A New Era for TAVR

Game-changing data will lead to paradigm shift in treatment of aortic stenosis.

Presentation of the PARTNER 3 and Evolut Low Risk trials at the American College of Cardiology Scientific Session in March was met with a standing ovation and applause, high praise from legends in the field and the overwhelming sense that transcatheter aortic valve replacement may soon replace surgical AVR as the treatment of choice for patients with symptomatic severe aortic stenosis.

“This is a historic moment, and all of us here [at ACC 2019] should recognize it as such,” Eugene Braunwald, MD, professor of medicine at Harvard Medical School and founding chairman of the TIMI Study Group at Brigham and Women’s Hospital, said during a panel discussion after presentations of the low-risk data. “1956 was the beginning of left heart catheterization and the measurement of gradients across the valve. The first truly successful aortic valve replacement was in 1962. In 2005, the beginning of TAVR. And, in 2019, these two magnificent contributions.”

Experts who spoke with Cardiology Today’s Intervention agreed that these trials in low-risk patients will be enormously influential and will change how physicians approach treatment of aortic stenosis, with the caveat that there will always be a place for surgery.

“We have seen this paradigm shift from an open surgical procedure to a less invasive approach in the management of other diseases. However, although TAVR is going to be the treatment of choice for the majority of patients, it’s incumbent on everyone to know that the procedure isn’t necessarily for all patients, and everybody should be educated about who is still best treated with surgery,” Michael J. Mack, MD, FACC, co-investigator of the PARTNER 3 trial, medical director of cardiovascular surgery at Baylor Scott and White Health and Cardiology Today’s Intervention Editorial Board Member, said in an interview.

‘TAVR Wins’

Given the performance of TAVR in high- and intermediate-risk patients with symptomatic severe aortic stenosis, the general expectation was that TAVR would be noninferior to surgery in low-risk patients. The fact that it proved superior to surgery took many by surprise.

In PARTNER 3, TAVR with a balloon-expandable valve (Sapien 3, Edwards Lifesciences) was superior to surgery for the primary composite endpoint of death, stroke or rehospitalization at 1 year. Similarly, in Evolut Low Risk, TAVR with a self-expanding supra-annular bioprosthesis (CoreValve Evolut R or Evolut Pro, Medtronic) was noninferior to surgery, with the estimated incidence of the primary endpoint of death or disabling stroke lower with TAVR at 2 years (Table).

During the discussion, Martin Leon, MD, co-investigator of PARTNER 3, director of the Center for Interventional Vascular Therapy at New York-Presbyterian/Columbia University Irving Medical Center and professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, addressed the inclusion of rehospitalization in the PARTNER 3 primary endpoint.

“When you look at the narratives on these rehospitalization events, it is fascinating,” he said. Rehospitalization events included sepsis, endocarditis, ischemic limbs, new pericardial effusions that have recurrent pleural effusions that end in thoracotomy and more. “These are relatively significant events to these low-risk patients, so we think that it is important to include this as part of a component endpoint in this low-risk substrate.”

Michael J. Reardon, MD, co-investigator for the Evolut Low Risk Trial and the Allison Family Distinguished Chair of Cardiovascular Research and professor of cardiovascular surgery at Houston Methodist Hospital, acknowledged the importance of hospitalizations, but explained that he and his colleagues focused on delivering an airtight data set that would leave little room for interpretation.

“We chose an endpoint of all-cause mortality and disabling stroke because we were worried that, going into a low-risk population, we had to have very objective endpoints at 2 years to convince the community,” Reardon told Cardiology Today’s Intervention.

Despite these differences, both trials arrived at the same conclusion.

“[These trials] were very important and very concordant with each other. Both valves essentially beat surgery in low-risk patients. One can discuss the statistical subtleties, but both trials showed superiority in several key outcomes,” Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School and Cardiology Today’s Intervention Chief Medical Editor, said in an interview. “At this point in time, across the surgical risk spectrum, TAVR wins.”

Benefits of a Minimally Invasive Procedure

The effect of TAVR on hard outcomes such as mortality and stroke in PARTNER 3 and Evolut Low Risk speaks for itself, but the data on softer endpoints shed light on other important factors that may make TAVR the most attractive treatment option in low-risk patients.

In both trials, procedural time, length of hospital stay and discharge to home or self-care favored TAVR over surgery. TAVR and surgery led to similar improvements in quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire, NYHA functional class and 6-minute walk distance at 1 year. However, at 30 days, these outcomes were better with TAVR, suggesting earlier recovery with the procedure compared with surgery.

“All patients appropriately would like to have their valve replaced through a less invasive approach, where general anesthesia and cardiopulmonary bypass and its subsequent risks are not necessary. There is also less risk for a lengthy hospitalization or other complications of surgery, such as bleeding and infections. Furthermore, the trials show that quality of life, at least early on, is significantly better with TAVR. Given a decision to undergo valve replacement, it’s clear what the patient would vote for, and the good news is that we now have some data to support that,” Robert O. Bonow, MD, Goldberg Distinguished Professor of Cardiology at the Northwestern University Feinberg School of Medicine and past president of the American Heart Association, told Cardiology Today’s Intervention.

Interestingly, in the Evolut Low Risk Trial, TAVR was also associated with superior hemodynamics with lower gradients, larger effective orifice areas and less patient-prosthetic mismatch.

“We do need to look at effective orifice area,” Reardon said. “If a patient is younger and going to live an active lifestyle, he or she needs an effective orifice area of about 2 cm/m2 or above to exercise without developing high gradients. One of the problems with all of our studies is that we only look at echocardiograms at rest and we ignore what happens if these people exercise. The patients studied in the higher-risk studies were about 85 years old and probably weren’t going to exercise. These low-risk, younger patients are.”

The advantages of TAVR are also likely to extend beyond patients to health care systems, particularly in terms of cost, according to Reardon.

“In the high-risk trials, TAVR was deemed cost-efficient, but ended up costing more than surgery. However, when you spend less time in the procedure room, don’t go to the ICU, are discharged in 2 days and are back at work within a week, I predict that, when we do the cost analysis of the low-risk trial, TAVR will not be cost-efficient, but rather cost-superior to surgery,” he said.

Questions of Valve Durability, Thrombosis

Despite the answers provided by the PARTNER 3 and Evolut Low Risk trials, significant gaps in knowledge remain.

Although surgery has been a mainstay of aortic stenosis treatment, long-term data are available on only a few surgical valves, according to Reardon. In fact, many surgeons now use rapid deployment, or sutureless, valves, such as the Intuity Elite system (Edwards Lifesciences) and Perceval system (LivaNova PLC) — devices that were not introduced much earlier than the two TAVR systems, meaning that long-term data on their durability are also sparse. However, this information is often not shared with patients, he said.

“Very few surgeons will tell their patients that the valve is new and that they’re unsure about its durability because they treat all surgical valves the same way,” Reardon told Cardiology Today’s Intervention.

Researchers said they hope to glean more information on TAVR durability after the 10-year follow-up for both studies are completed. Nevertheless, Leon said TAVR is no longer new and some data do exist on TAVR valve durability.

“We’ve had 17 years of experience. We have 5-year data, which is absolutely definitive, of no early structural valve deterioration, and two studies this year alone that look at 5- to 8-year data. So, at least so far, there isn’t a signal of early structural valve deterioration and the majority of surgical valves being used today and touted as being durable is based upon 2- to 4-year data,” Leon said during a presentation at ACC 2019.

The other major issue is valve thrombosis, according to Mack. He noted the FDA mandated that subgroups of patients from each trial undergo surveillance with CT scans at 30 days and 1 year to evaluate the incidence of valve thrombosis, which is thought to be higher with TAVR than surgery.

“The first results will be available at TCT 2019, so we’ll have some idea then of how big a deal valve thrombosis is,” Mack said. “These data will tell us what the incidence is, whether it affects valve durability and whether patients need anticoagulation or not.”

‘Default Therapy’

Until release of the PARTNER 3 and Evolut Low Risk results, interventional cardiologists and surgeons considered surgical AVR the standard for low-risk patients, sending the majority of patients with symptomatic severe aortic stenosis to the operating room instead of the cath lab. That concept, according to Mack, has been flipped around and TAVR will now be “the default therapy.”

“The challenge is that at least a third of the patients screened were excluded from [PARTNER 3] for reasons such as bicuspid valves, heavy calcium in the left ventricular outflow tract, low lying coronaries and significant concomitant CAD,” he said. “Therefore, TAVR isn’t for all low-risk patients; it’s for low-risk patients that were selected for the trial.”

Outside the scope of those not included in the trials, identifying patients who would do best with surgery can be complicated.

“When I see patients in my clinic, the first decision is whether they are a candidate for a biologic valve or a mechanical valve. If they are a candidate for a biologic valve, then we have to include TAVR in the conversation,” Reardon said.

In this situation, a patient’s age is an important consideration. Bioprosthetic valves are more likely to be used in patients aged 60 to 65 years and older, as the rate of structural valve deterioration is lower in elderly patients. Additionally, less is known about the durability of bioprosthetic valves, so should they fall short compared with mechanical valves, patients with a longer life expectancy may run the risk for reintervention later in life, Reardon noted.

Young patients who receive mechanical valves, however, are also at risk for bleeding, valve thrombosis and strokes and will require careful anticoagulation for the rest of their lives, according to Bonow. All of these knowns and unknowns, he said, must be carefully discussed with the patient.

Further investigation into several areas will be necessary going forward, according to Mack.

“First, there needs to be a trial of TAVR vs. surgical AVR in bicuspid aortic valves because we see a significant number of these patients. Second, we may need a trial of valve-in-valve vs. redo surgical AVR in low- and intermediate-risk patients. We’ve pretty much shifted to performing valve-in-valve procedures if a patient requires a second AVR because nobody wants to put a patient through another surgery. However, I’ve been increasingly concerned that valve-in-valve may not have the durability of a valve in a native leaflet. Plus, it’s the highest predictor of valve thrombosis.”

The question of asymptomatic patients is also worth exploring, Reardon noted.

“Right now, we don’t typically treat your aortic stenosis until you develop symptoms, fail an exercise test or have a very high flow, and the reason for that is nobody wanted to have heart surgery unless they thought they were going to die from their valve. However, aortic stenosis is still hurting the hearts of patients who are asymptomatic, and the longer we allow it to go on, the more the heart is hurt,” he said. “With a less-invasive therapy like TAVR, we may need to rethink the risk-benefit ratio of treatment for asymptomatic patients.”

Practical Considerations

Reardon said he is confident that the FDA will expand the indication of TAVR to include low-risk patients, based on the strength of the data. CMS will hopefully follow suit, he added, but since patients younger than 65 may also receive treatment, private insurers may resist reimbursement.

Interventionalists will also have to keep pace with new iterations in TAVR technology. In April, the FDA approved a mechanically expandable valve (Lotus Edge, Boston Scientific) for use in high-risk patients, making it the third TAVR system available on the U.S. market. This technology and others could eventually be brought to low-risk patients.

The overall expansion of TAVR to a broader population, however, will also bring other issues to light, according to M. Chadi Alraies, MD, interventional cardiology fellow at Wayne State University and Detroit Hospital.

“In the last 5 years, there have been a lot of openings for structural heart fellowships. If anything, we overtrained the number of candidates for the spots that are available,” he said in an interview. “There may be a shortage of heart valve centers available, but in terms of people who can implant the valve, there are enough there.”

Even the number of TAVR centers may change. In March, CMS proposed an update to the National Coverage Decision for TAVR that eases some of the volume requirements and could potentially result in an increase of 100 to 200 TAVR centers, which would be adequate for sufficient access to care, Mack said.

The increase in the number of patients being treated with TAVR will also significantly impact current hospitals and health care systems, according to James L. Januzzi, MD, cardiologist and director of the Dennis and Marilyn Barry Fellowship in Cardiovascular Research at Massachusetts General Hospital and Hutter Family Professor of Medicine at Harvard Medical School.

“The most important ramification of the TAVR results is not that TAVR works, but that hospitals and cath labs are going to have to entirely retool, because it’s not an insignificant effort to do TAVR. Now that essentially everyone with aortic stenosis might be considered eligible, it’s not unreasonable to suggest that cath labs may need to be reconstructed, expanded or changed,” he said.

Importantly, the role of the surgeon should not change, though, according to Karim Al-Azizi, MD, FACC, FSCAI, interventional cardiologist and structural heart disease fellow at The Heart Hospital Baylor Plano in Texas. In fact, the surgeon’s role is more important than ever, he said.

“Having scrubbed in the OR for surgical valve replacements, there is a lot that we do not see and visualize as cardiologists in general when looking at echocardiograms and, when it comes to critical decision-making, especially in high-risk anatomies, some factors may be beyond the cardiologist’s training or thinking,” he told Cardiology Today’s Intervention. “These studies started with a heart surgeon and a cardiologist; that’s how they were performed. If we want to maintain good outcomes, regardless of surgical risk, we should promote and maintain this relationship and it should be part of the culture moving forward rather than eliminating it because TAVR is a less invasive procedure with fewer potential complications, especially in low-risk patients.”

Embracing Change

All of these considerations speak, in many respects, to the fact that TAVR is not only now a mature procedure, but it is rapidly evolving, according to Reardon.

“The truth is that if we had run these low-risk trials 6 years ago, TAVR would have lost to surgery because we had not yet developed the procedural expertise and equipment that allowed us to win. As we moved from extreme risk to high risk to intermediate risk, we had a learning experience as we went along. I think if we run the trial again 5 years from now, TAVR would win even bigger because we see that the procedural risk of TAVR, which is low, is growing lower every year, whereas the procedural risk of surgery as a mature technology is not really changing,” he said.

Finally, a win for TAVR, Mack added, was not a loss for surgery.

“We, as surgeons, didn’t lose this. We had a very level playing field and we found out what was best for patients. That’s a winner, regardless of how it played out,” Mack told Cardiology Today’s Intervention. “We also saw this shift toward a less invasive therapy coming years ago, and there are many surgeons who have become very skilled in TAVR, and I hope that the community can fully embrace it now that we have these data.” – by Melissa Foster

• References:
• Leon M, et al.
• Reardon MJ, et al. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials.
• Mack M, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1814052.
• Popma JJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1816885.

• For more information:
• Karim Al-Azizi, MD, FACC, FSCAI, can be reached at karim.alazizi@gmail.com.
• M. Chadi Alraies, MD, can be reached at calraies@gmail.com; Twitter: @chadialraies.
• Deepak L. Bhatt, MD, MPH, can be reached at dlbhattmd@post.harvard.edu; Twitter: @dlbhattmd.
• Robert O. Bonow, MD, can be reached at robert.bonow@nm.org; Twitter: @bonowr.
• James L. Januzzi, MD, can be reached at jjanuzzi@partners.org.
• Michael J. Mack, MD, can be reached at michael.mack@bswhealth.org.
• Michael J. Reardon, MD, can be reached at mreardon@houstonmethodist.org.

Disclosures: PARTNER 3 was funded by Edwards Lifesciences. The Evolut Low Risk Trial was funded by Medtronic. Bhatt reports he has financial ties with multiple pharmaceutical and device companies. Braunwald reports he consults for Cardurion, Merck, MyoKardia, Novartis and The Medicines Company and received research grants from AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis and The Medicines Company. Leon reports he has received research support from Abbott, Boston Scientific, Edwards Lifesciences and Medtronic; consultant fees from Abbott, Boston Scientific, Medtronic, Meril Life Sciences and W.L. Gore and Associates; and is the co-investigator of the PARTNER 3 trial. Reardon reports he has received consultant fees paid to his institution from Medtronic. Al-Azizi, Alraies, Bonow and Januzzi report no relevant financial disclosures.