COAPT

Published

Stone GW, et al. "Transcatheter Mitral Valve Repair in Patients with Heart Failure". The New England Journal of Medicine. 2018. 379:2307-2318.
PubMed • Full text • PDF

Clinical Question

In patients with moderate-severe or severe mitral regurgitation (MR) due to annular dilation in the setting of heart failure with reduced ejection fraction (functional MR) and high surgical risk, does percutaneous mitral valve repair with the Mitra Clip leaflet approximation device reduce heart failure hospitalization or mortality?

Bottom Line

In patients with HFrEF (mean LVEF 31%, 61% ischemic) resulting in moderate-severe or severe functional MR, percutaneous mitral valve repair results in a 32.1% absolute reduction in heart failure hospitalization at 2 years compared to medical therapy alone. Device-based therapy was also associated with a 16% absolute reduction in all cause death. At 1 year, device-related complications occurred at a rate of 3.4%, meeting pre-specified criteria for safety.

Major Points

In patients with chronic heart failure with reduced ejection fraction (HFrEF), dilation of the mitral valve annulus commonly results in secondary or functional mitral regurgitation (MR). When functional MR becomes severe, it leads to a dramatic increase in heart failure-related complications including hospitalization, decreased quality of life, and shortened survival. Unfortunately, treatment of functional MR in this setting is challenging, as neither surgical repair or replacement has been shown to robustly improve symptoms or outcomes in this population. Furthermore, surgical risk is frequently very high since these patients frequently have severe heart failure.

The Mitra Clip is a percutaneous device that approximates the anterior and posterior leaflets of the mitral valve and reduces the severity of MR. In the EVEREST II RCT, use of the Mitra Clip was safer than surgical repair and reduced MR severity, although with less efficacy than open surgical repair. Importantly, patients with functional MR represented a small minority of patients in EVEREST II and outcomes in this small subgroup were similar with surgical or percutaneous repair, possibly due to an improved safety profile with Mitra Clip. Thus, a robust study of Mitra Clip specifically in patients with functional MR was needed in order to establish safety and efficacy of this approach.

The 2018 Cardiovascular Outcomes Assessment of the Mitra Clip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial randomized 614 patients with HFrEF (mean LVEF 31%, 61% ischemic) and moderate-severe or severe functional MR to percutaneous repair with Mitra Clip versus medical therapy alone and assessed for a primary outcome of hospitalization for heart failure. At 2 years, percutaneous mitral valve repair was associated with a 32.1% absolute reduction in heart failure hospitalization. Device-based therapy was also associated with a 16% absolute reduction in all cause death. MR severity remained moderate or lower in 95% of patients at 1 year. Device-related complications with Mitra Clip occurred at a rate of 3.4% at 1 year, meeting pre-specified criteria for safety. The benefit of Mitra Clip appeared consistent independent of etiology of cardiomyopathy, LV function or volume, or predicted risk of cardiac surgery.

Importantly, the smaller MITRA-FR study failed to demonstrate improvement in either heart failure related complications or mortality with Mitra Clip in a secondary MR population. The stark contrast between the negative result in MITRA-FR and very positive result in COAPT raise some concern regarding the reproducibility of either study. Two additional randomized studies are underway to clarify the efficacy of percutaneous mitral valve repair in patients with secondary MR. In the interim, COAPT does provide very encouraging evidence that percutaneous repair may improve outcomes in patients with severe heart failure and secondary MR.

Guidelines

As of September 2018, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, randomized, open-label, controlled trial
• N=614
  • Mitra Clip (N=302)
  • Medical therapy (N=312)
• Setting: United States and Canada
• Enrollment: December 27, 2012 - June 23, 2017
• Duration of follow-up: 2 years
• Analysis: Intention-to-treat
• Primary Outcome: Heart failure hospitalization
• Primary Safety Outcome: Device-related complication

Population

Inclusion Criteria

• Age ≥ 18 years
• Symptomatic secondary MR (moderate-severe or greater) due to ischemic or non-ischemic cardiomyopathy
• Adequately treated for coronary disease, LV dysfunction, MR, and heart failure
• NYHA class II or greater
• At least one hospitalization for heart failure in last year OR corrected BNP ≥ 300 pg/mL or corrected NTproBNP ≥ 1500 pg/mL
• Local heart team has determined that MV surgery will not be offered as a treatment option
• LVEF ≥ 20% and ≤ 50%
• LVIDs ≤ 70mm
• Primary MR jet is non-commissural, and implanting investigator deems Mitra Clip is feasible
• CK-MB obtained within prior 14 days is normal
• Transseptal catheterization and femoral vein access is feasible per Mitra Clip investigator
• Informed consent provided

Exclusion Criteria

• Untreated clinically significant coronary disease requiring revascularization
• CABG, PCI, or TAVR within 30 days
• Aortic or tricuspid valve requiring surgery or transcatheter intervention
• COPD requiring continuous home oxygen therapy or chronic outpatient steroid use
• CVA within 30 days
• Severe symptomatic carotid stenosis
• Carotid surgery or stenting within 30 days
• ACC/AHA Stage D heart failure
• Presence of any of the following:
  • Estimated PASP > 70 mmHg unless vasodilator therapy reduces PVR to < 3 Wood units or 3-4.5 Wood units with v wave less than twice the mean of PCWP
  • Hypertrophy cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, or any other structural heart disease causing heart failure other than dilated cardiomyopathy of either ischemic or non-ischemic etiology
  • Infiltrative cardiomyopathy
• Hemodynamic instability requiring inotropic support or mechanical assistance
• Physical evidence of right-sided CHF with echocardiographic evidence of moderate or severe RV dysfunction
• Implant of CRT or CRT-D within 30 days
• Mitral orifice area < 4.0cm2
• Leaflet anatomy which may preclude Mitra Clip implantation
• Hemodynamic instability, cardiogenic shock, or need for mechanical assistance
• Need for surgery within 12 months
• Life expectancy < 1 year
• Status 1 for cardiac transplant or history of cardiac transplant
• Modified Rankin score ≥ 4 for disability
• Echocardiographic evidence of intracardiac mass, thrombus, or vegetation
• Active infection requiring antibiotic therapy
• Prior mitral valve surgery or prosthesis
• TEE is contraindicated or high risk
• Pregnant or planning pregnancy within 12 months
• Known hypersensitivity or contraindication to procedural medications that cannot be adequately treated
• Subject belongs to vulnerable population or has any disorder that compromises his/her ability to give informed consent and/or comply with study procedures

Baseline Characteristics

From the medical therapy group.

• Demographics: Age 72.8 years, male 61.5%
• Comorbidities: BMI 27.1 DM 39.4%, HTN 80.4%, HLD 52.2%, hx MI 51.3%, hx PCI 49.0%, hx CABG 40.4%, hx CVA/TIA 15.7%, PAD 18.3%, COPD 23.1% AF 53.2%, GFR 47.8, anemia 62.7%
• Heart failure: ischemic CM 60.6%, NICM 39.4%, NYHA II 35.4%, NYHA III 54.0%, NYHA IV 10.6%, hospitalization in past year 56.1%, hx CRT 34.9%, ICD 32.4%, BNP 1017.1, NTproBNP 5943.9, LVIDd 6.2, LVIDs 5.3, LVEF 31.3%, RVSP 44.6
• Mitral regurgitation: moderate-severe 55.3%, severe 44.7%, EROA 0.40
• Procedural: STS risk 8.5%

Interventions

• Patients randomized 1:1 to percutaneous mitral valve repair or medical therapy
  • Mitra Clip (N=302)
  • Medical therapy (N=312)
• Prior to enrollment, MR confirmed to be moderate-severe or greater by echocardiographic core laboratory
• At each site, patients were assessed by a multidisciplinary heart team consisting of a heart failure specialist, interventional cardiologist, and cardiac surgeon with expertise in mitral valve disease
  • Interventional cardiologist confirmed that Mitral Clip was feasible
  • Cardiac surgeon confirmed that mitral valve surgery was not going to be offered
• Prior to enrollment, a central eligibility committee confirmed that patients met all eligibility criteria, had received all indicated medical therapy, and that surgical risk by STS was > 8% for mortality or surgical risk was otherwise extremely high
• Enrolled patients randomized to mitral valve intervention underwent Mitra Clip within 14 days after randomization
• Randomization was stratified according to trial site and cause of cardiomyopathy
• Clinical follow-up performed at 1 week and at 1, 6, 12, 18, and 24 months followed by annually until 5 years
• Follow-up assessments included echocardiography, 6-minute walk tests, and assessments of quality-of-life including KCCQ
• Cross-over was not permitted until 2 years of follow-up
• Device complication defined as single-leaflet device attachment, embolization of the device, endocarditis requiring surgery, mitral stenosis leading to mitral valve surgery, implantation of LVAD, heart transplantation, or any other device-related event leading to nonelective cardiac surgery
• Adverse events were adjudicated by independent committee with the use of source documents

Outcomes

Comparisons are percutaneous mitral valve repair versus medical therapy

Primary Outcomes

Hospitalization for heart failure (24 months)

160/446.5 (35.8%) vs. 283/416.8 (67.9%); HR 0.53 (95% CI 0.40-0.70); p < 0.001

Secondary Outcomes

All-cause mortality (12 months)

57 (19.1%) vs. 70 (23.2%); HR 0.81 (95% CI 0.57-1.15); p < 0.001 for noninferiority

All-cause mortality (24 months)

80 (29.1%) vs. 121 (46.1%); HR 0.62 (95% CI 0.46-0.82); p < 0.001

Mitral regurgitation moderate or lower (24 months)

199/210 (94.8%) vs. 82/175 (46.9%); p < 0.001

Change from baseline in LV end diastolic volume (12 months)

-3.7 +/- 5.1 vs. 17.1 +/- 5.1; mean difference -20.8 (95% CI -34.9 to -6.6); p = 0.004

NYHA class I or II (12 months)

171/237 (72.2%) vs. 115/232 (49.6%); p < 0.001

Change from baseline in KCCQ score (12 months)

12.5 +/- 1.8 vs. -3.6 +/- 1.9, mean difference 16.1 (95% CI 11.0 to 21.2); p < 0.001

Safety Outcomes

Freedom from device-related complication (12 months)

96.6% (lower 95% confidence limit 94.8%); p < 0.001 for comparison with goal 88.0%

Unplanned mitral valve intervention

10 (4.0%) vs. 15 (9.0%); HR 0.61 (95% CI 0.27-1.36); p = 0.23

Stroke

11 (4.4%) vs. 11 (5.1%); HR 0.96 (95% CI 0.42-0.22); p = 0.93

Myocardial infarction

12 (4.7%) vs. 14 (6.5%); HR 0.82 (95% CI 0.38-1.78); p = 0.62

LVAD or heart transplant

9 (4.4%) vs. 16 (7.1%); HR 0.34 (95% CI 0.13-0.87); p = 0.01

Subgroup Analyses

• There were no significant interactions between trial group and events according to age, sex, severity of MR, LV function or volume, the cause of cardiomyopathy, or the risk of surgery-related complications or death at baseline.

Criticisms

• Open-label design allows for bias in the assessment of outcomes. Verification of outcomes by an independent adjudication committee blinded to treatment assignment somewhat mitigates this bias.
• Long-term follow up (which is planned) is required to confirm the long-term stability of the apparent benefit of Mitra Clip and clarify any late complications.
• Contrast between the highly positive results of COAPT and the negative results of MITRA-FR raise some concern regarding the reproducibility of either study. Two additional RCTs are ongoing.

Funding

• Study supported by Abbott, who participated in site selection and management as well as data analysis.
• Authors with multiple ties to industry, including the study sponsor.