The cardiology community is paying close attention to developments related to transcatheter mitral valve replacement (TMVR) for mitral regurgitation. Although TMVR is in its infancy, one big question on everyone’s minds is whether its impact will be on the same scale as transcatheter aortic valve replacement (TAVR).
At many hospitals throughout the U.S. and indeed the world, cardiologists perform several TAVRs each week. The procedure has become commonplace for adults with aortic stenosis, many of whom are not ideal candidates for surgery or seek a less invasive approach. The number of TAVR procedures in the U.S. increased from 4,627 in 2012 to 24,808 in 2015, according to the American College of Cardiology/Society of Thoracic Surgeons (ACC/STS) Transcatheter Valve (TVT) Registry (J Am Coll Cardiol 2017;69:1215-30).
While many of cardiology’s stakeholders are hoping similar accomplishments can be achieved with TMVR, no TMVR devices have been cleared by the Food and Drug Administration and nearly all trials are early feasibility studies with small enrollments. The APOLLO trial, which is evaluating Medtronic’s Intrepid Trancatheter Mitral Valve Replacement System and enrolled its first patient in October, is the only pivotal, randomized study underway for a TMVR system. Results for APOLLO’s primary outcome—the composite of all-cause mortality, disabling stroke, reoperation or reintervention and cardiovascular hospitalization at one year—aren’t expected until 2021.
Although safety and efficacy data for TMVR devices are years away, some interventional cardiologists, cardiac surgeons, researchers and others in the field are cautiously optimistic about TMVR’s potential to help patients who have few options. They warn, however, it’s much too early to make predictions.
After performing five TMVR procedures as part of the Intrepid’s early feasibility study, Michael J. Reardon, MD, a thoracic and cardiac surgeon at Houston Methodist Hospital, says the device is easy to implant and that he’s had success each time, with no leakage and no obstruction of the mitral valve. Still, he cautions against drawing comparisons to TAVR.
“Everybody tends to look at TMVR as TAVR for the mitral valve, and it’s not,” Reardon says. “In many ways, it’s replicating the path that we saw in TAVR, but the disease processes are different. It’s probably going to advance at a slightly different rate.”
Long, complex road ahead
The pace of TMVR’s progress signals how different it is from TAVR. In 2002, cardiologists in France performed the first TAVR procedure in a 57-year-old man with aortic stenosis (Circulation 2002;106:3006-8). Within five years, several thousand patients had undergone the procedure. Th e first TMVR in a human, meanwhile, occurred in 2012 when an 86-year-old man with symptomatic severe mitral regurgitation received a CardiAQ valve in Denmark (Circ Cardiovasc Interv 2014;7:400-9). More than five years later, only 200 to 250 procedures have been performed, all in clinical trial settings.
“We’re seeing the [mitral interventions] field and the technology developing pretty rapidly, but it’s slower than [TAVR],” says Ted E. Feldman, MD, an interventional cardiologist at NorthShore University HealthSystem and Evanston Hospital in Evanston, Ill. “The difference in the rapidity of development [between TMVR and TAVR] reflects the difference in the complexity of the whole mitral apparatus.”
The mitral valve has a much larger orifice than the aortic valve, so TMVR devices must be bigger than TAVR systems, explains Feldman. And whereas the aortic valve is round, the mitral valve is shaped like the letter D, making it more difficult to reach.
TMVR and TAVR differ, as well, because the diseases they are intended to treat are so different. In comparison to aortic stenosis with its relatively homogenous disease process, mitral regurgitation presents a variety of treatment challenges depending on the cause and whether it is primary or degenerative, secondary or functional.
“I think the easy way for people to default into is to say [TMVR] is TAVR all over again,” says Michael Mack, MD, medical director of cardiothoracic surgery for the Baylor Health Care System in Waco, Texas. “And therefore, there are expectations of rapid growth and rapid adoption. But that’s not going to happen here. People shouldn’t have those same expectations. It’s a much longer road, and it’s a much more complex road.”
At TCT.17 in November, researchers presented early feasibility results from two studies evaluating TMVR devices: Intrepid and Tendyne (Abbott).
The Intrepid study enrolled 50 patients who had severe, symptomatic mitral regurgitation and were at high or extreme risk for conventional mitral valve replacement (J Am Coll Cardiol 2018;71:12-21). The device was successfully implanted in 48 patients. At 30 days, there were no disabling strokes or repeat interventions, while the mortality rate was 14 percent. In addition, 74 percent of patients had no mitral regurgitation at 30 days and the remaining 26 percent had mild disease.
The Tendyne study enrolled 30 patients with severe, symptomatic mitral regurgitation who were deemed by the heart team to be poor candidates for surgery. The device was successfully implanted in 28 patients. At one year, five patients had died and three had been rehospitalized for heart failure. None of the deaths were attributed to the procedure, and no patients suffered a stroke. Of the other 22 patients, 21 had no mitral regurgitation at one year.
The CardiAQ-Edwards Transcatheter Mitral Valve Replacement System (Edwards LifeSciences) also is being tested in an early feasibility study. In early 2017, Edwards paused enrollment of the trial to evaluate one of the valve’s features. The company resumed the trial a few months later, announcing a decision to pursue a transseptal, rather than transapical, delivery approach. Edwards expects to enroll 30 patients with symptomatic mitral regurgitation who are at high risk for open-heart surgery. Researchers are assessing the device’s safety as measured by freedom from device- or procedure-related adverse events.
Meanwhile, the aforementioned APOLLO trial may be the TMVR study that the field is watching most closely. Researchers expect to enroll up to 1,200 patients with severe, symptomatic mitral regurgitation. A cohort of 650 patients who are candidates for surgery and not eligible for mitral repair will be randomized to receive the Intrepid or undergo surgery, while another cohort of up to 550, deemed too high risk for surgery, will receive the Intrepid. All patients will be evaluated before and after the procedure, upon hospital discharge and at 30 days, six months and on an annual basis for the next five years.
“It’s still early experience, but there’s been significant improvement of outcomes and significant progress in a relatively short period of time,” says Mayra Guerrero, MD, who, like Feldman, is an interventional cardiologist at Evanston Hospital, NorthShore University HealthSystem, in Evanston, Ill. “TMVR will evolve in the next few years. It probably will be longer than TAVR, but perhaps not as long as we initially anticipated.”
Replace vs. repair
While cardiologists are eagerly awaiting more data on the safety and effectiveness of TMVR, they are also continuing to pursue another minimally invasive option: transcatheter mitral valve repair.
Currently, the field of transcatheter mitral repair is ahead of replacement, but the gap could tighten in the coming years as more trials are completed. Abbott’s MitraClip—the only FDA-approved transcather mitral valve repair device—is indicated for patients with symptomatic primary mitral regurgitation who are at high risk for mitral valve surgery. More than 50,000 patients worldwide have been treated with the MitraClip.
At TCT.17, researchers presented results of an ACC/STS TVT analysis of 2,952 patients who had received the MitraClip at 145 hospitals between November 2013 and September 2015 (J Am Coll Cardiol 2017;70:2315-27). The median age was 82 years old. Acute procedure success occurred in 91.8 percent of patients, while the in-hospital mortality rate was 2.7 percent. Of the 1,867 patients in the registry who also had Centers for Medicare & Medicaid Services claims data, 5.2 percent died within 30 days, 25.8 percent died within one year and 20.2 percent had a repeat hospitalization for heart failure within a year.
“The outcomes in registries are never as good as randomized trials,” Mack says. “That being said, I think we know that the device is generally safe. How efficacious it is still remains to be determined.”
Mack says the medical community will know more about transcatheter mitral valve repair when the COAPT trial results are presented, likely this fall. Mack is one of the co-primary investigators of the COAPT study, which has enrolled patients with symptomatic functional mitral regurgitation and heart failure who are not suitable candidates for open mitral valve surgery. The patients were randomized in a 1:1 ratio to receive the MitraClip device or to a control group that did not receive the device. MitraFrance, a similar trial, has been completed in Europe, with results expected this summer.
“If [the COAPT] trial is positive, the whole field [of transcatheter mitral valve repair] will be catalyzed significantly,” Mack says. “If it’s negative, it won’t kill the field, but it will cause significant pause and re-thinking and analysis to try to determine sub-groups that may benefit.”
Feldman says the early experience with MitraClip has been positive, especially with regard to safety. He believes that certain patients could benefit from the transcatheter treatment options but stresses that randomized trials are needed to make a final verdict on which should be treated via repair vs. replacement.
“The safety of repair procedures in general is balanced against the higher risks of replacement,” he says. “On the effectiveness side, the repair technologies are more likely to leave some residual regurgitation, whereas replacement by intention eliminates the regurgitation. For the time being, people often say if you can get rid of the regurgitation with replacement, why would you bother with repair? The answer is safety.”
Where will TMVR fit in the mitral regurgitation space? Reardon believes it could be particularly beneficial for patients with secondary mitral regurgitation. It also might turn out to be a better option than open mitral valve replacement with cardiopulmonary bypass for older, sicker patients with primary disease who are at high-risk for surgery.
“If we can find a less invasive way of doing mitral valve replacement, then a lot of people would really benefit,” Reardon says. “There are many, many people out there with secondary mitral regurgitation. TMVR is replicating what we can do for surgery for secondary mitral regurgitation, but in a much less invasive way because the incision is smaller but, most importantly, we don’t have to use the heart-lung machine.”
Part of the appeal of both repair and replacement technologies is the large number of patients who could be candidates for treatment. The American Heart Association says mitral regurgitation is the most common type of valvular heart disease in the U.S., occurring in 1.7 percent of adults, whereas aortic stenosis is estimated to be present in only 0.4 percent (Circulation 2017;137:1-458).
“I think that if TMVR matures into an acceptable therapy, there will be a large number of patients that can benefit from that,” Guerrero says. “If the fi eld develops as expected and can provide outcomes that are similar or better to surgery with good durability results and safety data, I think TMVR may be widely used in the future, as TAVR is today.”
And, though it’s early days, TMVR technology hasn’t lacked for investment. In 2015, large device manufacturers went on a buying spree, collectively investing billions of dollars to acquire TMVR-based companies. Edwards Lifesciences acquired CardiAQ Valve Technologies for up to $400 million, Medtronic bought Twelve Inc. for up to $458 million and Abbott purchased Tendyne Holdings Inc. for $250 million. Feldman estimates there are more than 30 startup companies with TMVR devices or device concepts.
“It shows they’re pretty serious about [TMVR] if they’re going to spend that much money acquiring technology,” Reardon says. “Nobody wants to miss the next wave.”