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Groundbreaking clinical results for CoreValve may transform treatment of aortic stenosis
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It was a watershed moment in the history of interventional cardiology. At the American College of Cardiology Scientific Sessions in March, researchers reported for the first time that transcatheter aortic valve replacement was superior at 1 year to surgical aortic valve replacement in a patient population.
David H. Adams, MD, presented results from
the US CoreValve High Risk Study in March
at the American College of Cardiology
Scientific Sessions.
Source: Mount Sinai
Patients with symptomatic severe aortic stenosis deemed high risk for surgery who underwent TAVR with the CoreValve self-expanding transcatheter valve (Medtronic) had a better rate of survival at 1 year compared with those who underwent surgical AVR (14.2% vs. 19.1%; absolute risk reduction, 4.9 percentage points; P<.001 for noninferiority; P=.04 for superiority), according to results from the US CoreValve High Risk Study.
“This was the first suggestion that there is a population of patients that could be treated with a [TAVR] device who might actually do better than patients treated with conventional surgery. That’s very provocative,” David H. Adams, MD, who presented the data at the ACC Scientific Sessions, told Cardiology Today. “If you had asked colleagues months before that presentation whether they believed it would be an equivalent trial, or whether they thought the CoreValve device had a superior outcome, I think most would have guessed it would be an equivalent outcome.” That had been the case in the 1A cohort of the earlier PARTNER trial, which compared outcomes in high-risk patients who underwent TAVR with the first Sapien balloon-expandable transcatheter valve (Edwards Lifesciences) with those who underwent surgical AVR.
Michael J.
Reardon
Howard C.
Herrmann
Since the presentation, the reaction in the cardiology community has been enthusiastic. “This is going to fundamentally change the way we treat valve surgery,” Michael J. Reardon, MD, professor of cardiothoracic surgery at Houston Methodist Debakey Heart and Vascular Center, said in an interview. “Having been in practice for over 30 years, this is the most exciting thing for me to see, ever. I’m looking at it like the early cardiologists who did angioplasty looked at that and said, ‘Wow, this is really going to change things.’”
However, experts said, more research is needed before there can be a definitive answer on who is best suited for treatment with CoreValve, who is best suited for treatment with Sapien, and who is best suited for treatment with surgery.
“There is likely to be continuing debate as to whether [CoreValve’s superiority vs. Sapien’s equivalence to surgery] is related to the device vs. the trial design,” Howard C. Herrmann, MD, professor of medicine at the Perelman School of Medicine at University of Pennsylvania and director of the interventional cardiology program and cardiac catheterization labs at the Hospital of the University of Pennsylvania, said in an interview. “My belief is that it is much more the latter.”
Mechanism and suitability
The CoreValve is a bioprosthetic porcine pericardial valve mounted in a nitinol stent, which is compressed into an 18F delivery catheter. When deployed, it self-expands when it comes into contact with warm blood. Unlike with a balloon-expandable valve, it can continue to expand after deployment.
The device was approved by the FDA in January for patients with severe aortic stenosis considered to be at extreme risk for surgical AVR, defined as those with a predicted risk for mortality, stroke or irreversible injury of 50% or greater at 30 days after surgery. An indication for high-risk patients, with an estimated risk for mortality of 15% or greater at 30 days after surgery, was approved in June by the FDA, which had announced that it had enough clinical evidence so as not to need to convene an advisory panel to help make its decision, according to Adams, who is the Marie-Josée and Henry R. Kravis professor of cardiothoracic surgery and chairman of the department of cardiovascular surgery at Mount Sinai Hospital. The expanded approval applied to the entire CoreValve platform.
Currently, Reardon said, patients recommended for TAVR tend to be those who are considered too frail for surgical AVR. “There are three basic criteria a patient has to show for the CoreValve and Edwards valve,” he said. “One is risk. The other is physiology: Is the aortic stenosis bad enough? The last is anatomy: Where are we going to put this valve in the patient’s heart? Does it match one of the valve sizes we have?”
Anatomy plays a large role in who receives a CoreValve device vs. who gets a Sapien device, Michael J. Mack, MD, chairman of cardiovascular medicine and surgery at the Baylor Scott and White Health Care System, Dallas, told Cardiology Today.
Michael J. Mack
Patients who should receive a Core-Valve device instead of a Sapien device include those with femoral arteries small enough to require an 18F delivery system and who are not candidates for alternative access, patients with large annuli, patients with “very small, heavily calcified aortic roots, especially women, in which a self-expanding rather than a balloon-expandable valve may be slightly less at risk for annular rupture,” small patients with a previous surgical valve and “patients with low-lying coronary arteries where you would be worried about coronary occlusion,” said Mack, a member of the Cardiology Today’s Intervention Editorial Board.
Conversely, he said, TAVR candidates who have a pre-existing conduction system abnormality should receive Sapien instead of CoreValve because the latter is associated with a higher rate of pacemaker implantation, as well as those who have “heavy, bulky, eccentric calcification of the valve. … You probably get less paravalvular leak with a balloon-expandable valve in that situation.”
The next frontier of research is patients at intermediate risk for surgical AVR. The SURTAVI trial is currently enrolling to test CoreValve in those patients, and Medtronic is in negotiations with the FDA to agree on a definition of intermediate risk, Adams said. The PARTNER 2A randomized trial with the smaller-sized Sapien XT balloon-expandable prosthesis in intermediate-risk patients has completed enrollment of more than 2,000 patients and is in the follow-up period, Herrmann said.
Until data from trials of TAVR in intermediate-risk patients are published, intermediate-risk patients should be treated with surgical AVR, Mack said.
Difficult comparisons
The findings from the trial of Core-Valve in high-risk patients represent a breakthrough, but it should not be interpreted that CoreValve is superior to surgery in all patients, nor that CoreValve is superior to the Sapien valves, experts said.
“Everyone wants to compare the Core-Valve data with the previous Edwards data, but it’s almost impossible to compare the two because of a number of differences within the trials,” Peter C. Block, MD, professor of medicine and cardiology at Emory University Hospital and Cardiology Today Section Editor, said in an interview. “The [Society of Thoracic Surgeons] score in the CoreValve trial was 7.5. The STS score in the Edwards surgical trial was around 5 points higher. And so to say that CoreValve is superior to surgery and the Edwards valve is not, it’s only equivalent, does not make sense because the patients had lower risk in the CoreValve trial and that’s exactly what you’d expect from the outcome. To try and compare these is foolish and really does not help much in terms of making decisions.”
Peter C. Block
A strong trial design may have been as much as a factor as the effectiveness of the device, said Herrmann, a Cardiology Today’s Intervention Editorial Board member.
“The CoreValve High-Risk Study learned from the earlier PARTNER experience and was much stricter on the need for CT scans and core lab analysis of the aorta and annulus dimensions,” he said. “The combination of not having a [transapical] arm, who are higher-risk patients, more careful sizing and selection, as well as a lower-overall-risk patient population was the likeliest explanation for the better results relative to surgery in this trial. A true benefit from the valve design cannot be excluded short of a head-to-head randomized trial” comparing the CoreValve and Sapien devices.
Adams said that the results of the CoreValve trial cannot be attributed to enrolling patients with lower risk, noting that it included patients with inadequate ileofemoral access who were treated with alternate approaches. “Just the opposite is true,” he said. “Patients at lower surgical risk would have an ever-lower surgical mortality, and this would make it more difficult for CoreValve to prove superior to surgery.”
Reardon said data from the CoreValve High-Risk Study and the 1A arm of the PARTNER trial offer some clues as to why the mortality curves differed. In both trials, the TAVR group had a better mortality rate early on, which was expected because TAVR is less invasive than surgery, but in PARTNER 1A, mortality rates became similar between the groups by 1 year, whereas in the CoreValve high-risk trial, the curves stayed separate.
“There are several encouraging things we are seeing,” Reardon said. “One is less stroke. If there was a major stroke in [either trial], the chance of death within a year was 50%. Another thing linked to death over time is kidney injury. It was statistically less with TAVR than in surgery in the high-risk [CoreValve] trial, which was not the case in the PARTNER trial. The other thing linked to death over time in the PARTNER trial was paravalvular leak, whether mild, moderate or severe. In CoreValve, there was no relationship.”
An explanation for the latter, Reardon said, is that Sapien is balloon-expandable, “and once you expand it, it gets no bigger. So the paravalvular leak at 30 days is pretty much what we’d expect at a year, and that’s what the investigators found. For CoreValve, nitinol keeps pushing out. We found that if you did paired analysis, 80% of the patients with moderate paravalvular leak at 30 days that were still alive and had another echocardiogram at 1 year got better. I think this decreasing paravalvular leak rate, which was already very small, kept this from having an effect on mortality, and that’s why those curves don’t come back together. CoreValve is kind of like braces for the heart, helping the annulus remodel and get better over time.”
Although statisticians have argued whether CoreValve actually demonstrated superiority to surgery in the trial of high-risk patients, “it’s a moot point,” Mack said.
“When you have two treatments that are roughly equivalent in terms of outcomes, the less invasive treatment beats out the more invasive treatment any day of the week,” he said. “Just because TAVR was noninferior to surgery means that TAVR was the winner.”
Making a CHOICE
Results from CHOICE, the first head-to-head trial to compare the CoreValve and Sapien devices in a group of 241 patients, were also presented at the ACC Scientific Sessions. However, experts remain divided about how to interpret the data.
Mohamed Abdel-Wahab, MD, head of the cardiac catheterization laboratory at Segeberger Kliniken, Bad Segeberg, Germany, and colleagues reported a rate of device success of 95.9% for Sapien XT vs. 77.5% for CoreValve (RR=1.24; 95% CI, 1.12-1.37). They also reported a reduced frequency of residual more-than-mild aortic regurgitation (4.1% vs. 18.3%; RR=0.23; 95% CI, 0.09-0.58) and less receipt of more than one valve (0.8% vs. 5.8%; P=.03) in the in the Sapien XT group. Mortality, vascular complication and bleeding rates were similar between the groups at 30 days, and the rate of pacemaker implantation was higher in the CoreValve group.
Reardon said, however, that the study design was flawed. Specifically, the study was conducted at only five centers, one of which handled approximately 70% of cases; investigators built in the assumption of superior event rates for Sapien; 3-D imaging to confirm correct valve size was not used in more than 20% of cases; the definition of “device success” was determined using an outdated method; and the rate of moderate-to-severe paravalvular leak in the Sapien group at 30 days was 0%, which is highly inconsistent with results of previous trials.
“It was a really interesting first shot out of the box, but it was a poorly designed trial that actually raises more questions than it answers,” Reardon said.
Mack noted that the centers involved “were all CoreValve users to begin with,” which gives the results some credibility. “Yes, it’s a relatively small series in relatively small centers, but it is the first head-to-head comparison, so I don’t think we can ignore it.”
Experts agree, however, that data beyond 30 days are needed.
“The take-away message is that they are both very good valves and we need longer-term follow-up to try to determine whether there is truly a difference in outcomes between these two valves,” Block said.
Alternative access options
Part of the work to determine which patients may benefit from CoreValve is research involving alternative access approaches. At the American Association for Thoracic Surgery annual meeting in April, Reardon presented the first data on extreme-risk patients treated with CoreValve via subclavian (n=70) or direct aortic (n=80) approaches.
The primary outcome was all-cause mortality or stroke at 12 months. At 1 year, the rate was 39.4% for those who received the CoreValve via an alternative approach vs. 26% among patients treated via the transfemoral approach. Among patients with paravalvular regurgitation at discharge, 85.7% improved within 1 year, and the rate was 2.4% at 12 months, Reardon said.
“We were on new ground with this and found that it was a reasonable way to treat these patients who had no other option,” he said. “But, the risk of the procedure is higher than for the transfemoral approach. Whether it’s because the procedure itself is more invasive or these patients have a higher-risk profile, which they indeed do, we do not have enough patients to give an answer to that.”
However, Mack noted that “most clinicians have given up on the subclavian approach” and “the direct aortic is still a sternotomy and it still is invasive.” At his institution, if a transfemoral approach is not possible, then a clinician usually opts for a transapical approach, which can be performed effectively with Sapien but not with CoreValve, he said.
At the Society for Cardiovascular Angiography and Interventions Scientific Sessions in May, Vikas Singh, MD, cardiology fellow at the University of Miami, presented results from the first three patients treated with CoreValve via the transcaval approach. The three patients were not candidates for the transfemoral, transaortic, subclavian or transaxillary approaches, nor for surgery, he said.
At 6 months, all three patients were free from complications and showed significant improvement in functional capacity, mean NYHA class improved from 3.3 to 1.3, and one patient required a pacemaker, according to data presented.
Advance heart valve care
Longer-term results for CoreValve are starting to emerge and can also help clinicians make decisions on good candidates. At EuroPCR 2014, researchers reported 2-year results from the ADVANCE registry of patients treated with CoreValve, indicating a 25.6% mortality rate, a 16.8% CV mortality rate and a 2.9% major stroke rate.
“Although those data are quite wonderful, one in four patients do not survive 2 years,” Block said. “We need to be better judges of who we choose for TAVR at the front end or we need more data telling us in which patients it simply should not be done. I think we are getting better at that; we know folks with chronic renal failure and severe chronic lung disease simply do not do well.”
In the future, TAVR is likely to be more widely performed than it is today, and the results of the high-risk arm of the Core-Valve trial may be one reason.
“Normally, we’re thinking about less invasive interventional procedures trying to be equivalent to the gold standard as opposed to superior to the gold standard of open surgery,” Adams said. “As [Eugene Braunwald, MD] later told me, ‘In 10 years when they look back on the field of TAVR, this presentation and paper will be one of the two or three that people always comment about as far as opening a new chapter.’” – by Erik Swain
Disclosures: Adams reports receiving royalties through his institution for patients from Edwards Lifesciences and Medtronic. Block is a site investigator for Edwards Lifesciences’ PARTNER trial and a past consultant for Medtronic, and has equity in Direct Flow Medical. Herrmann receives consultant honoraria for training courses from Edwards Lifesciences and his institution receives research funding from Boston Scientific, Edwards Lifesciences, Medtronic and St. Jude Medical. Mack serves on the executive committee of Edwards Lifesciences’ PARTNER trial but does not receive compensation except for travel expenses. Reardon serves on an advisory board for Medtronic for which his department receives compensation.