Digesting the Valve Degeneration Data: One Month Later, Reactions From TAVR Experts Range From ‘Disturbed’ to Indifferent

When news broke last month at EuroPCR—via a late-breaking study presented in the Main Arena no less—that TAVR may have a durability problem, the initial response among attendees varied from skepticism about the findings to dread over what they might mean as the field progresses toward younger patients.

The analysis, presented by Danny Dvir, MD (St. Paul's Hospital, Vancouver, Canada), showed that, among elderly patients who survive at least 5 years after TAVR with an early-generation balloon-expandable device (Edwards Lifesciences), approximately half would see their valves degenerate by 8 years.

Degeneration was defined as moderate/severe regurgitation and/or aortic stenosis (mean gradient > 20 mm Hg) that was not apparent within 30 days of the initial TAVR and was not related to endocarditis.

Farrel Hellig, MD (Sunninghill Hospital, Johannesburg, South Africa), who served as a panelist during the EuroPCR session, told TCTMD that soon afterward he headed to the faculty lounge and asked many there for their feedback.

Originally, he said, “I was quite disturbed by the findings. And I heard varying responses from people questioning the data and disbelieving it, and others thinking that the chosen endpoints weren’t correct.” Though the definition of degeneration could be quibbled with, Hellig noted, “I thought that [the analysis] was quite compelling. And at the time, I remember feeling, ‘Well, I thought this was coming, and here it is.’ It seemed impossible that this valve would not degenerate [eventually].”

To TCTMD, Dvir said he has received a lot of feedback in the month since EuroPCR. “Many different centers, interventional cardiologists, surgeons, analysts, and different people from industry have tried to understand the findings and potential implications,” he said.

"The important message . . . is that this is hypothesis generating,” Dvir emphasized. “We need to continue to study and learn about valve durability, and to run solid studies on low-risk patients, evaluating them in the long term and not only for a couple of years after implantation.”

This week, Dvir is at TVT 2016 in Chicago, IL, where he is offering an additional glimpse at his study cohort: case presentations for the two patients who have survived 10 years. Other presentations addressing the durability question are also dotted throughout the program.

Half of Valves in Surviving Patients Degenerate by 8 Years

Dvir’s EuroPCR analysis involved a study cohort of 378 patients who, after undergoing TAVR at either St. Paul’s Hospital in Vancouver or Hôpital Charles Nicolle in Rouen, France, were monitored using repeat echocardiographic exams during house visits for up to 10 years. Of the 100 patients who survived to 5 years, 35 showed signs of valve degeneration (66% regurgitation and 33% stenosis/mixed) by the end of follow-up. Median time to degeneration was 61 months.

What seemed to grab the most attention of EuroPCR attendees, however, was the Kaplan-Meier analysis: the curve for freedom from degeneration dropped from 94% at 4 years to 82% at 6 years and to approximately 50% at 8 years among surviving patients.

Chief among the concerns of skeptics is the small number of patients. As pointed out to TCTMD by Alec Vahanian, MD (Hôpital Bichat, Paris, France), who co-chaired the session, “If you have 40 patients at risk and two or three go wrong, it’ll change the figure completely.”

Thus, it’s important to place Dvir’s analysis in context alongside the long-term data coming out of randomized controlled trials and from registries worldwide that have failed to show any “red flags” for poor durability, he asserted.

Josep Rodés-Cabau, MD (Quebec Heart and Lung Institute, Laval, Canada), called attention to 5-year findings from PARTNER demonstrating “absolutely no difference” between transcatheter and surgical prostheses in terms of gradients, valve areas, or proportions of patients who had structural failure requiring valve replacement.

Though not at EuroPCR, Isaac George, MD (Columbia University Medical Center, New York, NY), who has expertise in both surgical and percutaneous approaches to aortic valve replacement, wrote in an email to TCTMD that he is “not overly alarmed” by the findings.

He pointed out several reasons why this analysis is not “generalizable to the current state of TAVR,” most notably that the procedures were done so early on. “The sizing, procedure, imaging, and procedural techniques have changed drastically,” he said, “and it is intuitive that these factors will affect long-term durability in a positive way.

“That being said, it has appropriately shifted the main conversation back to durability and excellent performance of the valve, which remain the most important parameters in low-risk patients,” George continued, pointing out that the issue is timely considering that two studies of low-risk patients—one using Sapien 3 (Edwards Lifesciences) and the other CoreValve Evolut R (Medtronic)—are starting in the United States.

Issues With Echocardiography

According to Rodés-Cabau, caution is needed when interpreting the echocardiographic findings of Dvir et al. One problem, he said, is that the analysis defines degeneration using a single cutoff rather than looking at changes in mean gradient versus baseline over time.

“If you have a patient leaving the hospital with a gradient of 13 [mm Hg] and after 2 years, he has a gradient of 21, honestly, this is not really significant probably,” Rodés-Cabau commented. Moreover, there could be variability in how the echocardiograms are interpreted, especially given the length of follow-up.

George similarly noted that a core lab did not analyze the echocardiograms, adding that “getting a working definition of valve degeneration is needed and will need to signify hemodynamic degeneration versus clinical need for reintervention.”

Additionally, Rodés-Cabau said, it doesn’t make sense to directly compare gradients between surgical and transcatheter bioprostheses. “The problem is not like with surgical valves, where you’re seeing new regurgitation [develop during follow-up]. Here, with the first-generation valves, most patients left the hospital with some degree of aortic regurgitation,” so it is difficult to put in perspective a measurement that’s done many years post-TAVR. Finally, it is hard to know when using transthoracic echocardiography whether a leak is paravalvular or valvular in origin, he added, saying that “more sophisticated means” are needed to make that distinction.

Rodés-Cabau stressed that the degeneration observed here was subclinical. “We have also reported subclinical changes, as early as 1 year after TAVR, in a small proportion of patients. Is this clinically relevant? We don’t know,” he said, adding, “There may be some patients who have a clear degeneration [or] leaflet failure. It exists. But does it exist in the proportion [about which] we’re talking? This is where I’m not sure at all.”

Are Valve Thrombosis and Degeneration Linked?

Indeed, the recently reported data bring to mind concerns raised in the New England Journal of Medicine over valve thrombosis. “Last year, there was a big emphasis on silent thrombosis,” Vahanian said. “But in the end, what’s new there? We really don’t know.”

Hellig said that, if anything, degeneration is a more worrisome complication. “The valve thrombosis seemed fairly easy to resolve. With a period of anticoagulation, it seemed like that would be a transient phenomenon. I think the impact of that seems to be less,” he commented, noting, “The question is whether undiagnosed valve thrombosis might predispose [devices to developing] this scenario” of degeneration.

Research is needed to see whether the two are linked, and if there is something that can be done to prevent degeneration from occurring, Hellig suggested.

Extending TAVR to Younger Patients

The biggest question raised by many at EuroPCR, and one that continues to be aired, is how heavily these signs of degeneration should weigh on the minds of cardiologists who want to extend TAVR to an ever younger, more low-risk patient population.

“We are aiming to treat lower-risk patients, and the guidelines will go in this way in the near future,” Vahanian said. As such, durability is an important issue, especially for a person whose lifespan might exceed that of their valve. Dvir’s data should not yet impact practice with regard to the elderly, “but it could have an impact as we move towards younger patients,” he noted.

Vahanian, pointing out that there were no young patients in Dvir’s analysis, emphasized that dedicated studies are required to understand the best path in younger patients.

Indeed, valves might not degenerate similarly between older versus younger patients, Dvir concurred. “I tend to believe that the bioprosthetic surgical valves implanted in younger patients tend to fail earlier,” and that this would also be the case for percutaneous valves, he said, adding, however, that there is not yet “scientific proof” for the phenomenon in the TAVR population. In the EuroPCR analysis, he noted, only renal failure—and not age—was predictive of degeneration.

Also predicting that degeneration would vary by patient age for TAVR as it does for surgery, George suggested: “I suspect the etiology . . . is the same in both valves, with subtle differences but similar biological effects.”

While Hellig said the EuroPCR presentation should “undoubtedly” factor into deliberations over age, he stressed that surgeons have also had to ask themselves the same set of questions in prior years. The choice is less one between TAVR versus surgery than about whether a bioprosthetic valve—however it’s implanted—is suitable in younger patients, Hellig noted. “But I think what manufacturers are going to have to be mindful of is that the [potential] to allow a second procedure down the line has to be taken into account in the initial design of the first implant.”

For most octogenarians, the valves will likely outlast the patients, he said. “But if we’re going to be putting it in 70-year-olds, we’re going to have to be thinking of redo procedures. . . . If we’re getting down to 60-year-olds, then we’re looking at potentially two procedures down the line, maybe even three. So I think there we’ve really got to be careful. But again that also applies to surgical AVR in these patients. That’s when you’ve got to think about a mechanical valve.”

That being said, “it’s the young patients who want freedom from anticoagulation,” Hellig added, “They’ve got lives to lead and sports to play and things like that. So it’s a very, very complicated decision that needs to be individualized for each patient.”

As of now, there is no reason to be alarmed that transcatheter bioprosthetic valves might be less durable than surgical, Hellig said. While many patients in Dvir’s study showed signs of degeneration, it would be another 2 to 5 years before they would require reintervention, thus putting the timing in the ballpark of the median time for reoperation after surgery of 10 to 15 years, he noted.

Dvir cautioned against using what his study found for TAVR to make any direct comparisons with surgical valves, since “it was not part of the scope of the analysis or the presentation.”

With TAVR, he said, it is difficult to assess long-term changes in valve function, because the patients are much older than those who undergo surgery and the first cases were only done a bit more than a decade ago.

Another barrier is that different surgical valve reports describe degeneration using different criteria, he said. Most of the definitions, though, involve reintervention, which is problematic when extending them to TAVR, given that many patients are so old that reintervention isn’t an option. “But we have other surrogate endpoints,” Dvir noted, adding that the next step will be analyzing surgical and percutaneous valve degeneration rates using a consistent definition.

A Call for Science

For his part, Vahanian argued that Dvir’s analysis should be a reminder of the need to approach these clinical questions with scientific rigor. Vahanian cautioned against overreacting but said that, as investigators, “we should listen to [these signals], try to understand, and try to look at the long-term consequences.”

Describing the response to the EuroPCR presentation as “really overdone,” Vahanian emphasized that it should not reflect poorly on Dvir and his colleagues. While not a “landmark study,” he said, the analysis is a “very interesting observation, and those who did the observation should be congratulated.”

The best thing for clinicians to do at this point is perform their procedures well and follow patients carefully, both at the hospital and the national level, Vahanian advised. “Then we’ll know what happens.”

If premature evidence gets to the public, it could get interpreted wrongly, he cautioned. “Patients will be scared, they will refuse treatment, and they will die, because we know the natural history of these patients is terrible.”

In his opinion, Dvir’s study serves as a “good lesson in how to present provocative and disruptive data” as well as how to then move forward from that news, Vahanian observed. “The more provocative and the more disruptive the data, the more cautious we should be.”

He urged: “Please, keep cool.”