This brief accredited activity contains text and a faculty expert video focusing on the latest guideline recommendations, recent controversies, and innovative treatment strategies for the management of chronic secondary mitral valve regurgitation. Highlights include methods for identifying patients who should receive transcatheter edge-to-edge repair (TEER), a review of the COAPT and MITRA-FR trials, indications for mitral surgery, and an inside look at some state-of-the-art transcatheter and surgical treatments being offered at Duke Health. 

SECONDARY MITRAL REGURGITATION: WHAT’S NEW? 

Mitral regurgitation (MR) is one of the most common heart valve abnormalities in the United States (US), affecting an estimated 2 to 4 million people.^[1] Primary MR occurs when the mitral valve undergoes degenerative changes, whereas secondary (functional) MR typically occurs as a result of left ventricular (LV) dysfunction and remodeling.^[1] Papillary muscle displacement and leaflet tethering associated with an abnormal and dilated left ventricle prohibit normal leaflet coaptation.^[2] The underlying causes are typically coronary artery disease and nonischemic cardiomyopathies; however, on occasion, atrial fibrillation may lead to atrial annular dilation and secondary MR.^[2]

In recent years, new insights and advances have emerged in the pathophysiology and management of secondary MR. Consequently, the joint American College of Cardiology and American Heart Association (ACC/AHA) guideline on valvular diseases was updated to reflect these developments.^[2] This activity reviews relevant 2020 ACC/AHA guideline updates for chronic secondary MR and discusses recent controversies and advances that are likely to influence clinical approaches to treatment.

DIAGNOSIS AND MEDICAL MANAGEMENT

In both primary and secondary MR, the 2020 ACC/AHA guideline recommends transthoracic echocardiography to establish the initial diagnosis and determine disease severity. Transthoracic echocardiography is an important modality to evaluate systolic dysfunction, LV remodeling, and pulmonary hypertension.^[2] Noninvasive imaging, coronary computed tomography angiography, or coronary arteriography can also help establish underlying causes of heart failure (HF) and chronic secondary MR.

The defining criteria for severe secondary MR remain controversial.^[2] Currently, the definition for primary and secondary MR is the same: a regurgitant volume of 60 mL or more and an effective regurgitant orifice area (EROA) of 40 mm² or greater. However, evidence suggests that an EROA of just 20 mm² or greater in secondary MR is associated with poor outcomes and excess mortality.^[2]

Transesophageal echocardiography can provide additional information about MR mechanisms and can be used for initial diagnostic testing and when transthoracic visualization is indeterminate or inadequate.^[3] In fact, exclusion criteria from recent clinical trials have helped clarify transesophageal echocardiography–detected specific valve morphologies in patients with secondary MR that would cause them to be less likely to benefit from transcatheter edge-to-edge repair (TEER).^[2,4] Based on this information, the 2020 ACC/AHA guideline recommends transesophageal echocardiography to determine suitability for transcatheter mitral valve interventions.^[2] Transesophageal echocardiography also plays an important role in guiding the surgical repair of severe secondary MR.^[3]

Managing chronic secondary MR poses many uncertainties, given that restoring mitral valve competence alone does not necessarily resolve underlying abnormalities in LV function.^[2] The 2020 ACC/AHA guideline recommends guideline-directed medical therapy (GDMT) as an initial treatment for patients with chronic, severe secondary MR and HF with reduced LV ejection fraction (LVEF).^[2] GDMT may reduce the severity of secondary MR primarily by decreasing LV volume. Standard treatments include diuretics, beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aldosterone antagonists. In patients with a left bundle branch block and severe reduction in LVEF, cardiac resynchronization therapy with the implantation of a biventricular pacemaker can improve LVEF, reduce LV volume, and improve secondary MR. These therapies can improve symptoms and prolong life in patients with HF and are likely to be effective in those with HF complicated by chronic secondary MR.^[2] After maximally tolerated GDMT, repeat assessment of symptoms and MR severity should be performed.

INTERVENTIONS: RECENT ADVANCES, RECOMMENDATIONS, AND CONTROVERSIES 

Perhaps the most important change to the 2020 ACC/AHA guideline is the upgraded recommendation from class 2b (weak-strength recommendation) to 2a (moderate-strength recommendation) that TEER is a reasonable option for symptomatic patients with chronic severe secondary MR related to LV systolic dysfunction, as well as that TEER can improve morbidity and mortality outcomes in patients with valve morphology suitable for TEER.^[2,4] According to the guideline, patients eligible for TEER should receive optimized GDMT and should have an^[2]:

• LVEF between 20% and 50%;
• LV end-systolic diameter of 70 mm or less; and
• Pulmonary artery systolic pressure of 70 mm Hg or less

These criteria are based on patient characteristics identified in the pivotal COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, published in 2018.^[4] The COAPT trial was a US- and Canada-based, multicenter, randomized trial that enrolled 614 patients with HF and moderate-to-severe or severe secondary MR who were symptomatic despite GDMT and cardiac resynchronization therapy. Patients had ischemic or nonischemic cardiomyopathy with an LVEF of 20% to 50%. Participants were assigned to undergo either transcatheter mitral valve repair plus medical therapy or medical therapy alone.^[4] The MitraClip (Abbott Laboratories, Abbott Park, Illinois) device was used in the trial for TEER (previously approved by the US Food and Drug Administration for the treatment of primary or degenerative MR in high-risk patients who cannot safely undergo surgical intervention).^[5]

The primary effectiveness endpoint of the COAPT study was hospitalizations for HF within the 24-month follow-up period.^[4] The primary safety endpoint was lack of device-related complications at 12 months. The mean ± standard deviation age of patients was 72.2 ± 11.2 years, and 36% were women. Approximately 61% of patients had ischemic cardiomyopathy, and 39% had nonischemic disease. The mean ± standard deviation LVEF was 31.3% ± 9.3%. Approximately 52% of patients had an MR grade of 3 or higher, and nearly 48% had a grade of 4 or higher. Approximately 70% had a high risk of surgery-related complications or death.^[4]

Patients who received the device-based intervention had significantly lower rates of hospitalization for HF, lower mortality rates, improved functional capacity, and better quality of life than those who received medical therapy alone (Table 1).^[4] Benefits were apparent across various patient subgroups and were independent of baseline MR grade and LV volume and function. The rate of implantation of an LV assist device (LVAD) or heart transplantation during follow-up was lower in the device-based intervention group as well.^[4]

Table 1. COAPT Trial: Primary and Select Secondary Endpoints*

CI = confidence interval; LVEDV = left ventricular end-diastolic volume; KCCQ = Kansas City Cardiomyopathy Questionnaire.
*Data derived from Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med. 2018;379(24):2307-2318.
^†Data presented as mean ± standard deviation.

Unlike the COAPT trial, the MITRA-FR (Percutaneous Repair With the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) trial found no significant difference in outcomes for those who underwent TEER versus medical therapy alone. The trial enrolled 304 patients with symptomatic HF, severe secondary MR, and an LVEF of 15% to 40%.^[6] Patients were randomized to either percutaneous mitral valve repair with the MitraClip device plus medical therapy or medical therapy alone. The primary efficacy outcome was a composite of death from any cause or hospitalization for HF at 12 months after randomization. Secondary outcomes included components of the primary outcome, death related to cardiovascular causes, and survival free from major adverse cardiovascular-related events. Results from MITRA-FR indicated no significant difference between the intervention and control group.^[6] The composite primary outcome of death from any cause or unplanned hospitalization for HF at 12 months occurred in 54.6% of patients in the intervention group and 51.3% in the control group (odds ratio, 1.16; 95% confidence interval, 0.73-1.84; P = .53).^[6]

The divergent results of the COAPT and MITRA-FR trials may potentially be explained by differences in inclusion criteria, echocardiographic assessment of MR severity, implementation of medical therapy, and the TEER technique used.^[7] Notably, patients in the COAPT trial had greater severity of MR, with a mean EROA of 41 mm², compared with a mean EROA of 31 mm² for those enrolled in the MITRA-FR trial. However, patients in the COAPT trial had less severe LV dilation, with a mean indexed LV end-diastolic volume of 101 mL/m² compared with 135 mL/m² in patients in the MITRA-FR trial, whereas the MITRA-FR patients had less severe mitral EROA (31 ± 10 mm²) than those in the COAPT trial (41 ± 15 mm²).^[2,4,6,7] The positive outcomes observed in the COAPT trial may be because of the disproportionately high severity of MR relative to LV size in the patients enrolled in the COAPT versus MITRA-FR trials; the inclusion criteria used in the COAPT trial are now recommended for patient selection in clinical practice.^[2,8] Based on results from the COAPT trial, in 2019, the US Food and Drug Administration expanded indications for the MitraClip device to include treatment of moderate-to-severe to severe secondary MR in patients with HF.^[5]

THE DUKE PERSPECTIVE 

Choosing Interventions for Severe Secondary MR

According to the 2020 ACC/AHA guideline update, mitral valve surgery is warranted in patients with chronic severe secondary MR when^[2]:

• Coronary artery bypass graft is undertaken to treat myocardial ischemia;
• LVEF is 50% or greater and atrial annular dilation and severe symptoms are present, despite treatment for HF, atrial fibrillation, or other comorbidities;
• LVEF is less than 50% and severe, persistent symptoms are present, despite optimal GDMT; or
• LVEF is 50% or less and coronary artery disease and severe symptoms are present, despite GDMT (in which case, chordal-sparing mitral valve replacement is a reasonable choice over downsized annuloplasty repair)

The 2014 CTSN (Cardiothoracic Surgical Trials Network) trial reported similar clinical outcomes in patients with chronic severe ischemic MR who underwent mitral valve repair compared with those who underwent mitral valve replacement; however, the study did find that replacement provided a more durable correction of MR.^[9,10] The CTSN trial and other studies that support the current ACC/AHA guideline recommendations concluded that, in some patients, surgical mitral repair had poor durability and no survival benefit.^[2,9,10]

Because of these findings, eligible patients with chronic secondary MR more commonly undergo mitral valve replacement instead of repair. It is now believed, however, that those studies supporting the current ACC/AHA guideline recommendations examined patients with very poor ventricular function, for whom cardiomyopathies played an important role in negative outcomes.^[9-11] Indeed, researchers at Duke have found that, in some patients with ischemic MR and relatively preserved ventricular function and dimensions, surgical mitral repair can be nearly as durable as it is in patients with degenerative mitral valve prolapse.^[11] Recent information suggests that there may also be a class of patients with secondary MR related to atrial dysfunction who tend to have relatively normal ejection fraction and often near-normal mitral leaflet anatomy.^[12] These patients typically have positive outcomes, with a relatively durable repair.^[11,12]

The ACC/AHA guideline now includes the option of TEER for severe symptomatic secondary MR for patients undergoing GDMT who meet COAPT criteria for LVEF and end-systolic diameter.^[2] An assessment by a cardiologist specializing in HF is required to assess GDMT and other options to treat advanced HF.

New Mitral Valve Replacement and Repair Options

Cardiology surgeons at Duke are able to offer innovative transcatheter and surgical treatments for secondary MR, including:

• Transcatheter mitral valve repair with mitral clip devices;
• Investigational devices for transcatheter mitral valve replacement;
• Robotic and thoracoscopic mitral valve replacement and repair; and
• Cardiac transplantation or state-of-the-art LVAD implantation for patients with advanced cardiomyopathy

Robotic and video-assisted minimally invasive thoracotomies and mini-thoracotomies are commonly used for mitral valve replacement and repair at Duke. To date, these technologies are not yet widely available across the US or globally. In select patients with secondary MR who have undergone previous cardiac surgery, surgeons at Duke recognize that the correct mini-thoracotomy approach can significantly reduce the risk of mortality and morbidity compared with second-time sternotomy.^[13] Transcatheter mitral replacement devices remain investigational at Duke and elsewhere, and ongoing clinical trials are in progress using novel transcatheter mitral replacement devices to address the issues of mitral annular size, prevention of LV outflow tract obstruction and paravalvular regurgitation, and transfemoral rather than transapical access. In addition, novel transcatheter mitral repair techniques using transcatheter annuloplasty devices are being studied.^[14]