The New England Journal of Medicine SEPTEMBER 23, 2018

Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT)

Gregg W. Stone, JoAnn Lindenfeld, William T. Abraham, et al.

Bottom Line

The COAPT trial demonstrated that transcatheter edge-to-edge mitral valve repair with the MitraClip, when added to maximally tolerated guideline-directed medical therapy, significantly reduces the rate of heart failure hospitalizations and improves survival in patients with symptomatic heart failure and moderate-to-severe or severe secondary mitral regurgitation.

Key Findings

1. The annualized rate of heart failure hospitalization through 24 months was significantly lower in the device group (35.8% per patient-year) compared to the control group (67.9% per patient-year), yielding a hazard ratio of 0.53 (95% CI 0.40–0.70; P<0.001).

2. At 24 months, all-cause mortality was 29.1% in the device group compared to 46.1% in the control group (hazard ratio 0.62; 95% CI 0.46–0.82; P<0.001).

3. The primary safety endpoint, freedom from device-related complications at 12 months, was 96.6%, which successfully exceeded the pre-specified performance goal of 88.0% (P<0.001).

4. Long-term data at 5 years confirmed the durability of these benefits, with the device group maintaining lower rates of heart failure hospitalization (33.1% vs. 57.2% per patient-year; HR 0.53) and mortality (57.3% vs. 67.2%; HR 0.72) compared to the control group.

Study Design

Design

RCT

Open-Label

Sample

614

Patients

Duration

60 mo

Median

Setting

Multicenter, US/Canada

Population Symptomatic heart failure patients with moderate-to-severe (3+) or severe (4+) secondary mitral regurgitation despite maximally tolerated guideline-directed medical therapy and determined not appropriate for surgery.

Intervention Transcatheter mitral valve repair with the MitraClip device plus guideline-directed medical therapy.

Comparator Guideline-directed medical therapy alone.

Outcome Annualized rate of all hospitalizations for heart failure through 24 months.

Study Limitations

• The trial was open-label, which may introduce observer bias, particularly regarding the primary endpoint of heart failure hospitalization, which can be influenced by clinical decision-making.

• The strict selection criteria (e.g., specific thresholds for MR severity and absence of severe LV remodeling) may limit the generalizability of these findings to a broader population of heart failure patients with secondary mitral regurgitation.

• The trial compared the intervention to guideline-directed medical therapy alone, without a sham control arm, potentially confounding the perceived benefits with the placebo effect of an invasive procedure.

• The observed benefits are specific to the MitraClip device and the specific patient phenotype identified by the heart team, as demonstrated by the divergent results of the contemporaneous MITRA-FR trial.

Clinical Significance

The COAPT trial shifted the treatment paradigm for secondary mitral regurgitation, establishing percutaneous edge-to-edge mitral repair as a gold-standard therapy for carefully selected heart failure patients who remain symptomatic despite optimization of guideline-directed medical therapy.

Historical Context

Prior to COAPT, the management of secondary (functional) mitral regurgitation in heart failure was largely limited to medical therapy, as surgical mitral valve repair had not consistently demonstrated improved mortality or hospitalization outcomes in this population. The neutral results of the MITRA-FR trial, published in parallel with COAPT, sparked significant academic debate regarding patient selection—specifically the importance of disproportionate versus proportionate MR—which remains a critical concept in contemporary interventional cardiology.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why is secondary (functional) mitral regurgitation (SMR) fundamentally described as a 'ventricular disease' rather than a 'valvular disease', and how does the COAPT trial's approach address this pathophysiology?

Key Response

In SMR, the valve leaflets and chordae are typically normal; the regurgitation is caused by left ventricular (LV) remodeling, dilation, and papillary muscle displacement which leads to leaflet tethering and failure of coaptation. COAPT demonstrated that mechanically reducing the regurgitant volume with MitraClip can break the vicious cycle of LV volume overload and further remodeling, provided the underlying ventricular failure is concurrently managed with guideline-directed medical therapy (GDMT).

Resident

A patient with NYHA Class III heart failure and 3+ secondary mitral regurgitation is being considered for MitraClip based on COAPT criteria. What specific echocardiographic and clinical thresholds must be met to justify the procedure over GDMT alone?

Key Response

Based on COAPT inclusion criteria, the patient must have an LV ejection fraction (LVEF) between 20-50%, a left ventricular end-systolic dimension (LVESD) of ≤70 mm, and must remain symptomatic despite 'maximally tolerated' GDMT. These thresholds are critical because they identify a population where the heart is not yet so dilated that the intervention would be futile.

Fellow

How do the concepts of 'proportionate' vs. 'disproportionate' mitral regurgitation explain the conflicting results between the COAPT and MITRA-FR trials regarding the efficacy of transcatheter edge-to-edge repair (TEER)?

Key Response

MITRA-FR included patients with 'proportionate' MR (regurgitation commensurate with the degree of LV dilation), where the ventricle was the primary driver of the prognosis. COAPT focused on 'disproportionate' MR, where the effective regurgitant orifice area (EROA) was large (average 0.41 cm²) relative to more modest LV volumes (EDV). TEER is most effective when the MR itself is the dominant driver of the patient's symptoms and risk, rather than a mere bystander to end-stage cardiomyopathy.

Attending

In the 'Heart Team' era, how should we define 'maximally tolerated GDMT' prior to MitraClip intervention to avoid therapeutic inertia while remaining true to the COAPT protocol?

Key Response

The COAPT protocol required optimization by a heart failure specialist, often including titration of ACEi/ARB/ARNI, beta-blockers, and MRAs to target doses or the highest tolerated dose. In modern practice, this now includes SGLT2 inhibitors. The challenge is ensuring patients are not rushed to the cath lab before these drugs can promote reverse remodeling, while also recognizing that severe MR often causes the hypotension that limits GDMT titration.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

COAPT utilized a joint-rank test (Finkelstein-Schoenfeld method) for its primary endpoint analysis. What are the statistical advantages of this hierarchical approach compared to a standard Cox proportional hazards model for time-to-first-event?

Key Response

Standard time-to-first-event analyses (like those used in many HF trials) treat all events as equal, often focusing on the first hospitalization. The joint-rank test prioritizes more severe outcomes (death) over less severe ones (hospitalization) and uses all available data rather than just the first event. This provides a more clinically relevant assessment of the total burden of disease and treatment effect.

Journal Editor

The COAPT trial utilized a Central Eligibility Committee to screen all candidates. How does this 'enrichment' strategy affect the internal validity of the trial versus its external generalizability to a standard community hospital setting?

Key Response

The committee ensured that only patients with truly severe MR and optimized GDMT entered the trial, maximizing internal validity and the likelihood of observing a treatment effect. However, this creates an 'idealized' population that may not reflect real-world practice, where echocardiographic interpretation of SMR is highly variable and GDMT optimization is often incomplete, potentially diluting the benefits seen in the trial.

Guideline Committee

Based on the COAPT results, how have the 2020 ACC/AHA Valvular Heart Disease guidelines changed the recommendation for TEER in secondary MR, and what are the specific 'Class of Recommendation' and 'Level of Evidence'?

Key Response

Following COAPT, the guidelines upgraded TEER (MitraClip) to a Class 2a (Level B-R) recommendation for patients with chronic severe secondary MR (Stage D) who remain symptomatic (NYHA II-IV) despite GDMT, provided their LVEF is 20-50% and LVESD ≤70 mm. This reflected a shift from viewing SMR as solely a medical management problem to one requiring a multidisciplinary 'Heart Team' interventional approach.

Clinical Landscape

Noteworthy Related Trials

2011

EVEREST II Trial

n = 279 · NEJM

Tested

Percutaneous mitral-valve repair (MitraClip)

Population

Patients with moderate-to-severe or severe mitral regurgitation

Comparator

Conventional mitral-valve surgery

Endpoint

Composite of death, surgery for mitral-valve dysfunction, or 3+ or 4+ mitral regurgitation

Key result: Percutaneous repair was found to be safer than surgery but less effective at reducing mitral regurgitation.

2018

MITRA-FR Trial

n = 304 · NEJM

Tested

Transcatheter mitral-valve repair (MitraClip)

Population

Patients with severe secondary mitral regurgitation and HFrEF

Comparator

Medical therapy alone

Endpoint

Composite of death or unplanned hospitalization for heart failure at 12 months

Key result: At 12 months, there was no significant difference in the primary endpoint between the intervention and control groups.

2018

RESOLVE Trial

n = 840 · JACC

Tested

Transcatheter edge-to-edge repair

Population

Patients undergoing transcatheter mitral valve repair

Comparator

Historical registry data

Endpoint

Leaflet motion abnormalities and clinical outcomes

Key result: The study identified reduced leaflet motion in a small percentage of patients, which did not appear to impact clinical outcomes.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis