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Percutaneous Mending of the Mitral Valve: A Status Report on Challenges and Progress

Profile of six ongoing studies aiming to overcome anatomic hurdles

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The use of catheter-based procedures rather than open surgery for treating structural heart disease has taken hold in the past decade, so much so that it’s now routinely considered for many cases of aortic valve replacement. But when it comes to mitral valve disease, percutaneous procedures are not so easy, simply because the mitral valve poses greater anatomic challenges for a transcatheter approach.

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Those difficulties are compounded by the fact that most patients with mitral valve disease prefer repair of the valve to replacement, explains Cleveland Clinic Cardiothoracic Surgery Chairman A. Marc Gillinov, MD. “To replicate the repair with a catheter is challenging,” he says, “because it requires many maneuvers. You tend to not get the kind of results with a catheter that you get with surgery.”

Even so, Dr. Gillinov and his colleagues at Cleveland Clinic are among those leading efforts on multiple fronts to overcome these challenges and offer minimally invasive options for patients with mitral valve disease. “Not all patients with mitral valve disease are candidates for surgery,” notes cardiothoracic surgeon Stephanie Mick, MD, “so it’s important to develop nonsurgical options so that we can offer treatment to more patients.”

“Mitral valve interventions are among the most exciting innovations in interventional cardiology, and they’re evolving at a rapid pace,” adds Samir Kapadia, MD, Section Head of Interventional Cardiology and Director of Cleveland Clinic’s Cardiac Catheterization Laboratory.

Efforts focus largely on functional MR

As the busiest center for mitral valve repair and replacement in North America, Cleveland Clinic manages more than enough cases to know that open surgery is safe and effective for most patients with degenerative mitral valve regurgitation (DMR). Yet for individuals with DMR who have comorbidities that render surgery too risky, the percutaneously placed MitraClip® device has proved a welcome option since its FDA approval as a repair device for severe DMR in late 2013.

However, for most patients with functional mitral valve regurgitation (FMR) — resulting from factors outside the leaflets themselves — surgery poses a greater risk and is typically less effective. But for these patients no minimally invasive repair or replacement options are currently available in the U.S. (though some have received CE Marks in Europe).

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“This has prompted a great deal of research into new device technologies largely targeting the population with FMR,” notes Cleveland Clinic interventional cardiologist Amar Krishnaswamy, MD. Cleveland Clinic is leading or participating in at least six trials of percutaneous repair and replacement devices for patients with FMR, all aiming for eventual FDA approval. A brief overview of those studies follows.

Percutaneous mitral malve repair: Edge-to-edge, direct or indirect annuloplasty

COAPT trial. This study is investigating use of the MitraClip device for patients with moderate-to-severe or severe FMR who are deemed inappropriate candidates for surgery. The device is a V-shaped clip delivered via the femoral vein, closing the mitral valve leaflets in an edge-to-edge fashion. Over 600 subjects were randomized in COAPT, with about half receiving the study device and all receiving standard care. The study has reached its 12-month safety and 24-month effectiveness end points, but no data have yet been presented. Cleveland Clinic is one of 83 COAPT study sites. Dr. Kapadia is on the trial’s steering committee, and Dr. Gillinov is on the central eligibility committee.

Transcatheter Treatment of Functional Mitral Regurgitation trial. This is a prospective, randomized, double-blind trial assessing the safety and efficacy of the investigational Carillon® Mitral Contour System in treating subjects with FMR associated with heart failure (control patients are being managed medically). The study device uses an indirect annuloplasty approach, with a nitinol wire placed in the coronary sinus via the internal jugular vein. This multicenter study launched in autumn 2017 with a target enrollment of 400 and expected completion in 2020. Drs. Kapadia and Gillinov join Cleveland Clinic’s Randall Starling, MD, MPH, as co-principal investigators of the trial.

ACTIVE. The ACTIVE trial is assessing the efficacy and safety of transcatheter mitral valve repair with the Cardioband annuloplasty system plus guideline-directed medical therapy versus guideline-directed medical therapy alone in patients with FMR and heart failure. Cardioband is an adjustable sutureless band that’s placed in the posterior annulus — i.e., direct annuloplasty — via the femoral artery. Adjustment can be performed on a beating heart to optimize correction of mitral regurgitation. The study began earlier this year, with an estimated enrollment of 375 patients and planned completion by December 2023. Cleveland Clinic is a participating center.

Dr. Kapadia reflects on these three trials by noting that while MitraClip is a safe device, it may limit future options for transcatheter mitral valve replacement if mitral regurgitation recurs or persists after treatment. In contrast, the devices in the other two trials potentially will allow for future transcatheter valve replacement. “It may be helpful not to burn bridges,” he says. “With MitraClip, you may not be able to go back later and replace the valve percutaneously. The Carillon and Cardioband devices may be more compatible with future options.”

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(Early) studies of transcatheter mitral valve replacement

Use of percutaneous techniques has been moving more slowly for replacement than for repair of the mitral valve. That has much to do with basic logistics of replacement in this setting: In contrast to aortic valve replacement, the native mitral valve cannot simply be pushed aside without risking left ventricular outflow tract obstruction (LVOTO).

“The question is how to avoid this obstruction in a percutaneous procedure,” Dr. Kapadia explains. “Transcatheter mitral valve replacement is an important tool in our armamentarium, but it will take some time to become extremely safe and reproducible. Until then, repair may be considered as a first step as long as it doesn’t prevent future options.”

“It’s fair to say that transcatheter mitral valve replacement is still in its infancy,” adds Dr. Mick, “but we are pleased to be involved in several early trials.” Those trials are just now getting off the ground, as detailed below.

Early Feasibility Study of the Tendyne Mitral Valve System. This trial is designed to “generate initial insights” on the safety and performance of the Tendyne valve, a self-expanding prosthesis with porcine pericardial leaflets. It’s delivered transapically and held in place by a tether from the valve to the left ventricular apex. The study includes up to 110 adults with symptomatic mitral regurgitation who are not candidates for conventional valve repair or replacement. Follow-up will continue through two years after implantation. Approximately 30 centers, including Cleveland Clinic, are participating. Completion is expected in 2018.

CardiAQ Early Feasibility Study. This 28-patient phase 1 study is evaluating the safety and function of the CardiAQ™ Transcatheter Mitral Valve for both DMR and FMR. The valve is constructed of bovine pericardium and can be delivered via transseptal or transapical routes. Completion is expected in 2021. Cleveland Clinic is a participating center.

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PRELUDE. The phase 1, single-arm PRELUDE study is assessing safety and performance of the Caisson TMVR system for treating patients with severe symptomatic MR (primary or secondary). This system consists of a self-expanding nitinol frame with a trileaflet porcine pericardial valve that nests in a D-shaped anchor designed to grip the native valve annulus. Delivery is via transfemoral route. The study began in 2016 and is expected to end in 2021. Dr. Kapadia is study co-director.

Another area of active exploration is implantation of a transcatheter aortic valve replacement (TAVR) prosthesis in patients with degeneration of a prior mitral valve prosthesis or mitral valve ring. These valve-in-valve and valve-in-ring procedures have been performed successfully at Cleveland Clinic, and the valve-in-valve application is approved by the FDA. As LVOTO is also a risk, patient eligibility for this option (vs. reoperation) requires a detailed assessment of clinical and anatomic factors.

Teamwork will be paramount

Despite this proliferation of efforts to percutaneously tame mitral valve disease, Dr. Gillinov notes that widespread transcatheter mitral valve repair and replacement “remains some years off” and is likely to never be as prevalent as TAVR has become. “Percutaneous mitral valve procedures are going to be much more specialized, especially for repairs,” he says. “They will need to be extremely team-based.”

Dr. Krishnaswamy welcomes this emphasis on teamwork. “Cleveland Clinic has always fostered strong collaboration among interventional cardiologists, cardiac surgeons and the imaging cardiologists who help visualize the structures of importance during these procedures,” he explains. “This collaboration helped us become pioneers in TAVR, and we are committed to building on it to help make transcatheter mitral valve procedures a beneficial option for many patients.”

Cleveland Clinic Heart & Vascular Institute Chairman Lars Svensson, MD, PhD, concurs: “This cross-collaboration between specialties is a great example of the teamwork that can be achieved by combining departments in a single institute focused on heart and vascular care, as we have done at Cleveland Clinic.”

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