New England Journal of Medicine December 13, 2018

Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation

Obadia JF, Messika-Zeitoun D, Leurent G, et al., for the MITRA-FR Investigators

Bottom Line

Among patients with severe secondary mitral regurgitation and heart failure, the addition of percutaneous mitral valve repair to medical therapy did not significantly reduce the 12-month composite risk of death or unplanned heart failure hospitalization compared with medical therapy alone.

Key Findings

1. At 12 months, the primary composite endpoint of all-cause death or unplanned heart failure hospitalization occurred in 54.6% (83 of 152) of the percutaneous repair group versus 51.3% (78 of 152) of the control group (OR 1.16; 95% CI, 0.73-1.84; P=0.53).

2. All-cause mortality at 12 months was not significantly different between the groups, occurring in 24.3% of the intervention group and 22.4% of the control group (HR 1.11; 95% CI, 0.69-1.77).

3. Unplanned hospitalization for heart failure occurred in 48.7% of the intervention group compared with 47.4% of the medical therapy alone group (HR 1.13; 95% CI, 0.81-1.56).

4. Procedural success (device implantation) was achieved in 95.8% of cases, but 14.6% of patients in the intervention group experienced at least one procedural complication, and 9% of treated patients had residual MR grade >2+ at discharge.

Study Design

Design

RCT

Open-Label

Sample

304

Patients

Duration

12 mo

Median

Setting

Multicenter, France

Population Symptomatic heart failure patients (NYHA class II-IV) with severe secondary mitral regurgitation (EROA >20 mm2 or regurgitant volume >30 mL/beat) and a left ventricular ejection fraction of 15% to 40%.

Intervention Percutaneous mitral valve repair using the MitraClip device plus guideline-directed medical therapy.

Comparator Guideline-directed medical therapy alone.

Outcome Composite of death from any cause or unplanned hospitalization for heart failure at 12 months.

Study Limitations

• The trial lacked a run-in phase with a centralized committee to rigorously optimize and standardize guideline-directed medical therapy (GDMT) prior to randomization, permitting varied and potentially sub-optimal medical regimens.

• Echocardiographic inclusion criteria for severe MR were relatively broad (EROA >20 mm2 or regurgitant volume >30 mL/beat), which enrolled a high proportion of patients whose primary pathology was profound left ventricular dilation (mean end-diastolic volume ~272 mL) rather than the valvular defect itself.

• The primary endpoint was assessed at 12 months, a relatively short follow-up duration to fully capture the long-term remodeling benefits of mitral valve repair, though subsequent 24-month data corroborated the negative primary findings.

• The relatively small sample size (N=304) limited the statistical power to detect small but potentially meaningful clinical benefits in subgroup analyses.

• Approximately 14% of patients in the intervention arm either did not receive the device or experienced a procedural failure, dampening the potential intention-to-treat effect size.

Clinical Significance

The MITRA-FR trial demonstrated that transcatheter edge-to-edge repair (TEER) with the MitraClip device does not improve outcomes in an unselected population of patients with severe secondary mitral regurgitation and advanced heart failure. These results sharply contrasted with the highly positive COAPT trial published simultaneously. The discordance highlighted the critical importance of patient selection, leading to the paradigm of 'proportionate' versus 'disproportionate' mitral regurgitation. MITRA-FR primarily enrolled patients with 'proportionate' MR—where the regurgitation was matched to profound left ventricular dilation (mean LVEDV ~135 mL/m2 indexed) and the regurgitant orifice was relatively smaller (mean EROA 31 mm2). In such cases, correcting the MR does not modify the underlying trajectory of the diseased, dilated left ventricle. The trial emphasized that TEER should be reserved for patients whose MR is 'disproportionate' to their degree of LV dysfunction.

Historical Context

Historically, secondary (functional) mitral regurgitation in heart failure was considered a disease of the ventricle, and surgical mitral valve repair failed to show definitive survival benefits. The development of the MitraClip provided a lower-risk percutaneous option, but evidence in functional MR was limited. In late 2018, both the MITRA-FR and COAPT trials were published simultaneously in the NEJM. MITRA-FR was entirely negative, while COAPT showed massive mortality and morbidity benefits. Rather than canceling each other out, the two landmark trials together revolutionized the structural cardiology field by identifying exactly which heart failure phenotypes benefit from valve intervention. MITRA-FR serves as the defining study for patients whose left ventricles are too dilated and too damaged to benefit from functional MR repair.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why is secondary (functional) mitral regurgitation primarily considered a disease of the left ventricle rather than a primary defect of the mitral valve itself, and how does this pathophysiology explain why simply repairing the valve did not improve outcomes in the MITRA-FR trial?

Key Response

Secondary MR occurs when left ventricular dilation and remodeling cause annular dilation and tethering of otherwise structurally normal mitral leaflets. Because the root cause is a failing, dilated myocardium, mechanically fixing the valve's leak does not stop the progression of the underlying myopathic process, explaining the lack of mortality or hospitalization benefit in patients whose primary issue is profound ventricular failure.

Resident

In patients with heart failure and severe secondary mitral regurgitation, why is it critical to maximally titrate guideline-directed medical therapy (GDMT) and consider cardiac resynchronization therapy (CRT) before referring the patient for percutaneous edge-to-edge repair?

Key Response

GDMT (including beta-blockers, ARNIs, and MRAs) and CRT promote reverse ventricular remodeling, which can spontaneously reduce the severity of secondary MR. Referring patients before medical optimization may lead to unnecessary procedures with no clinical benefit, as the patient's underlying heart failure remains inadequately treated, mirroring the non-optimized baseline risk seen in real-world scenarios.

Fellow

The MITRA-FR trial showed no benefit for percutaneous repair in secondary MR, whereas the COAPT trial showed a massive benefit. How does the conceptual framework of 'proportionate' versus 'disproportionate' mitral regurgitation explain these diametrically opposed trial results based on differences in LV end-diastolic volume (LVEDV) and effective regurgitant orifice area (EROA)?

Key Response

MITRA-FR enrolled patients with larger LVs and smaller EROAs (proportionate MR), meaning the regurgitation was an expected consequence of severe LV dilation and not the primary driver of disease. COAPT enrolled patients with smaller LVs and larger EROAs (disproportionate MR), meaning the severity of the leak was disproportionately high for the degree of dilation, making the MR itself a primary driver of pathology that was highly responsive to mechanical correction.

Attending

Given the divergent findings of MITRA-FR and COAPT, how should a multidisciplinary Heart Team approach patient selection for percutaneous edge-to-edge repair to avoid futility in the real-world management of secondary mitral regurgitation?

Key Response

The Heart Team must shift from simply 'fixing a leaky valve' to integrating comprehensive echocardiographic parameters (specifically LV end-systolic dimension and EROA) alongside a rigorous assessment of true refractoriness to maximally tolerated GDMT. MITRA-FR serves as a cautionary tale that treating proportionate MR in end-stage dilated cardiomyopathy is futile, and those patients should instead be directed toward advanced HF therapies like LVAD or transplant.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

MITRA-FR assessed its primary composite endpoint at 12 months, whereas COAPT used a 24-month primary endpoint. Methodologically, how does the timing of the primary endpoint affect the statistical power to detect a treatment effect in structural heart trials, particularly when weighing early periprocedural risks against delayed hemodynamic benefits?

Key Response

A 12-month endpoint may be too brief to capture the late benefits of reverse remodeling while fully absorbing early periprocedural complications. If the survival curves or hospitalization rates only begin to diverge after a year, an inappropriately short follow-up duration risks a Type II error (false negative) for long-term efficacy, highlighting a critical study design consideration for device interventions in chronic progressive diseases.

Journal Editor

A significant threat to validity in open-label trials comparing a device to medical therapy is the variable titration of medications post-randomization. As a peer reviewer, how does the lack of a centralized, aggressively monitored medication optimization protocol in MITRA-FR (unlike the central committee used in COAPT) impact the interpretation of its null result?

Key Response

Without strict central oversight of GDMT, investigators might unblindedly alter medical management, or patients might remain sub-optimally treated, causing the background risk of HF progression to overwhelm any potential device benefit. The lack of standardized run-in and continuous optimization introduces confounding by medical management, making it difficult to ascertain if the device truly failed or if the medical baseline was just too poorly controlled.

Guideline Committee

Current ACC/AHA Valvular Heart Disease guidelines give a Class 2a recommendation for transcatheter edge-to-edge repair in specific patients with secondary MR. How do the null results of MITRA-FR function as the essential 'negative control' that prevents a Class 1 blanket recommendation and shapes the exact anatomic and clinical criteria required by the current guidelines?

Key Response

Guideline committees use MITRA-FR to define the boundary of futility. By demonstrating that patients with extreme LV dilation (e.g., LVEDD > 70 mm) and lesser MR severity do not benefit, MITRA-FR forces the guidelines to restrict the Class 2a (Level of Evidence B-R) recommendation strictly to COAPT-like patients (LVEF 20-50%, LVESD <= 70 mm, EROA >= 0.3 cm2), ensuring the intervention is evidence-based and resource-conscious.

Clinical Landscape

Noteworthy Related Trials

2011

EVEREST II Trial

n = 279 · NEJM

Tested

Percutaneous mitral-valve repair using the MitraClip device

Population

Patients with grade 3+ or 4+ mitral regurgitation (primary or secondary)

Comparator

Conventional mitral-valve surgery

Endpoint

Composite of freedom from death, surgery for mitral-valve dysfunction, and grade 3+ or 4+ MR at 12 months

Key result: Percutaneous repair was less effective at reducing mitral regurgitation than surgery but was associated with superior safety and similar improvements in clinical outcomes.

2018

COAPT Trial

n = 614 · NEJM

Tested

Transcatheter mitral-valve repair (MitraClip) plus GDMT

Population

Patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation

Comparator

Guideline-directed medical therapy (GDMT) alone

Endpoint

All-cause hospitalizations for heart failure within 24 months

Key result: Transcatheter mitral-valve repair resulted in a significantly lower rate of hospitalization for heart failure and lower all-cause mortality compared to medical therapy alone.

2024

RESHAPE-HF2 Trial

n = 505 · NEJM

Tested

Transcatheter edge-to-edge mitral-valve repair (TEER) plus GDMT

Population

Heart failure patients with moderate-to-severe secondary mitral regurgitation

Comparator

Guideline-directed medical therapy (GDMT) alone

Endpoint

Composite of first or recurrent heart failure hospitalization or cardiovascular death at 24 months

Key result: Transcatheter repair significantly reduced the rate of heart failure hospitalizations and cardiovascular death compared to medical therapy alone.

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