Low-Risk Trials Cement a Role for TAVR Alongside—or in Place of—Surgery

NEW ORLEANS, LA (UPDATED)—Hotly anticipated new randomized clinical trials testing transcatheter aortic valve replacement in low-risk patients, for whom surgery is standard, provide strong evidence that TAVR has earned its rightful place in this patient population.

The two studies, PARTNER 3 and the Evolut TAVR in Low-Risk Patients trial, are scheduled for presentation during a late-breaking clinical trials session Sunday at the American College of Cardiology (ACC) 2019 Scientific Session. The embargo on the data was lifted Saturday, however, following the early release of the news by Reuters. While the trial designs had slightly different endpoints, the studies prove at the very least that TAVR is equivalent to surgery in the treatment of low-risk patients with aortic stenosis.

In the Evolut Low-Risk trial, which tested the self-expanding CoreValve, Evolut R, and Evolut PRO (Medtronic) valves in a low-risk patient population, the 24-month estimated incidence of death or disabling stroke was similar in the TAVR and surgical arms, meeting the definition of statistical noninferiority but not superiority.

The PARTNER 3 trial, however, exceeded noninferiority expectations, with investigators reporting that treatment with the balloon-expandable Sapien 3 transcatheter heart valve (Edwards Lifesciences) was better than surgery for the prevention of death, stroke, and rehospitalization at 1 year, the study’s primary endpoint.

Martin Leon, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), one of the lead PARTNER 3 investigators, said they were struck by the positive results. “We didn’t expect TAVR would be this good,” he told TCTMD. “From the standpoint of the hard primary endpoint, the trial was dramatically positive.”

For patients like those enrolled in the trial, it’s very difficult to argue that TAVR is not a dominant and superior therapy, said Leon.

“When you put it all together, at least up until 1 year this is a very exciting therapy, and it should probably allow you to have a much different discussion with patients,” he said. “Patients and referring doctors should feel empowered that—rather than relying on surgical risk stratification—good sense, understanding the anatomy, and the clinical circumstance will allow us to develop a shared decision-making process where patients have a choice between TAVR and surgery irrespective of risk profile.”

Michael Reardon, MD (Houston Methodist DeBakey Heart and Vascular Center, TX), the co-principal investigator of the Evolut Low-Risk TAVR trial, said there are clear clinical implications for patients, particularly with respect to one of their key secondary endpoints, one similar to the primary endpoint used in the PARTNER 3 trial.   

“As a surgeon, I sit down with patients every day who ask how they’re going to do,” said Reardon during the late-breaking clinical trial session. “I can tell them if they were in this trial and assigned to the TAVR arm, they were more likely to be alive, not have disabling stroke, and not have heart failure hospitalization. . . . I am glad to see that this composite endpoint shows a class effect for TAVR in both trials.”

Reardon said TAVR should be the preferred strategy across the entire risk spectrum of patients. When discussing treatment options in low-risk patients with severe aortic stenosis, unless he mentions the benefits of TAVR, “I have not truly given informed consent,” he added.

Richard Whitlock, MD, PhD (McMaster General Hospital/Population Health Research Institute, Hamilton, Canada), who was not involved with either trial but who is a member of his institution’s TAVR heart team, said it is difficult to compare clinical trials and praised both studies for excellent results. Nonetheless, while the low-risk TAVR trial with self-expanding valve was noninferior to surgery, the PARTNER 3 study with the Sapien 3 valve “knocked his socks off.”

The results, he said, will change the landscape of treatment for severe aortic stenosis.

“The one thing we can say is that this is a new era of valve replacement,” Whitlock told TCTMD. “There’s always been this turf war, which is unfortunate because I think it hinders patient care between surgeons and interventionalists. In many centers, it’s less so with TAVR because there really is a better team approach to care, but there are centers where cardiac surgeons and interventionalists are already butting heads over this. Cardiac surgeons are fooling themselves, though, if they don’t think the future of aortic valve [replacement] doesn’t lie with a fairly dominant position going to TAVR.”

Cardiac surgeons are fooling themselves, though, if they don’t think the future of aortic valve [replacement] doesn’t lie with a fairly dominant position going to TAVR. Richard Whitlock

Rishi Puri, MBBS, PhD (Cleveland Clinic, OH), who was not involved in the studies, called both trials “phenomenal,” stating that patients are the ones who stand to gain the most. “This is practice-changing,” he said. “It’s going to change the way we treat aortic valve disease forever. It’s huge.”

Both trials are now published in the New England Journal of Medicine following an embargo break ahead of the ACC presentation.

The Next Frontier in TAVR

PARTNER 3 included 1,000 patients with an STS Predicted Risk of Mortality of less than 4% (mean STS-PROM score 1.9%) treated at 71 centers. The average age of those treated was 73.4 years, and nearly 70% of patients were men.

The primary composite endpoint of death from any cause, stroke, and rehospitalization occurred in 8.5% of patients undergoing TAVR and 15.1% of patients treated with surgery (P < 0.001 for noninferiority; P = 0.001 for superiority). The risk of death or disabling stroke, the same endpoint used in the Medtronic-sponsored study, was 1.0% in the TAVR arm and 2.9% in the surgery patients, a difference that was statistically significant (HR 0.34; 95% CI 0.12-0.97). In an analysis of secondary endpoints, new-onset atrial fibrillation was lower among the TAVR-treated patients, while there was no difference in the need for new permanent pacemaker with the Sapien 3 device. Length of hospital stay was shorter among those treated with TAVR, while bleeding was significantly greater with surgery.

PARTNER 3: Primary and Secondary Endpoints

To TCTMD, Leon said the primary endpoint was customized to a low-risk patient population because they wanted a lower threshold for significant events. However, the secondary endpoints really speak to the power of the less invasive procedure, he added.

For example, from a patient’s perspective, only one-third of the TAVR patients underwent general anesthesia and very few were taken to the intensive care unit after the procedure. TAVR patients were hospitalized for shorter periods after valve replacement and the vast majority were discharged home or to self-care. “In the first 30 days, they have almost complete recovery to normal functional status,” said Leon.

All of this, said Leon, “is very powerful from the standpoint of a new therapy for low-risk patients.”    

In terms of the echocardiographic findings, the percentage of patients with moderate or severe paravalvular aortic regurgitation did not differ significantly between the TAVR group and surgical arm, although more patients in the TAVR arm did have mild paravalvular aortic regurgitation at 1 year than those treated surgically (29.4% vs 2.1%). Six patients total—five in the TAVR arm and one surgically treated patient—had evidence suggestive of valve thrombosis, including increased valve gradients and imaging showing restricted leaflet motion.

Evolut Low-Risk Trial

The Medtronic Evolut TAVR Low-Risk trial included 734 patients randomly assigned to TAVR and 734 to surgery. Like PARTNER 3, the mean age of patients was 74 years, the mean STS-PROM score was 1.9%, and two-thirds of treated patients were men. The vast majority of patients received the Evolut R and PRO valves, with just 3.6% treated with CoreValve. From a statistical perspective, the study used a Bayesian design, with the investigators conducting a prespecified interim analysis when 850 patients had reached 12 months of follow-up. 

This is practice changing. It’s going to change the way we treat aortic valve disease forever. Rishi Puri

The primary incidence of death or disabling stroke at 24 months—the study’s primary endpoint—was 5.3% in the TAVR arm and 6.7% in the surgery group, meeting the statistical definition of noninferiority. There was no difference in the risk of death at 24 months, which was 4.5% in both the TAVR and surgery arms, but the incidence of disabling stroke at 2 years was 1.1% with TAVR and 3.5% with surgery.

Commenting on their primary endpoint, Reardon said they chose death or disabling stroke because they knew “they would have to very convincing” to the surgical community. “We wanted to choose what we believed was the most objective endpoint in what was basically an open-label trial where patients know what [treatment] they’re going to get,” he said.

In terms of secondary endpoints, new-onset atrial fibrillation was significantly higher in the surgical arm while the incidence of new permanent pacemaker implantation was 17.4% with TAVR arm and 6.1% with surgery, a statistically significant difference. Aortic-valve hemodynamics improved in both groups, but mean aortic-valve gradients were lower at 12 months in the TAVR arm. Moderate or severe aortic regurgitation was present in 3.5% of TAVR patients at 30 days, but in just 0.5% of surgery patients. At 1 year, rates of moderate-to-severe aortic regurgitation were also higher with the Evolut device than with surgery.

“If you had a TAVR, you’re going to be out of the hospital in less than half the time as surgery patients and more likely to go directly home,” said Reardon. “The hemodynamics are what we’ve come to see in all the randomized trials with the supra-annular valve, that is single-digit mean gradients and [effective orifice areas] that are 2 [cm²] or above.”

In terms of limitations, the researchers state that complete 24-month follow-up has not yet been achieved for the entire cohort and just 22.3% of patients were treated with the latest-generation Evolut PRO.

Reardon said that pacemaker rates are “too high,” but there was heterogeneity across clinical centers, with some hospitals having much lower implantation rates than the trial average. For example, at his center, the pacemaker implantation rate was 5.6%. 

Commenting on the results of the trials, Chandan Devireddy, MD (Emory University School of Medicine, Atlanta, GA), said the PARTNER 3 data “pop” a little more than the Evolut data, but there are nuances in between the two trials. For example, the pacemaker rate with Evolut is “pretty high” and will be an issue for some physicians. However, the aortic valve area at 1 year is 2.3 cm² with the Evolut device, mainly attributable to the device’s supra-annular geometry, and 1.7 cm² with Sapien 3. Mean aortic-valve gradient is also lower with Evolut.

“The battle lines are going to be drawn along the endpoints physicians think are important,” Devireddy told TCTMD. “If you look just at the bread and butter, which is how did these procedures go, there are some notable differences.”

For Devireddy, he was particularly impressed with the very low rate of paravalvular leak at 1 year with Sapien 3 compared with Evolut. “We do know that moderate-to-severe paravalvular leak does carry a morbidity and mortality risk,” he said. On the whole, though, he believes supporters of either valve “are going to stay in their lane for now” and that only a head-to-head study will determine which valve outperforms the other.

Durability and Long-term Results

The PARTNER 3 investigators concede that their results do not address the issue of long-term structural valve deterioration and both trials plan to follow patients for at least a decade. Additionally, both trials have serial CT angiography substudies, looking to detect abnormalities in valve-leaflet function. Results from both of these substudies are anticipated for the TCT 2019 meeting.

To TCTMD, Whitlock said there is a need for long-term data given that the studies’ follow-up was relatively short. One of the major issues, he said, is that TAVR is already being offered at many centers to low-risk patients, and Whitlock worries devices may start going into younger and younger patients in whom it wasn’t studied.

“At our center, we’re fairly conservative,” he said. “When I look at these results, our take will be: ‘Fantastic, lower risk for patients at 1 year, but we really don’t know what the long-term results—the 5-year-plus outcomes—are going to be.’ We would hate throw a ton of these valves into 60-year-olds and then suddenly at 5 years realize these valves aren’t lasting and that patients are in need of a second intervention.”

In clinical practice, Whitlock said his group will adhere closely to the patients studied in both trials, which would be a low-risk patient roughly 75 years and older. He stressed it remains critical for the PARTNER 3 and Evolut Low-Risk Trial investigators to continue to follow these patients for the next 5 to 10 years in order to track any durability issues that could potentially arise with the transcatheter heart valves.

To TCTMD, Leon noted that roughly 10% of patients in PARTNER 3 were 65 years and younger, and that he would place a transcatheter heart valve in these younger patients. While durability remains an issue, he said he is confident in the procedure, noting there are considerable accumulated data—out to at least 5 years—showing these valves hold up. Moreover, most surgical valves haven’t been subjected to the same level of scrutiny facing transcatheter heart valves. “Yes, we’re going to follow people for at least 10 years, and it’s certainly a limitation, but we need to understand that limitation with perspective,” said Leon.

Similarly, Reardon said the number of surgical valves with known durability is low. “I can name a number of [surgical] valves introduced after both of these [transcatheter] valves, and they’re used on a daily basis by surgeons,” he said. “They get used on a daily basis by surgeons who say they’re going to work because they’re surgical valves. But if you’re a surgeon who lives long enough you’ll see valves that work that are going to fail.”

Trial Comparisons Are Difficult

The two trials vary so much that it makes direct comparisons difficult, Puri said. Both studies set out to show the same thing—lowering the risk threshold for TAVR in the setting of severe aortic stenosis—but went about it in different ways. They used different endpoints, statistical designs, and transcatheter valves.

And while the Evolut valves weren’t superior to surgery, Puri pointed to excellent results in the TAVR arm. For example, the rate of death or disabling stroke was just 0.8% at 30 days compared with 2.6% with surgery, a “clear winner for TAVR,” said Puri. Death from any cause at 30 days was also lower with TAVR—0.5% versus 1.3%—when compared with surgery. Like the others, Puri pointed to the higher rate of pacemaker implantation with Evolut as one of the downsides.  

To TCTMD, Sanjay Kaul, MD (Cedars Sinai Medical Center, Los Angeles, CA), said that cross-trial comparisons are invidious, but that nonetheless “we love to do it.” In his opinion, the Evolut Low-Risk TAVR trial is a more rigorous study than PARTNER 3 and its primary endpoint is more clinically meaningful. Additionally, the follow-up is longer, it included more patients, and the noninferiority margin was more stringent, he noted.

We’re going to tell our grandchildren and great-grandchildren that we were there when this incredible advance in the care of patients with aortic stenosis was presented. Eugene Braunwald

Moreover, rehospitalization is the most prevalent “and arguably least important” aspect of the primary endpoint in PARTNER 3, and it biases result toward TAVR given that hospitalizations are more likely in surgery patients. 

“In my opinion, PARTNER 3 is a trial designed to deliver a win for TAVR, not a trial to truly advance patient care,” Kaul wrote in an email. “Nearly 80% of all AVR interventions are done in the low-risk category. So, the rush to ‘capture the market’ seems to be a prime driver. I am disappointed that the FDA allowed such a trial design. What if the favorable data for TAVR at short-term (even in terms of hard endpoints of death or disabling stroke) do not hold up at long-term? How will the FDA respond in such a scenario if they already approved the indication based on 1-year data? Revoke the approved indication for low-risk patients? It’s very difficult to put the genie back in the bottle.”

In terms of whether TAVR should be the default strategy across the risk spectrum, Kaul said he would want to see longer-term follow-up data before making any recommendations on this low-risk population. 

While nearly all the experts are looking for longer-term follow-up, the majority of physicians see these two trials as good news for TAVR in the low-risk setting. To TCTMD, Puri said most physicians have all treated patients on the lower end of the risk spectrum, mainly because they simply don’t want to have surgery. Now, he said, we can say to these patients that “in good hands, we can achieve results that are as good as very good surgical results.”

Devireddy make a similar comment, stating that the paradigm for the treatment of severe, calcific aortic stenosis changed fundamentally today. “Patients do better with TAVR, in my opinion,” he said.

Commenting on the studies during the late-breaking trial session, Eugene Braunwald, MD (Brigham and Women’s Hospital, Boston, MA), noted that the surgical results in both trials were excellent. “In doing a trial like this, you can downgrade the surgery and of course TAVR would look terrific,” he said. “But the surgery here was as good as anything I’ve ever seen.”

The presentation of both trials is an historic moment, said Braunwald, one that cardiologists are unlikely to forget. “We’re going to tell our grandchildren and great-grandchildren that we were there when this incredible advance in the care of patients with aortic stenosis was presented,” he said.    

Note: Leon is a faculty member of the Cardiovascular Research Foundation, the publisher of TCTMD.