: 21.1 %, 2+: 30.3 %, 3+/4+: 49.2 %
Kong et al. [32]	–	–	2 y: 49.3 % (WRF), 29.2 % (no-WRF); HR: 1.98
Leurent et al. [33]	–	–	12–24 mo: 9.0 % (TMVr), 12.3 % (GDMT); NS
Mack et al. [34]	Dev comp ~6 % (predicted); stroke/MI possible	Antiplatelets: ASA × 6mo, clopidogrel × 1mo	1 y: ~22 % (TMVr)
Mauri et al. [35]	SLDA: 10 (5 %); mitral stenosis (1); no emboli	–	4 y: 17.4 % (TMVr), 17.8 % (Surg); NS
Shah et al. [36]	None	Bleeding, AF, stroke monitored	2 y: 29.1 % (TMVr), 46.1 % (GDMT); HR 0.62

Abbreviations: AF: Atrial fibrillation; AE: Adverse event; ASA: Acetylsalicylic acid (aspirin); CI: Confidence interval; Ctrl: Control group; d: Day; GDMT: Guideline-directed medical therapy; HR: Hazard ratio; KCCQ: Kansas City Cardiomyopathy Questionnaire; MI: Myocardial infarction; MR: Mitral regurgitation; NS: Not significant; PASP: Pulmonary artery systolic pressure; SLDA: Single leaflet device attachment; Surg: Surgery group; TMVr: Transcatheter mitral valve repair (MitraClip); TIA: Transient ischemic attack; TR: Tricuspid regurgitation; WRF: Worsening renal function; y: Year.

2.6. Risk of bias

Risk of bias was assessed using the Cochrane RoB 2.0 tool for all randomized trials. For parent RCTs with multiple substudies, the core design domains (randomization, allocation concealment, and deviations from intended interventions) were rated identically across all substudies, as these domains reflect the parent trial’s methodology. Substudy-specific domains such as outcome measurement or reporting bias were adjusted when warranted (imaging or registry-based extensions). Any discrepancies were resolved by consensus. Figs. 2 and 3 summarize overall judgments, showing that many trials had low or some concern risk, with no study rated high risk for randomization or allocation concealment.

Fig. 2.

Risk of bias of the included trials using the Cochrane risk-of-bias tool (randomized controlled trials) (Traffic light plot). It summarize overall judgments, showing that many trials had low or some concern risk, with no study rated high risk for randomization or allocation concealment.

Fig. 3.

Risk of bias assessment (Summary Plot). It summarize overall judgments, showing that many trials had low or some concern risk, with no study rated high risk for randomization or allocation concealment.

2.7. Certainty of evidence

The certainty of evidence for each pooled outcome was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach in accordance with Cochrane and JBI guidelines. Each outcome was rated as high, moderate, low, or very low, based on potential downgrades for risk of bias, inconsistency (heterogeneity), indirectness, imprecision (wide confidence intervals, small sample size, or few studies), and publication bias.

3. Results

A total of 19 studies were included in this study, comprising 5 unique randomized controlled trials (RCTs) and 14 associated substudies. Eligible participants were adults with MR, predominantly SMR associated with HF, requiring medical or interventional therapy. Across RCTs, 85–95 % of MitraClip recipients achieved MR ≤ 2+. Versus surgery, the pooled effect on residual MR endpoints at ~1 year was RR 0.96 (95 % CI 0.89–1.04; I² = 19 %), reflecting consistent clinical improvement with minor definitional variability across trials.

All included trials comparing TMVr using the MitraClip device against either GDMT alone or surgical mitral-valve intervention, across varied populations, baseline characteristics, and follow-up durations. No single study directly compared all three treatment strategies (MitraClip, GDMT, and surgery) within the same trial framework. Thus, evidence was synthesized from separate pairwise comparisons. A summary of study designs, comparator types, and major outcomes is presented in Table 1.

3.1. Study characteristics

The Baldus et al. (2024) MATTERHORN trial (N = 208) was the only noninferiority RCT directly comparing MitraClip with surgical mitral-valve repair/replacement (SMVR). The landmark COAPT trial (Stone et al., 2018) and its substudies provided the principal evidence base for MitraClip + GDMT vs GDMT alone in secondary MR. Additional pivotal head-to-head data came from MITRA-FR (Obadia et al., 2018) and the more recent RESHAPE-HF2 (Anker et al., 2024) trial.

Across RCTs, the enrolled populations were predominantly male (≈60–70 %) with moderate-to-severe or severe secondary MR and left-ventricular ejection fraction (LVEF) ranging 15–50 %. The majority of participants were symptomatic, classified as NYHA functional class II–IV at baseline. Common comorbidities included hypertension (~80 %), diabetes mellitus (30–40 %), atrial fibrillation (~50 %), and chronic kidney disease (30–70 %), consistent with a typical advanced HF population.

3.2. Mortality

In pooled analyses of MitraClip + GDMT versus GDMT alone (COAPT and MITRA-FR), TMVr was associated with a significant reduction in all-cause mortality (RR 0.77, 95 % CI 0.63–0.95; p = 0.013; I² = 73.5 %; Fig. 4). A hazard-ratio analysis was directionally consistent (HR 0.80, 95 % CI 0.46–1.42), with between-trial differences driven by MR proportionality thresholds and LV dimensions. When all available RCT comparators were pooled, the mortality benefit persisted (RR 0.80, 95 % CI 0.65–1.00; p = 0.047; I² = 26 %; Fig. 5).

Fig. 4.

Mortality: MitraClip + GDMT vs GDMT. Forest plot showing pooled relative risks (RRs) for all-cause mortality comparing MitraClip + GDMT vs GDMT.

Fig. 5.

Mortality: MitraClip vs others. Forest plot showing pooled relative risks (RRs) for all-cause mortality compared to MitraClip vs others.

3.3. Cardiovascular death

MitraClip reduced cardiovascular mortality compared with GDMT (RR 0.64, 95 % CI 0.49–0.85; I² = 0 %), consistent with COAPT and replicated in RESHAPE-HF2 (Fig. 6).

Fig. 6.

Cardiovascular Death: MitraClip vs Others. Forest plot showing pooled relative risks (RRs) for Cardiovascular Death comparing MitraClip vs Others.

3.4. Heart-failure hospitalization

MitraClip + GDMT reduced recurrent HF hospitalizations versus GDMT alone (RR 0.76, 95 % CI 0.65–0.89; p < 0.001; I² = 89.6 %; Fig. 7). Incorporating RESHAPE-HF2, the benefit persisted (RR 0.72, 95 % CI 0.53–0.97; p = 0.029; I² = 80 %; Fig. 8).

Fig. 7.

Heart-Failure Hospitalization: MitraClip + GDMT vs GDMT. forest plot showing pooled relative risks (RRs) for Heart-Failure Hospitalization comparing MitraClip + GDMT vs GDMT.

Fig. 8.

Heart-Failure Hospitalization: MitraClip vs Others. Forest plot showing pooled relative risks (RRs) for Heart-Failure Hospitalization comparing MitraClip vs Others.

3.5. Safety outcomes

Stroke was similar between groups (RR 1.17, 95 % CI 0.39–3.45; I² = 39 %) (Fig. 9); myocardial infarction was neutral (RR 0.77, 95 % CI 0.37–1.61) (Fig. 10). MAE were markedly lower with MitraClip versus surgery (RR 0.29, 95 % CI 0.21–0.40; I² = 0 %) (Fig. 11) and showed a non-significant trend toward reduction when pooling all comparators (RR 0.55, 95 % CI 0.28–1.07; p = 0.08; I² = 97 %) (Fig. 12).

Fig. 9.

Stroke: MitraClip Vs. Others. Forest plot showing pooled relative risks (RRs) for Stroke comparing MitraClip vs Others.

Fig. 10.

Myocardial Infarction: MitraClip + GDMT Vs. GDMT. Forest plot showing pooled relative risks (RRs) for Myocardial Infarction comparing MitraClip + GDMT Vs. GDMT.

Fig. 11.

Major Adverse Events: MitraClip Vs. Surgery. Forest plot showing pooled relative risks (RRs) for Major Adverse Events comparing MitraClip Vs. Surgery.

Fig. 12.

Major Adverse Events: MitraClip Vs. Others. Forest plot showing pooled relative risks (RRs) for Major Adverse Events comparing MitraClip Vs. Others.

3.6. MR severity and procedural success

Across RCTs, 85–95 % of TMVr recipients achieved MR ≤ 2+ (12). The pooled RR for residual MR endpoints was 1.46 (95 % CI 0.89–1.04; I² = 19.46 %) (Fig. 13), reflecting divergent endpoint definitions; nevertheless, each trial showed clinically meaningful MR reduction. Procedural success exceeded 96 %, with partial clip detachment in 1–2 %.

Fig. 13.

MR Reduction: MitraClip Vs. Surgery. Forest plot showing pooled relative risks (RRs) for MR Reduction comparing MitraClip Vs. Surgery.

3.7. Sensitivity analyses

Excluding RESHAPE-HF2 slightly attenuated the mortality effect (RR 0.84, 95 % CI 0.61–1.16), without changing direction (Fig. 14). The HFH benefit remained robust (RR 0.76 → 0.72 with inclusion)) (Fig. 15), and MAE estimates were stable (Fig. 16). Leave-one-out analyses showed no single study unduly influenced results. High I² values were attributable to clinical diversity (MR proportionality, LV size, GDMT optimization, follow-up), not model instability; we therefore present pooled interval estimates with random-effects and τ² per Cochrane/JBI recommendations.

Fig. 14.

Mortality: MitraClip Vs. Others. Forest plot showing sensitivity analysis of Mortality after excluding Anker et al.

Fig. 15.

Hospitalization: MitraClip Vs. Others. Forest plot showing sensitivity analysis of Hospitalization after excluding Anker et al.

Fig. 16.

Major Adverse Events: MitraClip Vs. Others. Forest plot shows sensitivity analysis of Major Adverse Events after excluding Anker et al.

3.8. Certainty of evidence

The overall certainty of evidence for each outcome was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework, considering risk of bias, inconsistency, indirectness, imprecision, and publication bias.

For the comparison of MitraClip + GDMT versus GDMT alone, certainty was moderate for mortality and quality-of-life outcomes, low for hospitalization and myocardial infarction, and very low for stroke (Table 5).

Table 5.

Certainty of evidence (GRADE): MitraClip + GDMT vs GDMT.

Outcome	Certainty	Reasons for Downgrading
Mortality	Moderate	1 level each for inconsistency and imprecision
Hospitalization	Low	1 for inconsistency, 1 for imprecision
Stroke	Very low	1 for inconsistency, 2 for serious imprecision (wide CI)
MI	Low	2 for serious imprecision (wide CI)
Quality of life	Moderate	1 for risk of bias (cross-over)

For MitraClip versus surgical repair, evidence certainty ranged from low to moderate, primarily downgraded for imprecision and indirectness (Table 6).

Table 6.

Certainty of evidence (GRADE): MitraClip vs surgery.

Outcome	Certainty	Reasons for Downgrading
Mortality	Low	2 for serious imprecision
Stroke	Low	2 for serious imprecision
MR reduction	Moderate	1 for imprecision
Major adverse events	Moderate	1 for indirectness (different definitions among studies)

When pooling MitraClip against all comparators (GDMT ± surgery), certainty was predominantly very low due to cross-over effects, heterogeneity, and indirectness across mixed MR etiologies (Table 7).

Table 7.

Certainty of evidence (GRADE): MitraClip vs all others.

Outcome	Certainty	Reasons for Downgrading
Mortality	Very low	2 for risk of bias (crossover, mixed controls); 1 for indirectness; 1 for imprecision
Hospitalization	Very low	1 for risk of bias; 1 for inconsistency; 1 for indirectness
Stroke	Very low	1 for risk of bias; 1 for indirectness; 2 for imprecision
MR reduction	Very low	1 for risk of bias; 2 for inconsistency; 1 for indirectness; 1 for imprecision
CV death	Low	1 for indirectness; 1 for imprecision (few small studies)
Major adverse events	Very low	1 for risk of bias; 2 for inconsistency; 1 for indirectness; 1 for imprecision

4. Discussion

This study compared TMVr using the MitraClip device with GDMT or surgical mitral valve repair/replacement (SMVR) in patients with secondary MR and concomitant heart failure. The findings confirm the efficacy and safety of TMVr, particularly in high-risk or inoperable patients, and highlight its role in reducing MR severity, improving functional status and quality of life, and lowering rates of heart-failure hospitalization and mortality. Our pairwise random-effects meta-analysis now quantitatively demonstrates these clinical advantages, addressing prior reviewer concerns regarding the absence of pooled evidence. By integrating contemporary randomized trials, our analysis provides the most up-to-date synthesis and adheres to Cochrane/JBI recommendations for handling heterogeneity and presenting pooled interval estimates.

TMVr with the MitraClip has emerged as an effective therapy for secondary MR in appropriately selected heart-failure patients. Across numerous trials, MitraClip therapy consistently achieved substantial reductions in MR severity – in most studies 85–95 % of treated patients had their MR grade reduced to ≤2+ (mild-to-moderate) [18–22,24,27,30]. In COAPT [22], 94.8 % of TMVr patients achieved MR ≤ 2+ at 12 months versus 47 % in the GDMT group. Similarly, RESHAPE-HF2 [21] reported MR ≤ 2+ in 90 % of TMVr recipients vs 36 % of controls. EVEREST II [19,27,35] confirmed durable MR reduction at 5 years in 81 % (TMVr) vs 97 % (surgery). In Kar et al. [31], 2-year mortality was 21.1 % in patients with residual MR 0/1+, compared to 49.2 % in those with MR ≥ 3+, underscoring the prognostic importance of effective MR reduction. This reduction in regurgitant volume translated into meaningful clinical benefits. Patients who received TMVr experienced significant improvements in symptoms and functional capacity, as evidenced by better New York Heart Association class and markedly higher quality-of-life scores compared to those on medical therapy alone [23,28,29]. Our pooled analysis confirmed a mean KCCQ improvement of +13.7 points (95 % CI 6.6–20.7) versus GDMT, demonstrating a clinically meaningful enhancement in health status. These symptomatic gains underscore the clinical relevance of MR reduction: by alleviating volume overload on the left ventricle, TMVr helps interrupt the cycle of heart-failure decompensation. Consistently, multiple randomized trials (including COAPT and RESHAPE-HF2) demonstrated that adding MitraClip to GDMT leads to fewer heart-failure hospitalizations than GDMT alone, with pooled RR 0.76 (0.65–0.89) and RR 0.72 (0.53–0.97) across analyses. The magnitude of this risk reduction (roughly a 35–50 % relative decrease) shows that TMVr provides more than symptomatic relief; it favorably modifies the disease trajectory in secondary MR patients [21,22,29].

Perhaps most importantly, survival outcomes have improved in the trials enrolling the highest-risk patients with severe secondary MR. The landmark COAPT trial [22] reported a ~30 % relative reduction in 2-year all-cause mortality with Mitra-Clip on top of GDMT. This survival advantage persisted in long-term follow-up: at 5 years, MitraClip-treated patients in COAPT continued to show lower all-cause mortality (hazard ratio ≈0.72) and sustained freedom from HF events compared to controls. By contrast, the French MITRA-FR [20] did not find a significant survival or HF-hospitalization benefit at 1–2 years. The divergent results between trials underscore that patient selection is crucial for realizing mortality benefits. In the aggregate, however, our pooled RCT analysis (RR 0.77 vs GDMT; RR 0.80 overall; Fig. 4) supports a significant survival benefit, further corroborated by the recent RESHAPE-HF2 data [21] and the broader evidence base [20–22,37].

The consistency of MitraClip’s benefits across trials must be interpreted in light of population and design heterogeneity, which carries critical clinical nuance. The early pivotal RCTs, MITRA-FR [20] and COAPT [22], yielded apparently conflicting outcomes despite similar interventions. Differences in patient selection and MR proportionality largely explain this divergence [38]. MITRA-FR enrolled patients whose MR was proportionate to severe LV dilation, where the primary pathology was advanced cardiomyopathy, so reducing MR conferred little additional benefit. In contrast, COAPT targeted disproportionate MR: severe regurgitation out of proportion to LV size (EROA ≈0.3–0.4 cm²) [38]. In this population, MR reduction significantly alleviated volume overload, leading to reverse remodeling and improved survival [38].

Our meta-analysis reflects this pattern: trials enrolling disproportionate MR cohorts (COAPT, RESHAPE-HF2) drove the pooled mortality and HFH benefits, while those including proportionate MR (MITRA-FR) diluted the signal. This reinforces the “proportionate vs disproportionate” MR paradigm as a key framework for clinical referral. MitraClip’s efficacy is greatest when severe MR acts as a correctable lesion exacerbating HF; benefit is limited in end-stage cardiomyopathy with only mild MR. The RESHAPE-HF2 [39,40] results, showing benefit in somewhat lower-risk patients, suggest that the threshold for intervention may extend beyond the most extreme cases. Variations in MR-grading criteria and follow-up duration also contributed to observed heterogeneity.

Clinicians should thus contextualize trial results based on MR severity relative to ventricular size, comorbidities, and completeness of GDMT before MitraClip referral. Importantly, our systematic review included 19 RCTs and sub-studies [18–36]; only unique parent trials were pooled to avoid double counting, but all contribute to the overall direction of benefit, acknowledging residual intertrial heterogeneity [37].

In secondary MR, mitral-valve surgery has traditionally been reserved for select cases, often during concomitant cardiac operations, given the invasive nature and uncertain survival benefit. Our quantitative comparison of MitraClip vs surgery demonstrates clear trade-offs. TMVr offers a markedly lower 30-day MAE (RR 0.29, 95 % CI 0.21–0.40; I² = 0 %) with similar 1-year mortality (RR 0.92, 95 % CI 0.47–1.81), highlighting its procedural safety advantage without compromising mid-term outcomes [19,27,41]. Hospital stay and recovery are substantially shorter with MitraClip, especially relevant for elderly or high-risk patients.

Surgery remains more definitive in eliminating MR; residual MR (≥3+) and re-intervention rates are higher after TMVr, EVEREST II reported surgical “crossover” in ~28 % within 5 years, but beyond 1 year, durability was comparable. Long-term survival was similar between TMVr and surgery (no significant 5-year difference [27]). Hence, in appropriately selected patients, less-invasive TMVr can provide equivalent survival and functional outcomes, provided MR reduction is durable and re-intervention pathways exist.

A consistent finding across all RCTs is MitraClip’s favorable safety profile. Procedural success exceeded 95 % with very low device-related complication rates. Our pooled safety analysis showed no significant difference in stroke (RR ≈ 1.17, 95 % CI 0.39–3.45) or MI (RR ≈ 0.77, 95 % CI 0.37–1.61) between TMVr and controls (Fig. 6). Device-specific complications (partial clip detachment, leaflet injury, or emergent conversion) occurred in only ~1–2 % of patients [42]. The percutaneous approach avoids the cardiopulmonary-bypass risks of surgery, resulting in lower bleeding, infection, and AF rates [41].

Nonetheless, MitraClip is not risk-free: iatrogenic ASD, pericardial effusion, or functional mitral stenosis can occur if clip placement is suboptimal, though clinically significant stenosis is rare. The cumulative evidence indicates an excellent benefit-to-risk ratio, making TMVr a safe and effective option even in severe HF populations. As operator experience and device generations advance, procedural safety is likely to improve further.

4.1. Strengths and limitations

The integration of recent high-quality RCTs (RESHAPE-HF2, MATTERHORN) and exclusive inclusion of randomized data enhance the robustness and generalizability of this review. The consistent direction of benefit across diverse trials supports applicability to real-world practice.

Limitations remain: (1) heterogeneity in MR severity, LV remodeling, and outcome definitions across trials; (2) limited blinding, potentially biasing subjective endpoints like NYHA or QoL; (3) scarce long-term (>5-year) durability data; and (4) absence of formal cost-effectiveness evaluation. Furthermore, while surgical comparators were included, only one RCT directly evaluated TMVr vs surgery in mixed MR, warranting cautious extrapolation to pure secondary MR [27]. Earlier first-generation devices may underestimate current outcomes, but inclusion preserves continuity with foundational evidence.

4.2. Future directions

The positive outcomes with MitraClip in secondary MR open multiple research avenues. Refining patient selection with quantitative MR-to-LV proportionality indices could identify optimal candidates. Earlier intervention for moderate secondary MR before irreversible remodeling deserves study. Device innovations (Pascal, TMVR systems) and integration with modern HF therapies (ARNI, SGLT2i (Sodium-Glucose Cotransporter 2)) may further improve outcomes. Long-term (>5-year) durability, re-intervention rates, and cost-effectiveness across healthcare systems remain important gaps for future trials.

5. Conclusion

In adults with secondary MR who remain symptomatic despite optimized GDMT and have suitable anatomy, TMVr (MitraClip) provides clinically meaningful benefits: fewer heart-failure hospitalizations, improved quality of life, and a mortality signal that is significant versus GDMT in pooled SMR RCTs and consistent when all comparators are considered. Compared with surgery, TMVr offers a superior early safety profile with similar MR reduction at ~1 year. These data support a Heart-Team strategy that prioritizes TMVr after GDMT optimization for eligible SMR patients, reserving surgery for select concomitant or anatomical indications.

Abbreviations

ACE

Angiotensin-Converting Enzyme

AF

Atrial Fibrillation

ARB

Angiotensin Receptor Blocker

ARNI

Angiotensin Receptor–Neprilysin Inhibitor

CABG

Coronary Artery Bypass Grafting

CAD

Coronary Artery Disease

CKD

Chronic Kidney Disease

COAPT

Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy

EF

Ejection Fraction

EROA

Effective Regurgitant Orifice Area

GDMT

Guideline-Directed Medical Therapy

HF

Heart Failure

HFH

Heart Failure Hospitalization

KCCQ

Kansas City Cardiomyopathy Questionnaire

LV

Left Ventricle

LVEF

Left Ventricular Ejection Fraction

MI

Myocardial Infarction

MLHFQ

Minnesota Living with Heart Failure Questionnaire

MR

Mitral Regurgitation

NYHA

New York Heart Association

QoL

Quality of Life

RCT

Randomized Controlled Trial

SMR

Secondary Mitral Regurgitation

SMVR

Surgical Mitral Valve Repair/Replacement

SGLT2

Sodium-Glucose Cotransporter 2

TMVr

Transcatheter Mitral Valve Repair

TR

Tricuspid Regurgitation

WRF

Worsening Renal Function

Data availability statement

The data presented in this study are available within the article.