Transformation in motion

Percutaneous valves have galvanized treatment of aortic stenosis, but their ultimate impact on patients with the disease in the US awaits the FDA’s decision.

Just over a year ago, the cardiology community got a highly anticipated look at transcatheter aortic valve replacement — also known as transcatheter aortic valve implantation — with the results of the Placement of Aortic Transcatheter Valves cohort B trial.

Cover illustration © Lisa Clark

These results, presented at the 2010 Transcatheter Cardiovascular Therapeutics Conference, had implications previously never seen before in the treatment of patients with aortic stenosis (AS). Not only was there a greater chance of survival for inoperable patients with severe AS with a transcatheter aortic valve replacement (TAVR) device (Sapien, Edwards Lifesciences) compared with standard medical therapy, but also the quality of life (QOL) in these patients, as was later reported, was significantly improved.

	Martin B. Leon

“TAVR not only saves lives but it also improves QOL. I think that is very important, because it’s not just that the patients live longer but their [QOL] is dramatically impacted,” said Martin B. Leon, MD, director of the Center for Interventional Vascular Therapy and professor of medicine at Columbia University, New York, and presenter of the initial results.

In fact, patients’ QOL improved by more than 20 points on the Kansas City Cardiomyopathy Questionnaire, a difference considered very large, according to David J. Cohen, MD, director of cardiovascular research at Saint-Lukes Mid America Heart Institute, Kansas City, Mo., who was involved in the QOL research. “We think this is very important because the group we are talking about is patients with inoperable AS and severe comorbidities; even if they were living longer, this group might not prefer that if they were not also feeling better. Improvement in QOL is at least as important as duration of life,” said Cohen, who is also a member of the Cardiology Today Intervention Editorial Board.

Since these data were presented, TAVR has continued to gain momentum with a bevy of studies published in general medical and cardiology journals. One such study, first presented at the American College of Cardiology meeting this past April and later published in The New England Journal of Medicine in June, looked at patients in the Placement of Aortic Transcatheter Valves (PARTNER) cohort A trial with severe AS eligible for surgery. According to results, mortality was comparable at 1 year with TAVR vs. surgery, with risk of stroke and vascular complications higher in the TAVR arm, and rates of major bleeding and new-onset irregular heart rhythms of atrial fibrillation higher in the surgical arm.

When performing TAVR, a large cath lab, or hybrid cath lab, is needed that can facilitate either catheterization or surgery. Images: John Webb, MD

Less than 2 months after these results were published, the FDA Circulatory System Devices Advisory Panel gave a strong vote of confidence to TAVR based on the PARTNER data, voting that there was reasonable assurance that the valve is safe, effective and that the benefits outweigh the risks in patients with severe AS.

Now, the device’s ultimate fate for patients in the United States rests with the FDA’s decision, which many in the industry are expecting either late this year or in early 2012.

Stroke, vascular complications top the concerns

One of the most pressing concerns with TAVR for many is the risk of stroke that has been well documented in clinical research. Among PARTNER cohort B patients, for example, the risk was more than fourfold for stroke in the TAVR arm vs. standard therapy arm (5% vs. 1.1%).

To improve these rates, research is currently being done to better understand who the patients are who develop stroke so that those with risk factors can be steered away from TAVR, Cohen said. He added that devices are being developed for the procedure “that are analogous to the embolic protection devices we use during procedures like carotid stenting for vein graft intervention that straddle across the carotid arteries and deflect and trap emboli before they can get to the brain.”

	Peter C. Block

Additionally, according to Peter C. Block, MD, professor of medicine and cardiology at Emory University, Atlanta, and co-author of PARTNER, “The length of time the catheter dwells in the transverse arch probably will reduce the possibility of stroke, though there are no data to support this. But it seems that as we get better at this, the likelihood is the risks will decrease. Also with smaller catheters and slicker technology, there is no question that we should be able to decrease the amount of interaction of catheter technology against the aortic wall, which probably is the main reason we have stroke.”

A large, multifaceted team is required to successfully execute TAVR.

Another concern with TAVR, and one that John Webb, MD, McLeod Professor of Heart Valve Intervention, University of British Columbia, Vancouver, said will improve with experience, is the rate of vascular complications, which were also substantially higher in the TAVR group in PARTNER cohort B patients. “Major vascular complications in PARTNER cohort B patients were about 16% [vs. 1.1% in the medical therapy arm], in cohort A patients they were down to 11% and in my center in the last year they’ve fallen to less than 2%,” Webb said.

Besides experience, this observation with declining rates of vascular complications can also be partly explained by the evolution in valve design. “When we started, we were talking about 24 French catheters that have an outer diameter of up to 9 mm. Now we have 18 French catheters, which is the standard size used outside the United States, and shortly these will be getting even smaller,” Webb said.

Edwards Lifesciences’ 24 French Sapien and 18 French Sapien XT valves.

Innovative valve development

Besides the Sapien valve system, other percutaneous valves are beginning to make a name for themselves in the category. One of the top contenders is the CoreValve (Medtronic). Unlike the Sapien valve, which is balloon-expandable, the CoreValve has a self-expanding stent design. The main advantage of this, Cohen said, is that it is easier to make the profile of the device lower because there is no balloon sitting inside the device to take up space.

	David J. Cohen

“The current version of the CoreValve device is already 18 French and only the newest generation of the Sapien valve [Sapien XT] is approaching that profile,” he said. “By virtue of being self-expanding, it obviates the need for rapid ventricular pacing while the device is being deployed, which, although patients do tolerate it quite well, makes it tricky to do the procedure in an awake patient, whereas the CoreValve device can be done a little easier in patients who are not fully under general anesthesia. The tradeoff is the CoreValve is a much longer device, which is thought to result in higher rates of heart block and needing a pacemaker after the device.”

Like the Sapien valve, the CoreValve also has a large experience worldwide, Webb said, adding, “It’s really only used transarterially, either through the femoral or the subclavian, and the results are very good with that as well, although I think they are arguably not as well-documented to date as the Sapien valve.”

A coronal maximum intensity projection of a deployed TAVR device.

Other companies with valves on the horizon include St. Jude Medical, Sadra Medical (recently acquired by Boston Scientific) and Chana. In addition, JeneValve and Symetis recently received CE mark approval for their second generation TAVR devices.

In general, Leon said, the newer valves are self-expanding and are developed to keep the profile down and make the device as small as possible. “The majority of these devices also have a recoverable feature [unlike the Sapien valve], which is to say that if you have difficultly positioning it, you can recover it and reposition it, which is thought to be an important advantage. And many of these devices have techniques that might reduce the severity of paravalvular leak,” he said.

Setting the stage

While the industry awaits the FDA’s vote, many have already begun to prepare for approval and what that will mean for practice. Unlike traditional angioplasty, there are several additional variables required for successfully performing TAVR. In fact, for Leon, the process is completely different.

Medtronic’s CoreValve features a self-expanding stent design.

“It starts from the fact that TAVR is a concept, and the concept is: You bring together a multidisciplinary team to treat patients with advanced disease who have been previously treated by various sub-specialists,” he said. “For the most part, the team consists of interventionalists, who are also clinical cardiologists; surgeons, who’ve taken care of patients with valvular heart disease; advanced imaging experts, particularly with echocardiography and CT angiography; and even anesthesiologists, as well as other nonphysician health care personnel.”

The environment is also very different. “This is a surgical procedure. Everything you would need to do in an operating room you have to be able to do in a cath lab,” Leon said. “The average cath lab is too small, so it has to be a large cath lab or what we call a hybrid cath lab that is set up from the beginning to do either surgery or catheterization.”

Also, according to Webb, “The stakes are higher in that the potential for risks is much more significant than the standard cath lab procedure, so it has to be performed perfectly to get the result you want.”

The early years of TAVR As with most transformative technologies, the results of clinical research with TAVR were the end result of many years of research and development. In the case of TAVR, the technology had been in the works for 12 years by the time the results of PARTNER became public knowledge, beginning back in 1998 as the collaboration between four individuals. “At that time, I was one of four people who helped to form a start-up company called Percutaneous Valve Technologies,” said Martin B. Leon, MD. “This also included Alain Cribier, MD, and two business engineers who used to work for Johnson & Johnson.” Working together, the four developed the first prototypes for a transcatheter, stent-based balloon-expandable system. “We helped design it, performed animal studies and Cribier did the first human case on April 16, 2002, which I was also involved in,” Leon said. The findings were then published in Circulation. Two years later, Percutaneous Valve Technologies was bought by Edwards Lifesciences. The momentum of this new procedure continued to build in the following years, with the first cases in the United States being performed in 2005 and the PARTNER trial starting enrollment 2 years afterward. As the years progressed, percutaneous valves were continually refined to feature a number of advancements over the earlier models, including smaller design (18 French vs. 24 French) and self-expandable models. Even the name of the procedure itself has been fine-tuned over the years. Although initially referred to as TAVR since aortic valve replacement (AVR) was the surgical name, this changed once the technology was commercialized in Europe, where the term TAVI became rampant, “because they said you are not really replacing the valve but implanting it. In fact the first New England Journal of Medicine study [published in 2010] used the term TAVI,” Leon said. The name quickly changed back in the US, however, when, according to Leon, CMS raised concerns. “CMS told us that if it’s not a replacement, we won’t get reimbursed like we should,” Leon said. “We explained that it really is a functional replacement, like when you do a mitral valve replacement surgically you don’t take out the valve but instead do what’s called valve-sparing mitral valve replacement where you leave intact the mitral valve for the most part. So, since this is a functional replacement and CMS was beginning to agitate about reimbursement, we went back to the original name of TAVR.”

Getting in the valve game

For interventionalists looking to enter the percutaneous valve arena, one of the most important things to keep in mind is the necessity of developing a team approach, Cohen said.

A look from above at the Sapien valve.

“This is a common theme in a lot of areas of interventional cardiology today, but in valves, it’s even more important because you’re teaming up with cardiac surgeons and anesthesiologists, as well as echocardiographers,” he said, adding that “working very closely with the cardiac surgeon is very critical to evaluate potential patients and determine whether they are better suited for traditional valve surgery or whether they are high enough risk that a percutaneous valve would be a more appropriate approach.”

Leon agreed. “[Interventionalists] do not have a history of working that closely or well with surgeons, but you have to form a team. If you want to be serious, you’re going to have to put some of those territorial issues aside and develop a team so that you can successfully approach this,” he said.

Not only must there be a strong team approach in place, but the center must also have strong interventional cardiology and surgical programs and a high volume due to the substantial risks involved with this procedure, according to Webb. “Low-volume programs are not likely to be able to obtain good results in a sustained fashion,” he said. “So there is a need for some centralization.”

Also not to be overlooked, according to Block, is the importance of getting the support of hospital administrators, “because it is going to be an expensive procedure and the question is whether small hospitals who do this intermittently or rarely should in fact be involved in a procedure that, on the front end, is very expensive and where the whole issue of reimbursement is very much in the air,” he said. “So it’s a little bit of a difficult game at this point for interventionalists who have not been involved in the initial trials to get into, but obviously they will. It just will require a lot of planning and teamwork with their hospital and colleagues to pull it together.” – by Brian Ellis

UPDATE: On November 2, The FDA approved the Sapien valve for the treatment of patients with severe aortic stenosis ineligible for surgery. More details into this approval along with in-depth clinical perspective will be available in the January/February issue of Cardiology Today Intervention.

References:

• Leon M. N Engl J Med. 2010;363:1597-1607.

• Smith CR. N Engl J Med. 2011;364: 2187-2198.

Disclosure: Dr. Block is a consultant for Medtronic and Direct Flow and has equity in Direct Flow, works at a site for the PARTNER trials, and is a member of the Circulatory System Devices Panel; Dr. Cohen has received research grant support from Edwards Lifesciences and Medtronic; Dr. Leon is on the executive committee for Edwards Lifesciences, is the principal investigator of the PARTNER trial, and has equity interest in Sadra and Claret; and Dr. Webb is a consultant to Edwards Lifesciences.