Early Results for Transcatheter Mitral Valve Replacement Reveal Complications and Challenges for the Long Road Ahead

WASHINGTON, DC—Cardiologists attending CRT 2016 finally got to see a range of early results from a handful of different transcatheter mitral valve devices and the numbers are daunting. As several experts pointed out to TCTMD, however, the deaths and complications seen in these earliest patients—very sick, high-risk, or non-surgical candidates—are not too dissimilar from the initial transcatheter aortic valve procedures. Moreover, while it’s very early days, some of the devices may be skirting the problems encountered by others.

The palpable air of sober second thoughts in several dedicated sessions here appears to stem from the sinking hopes that some of the hard-earned lessons in percutaneous aortic valve approaches would translate into swifter progress in the mitral space. Instead, the teams of interventionalists, surgeons, and others pioneering these devices are learning that the complex anatomy of the mitral valve coupled with more complicated hemodynamics make for an entirely different ballgame.

“We thought, ‘We have devices for the aortic valve, we have smart engineers: very shortly we’re going to have a smart device developed for the mitral valve,’” Danny Dvir, MD, of St. Paul’s Hospital (Vancouver, Canada), told TCTMD. “The issue is that the aortic valve is really just the end of a tube. It’s almost like putting a stent valve inside a vessel. But the mitral valve is really the center of the heart and everything is moving, and it’s not a circle, and we have many, many challenges.”

There have been rumors of complications and low survival for months, most notably when Edwards paused enrollment in a preliminary clinical trial of its Fortis transcatheter mitral valve. More head-scratching was prompted by the very public and ultimately successful pressure levied by investment group Engaged Capital, which convinced HeartWare International to drop plans to acquire Valtech Cardio on the grounds that its Cardioband transcatheter mitral annuloplasty technology was unlikely to deliver solid profits.

Early clinical results also raised some eyebrows. A paper in EuroIntervention in September 2015 summarizing early findings with 4 different transcatheter mitral valve devices cited 30-day mortality rates ranging from 38 to 50%. That was followed by a presentation at TCT 2015 where investigators reviewed early results among the very first patients treated with the Tendyne (Abbott), Twelve (Medtronic), Tiara (Neovasc), Fortis, and CardiAQ (both Edwards Lifesciences) devices and cited 30-day mortality in the range of 25-38.5%. One cardiologist who spoke with TCTMD decided not to refer a patient for an early feasibility trial after being informed that mortality in the series was in the range of 50-75%. 

Early Mitral Valve Replacement Outcomes

Numbers presented at CRT 2016 yesterday suggest that a combination of better patient selection, improved awareness of the hazards, and design innovations may be helping to bring those rates down, but the path has been a bumpy one.

Mayra Guerrero, MD, of NorthShore University HealthSystem (Chicago, IL), presented results for 81 patients from the Mitral Annulus Calcification (MAC) Global registry who underwent transcatheter mitral valve replacement using a transcatheter aortic valve (primarily Sapien XT/Sapien 3). Of the 81 patients who underwent the procedure, 21 died (25.9%) within 30 days, of which 8 were deemed cardiovascular deaths. These were 2 left ventricular outflow tract (LVOT) obstructions, 2 left ventricular perforations, 2 strokes, 1 complete AV block, and 1 myocardial infarction due to air emboli/pulmonary vein perforation. Of note, operators from 40 centers in 11 countries appeared to learn quickly. Technical success rose from 63% in the first 32 patients to 84% in the second half of the series. Likewise, 30-day mortality was 38% for the first 32 patients, falling to 22% for the second half. Complications were also halved.

Cardiothoracic surgeon Vinayak Bapat, MD, of Guy’s and St. Thomas’ Hospital (London, England), presented 30-day results for the halted Fortis valve first-in-human/clinical feasibility study. Of the 13 patients treated, 5 died within 30 days (38.5%), with 3 of those deaths as a result of procedural complications, 1 due to suspected valve thrombosis and the fifth due to respiratory failure. Bapat confirmed that the Fortis valve program remains on hold, but said that no formal announcement has been made by Edwards.

Dvir presented results for the Tiara transcatheter valve from Group 1 (special access/compassionate use) and the currently enrolling Group 2 (TIARA-I early feasibility clinical trial) cohorts. Of the 11 patients in which Tiara implantation has been attempted to date, 2 died after being converted to urgent surgery and a third patient died following what was initially thought to be a successful procedure. In fact, Dvir noted, this was an 89-year-old woman treated during a TCT 2015 live case who had excellent acute results but died 4 days later from erosion of the septum.

Howard C. Herrmann, MD, of the Hospital of the University of Pennsylvania (Philadelphia, PA), presented results for 12 patients treated with the CardiaAQ transcatheter mitral valve (Edwards Lifesciences) under compassionate use. There were 2 procedure-related deaths in this series—1 due to interaction with a mechanical aortic valve, the other due to malpositioning related to sub-leaflet calcification. An additional 4 deaths within the first 36 days have occurred in the cohort but were deemed unrelated to the valve. The US early feasibility trial is now enrolling, Herrmann said. 

Paul Sorajja, MD, of Abbott Northwestern Hospital (Minneapolis, MN), provided some of the most promising early results for all the devices featured in the CRT session. Thirty-day outcomes in the first 10 patients treated with the Tendyne (Abbott) device show implantation success in all patients and no deaths. The first 3 patients have survived beyond 200 days. Results for 28 patients will be presented at the upcoming ACC 2016 meeting, he said.

Finally, Ian Meredith, MD, of Monash Medical Centre (Melbourne, Australia), presented early results with the Twelve Intrepid mitral valve (Medtronic). Out of 11 patients, 3 have died so far, 1 following unsuccessful device deployment and others at day 28 and day 54. One patient has survived a year in NYHA class II heart failure 

Innovation Explosion

All of the devices have markedly different designs, relying on different strategies for the fundamental problem of how to fix the device in place using a mix of barbs, tines, tabs, clips, paddles, anchors, and tethers.

“The challenge is, you need to find a way to anchor this system at the level of the mitral annulus when you have a very thin-walled left atrium on top and a very muscular left ventricle on the bottom,” Anita Asgar, MD, of the Montreal Heart Institute in Canada, explained. “Too much footprint in the left ventricle can compromise the LVOT and cause what some people are seeing, which is LVOT obstruction either by the device itself of by the native mitral valve that’s left in place.”

For cardiovascular pathologist Renu Virmani, MD, of the CVPath Institute (Gaithersburg, MD), these kinds of problems have convinced her that for the time being, percutaneous repair rather than replacement is the way to go.

The current devices, she says, simply “occupy too much space. They are difficult to place, and at the moment, they’re just not perfect. They will need to be remodeled and made into next-generation devices. We need to start somewhere, and eventually we may succeed, but at the moment I’m not convinced.”

Early results for mitral valve repair with a range of different percutaneous strategies—leaflet clips, annuloplasty rings, and coronary sinuplasty—were also presented in sessions at CRT 2015 and Virmani, for one, believes these hold more immediate promise in mitral valve disease.

“I really think we have to be careful with what we’re doing with our patients and our interventions will succeed if we go one step at a time, rather than going ten steps in one go,” she told TCTMD. Strategies that implant a band or ring are the natural first step, she believes, then that band can be used to anchor the percutaneous valve.

Alec Vahanian, MD, of Hopital Bichat (Paris, France), has led the studies for the Cardioband device. He openly acknowledged his bias in favor of the “band” approach but pointed out that the improved safety of a low-profile ring, perhaps coupled with the MitraClip, may be the preferable approach in the near future.

The MitraClip alone, he reported to TCTMD, is gaining traction in Europe. “Definitely in primary [mitral regurgitation] it reproduces a technique that is not very popular among surgeons, but at least we know it works, even if it’s not perfect,” Vahanian said.

The Trade-Off of Safety and Efficacy

Indeed, the idea that the repair devices “aren’t perfect, but at least they’re safe” was a recurring theme in discussions here. 

A decade ago, said Dvir, he predicted that the MitraClip would never last. “Even in surgery they’ve abandoned that approach. But [the MitraClips] are still here, and I can tell you they will be here in the upcoming years as well. And that’s because the device is safe. It’s not very effective . . . but it’s a safe device.”

With transcatheter mitral valve replacement, the field has the “opposite” problem. “We have many different transcatheter valves implanted in the mitral position and they are very, very effective—the opposite of the mitral clip,” said Dvir. “But they are not so safe. The majority are transapical delivery, they are large devices, their anchoring is bulky and we see issues, especially with malposition.”

Gregg Stone, MD, Columbia University Medical Center (New York, NY), put it differently, noting that the higher the risk of any new device, the greater the efficacy is going to have to be. 

“Transcatheter mitral valves have the potential to do a more reproducible job in eliminating mitral valve regurgitation, but for the foreseeable future, the complication profile is going to be substantially higher,” he said in a CRT session. “So the question is, do you get enough efficacy to more than overcome for that increased complication profile?”

Clearly that’s something that the device-makers are grappling with now. And according to Carlos Ruiz, MD, of Hackensack University Medical Center in New Jersey, companies in recent years have poured more than $2.2 billion dollars into the mitral valve race. He showed a slide crammed with names of the more than 30 devices that have tried to find their niche in that space since 2000, saying, “The mitral valve is a high tree to climb.”

Many of the experts who spoke with TCTMD, however, pointed to the trickle of mitral valve disease patients who are living with transcatheter bioprosthetics for 6 or 8 months and beyond, with excellent device function and lasting improvements in heart function. With cautious optimism, and despite clear setbacks, some believe this is likely a tree worth climbing. Indeed, as Juan Granada, MD, of the CRF Skirball Center for Innovation (Orangeburg, NY), observed, just a few years ago people were questioning whether a device could even be deployed in an area with no structural support.

“I believe now, at least with a handful of patients with long-term clinical data, we have a very good proof-of-concept that if it is done right, you can really get these valves in place, secured in position, and functioning over time. It is very early, don’t get me wrong, but I believe that we’re all getting convinced that it is possible to develop this technology.”

Granada pointed to what he views as very positive early data with both the Tendyne and Twelve devices. “It is still early, [there are] a lot of complications, a lot of issues, but as the technology progresses and we understand the challenges and opportunities . . . I really think this is going to be a disruptive field,” he said. “Mitral valve surgery is one of the procedures which still carries a significant amount of morbidity and mortality, and it affects a younger population, not like TAVR, which is almost exclusively an elderly population.”

The comparisons with the TAVR experience will continue to both inspire and haunt this field. Although the early complication rate with transcatheter mitral valves may be reminiscent of the earliest days with TAVR, the reality is that survival rates climbed quickly in the first-in-human TAVR studies; there were also far fewer centers with transcatheter mitral valve experience, and fewer companies holding their cards close to their chests and vying to be the frontrunner.

And while that may make sense for device makers, it may not for physicians trying to do their best by their patients. That point was driven home by Guerrero who, after presenting outcomes and complications in the MAC registry, reminded the audience that the best way to deal with complications in transcatheter mitral valve implantation is to avoid them in the first place. Her final slide was her contact information.

“Please don’t work in isolation,” she said. “You don’t have to repeat our mistakes. Please feel free to call.”