Will the MitraClip and Other Gadgets Make Headway in Functional MR?

WASHINGTON, DC—Amid increasing signs that full mitral valve replacement using a percutaneous approach may not be as close to prime time as first hoped, all eyes are turning to a series of transcatheter mitral valve repair studies edging towards completion. 

Leading the field is the MitraClip (Abbott), already approved in the United States, Europe, and elsewhere for severely symptomatic patients with chronic severe primary mitral regurgitation (MR) at high risk for surgery. Unknown is whether this percutaneous edge-to-edge repair approach also works well in the much broader group of patients with functional MR.

A number of updates presented earlier this week at CRT 2016 hint that symptom improvement using the clip is possible in patients with secondary mitral regurgitation, but it remains an open question just how durable that improved function will prove over time and, more importantly, whether repair procedures will actually save lives.

In a range of different CRT sessions, including a satellite symposium, Ted Feldman, MD, of NorthShore University Health System (Evanston, IL), presented some updates from COAPT, the US trial many hope will settle the issue. The study is randomizing 430 patients with class 3 or greater functional regurgitation and symptomatic heart failure to either MitraClip or optimal medical therapy. The primary efficacy endpoint is recurrent heart failure hospitalizations, and the primary composite safety endpoint entails a slate of possible complications.

According to Feldman, the trial, after struggling with sluggish recruitment, has enrolled 80% of patients at 81 active sites, meaning the study needs only 80 more subjects to meet its recruitment target.

What’s more, he noted, there are at least 3 other randomized trials already underway that, with COAPT, will ultimately lead to answers in more than 1,300 functional MR patients. These include the French MITRA-FR trial, which has enrolled roughly 60% of 288 patients to date, the European RESHAPE-HF2 with approximately 10% of a planned 420 patients enrolled so far, and finally the German MATTERHORN, which is comparing MitraClip to surgery in 210 lower-risk patients.

Beyond that, Feldman said, there are several thousand patients worldwide participating in registries—many of them prospective, some with their own core labs. And remarkably, he continued, “if you look at these results, they are all the same.”

Almost universally, registries large and small are reporting a 1-month mortality rate in the range of the 6% seen in the ACC/STS TVT Registry, Feldman said. Similar findings have been seen in across at least 10 different registries, he noted; 80% of patients in these studies are being discharged home, and mean 12-month NYHA class is in the range of I-II in 80% of patients.

Insisting that any predictions he might have for COAPT are just a “guess,” Feldman nevertheless hedged his bets that the trial will be positive. “Based on our prior experience with MitraClip, [where] we see that our patients feel better and we have a lot of data to suggest that they stay out of the hospital after MitraClip therapy compared to not, we really do expect a positive trial.”

But there are a couple of caveats, he warned. For one, he expects a significant proportion of COAPT patients will prove to be CRT nonresponders (to be eligible to be in the study, patients had to be “adequately treated for heart failure, including with CRT if needed)—“and we really don’t know how they are going to do,” he said. Another factor will be operator experience: case volume has been shown to be a huge predictor of success with the MitraClip, yet the COAPT trial has pushed for an expanded number of centers. “We have a lot of newer sites and that’s clearly going to have some effect on the outcomes of the trial, and we hope that’s going to be very modest,” Feldman commented.

Less Certainty, More Questions

In interviews with TCTMD, however, a range of experts appeared to have mixed feelings about just how significant the impact of the MitraClip will be, despite its widespread use, especially in Germany, Switzerland, and Italy. 

Companies developing strategies for mitral valve repair have been “very excited” about the sheer number of patients that could possibly be treated, Anita Asgar, MD, of the Montreal Heart Institute in Canada, told TCTMD.

“But if you dig deeper to try to understand what is the type of mitral regurgitation they have, a lot of these patients are going to have secondary MR, functional MR. Here things become a lot more murky. . . . MR is not that simple,” she stressed. “If you have functional MR, meaning the ventricle is the predominant problem and MR occurs as a result of the anatomical changes that have happened . . . now you're not just dealing with pure MR [and] you have to deal with the consequences of the initial disease, which if you don’t treat will naturally progress.

“So I suspect you’re not going to decrease mortality [with MitraClip], you’re just going to shift it back,” Asgar continued. “Patients will eventually succumb to their underlying condition. Then the question becomes, are you trying to deal with quality of life, or something else?” To be a truly disruptive technology, she added, a new device or approach is going to have to have an impact on mortality.

In fact, COAPT stands apart from the other ongoing trials in that its primary efficacy endpoint does not include mortality. Both MITRA-FR and RESHAPE-HF2 have the co-primary endpoints of all-cause mortality and unplanned hospitalizations for heart failure. MATTERHORN has a composite of death, rehospitalization for heart failure, reintervention, need for a left ventricular assist device implantation and stroke—whichever comes first—within 12 months.

Alec Vahanian , MD, of Hopital Bichat (Paris, France), noted that over 30,000 MitraClip devices have been implanted worldwide and that the target population, despite guidelines specifying use in primary, degenerative MR, is comprised of functional MR patients, he said. “What we know today from thousands of patients treated in this patient group is there is a strong feeling that it improves symptoms. But the question is, how much are we willing to pay just to improve symptoms? Because today, we have no firm proof of efficacy on mortality and we have to face the costs.”

Even Feldman, despite his cautious optimism, readily acknowledges the unknowns in patients with mitral regurgitation and heart failure—the vast majority of patients. “The problem here is that we don’t know, in individual patients, whether the ventricle or the mitral regurgitation is the worse part of it, and simply repairing the MR even if it is a perfect fix, by whatever method, doesn’t immediately change the left ventricle,” he told TCTMD. “So an LV failure patient—we know they do worse when they have MR associated with LV failure, but it’s not so clear that making the MR diminish or go away will make them live longer.”

Other Approaches to Mitral Valve Repair

Of course, the MitraClip is not the only device in this space. The past few years have seen a flurry of innovation leading to different percutaneous products, most prominently catheter-placed annuloplasty rings. Vahanian presented early results for the Cardioband (Valtech) device in 50 patients with NYHA Class II-IV heart failure at baseline. In this early series, 2 patients died and 5 experienced other serious complications within the first 30 days. The 22 patients for whom 12-month follow-up was available had experienced significant improvements in 6-minute walk time, quality of life, and NYHA Class.

To TCTMD, Vahanian acknowledged that as principal investigator in the study he is, of course, “biased,” but said he believes the device holds promise, since it reproduces a procedure that remains popular with surgeons today. This stands in contrast to the MitraClip, which replicates edge-to-edge repair, a technique “largely abandoned” by surgeons as an isolated procedure. A similar approach involves mitral cerclage annuloplasty. A first-in-human trial for that method is underway now in Korea, and early results will be presented at the upcoming ACC 2016 meeting. Meanwhile, the CLINCH pilot study in Germany is looking at whether the addition of the transcatheter coronary sinuloplasty using the Carillon mitral contour system (Cardiac Dimensions) improves outcomes in patients who have already received the MitraClip.

Any approaches that entail implanting a ring also opens the door to a third option, Vahanian noted: that of implanting a less complicated valve using the ring or band to anchor the device. This strategy solves the key problem that dedicated percutaneous mitral valves are battling now, that of finding a safe and secure way to hold the devices in place.

“This has the theoretical advantage of being more versatile, because it hard for me to imagine how one device can treat all mitral regurgitation—the disease and the dysfunction of the valve are often completely different,” he suggested. “On the other hand, if you put in the annuloplasty ring, and then a valve, it will work for almost any kind of regurgitation, but the disadvantage is that it will be a more complex procedure than just putting in a new valve.”

At CRT 2016, cardiovascular pathologist and long-time device clairvoyant Renu Virmani, of CVPath Institute (Gaithersburg, MD), told TCTMD that of all the emerging, minimally invasive strategies to address mitral valve disease, she’s putting her money on an approach that involves placing a band or ring and using that to anchor a valve.

As with investigational devices for full mitral valve replacement, all of these newer strategies being tested for mitral valve repair have only been used in small numbers of patients, leaving open questions on long-term safety, efficacy, and durability. And while the MitraClip has now been used in tens of thousands of patients, clear-cut answers are still several years away.

Source: 
Presentations at: CRT; February 21, 2016; Washington, DC. 

Disclosures:

• Feldman reports receiving grant support from Abbott, BSC, Cardiokinetics, Edwards, and WL Gore and consulting for Abbott, Boston Scientific, Coherex, Edwards, JenaValve, Mitralign, Daiichi Sankyo-Lilly, and WL Gore. 
• Asgar reports serving on the speaker’s bureau for Abbott Vascular and being a consultant to Gore and Medtronic. 
• Vahanian reports receiving honoraria, speaker’s bureau, and/or other financial or material support from Abbott, Edwards Lifesciences, and Valtech. 

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