Higher Reintervention Risk With TAVI Emerges at 6 to 7 Years in Evolut Low Risk Trial

While there is no significant difference in the risk of all-cause mortality or disabling stroke in midterm follow-up of the Evolut Low Risk trial, new findings with the self-expanding bioprosthesis (Medtronic) have raised some concerns about durability.

By 6 years, the primary endpoint occurred in 23.3% of patients treated with TAVI and 20.4% of those who underwent surgery (P = 0.43), with the event curves crossing at 5 years to numerically favor surgery, investigators report in a paper published earlier this week in JACC.

However, it was the aortic valve reinterventions that generated questions. At 6 years, there was a nonsignificant 2.2% difference in the rate of reintervention favoring SAVR. By 7 years, in the subset of patients with available data, the 3.8% difference favoring surgery was statistically significant.

“I believe this data meaningfully contributes to our understanding of TAVR and our understanding of surgery and the treatment of aortic stenosis,” lead author John Forrest, MD (Yale University School of Medicine, New Haven, CT), told TCTMD. “I think it helps us in our shared decision-making process. There may be instances where we look at this data and think, ‘In this patient, I might do something different now.’ Broadly speaking, though, is it going to change my entire practice? No. It’s a piece of data that contributes to an ever-emerging field.”

Regarding the increased risk of reintervention, Forrest stressed that while the results are important, the difference should be put into clinical context. Out of every 100 people who undergo surgery, 94 won’t require reintervention by 7 years; on the TAVR side, a little more than 90 won’t either, he said.

“I would emphasize that this is a story that is not finished,” said Forrest, noting that follow-up is planned for 10 years. “We don’t know what’s going to happen as we follow these patients. We need to recognize that this represents one of the first two studies to truly look at this [low-risk] population.”  

Tsuyoshi Kaneko, MD (WashU Medicine, St. Louis, MO), a cardiothoracic surgeon, called the follow-up data “critical and impactful,” noting the study has created some buzz in the community. The Evolut Low Risk trial now provides solid, randomized trial evidence that “there are some signals of increased risk of reintervention with this particular valve that was utilized,” said Kaneko.

While reintervention has been criticized as a surrogate for structural valve deterioration, the follow-up clearly shows there is a significant difference when it comes to TAVI with the self-expanding valve and surgery, he said.  

I would emphasize that this is a story that is not finished. John Forrest

“One thing that’s a little different here is that this is a low-risk patient population,” Kaneko told TCTMD, noting that the mean age at the time of implantation was 74 years. “We will most definitely bring up this [risk of reintervention] in the heart team [meeting], because it will certainly affect this younger patient population that will likely outlive the valve.”

Richard Whitlock, MD (McMaster University/Population Health Research Institute, Hamilton, Canada), another surgeon, praised the researchers for recognizing the importance of their findings and conducting different analyses to understand the mechanism of failure. Like Kaneko, he was taken aback by the rate of early reintervention in this low-risk group.

“In your low-risk patients who are on the younger side—depending on your geography, say 65 to 75 years—this [risk of reintervention] needs to be discussed,” he told TCTMD. “You can [now] say [that] we can do TAVR safely with equivalent outcomes to surgery, with the data suggesting up until about 6 years, and then there is a concerning trend for failure. Then they’ll require a reintervention. and two-thirds of those reinterventions will be surgery. By then, you’re taking an older patient and exposing them to an open-chest surgery.” 

For interventional cardiologist Ole De Backer, MD, PhD (Rigshospitalet, Copenhagen University Hospital, Denmark), however, the results don’t line up with his prior experience. He noted they observed no difference in clinical outcomes nor any difference in the risk reintervention, structural valve deterioration, or valve failure at 10 years in the NOTION trial of low-risk patients.

“There was no signal of harm,” he told TCTMD, noting that NOTION even used the first-generation CoreValve platform (Medtronic). “There was no signal of more reintervention. I also don’t see this in my practice, and we do a lot of Evolut implants. Our reintervention rates on these patients being treated with Evolut in daily clinical practice are extremely low.”

The analysis is accompanied by an editorial by Aakriti Gupta, MD (Cedars-Sinai Medical Center, Los Angeles, CA), and David Cohen, MD (Cardiovascular Research Foundation, New York, and St. Francis Hospital, Roslyn, NY), as well as a viewpoint from Ziad Ali, MD, DPhil (St. Francis Hospital), and another from JACC Editor-in-Chief Harlan Krumholz, MD (Yale School of Medicine), and Sanket Dhruva, MD (University of California, San Francisco).

Data Out to 7 Years

The Evolut Low Risk trial, along with PARTNER 3, established TAVI as a safe and effective treatment for low-risk patients with severe aortic stenosis, with the US Food and Drug Administration expanding the procedure’s indication to include the low-risk group following both trials. Valvular guidelines on both sides of the Atlantic followed suit and now recommend TAVI across the spectrum of surgical risk.

Follow-up from the Evolut Low Risk at 3, 4, and 5 years showed that the device—mostly the Evolut R and PRO iterations, which are no longer commercially available—held up well compared to surgery.

The 6-year results include 1,414 patients at low risk for surgery who underwent TAVI between 2016 and 2019. As noted, there was no statistically significant difference in the primary endpoint of all-cause mortality or disabling stroke through 6 years, but event curves crossed at 5 years to numerically favor surgery. Forrest pointed out that cardiovascular mortality was nearly identical between groups at 6 years, while the risk of noncardiovascular mortality trended greater with TAVI: 11.0% vs 8.7% with surgery (P = 0.24).  

The reintervention rate was 5.5% in the TAVI-treated patients and 3.3% in those who underwent surgery (P = 0.07), a difference that was statistically significant at 7 years when the analysis was expanded to include those patients with sufficient follow-up (9.8% vs 6.0%; P = 0.02).

They’ll require a reintervention, and two-thirds of those reinterventions will be surgery. Richard Whitlock

“There are obvious limitations with looking forward—it’s not complete data, it was earlier in the study—but I do think it was an appropriate thing to do given the number of patients who had reached 7 years,” said Forrest.

At years 6 and 7, the rate of reintervention for aortic stenosis was not different between the two interventions, but the difference in reintervention due to aortic regurgitation was statistically significant and favored surgery at both time points.

By 7 years, 39 of the 60 patients who needed a reintervention after TAVI had the bioprosthesis surgically explanted and 21 had a redo procedure. One patient who had the valve explanted and another who had a redo TAVI died within 30 days or before discharge. Four patients in the surgery arm who required an intervention died, including three who had redo surgery and one who underwent a TAVI-in-TAVI procedure.

De Backer said he was surprised so many TAVI patients requiring reintervention went for surgery.

“If we have a TAVI patient who needs a reintervention, which I don’t see as a major issue, we will always try to offer him a redo TAVR and not go for a surgical option,” he said. “I don’t know if this is due to American practice or if it was because a couple of years ago where TAV-in-TAV was not that well integrated yet.”

However, these data show that even though they are sent for surgery, they aren’t paying a price with a higher risk of mortality, said De Backer.

Mechanisms of Action

During the trial, there were no instructions regarding maximal balloon size for postdilation, but clinical experience after approval led to concerns that excessive postdilation could damage the leaflets and lead to aortic regurgitation. This resulted in a 2020 corrective field action and a change in the Instructions for Use (IFU) that warned about risks of postdilation with a balloon that exceeded the valve’s waist.

Investigators performed an exploratory analysis to see if there was any association with postdilation. For valves that weren’t postdilated, the reintervention rate for aortic regurgitation was 4.3%. For valves that were postdilated with a balloon based on the 2020 IFU guidance, the rate was also 4.3%. In cases where postdilation didn’t follow the guidance, the rate of reintervention was 9.3%. The reintervention rate after off-guidance postdilation was highest in patients who received a 34-mm Evolut R (19.1%).

One thing that’s a little different here is that this is a low-risk patient population. Tsuyoshi Kaneko

These findings, stress investigators, should be considered hypothesis-generating only.

“I think an important message here is not that postdilatation is harmful because, in fact, even though you may have anatomy that’s more challenging and other things, when you postdilate, you actually get a result that is equivalent,” said Forrest. “If you postdilate with a balloon that’s larger than the waist [off-IFU guidance], you significantly increase your risk of needing reintervention.”

To TCTMD, De Backer said postdilation helps explain the rate of reintervention.

“It doesn’t point to one specific cause, but clearly there’s some relationship with off-guidance use of postdilatation of certain types of valves, especially Evolut 34 [mm],” he said. That’s not a surprise because the 34-mm Evolut R has a waist of just 24 mm, he added. “Unfortunately, 7 or 8 years ago when these patients were treated, operators were not aware that they could damage the leaflets by using too large a size of balloon for postdilatation.”

De Backer, who has conducted bench testing with the Evolut valve platforms, said the study is a reminder to appropriately predilate when using self-expanding valves to avoid aggressive postdilation after the valve is implanted. Today, operators are much more careful in their selection of balloons with the Evolut platform “because we know this valve has a particular waist that we have to respect.”

In the editorial, Gupta and Cohen point out that while postdilation is an intuitive explanation, the evidence backing it is “circumstantial.” Postdilation is usually the result of suboptimal valve expansion or paravalvular leak, and this might be the result of greater anatomic complexity. “Off-guidance postdilation may therefore function both as a cause of valve injury and as a marker for a challenging substrate,” they write.

What Will the Future Hold?

In PARTNER 3, which now has data published out to 7 years, there was no significant difference in the risk of aortic-valve reintervention between surgery and TAVI with the Sapien 3 balloon-expandable valve.

Kaneko stressed that comparing outcomes between two different trials—PARTNER 3 and Evolut Low Risk—is fraught, but said the reintervention rates seen in both trials will be “a piece of the puzzle” when teasing out the best treatment option for low-risk patients. These new data, he said, emphasize the importance of lifetime management, specifically in thinking down the road to the second procedure when treating low-risk patients with longer life expectancies.

I also don’t see this in my practice, and we do a lot of Evolut implants. Ole De Backer

Whitlock believes the higher rate of reintervention is device-specific, but noted the technology keeps changing and implantation techniques modified as more is learned. Like others, he said there is a continued need for vigilance, pointing out the need for reintervention means patients are redeveloping valvular disease, with all of its deleterious effects on the heart. For this reason, keeping a watchful eye on clinical outcomes over the next 3 years will be critical.

Regarding the numerically higher rate of all-cause mortality or disabling stroke with TAVI, Kaneko reiterated that the difference between treatments was not statistically significant and that further follow-up is planned.

“We have to remember that the mortality curve in PARTNER 3 crossed around year 3,” he said. “Then, people thought it was going to continue to separate, but it hasn’t. So, the [primary endpoint] is a snapshot of where we are right now, and we have to continue to wait for the 10-year follow-up. That being said, the curve crossing is itself a significant signal that we have to watch this carefully in the long term.”

To TCTMD, Cohen also pointed to the crossing mortality curves in PARTNER 3.

“In both studies, the finding seems to be driven mainly by excess noncardiovascular mortality and is not at all statistically significant at this point,” he said in an email. “My conclusion is that these trends warrant continued vigilance but are not all that concerning to me at the moment. Additional follow-up in both trials will be critical.”