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Low-risk TAVR trials represent ‘historic moment’ in care of aortic stenosis
NEW ORLEANS — Transcatheter aortic valve replacement — already a mainstay of treatment for intermediate- and high-risk patients with severe aortic stenosis — may soon become the preferred therapy for low-risk patients as well.
Two studies presented at the American College of Cardiology Scientific Session — the PARTNER 3 and Evolut Low Risk trials — showed that the procedure, with two different valves, is not only comparable to, and in some aspects better than, surgery in terms of safety and efficacy.
“What we’re seeing here is a class effect of TAVR, and we have to recognize it as such,” Michael J. Reardon, MD, professor and Allison Family Distinguished Chair of Cardiovascular Research at Houston Methodist Hospital, said after his presentation of the Evolut Low Risk study. “We’ve been seeing it creep up on as we’ve moved to treating lower-and-lower-risk patients. This procedure is evolving and improving at such a rapid rate that it’s hard to imagine what we’re going to see 5 years from now.”
PARTNER 3
In the international, multicenter PARTNER 3 trial, which was simultaneously published in The New England Journal of Medicine, 1,000 patients (mean age, 73 years) with severe aortic stenosis and a mean Society of Thoracic Surgeons risk score of 1.9% were randomly assigned to TAVR with a balloon-expandable valve (Sapien 3 system, Edwards Lifesciences) or surgical aortic valve replacement.
“There has been strong evidence supporting TAVR in defined patient cohorts, but PARTNER 3 is designed to really answer the important question of the relative value and importance of the procedure in a low-surgical-risk cohort,” Martin B. 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, said during his presentation of the trial.
At 1 year, the rate of the primary endpoint of a composite of death, stroke or rehospitalization in the TAVR group was nearly half that of the surgery group (8.5% vs. 15.1%; P < .001 for noninferiority; HR = 0.54; 95% CI, 0.37-0.79; P = .02 for superiority).
One-year mortality was also lower with TAVR vs. surgery (1% vs. 2.5%; HR = 0.41; 95% CI, 0.14-1.17), as were the rates of all stroke (1.2% vs. 3.1%; HR = 0.38; 95% CI, 0.15-1), death or disabling stroke (1% vs. 2.9%; HR = 0.34; 95% CI, 0.12-0.97) and rehospitalization (7.3% vs. 11%; HR = 0.65; 95% CI, 0.42-1).
The treatment effect was clearly preserved in the intention-to-treat population and there was no heterogeneity across subgroups, Leon noted.
In terms of secondary endpoints, TAVR compared with surgery was associated with a lower rate of stroke (P = .02) and lower rates of death or stroke (P = .01) and new-onset atrial fibrillation (P < .001) at 30 days. The index hospitalization time was also shorter with TAVR (P < .001) and the risk for a poor treatment outcome, including death or a low Kansas City Cardiomyopathy Questionnaire score (P < .001), at 30 days was lower with TAVR.
Additionally, patients who underwent TAVR had a more rapid 30-day functional recovery based on 6-minute walk tests and other self-reported quality-of-life measures.
“Functional assessments of early recovery favor TAVR at 30 days, but they essentially equalize at 12 months,” Leon said.
Major vascular complications, new permanent pacemaker insertions or moderate or severe paravalvular regurgitation did not differ significantly between treatment groups. Mild paravalvular regurgitation, however, was with surgery vs. TAVR.
“Based upon these findings, TAVR, through 1 year, should be considered the preferred therapy in low-surgical-risk aortic stenosis patients,” Leon said. “The choice of TAVR vs. surgery in aortic stenosis patients should be a shared-decision making process, respecting patient preferences, understanding knowledge gaps, especially in younger patients, and considering clinical and anatomic factors.”
More follow-up is still necessary, though, he added, and patients in this trial will be followed for 10 years.
Evolut Low Risk Trial
Similarly, results from the Evolut Low Risk Trial, which was also published simultaneously in NEJM, showed promise for the use of TAVR with a self-expanding supra-annular bioprosthesis (CoreValve, Evolut R or Evolut PRO; Medtronic) in patients with severe aortic stenosis who are at low surgical risk.
In the international, multicenter, prospective, noninferiority trial, Reardon and colleagues randomly assigned 1,468 low-risk patients (mean age, 74 years) with severe aortic stenosis to TAVR or surgery and used a Bayesian adaptive design that prespecified an “early-win” interim analysis when 850 patients reached 1-year follow-up, and prespecified criteria for success was posterior probability > 0.972.
The primary endpoint was a composite of all-cause mortality or disabling stroke at 2 years.
“Knowing that we were moving into a low-risk population and it might be hard to convince some people, we wanted to use endpoints that were objective and impactful since this was essentially an open-label trial,” Reardon said.
The 24-month estimated incidence of the primary endpoint was lower for the TAVR group vs. the surgery group and met the criteria for noninferiority (5.3% vs. 6.7%; posterior probability of noninferiority > 0.999).
At 30 days, patients who underwent TAVR compared with surgery had lower incidences of disabling stroke (0.5% vs. 1.7%), life-threatening or disabling bleeding (2.4% vs. 7.5%), acute kidney injury (0.9% vs. 2.8%) and AF (7.7% vs. 35.4%). Average hospital stay was also shorter with TAVR than surgery (6.2 vs. 2.6 days).
However, patients who underwent TAVR had higher incidences of moderate or severe aortic regurgitation (3.5% vs. 0.5%) and pacemaker implantation (17.4% vs. 6.1%).
At 12 months, aortic valve gradients were lower in the TAVR group (8.6 mm Hg vs. 11.2 mm Hg) and effective orifice areas were larger (2.3 cm2 vs. 2 cm2). Rates of major stroke and all-cause mortality were also lower with TAVR at 12 months, but the differences were not statistically significant.
Also at 1 year, Kaplan-Meier curves were lower for TAVR vs. surgery for all-cause mortality or disabling stroke (2.7% vs. 4.6%) and HF hospitalizations (3.1% vs. 6.4%).
Additionally, procedural time and hospital stay after the procedure were significantly shorter with TAVR than with surgery.
Notably, Reardon said, prosthesis-patient mismatch at 1 month and 1 year were significantly better with TAVR than surgery.
NYHA functional class and KCCQ scores improved more with TAVR vs. surgery at 30 days, but they were comparable at 1 year.
“At 1 year, both groups had excellent survival. TAVR showed fewer disabling strokes and HF hospitalizations with superior hemodynamics manifest by lower gradients and larger effective orifice areas, and as we move into low-risk patients, I think effective orifice area will be critical,” Reardon said.
During a discussion following the presentations, Eugene Braunwald, MD, professor of medicine at Harvard Medical School and a Cardiology Today Editorial Board member, called the presentation of the PARTNER 3 and Evolut Low Risk trials a “historic moment.”
“We should all recognize this and are going to tell our grandchildren and great grandchildren about the time these incredible advances in care of patients with aortic stenosis were presented,” he said. – by Melissa Foster, with additional reporting by Katie Kalvaitis and Erik Swain
References:
Leon M, et al.
Reardon MJ, et al. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials. Both 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.
Disclosures: PARTNER 3 was funded by Edwards Lifesciences. Leon reports he has received research support from Abbott, Boston Scientific, Edwards Lifesciences and Medtronic; he has received consulting fees from Abbott, Boston Scientific, Gore, Medtronic, Meril Life Sciences; and he is the co-principal investigator of the PARTNER 3 trial. The Evolut Low Risk Trial was funded by Medtronic. Reardon reports he has received consultant fees paid to his institution from Medtronic.
Perspective
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In the PARTNER 3 trial, TAVR was at least equivalent or superior to surgical aortic valve replacement after 1 year, not only in terms of the primary endpoint but also in endpoints such as atrial fibrillation and quality of life, in a low-risk, asymptomatic population. The results suggest that, going forward, TAVR will potentially become the treatment of choice for patients with aortic stenosis and we will likely see an increase in its use. We already know that about 50% of patients in the United States are receiving TAVR vs. surgical AVR, and this will only continue to grow in a dramatic way.
However, these findings do not necessarily mean that TAVR is for every patient. The study population was older, so the findings still do not speak to the younger population or the durability of the procedure over decades. Yet, this certainly impacts a younger population that might consider undergoing TAVR and perhaps even consider a second or third TAVR down the road, if necessary, later in life. This shows that a measured heart team approach, including input from the surgeon and cardiologist, is required to decide what is best for individual patients.
The Evolut Low Risk trial also showed that TAVR was noninferior to surgery. The device did show superiority in this study as well, but the studies should not be compared, because they are different. In both cases, equivalency is something that is very generalizable to surgery and therefore, this less invasive percutaneous approach will be greatly favored in this patient population.
In looking at the two valves, there are advantages to both for different case scenarios. However, because of the pacemaker concern, the CoreValve may be chosen less in younger patients who want to avoid pacemaker implantation.
In terms of future study, newer iterations of both valves as well as newer valves will be coming on to the market, which will hopefully put a downward pressure on price. Even length of hospital stay, same-day discharge and reductions in other complications, such as pacemaker implantation and paravalvular leak, are areas ripe for further research. We could look at this in the same way we looked at the stent evolution that’s occurred over the last 20 years. We anticipate the development of these new valves will positively impact even better outcomes, recovery times, and cost with future TAVR trials.
Perspective
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The TAVR vs. surgical AVR 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. From a common-sense perspective, it looks like TAVR is better. We knew about the value of TAVR in higher-risk and intermediate-risk patients, and now to add a proven evidence base for TAVR in low-risk patients is game-changing. It is randomized clinical trials such at these that allow us to change practice and to allow our colleagues who refer patients to us to say that TAVR is the way to go. At this point in time, across the surgical risk spectrum, TAVR wins.
This does not mean that surgical AVR is dead. It still has an important role, and we do not yet have many years of important durability data for the TAVR valves in low-risk patients, though I suspect it will end up looking pretty good. There remain questions about the best approach in patients with bicuspid valves and those with aortic regurgitation as the predominant etiology. Nonetheless, this is a huge win for structural heart disease specialists and interventional cardiology, and most of all for patients.
Perspective
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A subtle difference between the two trials is the follow-up period. PARTNER 3 was 1 year and the Evolut Low Risk Trial was 2 years. The outcomes were comparable in terms of all-cause mortality being less in balloon-expandable TAVR than surgery and being noninferior in self-expanding TAVR compared with surgery. Stroke, revascularization and MI were all lower with TAVR in both studies.
This is a good opportunity to discuss low-risk TAVR options. Someone who is younger than 60 years old and has no comorbidities is a perfect surgical candidate. Are we ready to offer them TAVR? What are the pitfalls of TAVR over surgery for these patients? Younger patients with aortic stenosis are often highly functional and have jobs. Surgery takes at least 1 week of hospitalization and 3 months of recovery, compared with TAVR, where a patient can be discharged the next day and be functioning in 1 week.
Another question is whether we wait for the guidelines to recommend TAVR in low-risk patients before we offer it to them. We need to make sure we have enough evidence and have covered all the bases legally and in other aspects.
The trials also raise questions about the durability of the valves. We are putting these valves in a younger population whose life expectancy can be more than 20 years. Are these valves durable enough to last that long? German registries have shown that these valves are durable for at least 10 years, but there is a 20% chance of reimplantation or new TAVR. Most patients who have gotten TAVR valves are older, so many of them have died before there can be longer follow-up than that. However, the intermediate-risk TAVR studies represent a good chance to follow a somewhat younger cohort; so far, these patients have done well and the valves have lasted long. Patients should be advised that there is a small chance that within 10 years we will have to re-implant another valve inside the valve they just received.
The expansion of TAVR to a broader population raises questions about whether there are enough operators to perform it. 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. We also have to understand that TAVR is not a one-person job. It involves a heart valve team with a surgical backup, a TAVR coordinator that funnels the cases and a good imaging center than can evaluate the valves. There may be a shortage of heart valve centers available, but in terms of the people who can implant the valve, there are enough there.
Perspective
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Without a doubt, March 17 was one of the most historic days in decades for CV medicine. On this day, the long-awaited data on TAVR vs. surgical AVR for the low-risk patient population were presented. These studies are a monumental step toward proving that with less-invasive management of aortic stenosis, patients will do as well as with, and in fact even better than, surgical replacement of the aortic valve. This is a fantastic result for our patients with aortic stenosis.
The span of treatment with TAVR will now extend from the highest-risk to the lowest-risk patients who require AVR. This meeting will be remembered for that.
Perspective
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When we unblinded the PARTNER 3 results, it was surprising and exciting. The most important finding was that surgery was outstanding. The surgical outcomes were incredible and impeccable. Mortality, stroke and hemodynamics were very good with surgery. But despite that, TAVR was better than surgery. We were surprised and even skeptical that we may be missing something, because the death, stroke, disabling stroke, hospitalization, pacemaker implantation and paravalvular leak outcomes, acute kidney failure, AF, bleeding, among others, were better with TAVR. How to put it all together was a challenge.
The paradigm shift is that irrespective of your surgical risk, TAVR is better, if your anatomy supports it. We are moving from risk assessment to anatomical assessment. If the patient is low risk for TAVR, do TAVR, and if the patient is high risk for TAVR, consider the risks and benefits of TAVR vs. surgery. And 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 patients and we can give them TAVR.
After the unveiling of these trials, the strategy going forward should be TAVR first, and surgery in patients who are not optimal candidates for TAVR. Who are not the optimal candidates is an important question. Such patients may include those who are younger, perhaps less than 60 years; those with bicuspid aortic valves; patients who need other surgeries such as for CAD, mitral valve disease, tricuspid valve disease and aortic aneurysms; and patients with a very severely calcified annulus that could impact the sealing of the valve. These are anatomical challenges that we need to entertain. We have to properly select patients so the procedure can be done without mortality or stroke.
At Cleveland Clinic, 2018 was the first year where more TAVRs were performed than isolated surgical AVRs. This gap will likely get wider over time in the U.S.
The two TAVR systems appear to be similar, except for a higher pacemaker and paravalvular leak rate but somewhat better hemodynamics in the self-expanding system. Durability will determine which valve is better in the long run. In the meantime, valve selection will depend on anatomy of the root and operator expertise.
With these data, it is more important that cardiologists and cardiac surgeons work together in a partnership. We should certainly have heart team evaluation including surgeon and cardiologist before a treatment is decided upon. With these data we are trusting in the technology and with close collaboration with surgery, we have developed special respect for each others’ expertise, which is a huge difference from the past.