Valve Degeneration Data Dearth Spurs Calls for Universal Definitions and Clinical Guidance

CHICAGO, IL—Interventionalists and surgeons are still digesting the results of a provocative study on transcatheter valve degeneration released at EuroPCR 2016, but already, experts are questioning the definition of degeneration used in the study and proposing new ones. 

As reported by TCTMD, Danny Dvir, MD (St Paul’s Hospital, Vancouver, Canada), combined two cohorts of elderly, surgery-ineligible patients from Rouen, France, and Vancouver, where physicians were the first to test the procedure in the early 2000s. Long-term results suggested that a high proportion of the earliest TAVR devices showed signs of deterioration within 8 years of implantation. Valve degeneration in Dvir’s study was defined as at least moderate regurgitation and/or mean gradient >20 mm Hg that was not apparent in the first 30 days postintervention and was not related to endocarditis.

On Friday at TVT 2016, however, representatives from both sites separately took to the stage to present data on their own patients, with each presenter using different definitions of degeneration. This time, the numbers looked a little less dramatic.

The Rouen Patients

Helene Eltchaninoff, MD (University of Rouen, France), presented long-term results for the 239 patients who survived beyond 5 years in the Rouen cohort. In the ensuing years, 194 patients have died and five were lost to follow-up, leaving a total of 686 patient-years. The longest available follow-up was 9 years and by this point, only two patients remained alive.

Eltchaninoff pointed out—as many others have done in the interim—that in the surgical literature, structural valve degeneration is typically defined by the hard endpoint of reoperation.

One 2015 report of surgical valve degeneration—cited widely at TVT 2016—by Bourguignon et al appears to be the first to use a definition of degeneration in the surgical space that includes echocardiographic data: a mean transvalvular gradient > 40 mm Hg or severe aortic regurgitation, even if the patient was asymptomatic.

Applying this definition to the Rouen cohort, no patient had a mean gradient above the 40 mm Hg cutoff and only one patient had severe aortic regurgitation plus an elevated gradient leading to reintervention, Eltchaninoff said.

She then proposed a different definition of degeneration, this one using a mean transvalvular gradient of > 20 mm Hg but in combination with an increase of at least 10 mm Hg from the 30-day echo or aortic regurgitation grade 3 or higher (moderately severe/severe) not present at day 30.

Using this definition, four patients in the Rouen cohort met the criteria for degeneration, with two deemed “possible,” one “probable,” and one “definite.”

Having a standardized definition of structural valve degeneration is “key,” Eltchaninoff concluded, and should be “universal” and clearly defined in the guidelines. For now, she continued, the condition seems rare “and doesn’t appear to be associated with an increased risk when compared with conventional bioprostheses.”

The Vancouver Patients

Next up was John Webb, MD (St. Paul’s Hospital), presenting a reanalysis of the 266 Vancouver patients. Of note, Webb was listed as the senior author on Dvir’s title slide in Paris, and Dvir was the lone co-author on Webb’s title slide here in Chicago. In his TVT 2016 presentation, Webb defined structural valve degeneration as severe stenosis and/or regurgitation, or reintervention. Using this definition, only five patients, or 1.9%, were deemed to have valve degeneration.

Expressed as a Kaplan-Meier curve, freedom from degeneration at 8 years (seven patients still living) in Webb’s analysis was 84.6%—a far cry from the 50% presented by Dvir in Paris last month.

“For now, I think what is important is that we use a definition that matches that used for surgical valves,” Webb told TCTMD. “You can’t compare reports of structural valve degeneration if they use different definitions.” Those in the surgery community, he continued, “use ‘freedom from repeat aortic valve replacement’ most often. This is weak. Some now use ‘freedom from redo aortic valve replacement or severe [aortic stenosis] or severe [aortic regurgitation],’ which is better. We should report both to allow comparisons.”

Many Opinions, Few Hard Answers

Speaking with TCTMD, Dvir joked that he hasn’t been able to keep up on his email inbox since his presentation last month, but also said that he believes his findings were blown out of proportion. His intent was to apply a definition of degeneration that could be used to track transcatheter valve durability as longer-term data emerge from increasingly lower-risk patients.

But just what the best definition should be remained one of the most contentious talking points of TVT 2016. Definitions based on echocardiographic findings are tricky since, as Webb pointed out following his presentation, it’s very difficult to get elderly patients back to the hospital for imaging tests after 5 years, particularly if they aren’t feeling symptoms.

Moreover, Webb added, “The problem is, we don’t have this data on surgical valves with a gradient over 20 mm Hg. It’s a brand new definition, and people can’t equate this with failure. It’s not failure to have a gradient of 20.”

A number of presenters last week showed another slide of Dvir’s, this one from the VIVID registry tracking 1,590 patients who’ve undergone TAVR in failing surgical valve bioprostheses. In this analysis, most patients were having their valve-in-valve procedure 7 to 11 years after surgery.

Those numbers, many pointed out, are not too dissimilar from what seems to be emerging in the albeit very preliminary data from the first-generation TAVR devices.

Pieter Kappetein, MD (Erasmus University Medical Center, Rotterdam, the Netherlands), however, who provided the “surgeon’s perspective” on valve degeneration following Eltchaninoff and Webb, took issue with the VIVID slide, pointing out that the denominator is unknown. This slide doesn’t capture the patients who may be healthy, with functioning surgical bioprostheses, and “living in the Bahamas,” he said.

But Kappetein did make the point while many surgical valves over the last 60 years have proved durable “a lot of valves were put on the market that had to be withdrawn for early valve failure —the best example of this is the Toronto valve.”

What’s evident, he said, echoing the conclusions of Eltchaninoff and Webb, is that “clear definitions of failure are needed” to be able to compare surgical and transcatheter valves, but it’s also important to remember that “reoperation for valve failure is not the same as a failing valve.”

And while it’s not yet apparent whether transcatheter valve durability will match that seen for surgical valves, a better question might be, “do patients really care?” he said.

“Suppose a surgical heart valve lasts 12 years and a transcatheter heart valve lasts 10 years or 9 years,” Kappetein asked his audience. “If you’re 75 years of age, you care about being out of the hospital fast, fast recovery. [Whether] that valve lasts 3 years longer or more, probably doesn’t matter to you.”

Implications for Patients

Conversations in the hallways of TVT 2016 and among panelists in sessions also tackling the valve degeneration issue appeared to swing two ways.

One set of discussions was clinical, focusing on what matters for patients in real-world situations, since it’s impossible to know in any given patient whether or when their transcatheter valve will begin to deteriorate in their lifetime. So choosing a transvalvular gradient, or a change in gradient, that points to a device in trouble may not be one size fits all.

“A 20 mm Hg gradient doesn’t really matter perhaps for an 80-year-old, but it might for a 75-year-old or 65-year-old who exercises,” Kappetein pointed out. “And then that gradient may go up to 40 or 50 and then if that happens for a long time, that may have an impact on life expectancy. It may mean that you need different criteria for different age groups.”

Likewise Dvir, asked what he thought of Eltchaninoff’s revised definition of degeneration, didn’t bite. “Valve degeneration is a continuous process,” he told TCTMD. “It should be defined in stages. You should not use a single threshold,” particularly when patient age and kidney function are factors that influence valve performance long term. But at the same time, Dvir continued, a definition of degeneration based on reintervention is also not appropriate, particularly for older patients who would not be candidates for repeat procedures.

Implications for Research

But the other focus of the degeneration discussions was the development pathway for transcatheter devices and the implications for research as TAVR moves into lower-risk and younger patients.

“We’ve learned that freedom from reoperation for structural valve degeneration in surgical valves does not reflect freedom from structural valve degeneration overall, so you cannot take the surgical data and say hey, everything is all right on the surgical side but things are not on the TAVR side,” Hendrik Treede, MD, PhD (University Hospital Halle (Saale), Halle, Germany), said in a separate TVT 2016 session.

“To date there is no evidence that TAVR valves degenerate earlier than surgical valves—the patients are much too few,” he continued. “But I’m still convinced that we need longer-term data on transcatheter valves before we can really take these devices into a lower risk or younger patients, because it may well be that there is less durability. We just don’t know it at this time point.”

To TCTMD, Kappetein said he still believes transcatheter valve leaflets are intrinsically more vulnerable to degeneration, with the condition related to crimping, torsion during delivery, as well as the noncircular expansion and nonsymmetrical opening and closing of the valves. In his talk following Eltchaninoff and Webb’s presentations, he reminded the audience that surgeons are taught to never even touch the leaflets with their forceps during implantation “because that’s where the calcification process will start.”

Everyone who spoke at TVT 2016 appeared to agree: more patient follow-up is needed to understand TAVR valve durability. And while some said this is a reason to pause TAVR’s march into younger patients, others pointed out that the reality of the research conundrum is that until younger patients actually receive a new technology, it’s not possible to properly study its performance and durability long-term.

At the same time, there’s a pressing need for interventional and surgical guidelines and for professional societies to adopt the same recommendations and definitions in clinical practice and in the study of new devices—both surgical and transcatheter—entering the market, many said.

Both Treede and Raj Makkar, MD (Cedars-Sinai Medical Center, Los Angeles, CA), made the point that the current surgical valve replacement guidelines do not recommend echocardiography until 5 years after implantation. “I do think it’s time to change that if we’re going to look at TAVR and surgical valves in the same light,” Makkar said. “I do think I think the societies need to have some kind of uniform guidelines as to when echo should be performed.” 

 

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Disclosures:

 

• Kappetein reports having no conflicts of interest. 
• Eltchaninoff reports receiving consulting fees from Edwards Lifesciences. 
• Webb reports receiving grant/research support and consulting fees/honoraria from Edwards Lifesciences, St Jude Medical, and Abbott. 
• Treede reports receiving grant/research support from Edwards Lifesciences, JenaValve, and Symetis; consulting fees/honoraria from Medtronic, Biotronik, LivaNova, and Millipede; and holding major stock/equity in TriCares. 

 

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