The Changing Face of TAVR

With the November 2011 FDA approval of the Sapien valve, transcatheter aortic valve replacement became available in the United States, offering a less invasive alternative — and hope for improved quality of life — to patients with inoperable aortic stenosis. Then, less than a year after this development, the FDA approved an expanded indication for the Sapien device to include the treatment of high-risk surgical candidates.

Since becoming an option for high-risk patients, TAVR has increasingly become the preferred treatment in this patient population, according to Howard C. Herrmann, MD, director of the Interventional Cardiology Program and Cardiac Catheterization Labs at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

“When given a choice, patients who are in the high-risk category and are eligible for TAVR invariably choose TAVR,” Herrmann said. “Using the baseball analogy of ‘tie goes to the runner,’ in this case, tie goes to the less invasive therapy.”

Robert Kipperman, MD, associate director, Advanced Interventional Therapeutics Program, Morristown Medical Center, Morristown, N.J., agreed. “Over time, the volume has increased and I do feel TAVR is the preferred treatment,” he said. “As the word has gotten out, many patients are being treated who would have not been referred in the past.”

The appeal of a less invasive procedure, along with promising clinical trial data, continues to drive the momentum toward the increased use of TAVR in treating patients with aortic stenosis (AS). Surgery is still considered superior in low- and moderate-risk patients with AS, and TAVR has been linked to increased stroke, vascular complications and paravalvular leak. However, the promise of a less invasive alternative has spurred device manufacturers to rectify these flaws through next-generation TAVR devices. These investigational devices, which include the second-generation Sapien XT (Edwards Lifesciences) and third-generation Sapien 3, are designed to improve upon the technology of the original Sapien.

“The future devices are going to be lower profile, retrievable, and with more versatility in terms of access and positioning,” said Faisal G. Bakaeen, MD, chief of cardiothoracic surgery at the Michael E. DeBakey VA Medical Center and associate professor of surgery at Baylor College of Medicine, Houston. “There are going to be less paravalvular leaks and access complications.”

According to Bakaeen, it is not yet clear which of the investigational valves is superior, or which will ultimately prevail in the race for FDA approval.

“It is a horse race,” he said. “Obviously, [Sapien XT] and CoreValve are ahead of the game, but the competition is fierce. Product quality and ease of use are going to be important considerations.”

The Evolution of Sapien

Besides receiving FDA approval for inoperable and high-risk surgical candidates, the Sapien valve can also be implanted via the transfemoral and transapical access routes. Initially approved for transapical access in October 2012, the FDA approved an update to the Ascendra transapical delivery system, Ascendra 3, in July. The Ascendra 3 system can be used with Sapien and features a nose cone, improved user controls, shorter working length and an ergonomic sheath.

“This new technology will greatly enhance our ability to deliver the Sapien transcatheter heart valves to our patients,” Bakaeen said.

Although not yet FDA approved, the Sapien XT valve marks the next step in the development of Sapien transcatheter valve, utilizing the lower-profile 18F Novaflex transfemoral delivery system. It has a balloon-expandable cobalt chromium frame and bovine pericardial tissue leaflets. The Sapien XT treats an annulus size range of 18 mm to 27 mm, and all valve sizes are available for transapical or transfemoral delivery. The Sapien XT has gained a CE mark, but remains investigational in the United States.

The Sapien XT device was compared with the original Sapien valve in the PARTNER II cohort B trial, which enrolled 560 patients considered unfit for traditional open-heart surgery at 28 hospitals in the United States. Patients were randomly assigned to receive either the Sapien or the Sapien XT valve.

“Results at 1 year [showed] similar outcomes in mortality and MACE between the Sapien XT and Sapien valves, yet fewer vascular events with the lower-profile Sapien XT valve,” Bakaeen said.

According to Herrmann, the feature that sets the Sapien XT apart is its significantly smaller size, which limits the vascular complications seen with Sapien. He said the PARTNER II cohort B trial demonstrated that in the primary endpoint, which was all-cause mortality, disabling stroke and rehospitalization at 1 year, there was no difference between Sapien and Sapien XT, but vascular complications were reduced from 15.5% to 9.6%, and disabling bleeding from 12.6% to 7.8%.

“Those are impressive differences, and the great majority of that, if not all of it, is attributable to the smaller size of the device,” he said.

The PARTNER II cohort A trial will evaluate the Sapien XT device vs. surgery in intermediate-risk patients, Herrmann said.

“This trial and the SURTAVI trials are the two large-scale trials that are looking at the intermediate risk group, with STS score of 4% to 8%, which could extend the market from extreme risk and high risk down to intermediate risk,” he said.

Horst E. Sievert, MD, director of the CardioVascular Center Frankfurt in Germany, said although he considers the Sapien XT a definite improvement on the original Sapien, he has even higher hopes for the newer device from Edwards Lifesciences: the Sapien 3. In August, Edwards Lifesciences received conditional investigational device exemption (IDE) approval from the FDA to initiate a clinical trial of the Sapien 3 valve that will assess the device in high-risk and inoperable patients with severe symptomatic AS.

“I am hopeful for the Sapien 3 valve, which provides a fabric cuff to protect against paravalvular leak, has a new frame geometry for better radial strength, and can be delivered with the new 14F expandable sheath or ‘eSheath,’” he said.

“Not only is [Sapien 3] smaller than XT, but it also has additional attributes that we think are going to make it even better,” Herrmann said. “It’s a little bit longer, which should improve placement. It also has the skirt on the outside of the valve frame, as well as a new design. Hopefully, these improvements will optimize positioning and reduce paravalvular aortic insufficiency.”

CoreValve: Significant Regulatory Strides

The original CoreValve (Medtronic) received CE mark approval in 2007. An updated version of the device, the CoreValve Evolut 23 mm valve, gained CE mark designation in 2012. The newer version utilizes TruFit Technology, which encourages sealing between the prosthetic and native valves. Sievert said the newer version also offers reduced height, better coronary access and a sheath with a smaller outer diameter (18F), which will likely reduce vascular complications.

“The EnVeo delivery system promises better deployment, an improved release mechanism, redesigned loading and packaging, and also has an optional shorter-length catheter for subclavian and direct aortic access,” Sievert said. “CoreValve has also shown promise for native noncalcific aortic regurgitation.”

The CoreValve can treat valves with annulus diameters between 18 mm and 29 mm, which is currently the broadest size range available. It is restricted to investigational use in the United States.

Bakaeen said Medtronic gained FDA conditional approval to begin studying the CoreValve in intermediate-risk patients as part of the Medtronic CoreValve SURTAVI trial.

“The SURTAVI trial will be the largest global, randomized controlled trial on TAVR to date, including approximately 2,500 patients,” Bakaeen said. “The trial will evaluate whether the CoreValve is noninferior to surgical aortic valve replacement, based on the composite primary endpoint of all-cause mortality and disabling stroke at 24 months.”

Enrollment for SURTAVI began in November 2011, and the study will have a 5-year follow-up. Bakaeen said Medtronic also received a CE mark for valve-in-valve (VIV) procedures using the CoreValve and CoreValve Evolut systems in degenerated bioprosthetic surgical aortic valves.

“This is the first regulatory approval for VIV procedures,” he said. “Results from the largest global VIV registry, published in Circulation in November, showed the VIV approach resulted in considerable hemodynamic improvements, including a decrease in valve gradients.”

JenaValve: Positioning ‘Feelers’

The CE-mark approved JenaValve (JenaValve Technology) is made up of a porcine root valve sewn onto a nitinol self-expanding stent. This root valve is fitted with an outer porcine pericardial patch (referred to as a “skirt”) before being affixed to the stent. It is delivered using the transapical route.

“It has anatomical positioning feelers with a special clipping mechanism that grabs onto the valves, allowing anatomically correct positioning,” Sievert said. “There is reportedly no rapid pacing needed during this procedure.”

This anatomical orienting, according to Herrmann, is a common feature among some of the newer valves, and may be useful in preventing aortic insufficiency.

“We know aortic insufficiency, especially when it’s more than moderate, is associated with increased mortality,” he said. “And some of the newer valves, such as the JenaValve, the Symetis [Symetis] and the Engager [Medtronic], all aim to prevent aortic insufficiency by being more anatomically oriented.”

This anatomical positioning, however, comes with disadvantages, Herrmann said.

“The price one pays for that is a larger valve and transapical insertion,” he said. “Some of the hope is that by reorienting these valves and making them more anatomically correct, they will be able to reduce coronary obstruction and paravalvular leaks. Whether that’s an adequate trade-off for having to go transapical is a separate study.”

Sievert said a transfemoral delivery system for the JenaValve is forthcoming, and the valve has produced positive post-market results in the JUPITER registry. The first results showed “high procedural success rates” and “excellent clinical outcomes,” according to a company press release. The device also yielded low rates of paravalvular leak.

“This valve is very promising for aortic regurgitation and has had good first results,” Sievert said.

Self-Sealing Technology with Symetis Acurate

The Symetis Acurate valve is a transapical valve featuring a self-expanding nitinol frame and stabilization arches. It consists of an upper crown for supra-annular anchoring, a skirt for sealing the bioprosthesis and a lower crown that protrudes only minimally into the left ventricle. This minimal protrusion may decrease risk of conduction system defects, Sievert said. “The delivery system is sheathless with an isodiametric shaft and a two-step delivery,” he said. “A transfemoral system has also been developed, with data shown at London Valves 2012.”

Christian W. Hamm, MD, PhD, professor of internal medicine and cardiology and director of the Kerckhoff Heart and Thorax Centre, Bad Nauheim, Germany, was a co-investigator in the transfemoral study, and said his experience with it has been positive.

“We think this is a very good valve,” he said. “In our experience, it looks like the rates of aortic regurgitation and pacemaker [implantation] are very low, and it seems to be very elegant and easy to place.”

In the transfemoral study, the Symetis valve demonstrated a very low rate of paravalvular leak, with only 2.7% of patients showing a leak higher than grade 2 at follow-up. The Symetis features a “self-seating and self-sealing” technology, which optimizes the fit of the bioprosthesis and reduces risk of incorrect placement.

“It’s still in very early stages, and we have to improve some of the minor details. In general, it looks like a very good valve,” Hamm said.

Lotus Valve: Repositionable and Retrievable

Formerly known as the Sadra valve, the Lotus valve (Boston Scientific) is a preloaded valve delivered over an 18F introducer system. It features an adaptive cuff to prevent paravalvular leak, and comes in 23 mm and 27 mm sizes.

“It is very repositionable and retrievable, with an adaptive seal designed to minimize paravalvular leak and early functioning to allow for controlled deployment,” Sievert said.

The Lotus valve has been studied in the REPRISE I and REPRISE II trials. One-year results from REPRISE I showed the Lotus to be safe and efficacious in patients with severe AS. There was no moderate or severe paravalvular aortic regurgitation at follow-up. Results from REPRISE II trial, which studied the valve in patients with severe AS at high risk for surgery, showed successful implantation of the device in all of the first 60 patients. No cases of severe paravalvular leak were seen. The REPRISE II trial has been extended to enroll an additional 130 patients at 20 sites in Europe, Boston Scientific said in a press release.

Open Cell Design with Portico Valve

The Portico valve (St. Jude Medical) consists of leaflets made of bovine pericardial tissue sutured in a self-expanding nitinol stent. It is designed for transfemoral (18F delivery system via transfemoral sheath) and transapical (24F delivery system with integrated sheath) use. The stent frame has an open cell design, which permits easy access to the coronary arteries. According to Sievert, the Portico valve is unique in that the leaflets coapt together whether in a round or an oval annulus, and the larger cell sizes also reduce interference from external calcium and, therefore, decrease paravalvular leak.

“The valve is non-flared, so there will probably be less impingement on the atrioventricular node,” Sievert said. “It does not require pacing. It can also be prepped at room temperature.”

Sievert said that similar to the CoreValve, the Portico transfemoral system features an 18F sheath and has leaflet functionality after partial deployment.

“The Portico transfemoral valve looks similar to the CoreValve, but has unique features,” he said. “Ulrich Schäfer, MD, presented 1-year data at EuroPCR 2013. A transapical platform for this valve has also been developed, with first-in-man [research] already performed; shorter transaortic and subclavian delivery systems have also been developed.”

Direct Flow Valve: Double-Ring Design

The Direct Flow Valve (Direct Flow Medical) features a metal-free polymer frame, which is expanded using pressurized saline and contrast for placement, evaluation and adjustment. Its double-ring design creates a tight seal around the annulus, according to the Direct Flow Medical website.

“The Direct Flow valve is unique because it has a double-ring design for a durable seal, both of which can be inflated independently,” Sievert said. “There is no metal frame. It is fully repositionable in any plane by three positions and fills lumens. There is no rapid pacing needed, and valves have been deployed without postdilation. It requires only an 18F sheath.”

According to data from the 100-patient DISCOVER CE mark trial of the Direct Flow Valve, which was presented at EuroPCR 2013, the valve achieved 99% freedom from all-cause mortality at 30 days.

TAVR of the Future

In the years ahead, TAVR and other structural heart interventions, some interventionalists maintain, will be performed in tandem with surgeons in hybrid ORs, or even cath labs.

“I’m sure we’re going to be seeing quite a few hybrid ORs, not only for aortic valves, but also for mitral valves and all other structural heart disease interventions,” Hamm said. “There will be closer collaboration with surgeons.”

Increasingly in the future, TAVR will likely be performed without the use of periprocedural transthoracic echocardiography and general anesthesia, Sievert said, as the absence of both has advantages for patient care.

Sievert added that although collaboration in hybrid ORs has its advantages, more and more TAVR cases are now being performed in cath labs, not hybrid ORs.

“This happens for a variety of reasons. One, not many cases actually turn over to surgery — about 3% in the early data, and today far less than 1%,” he said. “Two, of the cases that do turn over, there is a high procedural mortality and morbidity that comes from surgical turnover — many do not make it off the table. It is not as if surgery is 100% safe and 100% the answer.”

Another reason for this shift, Sievert said, is the increased skill of operators and the growing number of percutaneous solutions to common problems.

“Many of the reasons why a case would potentially turn over — vascular complication, valve embolization, coronary obstruction — have percutaneous fixes that should be tried first before rushing to surgical turnover, which is not the best idea all of the time,” he said. “Also, as operators become more experienced, many of these complications are avoided or fixed percutaneously — with labs after 300 cases having turnover rates as low as 0.8%.

“This isn’t to say that surgeons are not needed,” Sievert continued. “However, there is a cost to everything we do. By saying that all procedures need to be performed in a hybrid room, we are increasing costs to patients and limiting access to patients who need it.”

Sievert said at his lab, he and colleagues do “floating” cardiac surgery, performing cases in a lab that has the capacity for surgical conversion with surgeons who have been invited onsite.

“In the future, TAVR will go the way of PCI — there will be low-risk cases that we’ll say can be done without surgical backup, and there will be high-risk cases that we’ll say should be performed with surgical backup in a hybrid room,” he said. “Needless to say, surgeons can and should do TAVR regardless. We should be careful that we do not make current guidelines, which are based on data from the past 5 years, into laws that hinder us from moving forward in the future.” – by Jennifer Byrne

Disclosure: Bakaeen and Kipperman report no relevant financial disclosures. Hamm serves on the advisory board of Medtronic. Herrmann receives consulting fees from Paeion Medical, Siemens Healthcare and St. Jude Medical; and his institution receives research funding from Abbott Vascular, Edwards Lifesciences, Gore Medical, Siemens Healthcare and St. Jude Medical. Sievert has received consulting fees, travel expenses and study honoraria from Boston Scientific and Medtronic; and grant/research support from St. Jude Medical.