Amid Sluggish Trial Enrollment, Transcatheter Mitral Valve Field Asks: Just How Big Is the Unmet Need?

WASHINGTON, DC—Despite the explosion of new valve technologies, enrollment in the early feasibility trials remains slow going, physicians and researchers acknowledged in a wide-ranging session devoted to transcatheter mitral valve implantation at CRT 2017 last week.

Speaking at the meeting in Washington, DC, Michael Mack, MD (Heart Hospital Baylor, Plano, TX), one of the moderators for the session, noted that physicians have consistently heard for years about the large unmet need for the percutaneous treatment of patients with severe mitral regurgitation (MR).

And yet for researchers involved in the early clinical trials, “patients aren’t exactly falling out of the skies,” he said.

For his part, Mack asked the panel of assembled experts—a group who presented updated data on a number of transcatheter mitral valve replacement devices, including Tiara (Neovasc), CardiAQ (Edwards Lifesciences), Tendyne (Abbott), and Twelve (Medtronic), among others—whether there were as many patients in need of percutaneous replacement as initially forecast. Or, Mack postulated, were heart failure doctors simply hanging onto these patients to treat them with pharmacotherapy, or were all receiving transcatheter repair with the MitraClip (Abbott Vascular)?

Patients aren’t exactly falling out of the skies. Michael Mack

“I guess we don’t yet have the best devices,” said Danny Dvir, MD (University of Washington, Seattle), in response to the question. “Some devices are safe, some devices are effective, but we eventually need something that is both very safe and highly effective.”

Speaking during the session, Howard Herrmann, MD (University of Pennsylvania Perelman School of Medicine, Philadelphia), said there remains a fair amount of “hype and hope” in the transcatheter mitral valve implantation field. While the rationale for percutaneous replacement is to avoid some of the risks and discomforts of surgery, there is a need to balance the efficacy and safety in light of the patient’s age, frailty, comorbidities, and treatment goals.  

“It’s a slow-moving field with a number of hurdles we’re all continuing to try to surmount,” Herrmann told TCTMD.

Difficulty Finding the Right Patients

Francesco Maisano, MD (University Hospital Zurich, Switzerland), agreed that enrollment in the clinical trials is “very, very slow.” Depending on the device and trial, in the worst-case scenario just one out of every 10 patients with MR is included in an early feasibility study. At best, one patient out of every three is included.

“For me personally, less than 20% of patients are eligible from an anatomic standpoint,” Maisano told TCTMD. “It’s obviously not a real fair assumption, though, because we’re only looking at a subgroup of patients. This number doesn’t represent the total [MR] population. In the population we’re looking at right now—patients with functional or degenerative MR with some degree of preserved function, usually those with not too large a ventricle—the refusal rate is very high.”  

The evolution of the transcatheter mitral valve replacement field started with “tremendous enthusiasm,” which was followed by large investment from industry, he added. One year later, though, there are still significant discussions about feasibility and safety. To date, fewer than 300 patients have been implanted with early-stage devices, yet dozens of companies are racing to develop mitral valve replacement technology. 

“It’s not a matter of the complexity of the procedure,” said Maisano. “It’s a matter of the difficulty in finding the right patients.”

Herrmann said the reason for the slow enrollment into clinical trials is multifactorial, but he does believe the market is overestimated, noting that one of the most important unanswered questions is whether every patient with MR needs to be treated.

“This is not like aortic stenosis where people are going to die of their critical disease,” he said. “It’s really about symptom improvement and how severe their MR is. There may be hundreds of thousands of patients with moderate MR who are compensated reasonably well and have class II [NYHA] symptoms. They don’t need to take the risk, even if it’s [as low as] 1%, which it certainly is not yet for transcatheter mitral valve replacement.”

The bottom line, said Herrmann, is that “we don’t know whether treating functional MR, which is the majority of these patients, does anything for survival.”

Limited Data, Few Patients

During the CRT 2017 session, researchers provided updates on the various devices, noting that high rates of mortality have disappointed physicians, although this might be expected given that very sick patients with multiple comorbidities have been treated in various compassionate use programs. Dvir presented data on the Tiara valve, pointing out that the second patient ever implanted is alive and well with a perfectly functioning Tiara valve, almost 3 years after implantation. In total, 24 patients have been treated, with short-term outcomes showing three deaths at 30 days.

With CardiAQ, Herrmann noted the US early feasibility study had been stopped in January, as reported by TCTMD, but investigators have since resumed screening. So far, 11 patients with functional and degenerative MR have been treated with the second-generation CardiAQ device. Technical success was achieved in 82% of cases, but there were two procedure-related deaths and four non-valve-related deaths (all four patients had died by day 36, but these patients had good valve function at the time of their death). 

Neil Moat, MBBS (Royal Brompton Hospital, London, England), presented data from 30 patients treated with Tendyne in the global feasibility study. At 30 days, there was one noncardiac death and four rehospitalizations for heart failure. In long-term follow-up of five patients treated at his hospital in the compassionate use program, three patients were alive at 2 years.    

Additionally, Eberhard Grube, MD (University Hospital, Bonn, Germany), presented data on 38 patients with functional and degenerative MR treated with the Twelve valve and reported that eight patients had died, including four from causes not related to the valve or procedure. In total, four patients had survived at least 18 months, including one for nearly 2 years.    

Finally, Alaide Chieffo, MD (San Raffaele Hospital, Milan, Italy), provided data on an early investigational valve still in animal testing. The first-in-man study with the Cephea (Cephea Valve Technologies) device is expected to start shortly, she said. 

Easier to Find Valve Repair Patients

Speaking with TCTMD, Dvir said he believes transcatheter mitral valve replacement will eventually triumph over repair procedures, mainly because the results are likely to be durable and reproducible. At present, transcatheter mitral valve replacement appears to be very effective for eliminating MR, but the safety of the current procedure is debated, he said.

In contrast, more than 40,000 patients worldwide have received the MitraClip for mitral valve repair, and the high safety profile of MitraClip implantation is well-documented.

“In the early days, we thought we must eliminate the valvular abnormality and replace the valve, but I must say I’m not so sure transcatheter repair would not be a legitimate approach and will have more support, both from industry and different facilities, to grow,” said Dvir. “The ease of finding patients for transcatheter repair is remarkably greater than finding patients for mitral valve replacement. I think it’s a signal.”

Dvir said the slow enrollment in the replacement studies, by contrast, stems from physician concerns over the proper sizing of the replacement device, the risk of left ventricular outflow tract (LVOT) obstruction, the suitability of patients for transapical access, and mechanical complications with the device after the procedure. While Dvir was not speaking of any one particular valve, he said the slow enrollment of patients into transcatheter replacement trials means something. “It means we’re trying to be selective and that we are concerned,” he said. “We can’t underestimate the need for safety. Safety is a major part of our attempts to drive patients to a less invasive approach. This is why we’re doing this transcatheter. We want safe procedures for our high-risk patients.”

In fact, Dvir said interventional cardiologists performing the less invasive approach would be willing to trade off efficacy as long as percutaneous mitral valve replacement maintained a high safety standard. He noted the mortality rate in the vast majority of these early trials is still significantly higher than physicians and patients are willing to accept.

Mayra Guerrero, MD (Evanston Hospital, IL), who spoke during the CRT session, said the slow enrollment reflects good clinical judgment given all the unknowns. “You don’t want to move too fast,” she said. 

Repair First, Replace Next?

To TCTMD, Maisano said the current inclusion criteria for the mitral-valve replacement trials include intermediate-risk patients with functional/degenerative MR and a selective range of annular dimensions (there is currently a limitation of device sizes).

“The difficult question is who is the ideal candidate overall for valve replacement,” he said. “These are not the typical trial candidates. If you project replacement into clinical practice, it can’t be a solution for early-stage MR because for patients in this early stage, we’re still debating whether repairing the valve is better than just giving drugs. So, how do you challenge a very low-risk procedure like repair in this setting?”

Ideally, replacement will likely be best suited for end-stage heart-failure patients, he said. “One of the biggest challenges of replacement is that physicians [limit] their alternatives for down the road,” said Maisano. By contrast, “for most repair procedures, repair can be a first attempt, which leaves a small footprint. In case it fails, you can still do a replacement.”

On the other hand, the advantage of replacement is that it will—in theory—be a simple-to-do procedure and will potentially require less skill, less understanding of the pathology and physiology, and less decision-making. In principal, it could be more widely adopted. He added that while the replacement procedure is reproducible, the risk profile is not comparable to the early stages of mitral valve repair.

“If you look at the early stage of MitraClip, it started as a totally new procedure, and although not always effective, the mortality rate has always been less than 10%,” said Maisano. “In replacement, the average mortality rate is 20%, if not higher, depending on the technology. . . . It’s a high-risk procedure.”

Looking Into the Crystal Ball

During the session, Herrmann echoed something that has been said previously, namely that transcatheter mitral valve implantation is not simply a mitral TAVR. The disease has multiple etiologies, it’s not a disease of the elderly (mean age is 60 years), and the potential damage caused to adjacent coronary arteries, LVOT, and conduction system are substantial, not to mention risks of embolization and thrombosis.

For Maisano, the future of transcatheter mitral valve replacement depends on a number of factors. First, transseptal access needs to become more readily available. Second, the devices need to become less intrusive, particularly to diminish the risk of LVOT obstruction. And third, more research is needed on the durability of the valves. He said the tissue valves fare worse in the mitral position than in the aortic annulus because the mitral valve functions at much higher pressures, meaning the degenerative rate is 30% to 40% faster than in the aorta. 

Additionally, Maisano expects the uptake of transcatheter mitral valve replacement to follow the same trajectory as surgery. When mitral valve replacement surgery became available, nearly all surgeons abandoned repair because the replacement procedure was easier and more reproducible. Over time, the pendulum shifted back toward repair because of the safety of the procedure and the ability of high-volume surgical centers of excellence to perform repairs effectively.

“I can imagine as soon as replacement becomes available, a number of physicians not involved in repair will jump on this train and start implanting replacement devices,” said Maisano. “You will see the consequences of this only in 5 years. I imagine a dark age where we’ll have no control over the development of the market. Only after 5 years will we see the consequences of providing replacement to everybody.”