This transcript has been edited for clarity.
Wayne B. Batchelor, MD, MHS: Hello. I am Wayne Batchelor from the Inova Heart and Vascular Institute. I am joined here today by Catherine Otto from the University of Washington School of Medicine in Seattle. Today we are going to discuss the use of MitraClip in secondary or functional mitral regurgitation (MR).
Catherine, let's go over the topline results from the trials.
Catherine M. Otto, MD: We have two well-designed, well-conduced randomized controlled trials using the mitral valve clip for secondary MR. They found very different results. In MITRA-FR they found no difference in outcomes at 1 year between patients randomized to the clip versus standard guideline-directed medical therapy. In contrast, COAPT had a similar study design, slightly different ejection fraction criteria, perhaps slightly different mitral regurgitant severity, but it found a dramatic difference in the 2-year outcome of mortality and recurrent heart failure admissions. In fact, the mortality difference was huge: 29% with the clip versus 46% with continued medical therapy. Those are impressive results, although I am a little disappointed that it is still so high in both arms of the study.
Batchelor: What has caught the attention of a lot of people are the dramatic differences and the disparate results between the two trials, especially in regard to the hard endpoint of mortality. The number needed to treat was only 6 (in COAPT). It is really fascinating.
What do you think causes these different trial results? What is the inherent reason for it?
Otto: It is really difficult to tell from the published data exactly what the differences might be in terms of the different outcomes. There has been a lot of speculation that maybe the medical therapy was more complete in one study versus the other, or maybe the clip was put in more efficiently and resulted in less MR in one study versus the other, but I have to say that as a non-interventionalist who is not able to know what happened behind the scenes, if I look at the published data, I do not think it is really obvious.
There have been a couple of theories out there. One theory is that the MR was more predominantly secondary and not as severe in one study versus the other, with various discussions about the need to quantitate MR differently. Maybe we need to look at regurgitant fraction or the amount of regurgitation compared with how big the heart is. Maybe there is something there that we have not identified yet.
Batchelor: As an interventional cardiologist with an interest in clinical trials, I look at these results both from the clinical trial perspective and from an interventional cardiologist perspective. On the clinical trial design side, although at first blush it looks like the trials were very similar, they actually enrolled different types of patients. The mandate for guideline-directed medical therapy in COAPT excluded a number of patients. I know, because when I called to enroll, often my patients would be turned down because they were not on optimal medical therapy. We had to force the medical therapy and ensure that they really still had severe MR. That resulted in a number of patients not being enrolled in COAPT who probably got into MITRA-FR.
Second, the degree of regurgitation was more at the offset of COAPT than in MITRA-FR. The effective regurgitant orifice area in COAPT was about 0.4 versus 0.3 in MITRA-FR. The reduction was more for the interventionalist in COAPT versus MITRA-FR, and the durability of those results was also better. More patients had less regurgitation in follow-up.
I think that when you look under the hood, the trials—although they look very similar —the way this rolled out and the treatment modalities and the effectiveness of them were actually a little bit different.
Otto: That gets at two really important issues in both trials. In COAPT, for example, even in the medical therapy arm, even though the idea was that they were on optimal medical therapy and cardiac resynchronization therapy (CRT) if appropriate, and none of them had 1+ to 2+ MR at study entry, they all had 3+ to 4+ MR; they all had moderate to severe. But at 2 years, almost 40% had 1+ to 2+ MR. Even though we think they were on the best therapy when they entered, they still got better in some cases. I do not know if that is a survivorship bias or what is going on. I think that is important.
The second point is just what you said: I think we need to look at the individual patient-level data in both studies, perhaps combined to look at what exact hemodynamic or anatomic parameters show which patients are going to get an adequate reduction MR, which are going to benefit in terms of outcomes.
Proportionate and Disproportionate MR
Batchelor: An interesting insight has recently been put forth by Paul Grayburn and Milton Packer at Baylor —it's the concept of disproportionate versus proportionate MR. I thought we might want to discuss that briefly. Their contention is that in MITRA-FR, the degree of MR was what you would expect for the degree of left ventricular (LV) dilatation. Naturally, as the left ventricle dilates, we see more MR in secondary MR. In COAPT, the degree of MR was significantly greater than that expected for the LV dilatation. In COAPT, the left ventricles were not as dilated, and the regurgitation was worse. In MITRA-FR, the left ventricles were more dilated and the MR was less at the onset of the study.
Do you want to help us understand a little bit more? You are the echo expert. What is disproportionate versus proportionate MR, and is it something that we should hang our hat on in terms of treatment decisions?
Otto: I think that this idea of disproportionate MR is helpful, and the proposal that you mentioned is one approach. There are other ways of thinking about it in terms of the amount of regurgitation versus LV size or regurgitant fraction, for example. I do not think we know the ideal measure. It actually gets to the point where you wonder if the people with disproportionate MR really had secondary MR. Secondary MR should be proportionate. That is what secondary MR is defined as being. Are we really including some primary MR versus secondary? As an echocardiographer, I know how difficult that can be to separate, because these are older patients; they have heart failure; yes, they have a dilated ventricle and mitral leaflet tethering, but they also might have thickened leaflets, a little calcium, maybe a little annular calcium. Some of them have a little bit of prolapse; how much of this is primary versus secondary MR?
Who Is a Candidate for MitraClip?
Batchelor: A lot of individuals are now asking, how do we roll this out to the US community? The FDA has approved the MitraClip for this indication. In COAPT, all of these patients were seen by heart failure experts and a heart team, and were carefully scrutinized in terms of medical therapy. I think there are only about 1000 advanced heart failure specialists in the United States right now. How do we take the COAPT results and apply them to the community of cardiologists out there and make sure that we get COAPT-like results? Any thoughts?
Otto: That is the real question. I think it is all about patient selection. You have somebody with heart failure with reduced ejection fraction who has significant MR, and first they have to receive optimal guideline-directed medical therapy. As you point out, heart failure experts are sometimes very good at tweaking those medications and getting patients who have been treated by a cardiologist even better at a heart failure center. If they cannot all do that, that is reality but the best medical therapy; CRT in those who are eligible should be performed because we do see a reduction in MR with those strategies.
If, after that, they clearly still have severe MR —quantitated, hopefully —and they have symptoms that are related to the MR, particularly if they are having recurrent heart failure hospitalizations, a significantly limited quality of life, and poor exercise capacity, then that is where we go to the next step: Do we consider them? You know, as an interventionalist, that even then not all of those patients are going to be eligible, because we now need to look at the 3D anatomy of the mitral valve on echo; the imaging and interventional experts need to get together and say, "Is this valve amenable to MitraClip?"; and only then should we present the option of a MitraClip to the patient to try to improve their symptoms, assuming they are high risk for surgery or surgery is not appropriate. Based on the COAPT results, we could potentially prolong their life. Again, we are prolonging their life, but we are not restoring them to a normal life span.
Batchelor: I think the one clear take-home message from these two trials is that it is going to take a lot of careful decision-making to decide who is going to really benefit from this therapy. It is going to probably bring heart failure experts, interventional cardiologists, surgeons, and the whole heart team together like never before, kind of like TAVR (transcatheter aortic valve replacement), in order to make these decisions. It is going to be very, very interesting to see how that rolls out.
There is another study that is still ongoing in Europe: RESHAPE-HF2. It is an 800-patient study and will not be completed probably for another couple of years. With one trial showing basically neutrality or no effect and another trial showing what I would call an out-of-the-ballpark homerun for MitraClip, where should we stand in regard to the recommendations we would make to our patients? When this rolls out, are you going to be recommending the MitraClip therapy or are you going to wait for RESHAPE-HF2?
Otto: Additional trials are going to refine our ability to select patients. I already send patients for MitraClip. I am at a center that enrolled patients in the trial. Again, it is very carefully selected patients who meet the criteria in the COAPT trial. As clinicians, it is pretty easy to say, "Okay, it's approved; let's just do it. For this particular device, I think we have to go back and look at exactly which patients are going to benefit.
Batchelor: That is a good point. I know that there is a kneejerk response that we all have as interventionalist cardiologists —to do something —but when you see the V-wave sometimes completely abolished in these patients and the mean wedge pressure drop by 5 to 10 points, it just seems to me that if we are not causing mitral stenosis and we are knocking out that much regurgitation, in the appropriately selected patient it does feel like you are doing something. We are not always right with that feel in terms of translating the real clinical benefit. For the interventional cardiologists out there who felt that we were having an impact on this disease state, it was at least a relief to see that the COAPT trial showed this, but many of us were very concerned about our ability to replicate those trial results and the need to really tease that out.
Otto: I think that when you see that, you have selected the right patient. It's the ones in whom that does not happen who we should not be subjecting to the risk or the cost of the procedure.
Batchelor: Let's talk about risks of the procedure. What was interesting in COAPT was that the device success rate and lack of complications, even at a year, was exceedingly low. We are talking about an almost 97% safety and efficacy. The one thing that does factor into this decision-making, if it was a high-risk procedure, is that the threshold should be even higher. As an implanter, I was surprised at how relatively safe the procedure was. I thought that we would see more complications. That is not a plug purely for the device; that is just to put it into context in terms of some of the other things we do which are even riskier, and we still do procedures that have class IIa and IIb indications in cardiovascular medicine.
Otto: I think the risks from a physician point of view are pretty low, but from a patient point of view they might not be perceived quite the same. Granted, the presentation today showed that quality of life improves significantly with the MitraClip, which is excellent news and very reassuring. But for some patients, even the preparation for a MitraClip —having the transesophageal echo, having to see multiple doctors, and then the procedure itself—dissuades them from pursuing it. They may decline to be considered because they don't want to undergo the additional procedures needed to see if they would benefit when they are already ill, depending on their age and frailty.
Batchelor: It will be very interesting to see how this rolls out over the next couple of years. Hopefully we will have a lot more granularity and specificity on the types of patients who will benefit the most. I look forward to seeing that. It will be interesting to see how we actually roll this out to the cardiology community at large to figure out who should get the procedure, what kind of screening process they should go through, and to make sure that we are doing the right thing so that we get the COAPT-type results. Any thoughts on that?
Otto: I totally agree. I think we should do the right thing, which in some patients is going to be doing the mitral clip procedure to reduce their MR and improve quality of life, and in other patients it's going to be continuing medical therapy. That really is going to be the question: How do we optimally select patients in the community?
Batchelor: It is a very exciting time in interventional cardiology, heart failure, and valvular heart disease. I think we are going to get some really interesting results in the next year or two that will probably even further refine our decision-making. Thank you.
Otto: Thank you for having me.
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Cite this: MitraClip for Secondary Mitral Regurgitation: Patient Selection Key for COAPT-Like Results - Medscape - Apr 04, 2019.