A ‘win’ for TAVR signals 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 were 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 should recognize it as such,” Eugene Braunwald, MD, professor of medicine at Harvard Medical School, founding chairman of the TIMI Study Group at Brigham and Women’s Hospital and a Cardiology Today Editorial Board Member, said during a panel discussion after the presentations at ACC 2019. “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 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.
“If a low-risk patient matches the population studied in these trials and has severe aortic stenosis, he or she is probably a candidate for a biologic valve and TAVR should be part of the discussion,” Michael J. Reardon, MD, Allison Family Distinguished Chair of Cardiovascular Research and professor of cardiovascular surgery at Houston Methodist Hospital and co-principal investigator for the Evolut Low Risk trial, said in an interview. “However, this does not mean that every patient who is a candidate for TAVR should undergo the procedure. We still need to discuss these low-risk patients with surgeons to be sure that not everybody undergoes TAVR, because some patients should still go to surgery.”
After a number of trials demonstrating safety and efficacy of TAVR in patients with extreme, high and intermediate surgical risk, PARTNER 3 and Evolut Low Risk, which were designed to evaluate low-risk patients, were viewed as the next pieces of the puzzle. The general expectation was that TAVR would be noninferior to surgery in this patient population, but the results took many by surprise, several experts told Cardiology Today.
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 (8.5% vs. 15.1%; HR = 0.54; 95% CI, 0.37-0.79). 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 (5.3% vs. 6.7%; posterior probability of noninferiority > 0.999).
“When we unblinded the PARTNER 3 results, it was surprising and exciting,” investigator Samir Kapadia, MD, professor of medicine, section head of interventional cardiology and director of cardiac catheterization laboratories at Cleveland Clinic, told Cardiology Today. “We were surprised and even skeptical that we may be missing something because the death, stroke, disabling stroke, hospitalization, pacemaker implantation, paravalvular leak outcomes, acute kidney failure, atrial fibrillation and bleeding, among other outcomes, were better with TAVR. How to put it all together was a challenge.”
The TAVR data took center stage at ACC 2019, but the outcomes with surgery hammered home how far treatment of aortic stenosis has come and provided a rigorous standard against which TAVR could be tested, according to Braunwald.
“First, what impressed me enormously was how good the surgery was because in doing a trial like this, you could downgrade the surgery and, of course, TAVR will look terrific, but the surgery [in these trials] is as good as I’ve ever seen. Second, the fact that the two separate groups using two different valves in two separate trials have come to very similar conclusions doesn’t double the acceptability, but it quadruples it,” Braunwald said during the panel discussion.
Benefits in healthier patients
The data on stroke and mortality observed in PARTNER 3 and Evolut Low Risk are striking, but the trials’ other findings could perhaps have an even greater impact on the conversation regarding AVR between the cardiologist and the patient.
For instance, procedural time, length of hospital stay and discharge to home or self-care favored TAVR over surgery in both trials. Further, 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, as compared with surgery.
For low-risk patients, the possibility of a shorter recovery time is likely to be appealing, according to Robert O. Bonow, MD, Goldberg Distinguished Professor of Cardiology at Northwestern University Feinberg School of Medicine and past president of the American Heart Association.
“All patients appropriately would like to have their valve replaced through a less-invasive approach, where general anesthesia and cardiopulmonary bypass and the 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 is significantly better, at least early on, 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,” Bonow said.
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.”
The question of valve durability
Despite the answers provided by PARTNER 3 and Evolut Low Risk, significant gaps in knowledge remain — one of which is a lack of information on valve durability.
Although surgery has long 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.
Researchers said they hope to glean more information on TAVR durability after the 10-year follow-up for both studies are completed. Nevertheless, Martin Leon, MD, director of the Center for Interventional Vascular Therapy at New York-Presbyterian/Columbia University Irving Medical Center, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and co-primary investigator for PARTNER 3, 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.
Appropriate patient selection is key
In light of the new low-risk data, cardiologists may deem more patients to be appropriate candidates for TAVR, but surgery is still a great option. Identifying which patients will fare better with which intervention, however, can be complicated, experts told Cardiology Today.
“When I see patients in my clinic, my 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 that situation, age plays an important role in identifying which patients may be more appropriate for surgery, he noted.
For instance, 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. Consequently, in the case of younger patients, surgical AVR with a mechanical valve would likely be a better option, according to Reardon.
However, there are other questions to consider.
“In this low-risk group, surgical mortality risk is almost not the issue — the real issue is what are the long-term concerns related to the device, whether it’s a surgical mechanical valve or a bioprosthetic valve implanted surgically or via a catheter. Patients have to understand these issues,” Bonow said.
Young patients who receive mechanical valves, for example, are at risk for bleeding, valve thrombosis and strokes and will require careful anticoagulation for the rest of their lives. The tradeoff, however, is that cardiologists are concerned about bioprosthetic valve durability in a younger population and the need for possible reintervention in the future. With a TAVR valve, the second intervention would be a difficult surgical procedure or a valve-in-valve procedure, according to Bonow.
“We have good data on valve-in-valve, but we have less data on 55-year-olds with a TAVR valve who may need a valve-in-valve at age 65 and then another at age 75 or 80, so I’m leery of moving the bar down in younger patients too quickly,” he said. “However, patients are going to drive this and, if I’m not mistaken, once my 55- or 60-year-old patients realize that TAVR is approved for them, they would prefer to have that done. It’s going to be an important discussion to have with patients about what we know and what we don’t know.”
It is also important to account for the patient’s anatomy when determining if TAVR is appropriate.
“We are moving away from risk assessment to anatomical assessment,” Kapadia said. “We determine the risk for TAVR through anatomy: If the annulus is not going to be calcified, the coronary arteries are not too close and there will not be paravalvular leak, these are the best candidates and we can give them TAVR.”
Patients who are not optimal candidates for TAVR include those with bicuspid aortic valves; those who need other surgeries, such as for CAD, mitral valve disease, tricuspid valve disease and aortic aneurysms; and those with a very severely calcified annulus that could affect the sealing of the valve, he added.
Importantly, many of these patients were excluded from the trials, Reardon noted.
Looking ahead, study of those patients excluded from the low-risk trials will be necessary. Beyond that, experts who spoke with Cardiology Today identified several other areas of future research.
One is the cost of TAVR compared with surgery, with some concerns that the up-front cost of TAVR is greater than surgery. However, the general sentiment is TAVR will save money in the long run.
“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,” Reardon said.
The question of asymptomatic patients is also worth exploring, he 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,” Reardon said. “With a less-invasive therapy like TAVR, we may need to rethink the risk-benefit ratio of treatment for asymptomatic patients.”
Outside of the clinical implications, cardiologists will have to wait and see how the data from PARTNER 3 and Evolut Low Risk affect everyday practice.
“We’re all enthusiastic about these results, with the caveat that the next steps are going to be interesting. What are the regulatory issues going to be? What will the guidelines say and when will they be published? What about reimbursement?” Bonow said.
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 would hopefully follow suit, he added, but since patients younger than 65 years may also receive treatment, private insurers may resist reimbursement.
The overall expansion of TAVR to a broader population will also bring other issues to light, according to M. Chadi Alraies, MD, interventional cardiology fellow at Wayne State University and Detroit Hospital and a Cardiology Today Next Gen Innovator.
“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 lack of TAVR centers, however, may change. The CMS’ update to the National Coverage Determination for TAVR proposed in March eases some of the volume requirements for new TAVR centers and requires sign-off from only one surgeon as opposed to two before a patient is evaluated for TAVR.
This increase in volume, though, will also significantly affect 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 the 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 told Cardiology Today.
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. 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. – by Melissa Foster, with additional reporting by Katie Kalvaitis and Erik Swain
- Leon M, et al. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.
- 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.
- Reardon MJ, et al. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.
- For more information:
- M. Chadi Alraies, MD, can be reached at firstname.lastname@example.org; Twitter: @chadialraies.
- Robert O. Bonow, MD, can be reached at email@example.com; Twitter: @bonowr.
- James L. Januzzi, MD, can be reached at firstname.lastname@example.org.
- Samir Kapadia, MD, can be reached at email@example.com.
- Michael J. Reardon, MD, can be reached at firstname.lastname@example.org.
Disclosures: PARTNER 3 was funded by Edwards Lifesciences. The Evolut Low Risk trial was funded by Medtronic. 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, Gore, Medtronic and Meril Life Sciences; and is the co-principal investigator of the PARTNER 3 trial. Kapadia reports he was a member of the steering committee for the PARTNER 3 trial. Reardon reports he has received consultant fees paid to his institution from Medtronic. Alraies, Bonow and Januzzi report no relevant financial disclosures.