Low-Risk TAVR Studies: Divergent Long-Term Results 

The latest results from long-term follow-up of the two trials evaluating transcatheter aortic-valve replacement (TAVR) vs surgery in patients with low surgical risk have shown different results.

The PARTNER-3 and Evolut trials were heralded as a landmark advance in medicine when the 1-year results from the two studies were presented back in 2019. Both trials suggested benefits of the less-invasive TAVR approach over surgery.

But because these low-surgical-risk patients are younger and will likely have a longer lifespan than will higher risk patients for whom the TAVR technique was first established, patient outcomes and information on how the TAVR devices hold up over the long-term are critical to inform clinical decision-making.

Latest results from the two trials show that the initial benefits of TAVR over surgery seen in PARTNER-3 seem to have attenuated over the longer-term, with main outcomes looking very similar in both groups after 5 years.

However, in the Evolut trial, the early benefit in all-cause mortality or disabling stroke seen in the TAVR group is continuing to increase, with current results showing a 26% relative reduction in this endpoint with TAVR vs surgery at 4 years.

The 5-year results of the PARTNER-3 trial and the 4-year results of the Evolut study were presented this week at the Transcatheter Cardiovascular Therapeutics 2023 meeting, held in San Francisco. Both sets of results were simultaneously published online: PARTNER-3 in The New England Journal of Medicine and Evolut in JACC.

Marty Leon, MD, of NewYork-Presbyterian Columbia University Irving Medical Center, who presented the PARTNER-3 results, told theheart.org | Medscape Cardiology that both trials are good news for TAVR:

"Both trials have clearly reaffirmed clinical and echocardiographic benefits of TAVR as a meaningful alternative therapy to surgery in low-risk severe symptomatic aortic stenosis patients."

Michael Reardon, MD, Houston Methodist Debakey Heart & Vascular Center, who presented the Evolut results, agreed that both trials were positive for TAVR "as TAVR just has to be as good as surgery to be a winner because clearly it is a lot less invasive."

But Reardon added that, "In making that decision for younger lower-risk patients, then the Evolut valve is the only TAVR valve that has shown superior hemodynamics and durability at all time points with excellent outcomes and widening benefits compared with surgery over the first 4 years."

PARTNER-3

The PARTNER-3 trial randomly assigned 1000 patients with severe symptomatic aortic stenosis and low surgical risk to undergo either TAVR with the SAPIEN 3 transcatheter heart valve or surgery.

The results at 5 years show no difference in the two primary composite outcomes between TAVR and surgery patients.

The incidence of the composite end point of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure was similar in the TAVR group and the surgery group, occurring in 22.8% of patients in the TAVR group and 27.2% in the surgery group, which is a nonsignificant difference (P = .07).

The incidence of the individual components of the composite end point were also similar in the two groups. Death occurred in 10.0% in the TAVR group and 8.2% in the surgery group; stroke in 5.8% of the TAVR group and 6.4% of the surgery group; and rehospitalization in 13.7% and 17.4%, respectively.

Aortic-valve durability also looked similar in the two groups. The hemodynamic performance of the valve, assessed according to the mean valve gradient, was 12.8 mm Hg in the TAVR group and 11.7 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group.

Among the secondary end points, atrial fibrillation and bleeding appeared to be less frequent in the TAVR group than in the surgery group, whereas paravalvular aortic regurgitation, valve thrombosis, and pacemaker implantation appeared to be less frequent in the surgery group.

Functional and health-status outcomes assessed according to New York Heart Association class, quality of life scores, and the percentage of patients who were alive and well at 5 years appeared to be similar in the two groups.

"These data are reassuring," Leon said. "Cardiovascular mortality occurred at a rate of about 1% per year with both therapies, strokes at the rate of 1% per year with both therapies, and hospitalization for cardiovascular reasons about 3% per year with both therapies. For patients in their 70s, these are very good numbers."

Along with showing similar outcomes for TAVR and surgery at 5 years, he added, "the need for re-intervention was particularly low (2%-3%) and equivalent for both approaches. And structural valve deterioration was also very low and equivalent in both groups."

Evolut Low-Risk Trial

The Evolut trial enrolled 1414 patients with low surgical risk who were randomly assigned to TAVR, a self-expanding supra-annular CoreValve Evolut R PRO, or surgery.

By 4 years, the primary endpoint of all-cause mortality or disabling stroke had occurred in 10.7% of the TAVR group and 14.1% in the surgery group (hazard ratio [HR], 0.74; P = .05), representing a 26% relative reduction with TAVR.

The absolute difference between treatment arms for the primary endpoint continued to increase over time: 1.8% at 1 year, 2.0% at 2 years, 2.9% at 3 years, and 3.4% at 4 years.

Rates of the primary endpoint components were all-cause mortality 9.0% with TAVR vs 12.1% with surgery (P = .07); and disabling stroke was 2.9% with TAVR) vs 3.8% for surgery (P = .32). Aortic valve rehospitalization was 10.3% with TAVR vs 12.1% with surgery (P = .27).

The composite of all-cause mortality, disabling stroke, or aortic valve rehospitalization was significantly lower with TAVR compared with surgery (18.0% vs 22.4%; HR, 0.78; P = .04).

New permanent pacemaker implantation was significantly higher in the TAVR group (24.6% vs 9.9%).

Indicators of valve performance including aortic valve reintervention (1.3% TAVR vs 1.7% surgery); clinical or subclinical valve thrombosis (0.7% TAVR vs 0.6% surgery); and valve endocarditis (0.9% TAVR vs 2.2% surgery) were similarly low between groups, the authors report.

TAVR patients had sustained improvement in hemodynamics as measured by echocardiography, with significantly lower aortic valve mean gradients (9.8 mm Hg TAVR vs 12.1 mm Hg surgery) and greater effective orifice area (2.1 cm² TAVR vs 2.0 cm² surgery).

At 4 years, 84.7% of TAVR patients and 98.4% of surgery patients had no or trace paravalvular regurgitation, and there was no difference between groups in moderate or greater paravalvular regurgitation (0.4% TAVR vs 0.0% surgery).

"The Evolut valve has shown a superior performance to surgery," Reardon concluded. "It has less structural valve deterioration, less severe patient prosthetic mismatch, and superior hemodynamics compared to surgery. All these factors are translating into a widening difference in clinical event curves year on year with the Evolut valve vs surgery."

Why the Difference Between Trials?

The big question is why the early benefit seen with TAVR vs surgery in both trials was attenuated by 5 years in PARTNER-3 but seemed to become greater each year in the Evolut trial. There were no definite explanations for these observations, but several possibilities were suggested.

Leon noted that with trials of intervention vs surgery, it is common for the intervention group to do better in the beginning and for surgery to catch up a bit in later years. "So, it is not that much of a surprise to see outcomes plateauing in PARTNER-3."

But he also suggested some other factors that may have played a role, one of which was the COVID pandemic.

"During the 2-year COVID period more than 75% of the deaths and strokes in the trial occurred in the TAVR patients," he said. "Surgery patients were getting more anticoagulation because they had more paroxysmal [atrial fibrillation]. We know that COVID is a stimulus of thrombogenic events so in an odd way we think there may have been some cardioprotective effects from anticoagulation therapy in the surgery group."

He also pointed out that though hospitalization and strokes were slightly lower with TAVR vs surgery in the PARTNER-3 trial, mortality was slightly greater in the TAVR group.

"There was a 2:1 ratio in the TAVR and surgery groups in non-cardiovascular deaths which influenced the all-cause mortality numbers," he noted.

Mortality Rates in the Surgery Groups

Leon also pointed out differences in the mortality rates in the surgery groups in the two trials, which he suggested may contribute to the explanation for the different longer-term results.

"The baseline characteristics for patients in these two trials were almost identical, and results at 1 year were very similar, but for whatever reason, over the course of a few years, the outcomes in the Evolut trial were different to those in PARTNER-3, and in particular the difference was in the surgical arms, with a higher event rate in the surgical arm in Evolut than in the surgery arm in PARTNER-3," he said. "When the control does not perform well it is a lot easier to show that the experimental arm is better."

"When you look at the TAVR arms in both studies at each time point they are either similar or PARTNER-3 is actually lower," he added. "That is why it is so difficult to compare these two trials."

But Reardon dismissed this argument.

"What determines long-term survival after a procedure is the intrinsic risk level of the patients," he said. "Overall mortality rates differ between the two trials because the PARTNER-3 trial enrolled a lower end of a low-risk population while Evolut enrolled an upper end of a low-risk population. You cannot look at absolute numbers between trials. That is intellectually and scientifically invalid."

"It is the relative difference between surgery and TAVR that we are interested in, and we see in Evolut that the relative difference between the two procedures in terms of benefit with TAVR is widening every year," he added. "That is because the superior valve performance and hemodynamics of the Evolut valve compared to surgery has translated into excellent clinical outcomes.

"In the PARTNER-3 trial – their curves are coming together. I think that is worrisome, but I don't want to draw conclusions about their trial," Reardon said. "All I know is that in our trial, we have excellent outcomes that are getting better year after year."

Competition Between Valves

The different results of the two trials is inevitably producing some competition between the two products.

Reardon said: "In terms of which valve to use, clinicians will want to choose a valve that has the best durability and shows the best survival vs surgery and that is clearly the Evolut valve. I think the writing is on the wall. Some clinicians are going to wait for longer term data, but the question is do we have enough long-term data now."

But Leon countered: "There's never been a head-to-head device to suggest that the self- expanding device performs better than the balloon expanding device. We always think about them as being similar in terms of performance. There is an aggressive effort to suggest that by virtue of the current trial results there was a superior outcome with the Medtronic device, but it's hard to explain why that would be the case, and we should not compare between the two trials."

Both Leon and Reardon stressed that longer-term follow-up is critical because some surgical valves are known to fail between 5-10 years, and it is not known how the TAVR valves will perform over that period.

Both the PARTNER-3 and Evolut trials are planning to keep following patients out to 10 years.

For the time being though, both Leon and Reardon agreed that these current results will probably accelerate the already rapid transition from surgery to TAVR in low-risk patients.

"TAVR will be the default therapy," Leon commented. "It will be the first choice for patients. Whether TAVR is superior to surgery in terms of outcomes or just the same, there are sufficient benefits from a logistic and patient perspective that most people would prefer to have the less invasive therapy. TAVR is a one-day procedure, there is no need for general anesthetic, a lot of the secondary outcomes that are so problematic with surgery don't exist, and the ability to be in a symptom-free state is dramatically accelerated."

"This was the first serious foray into the low-risk population with TAVR," he added. "We had an age cut of 65 years, but the vast majority of patients in both trials were over 70. We could now start looking at younger patient populations."

But Reardon said that these younger patients are already being given TAVR, and future trials randomizing between TAVR and surgery may not be possible.

"Even though US guidelines still recommend surgery for patients under 65 years, patients want TAVR, and they get TAVR," he said. "Recent data shows that in 2021, use of TAVR rose to 47.5% in patients under 65 needing isolated aortic valve replacement. That doesn't meet the guidelines but there's clearly a big shift going on. These results will just keep that momentum going."

The PARTNER-3 trial was f unded by Edwards Lifesciences. The Evolut study was funded by Medtronic. Leon reports grant support from Edwards Lifesciences and Medtronic. Reardon receives research grants from Medtronic.

Transcatheter Cardiovascular Therapeutics (TCT) 2023. Presented October 24.

N Eng J Med. Published online October 24, 2023. Abstract

J Am Coll Cardiol. Published online October 24, 2023. Abstract

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