The MitraClip COAPT Trial and the Status of Transcatheter Mitral Valve Repair

What is the difference between functional and degenerative mitral regurgitation and their treatment pathways?

Patients with mitral valve disease fall into two general categories. One is degenerative mitral regurgitation; the other is functional mitral regurgitation. 

The treatment and response to treatment is profoundly different for both. Degenerative or primary mitral regurgitation means there is something intrinsically wrong with the mitral valve itself that causes it to leak. The leak is usually the result of a floppy leaflet, called prolapse, or a ruptured cord that caused the leaflet to become partially detached, called flail. Most cases of degenerative mitral regurgitation are treated with surgery, where patients undergo mitral valve repair. However, a number of high-risk patients who are judged by a heart team to be too high risk for surgery  can appropriately be treated with the MitraClip device (Abbott Vascular), which is approved by the U.S. FDA for the treatment of high-risk patients with degenerative mitral regurgitation. The second category of mitral regurgitation, functional or secondary mitral regurgitation, does not involve an abnormality of the valve itself, but is a disease of the left ventricle, termed either ischemic or non-ischemic cardiomyopathy. In other words, the ventricle becomes enlarged and doesn’t contract as it is supposed to, either due to ischemic heart disease or other causes, called idiopathic dilated cardiomyopathy. Then the left ventricle enlarges, leading to tethering of the mitral valve leaflets, in turn causing them not to coapt, or meet in the center. This is called secondary or functional mitral regurgitation. In Europe, about 80% of MitraClip use is for functional mitral regurgitation. In the United States, the FDA has approved a trial called the COAPT trial, where patients with functional mitral regurgitation are optimized on medical therapy, and then randomized between continuing medical therapy and the MitraClip device. The COAPT trial is currently enrolling patients and the results will be forthcoming. So, in the U.S., the treatment options for patients with degenerative mitral valve disease include a MitraClip if the patient is high risk for surgical repair. If the patient is not high risk, they are better treated with surgery. For functional mitral regurgitation in patients who are not candidates for surgery, the only real option for treatment now in the U.S. is to be enrolled in the COAPT trial, with a 50-50 chance of getting the MitraClip.  

Can you tell us more about the COAPT trial?

In this trial, patients with functional mitral regurgitation are randomized to receive either optimal guideline-                  directed medical therapy or optimal guideline-directed medical therapy plus the MitraClip device. The design of the COAPT trial arose from experience in patients with functional mitral regurgitation in the EVEREST II trial, as well as the European commercial experience. About 20% of the patients in the EVEREST II trial had functional mitral regurgitation and there was a signal in the high-risk cohort that perhaps these patients benefited from the MitraClip. After MitraClip’s commercial approval in Europe, clinical practice started out mainly with its use in degenerative disease, but has now migrated so that about 80% of patients receiving the MitraClip have functional mitral regurgitation. Since the EVEREST II data was insufficient due to very few patients treated, although there was a signal of potential benefit, in the U.S., the FDA asked for a trial in which MitraClip would be randomized to the current standard of care. A debate then occurred about what exactly the current standard of care is, because there are some functional mitral regurgitation patients that are currently best treated with surgery with placement of an undersized annuloplasty ring or valve sparing mitral valve replacement. The general consensus, however, was that most functional mitral regurgitation patients are not treated with surgery, but are treated medically. Therefore, medical therapy became the control arm of the COAPT trial. COAPT has four principal investigators:  Gregg Stone, an interventional cardiologist from Columbia in New York, and two heart failure specialists, Bill Abraham from Ohio State University, and Joann Lindenfeld from the University of Colorado as well as myself. The reason is that we are primarily studying a heart failure population and a potential new treatment for heart failure. It has never been shown that correcting functional mitral regurgitation makes a difference in life expectancy or quality of life. We will learn, hopefully, from this trial whether intervening and correcting functional mitral regurgitation will do anything to change the course of the disease. If it does, that will have significant repercussions for many other devices that are being developed to treat mitral valve disease via a transcatheter approach. The greatest opportunity to help patients with transcatheter therapy is in the functional mitral regurgitation population, not degenerative. 

It could be that treatment doesn’t change the course of the disease, but still improves symptoms.

Yes, that is a possibility. There has never been a randomized trial done in this group of patients. There is some thought that yes, we help symptoms for a period of time, even though overall survival or life expectancy may not change. COAPT is designed so that the primary endpoint of the trial is recurrent hospitalizations for heart failure, not survival. It is an objective way of getting at the idea that we may be able to improve quality of life and functional outcomes, but without necessarily prolonging survival, and would be manifested by patients not having to go into the hospital as frequently due to decompensated congestive heart failure. 

How far out are you looking at repeat hospitalization?

Twelve months.

Can you share your own experience with the MitraClip procedure?

We did not participate in the EVEREST II trial, but have been using the MitraClip for about four years now and have done about 20 cases altogether. I personally have done about 16 to 17 cases. Even though the MitraClip was based upon an approach invented by a surgeon, Ottavio Alfieri, the Alfieri repair is not a common procedure and it wasn’t intuitively obvious to me, at the start, that the MitraClip would work. That being said, we have had some very dramatic experiences in patients who have benefited enormously from the MitraClip. However, I still don’t think we have a clear handle on which patients will benefit the most and which will not. 

All our procedures are done by a surgeon and a cardiologist working together in a cath lab. Expert three-dimensional echo is key, so an imaging specialist is the most valuable part of the procedure. The imaging specialist is the navigator that gets us where we want to go and tells us when we are there. It’s almost like we are puppets being pulled by his string, because imaging makes all the difference in terms of being able to do this procedure. 

What about post procedure care?

Post procedure, there really isn’t a whole lot of care required. It is similar to a left heart catheterization done in the cath lab. Virtually all of our MitraClip patients go home the next day. 

You mentioned that the MitraClip procedure didn’t seem intuitive to you. Why is that?

In surgery, we fix what the problem is with the valve. If there is a ruptured cord, we make new cords. If there is a flail portion to the leaflet, we cut out that portion and sew it back together, and then we put a ring around it, called an annuloplasty ring, to correct any stretching that may occur. The MitraClip is based on an operation called the Alfieri procedure, in which the two free edges of the mitral leaflets are sewn or clipped together. In surgery, we used the Alfieri method as a bailout procedure when for whatever reason, we couldn’t do our conventional techniques. Basically, it converts a single mitral valve orifice into a double orifice, and doesn’t really correct the problem per se, but surprisingly, it does work. Whereas surgeons traditionally have employed it as a last-ditch effort when we couldn’t repair the valve otherwise, it actually does work with the MitraClip, and even better than we would have predicted. 

As a surgeon, how do your skills and experience help you perform this procedure? 

I do percutaneous mitral valve repair cases with cardiologists, and I find it a lot easier for me, as a surgeon, to grasp what’s going on, because I have seen this valve a couple thousand times over my career. I can think three-dimensionally about what I am looking at, including the position of the device in relationship to the valve. I would say that surgeons have that spatial orientation and ability to think in 3D, and to translate what we see on a 3D echo to what is actually seen in an operating room. It gives me a significant advantage. My deficiency is that I don’t have the wire skills of an interventional cardiologist, so even though I have experience with hundreds and hundreds of cases of transcatheter aortic valve replacement (TAVR) and several cases of MitraClip, and do have some skill set there, I would be deluding myself if I thought I could ever be as good as an interventional cardiologist in terms of wire skills. That being said, the wire skills required for a MitraClip procedure are relatively simple; once a transseptal puncture is mastered, the procedure is basically turning knobs on the device in response to the directions from the imaging. I think that is why an approach with both disciplines together is an advantage to doing these procedures. 

What do you recommend to create a successful team?

First, it has to be a collaborative approach between heart failure specialists, interventional cardiology and cardiac surgery. At our institution, we started back in 1999, when one of our interventional cardiologists, David Brown, taught me how to do left heart catheterizations. It was not that I felt I needed to become a cardiologist, but I wanted it because we had experiments going on in the animal laboratory for which I needed that skill set. It gave me an appreciation of what goes on in the cath lab. Our partnership then got taken to another level with the PARTNER trial of TAVR, in which we worked very closely together, and has now evolved even further with the MitraClip device. Right now, in our procedures, we actually have six physicians involved. We have an anesthesiologist, because these procedures are done under general anesthesia, we have an imaging cardiologist, Paul Grayburn, and then an interventional cardiologist, David Brown, and myself, a surgeon. We are expanding our team now, so we have a younger cardiac surgeon, Rob Smith, and a younger interventional cardiologist, Molly Szerlip, that we are training on these procedures. I think a collaborative approach from multiple specialties has very much been a key to success. 

The other big component is figuring out who is a good candidate for MitraClip and who isn’t. That is done in a multidisciplinary clinic. We initially set up an aortic valve clinic for TAVR procedures for high-risk aortic valve patients, and now we have done the same for mitral valve patients. The clinic is staffed by both surgeons and cardiologists. In evaluating patients, the other advantage that a surgeon brings to the table is a good instinct about who is going to get through surgery without problems and who isn’t. Often it is the surgeon who pushes the patient toward non-surgical therapy, because we know that even though a surgical procedure can be accomplished, that patient is going to take a long time to recover from it. If we can accomplish the same or close to the same by a less invasive approach, it is in that individual patient’s best interest. 

How does your team select patients for the MitraClip?

There are a couple different criteria by which we select patients. First, we decide: 1) Do they have mitral regurgitation; 2) Is it severe; and 3) What type of mitral regurgitation is it? That routinely involves repeating the echo when we first see the patient at our institution, because outside echo studies frequently are not sophisticated enough. Once we determine that the patient has mitral regurgitation, it is severe, and then whether it is degenerative or functional, we judge the patient’s risk with the Society of Thoracic Surgeons (STS) risk calculator. If the risk is high — greater than an 8% risk with surgery — then the patient is considered high-risk. Several other factors are considered as well, including frailty, debility, multiple previous operations, and previous radiation to the chest for treatment of Hodgkin’s disease in younger years. The other thing we have to decide is whether the heart disease too advanced, and perhaps this patient would be better treated with a heart transplant or a left ventricular assist device, because just fixing the mitral regurgitation itself isn’t going to make much of a difference. That is where the heart failure specialist is key in this multidisciplinary setting, to help figure out what among the myriad of options is best for the patient.

What do you think about the future of percutaneous treatment of mitral valve disease?

Way back when structural heart disease therapy and transcatheter approaches to treatment first began, in the late 1990’s and early 2000’s, I thought that the treatment of mitral valve disease would go much more rapidly than aortic valve disease. I was wrong. First, I thought that the critical unmet need was much greater with mitral than with aortic. Second, I thought what would happen if the procedure didn’t work would also influence its development, because if a transcatheter mitral valve repair fails, the patient just has continuation of heart failure, but with aortic, the patient can die. Clearly, history has shown that this was not the case, and that transcatheter treatment of aortic stenosis, for a whole host of reasons, went much quicker than mitral. But I believe right now that we are on the cusp of seeing the transcatheter approach to mitral valve disease explode. MitraClip has paved the way for it, but there are a number of mitral valve repair technologies — and now, mitral valve replacement technologies — that will undergo their first-in-man studies this year. Over the next four to five years, we will see this space of transcatheter mitral valve disease explode like TAVR did for aortic valve disease in the mid-2000’s.

Disclosure: Dr. Michael Mack reports he is co-principal investigator of the COAPT trial, Abbott Vascular, Inc. is the trial sponsor, and he is uncompensated.

Dr. Michael Mack can be contacted at: michaema@baylorhealth.edu