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Life-work in Engineering of Improved Heart Valve

Curator and Reporter: Larry H Bernstein, MD, FCAP

 

An authority and author of the book on cardiovascular valve devices is challenged by patient’s mother to go beyond what is available.  The results are splendid after re-engineering the design to the problem.

 

Reverse Engineering A Human Heart Valve

By Jim Pomager

aortic valve - a remarkable piece of biomechanical engineering

aortic valve – a remarkable piece of biomechanical engineering

 

 

 

The aortic valve is a remarkable piece of biomechanical engineering. On any given day, the leaflets (or cusps) of a healthy aortic valve will open and close 100,000+ times, allowing the proper amount of blood to flow from the heart to the rest of the body. Over a lifetime, a healthy valve endures more than 3.4 billion heartbeats.

Unfortunately, the aortic valve doesn’t always remain healthy. (What organ does?) According to the American Heart Association, up to 1.5 million people in the United States suffer from aortic stenosis (AS), a calcification of the aortic valve that narrows its opening and restricts blood flow. In the early stages, the disease is often asymptomatic, but as it progresses, it can cause chest pain, weakness, and difficulty breathing. And in approximately 300,000 people worldwide, the condition develops into severe AS, which has a one-year survival rate of approximately 50 percent, if left untreated.

Fortunately, there are treatment options.  The most common and successful is aortic valve replacement (AVR), wherein a mechanical or tissue-based valve is substituted for the diseased valve. For decades, replacement valves were implanted via open heart surgery, which involves an extended hospital stay and months of recovery. But in recent years, a promising new approach has emerged: transcatheter aortic valve implementation (TAVI), also known as transcatheter aortic valve replacement (TAVR). In TAVI, a tissue-based artificial valve is delivered into the diseased heart valve via a blood vessel, rather than through a large incision in the chest.

TAVI has many benefits, the most obvious (and compelling) of which is its noninvasiveness, which means shorter recovery times and faster attainment of quality-of-life outcomes for the patient. Replacement of a transcatheter aortic valve (TAV) can also be a minimally invasive exercise — a second TAV can simply be implanted within the first.

On the other hand, the use of TAVI procedures in U.S. hospitals is not yet widespread (though it is growing rapidly). The longevity of current-generation TAVs also remains unknown because it is an emerging technology, compared to evidence of 15+ years for surgically implanted heart valves. Plus, TAVI is only approved in the U.S. for use in AS patients who are either ineligible for surgical valve replacement or at high risk. (TAVI has been available in Europe since 2007, and clinical trials are underway in the U.S. for its use in intermediate-risk patients.)

What’s really needed is an improved TAV — one that outperforms current transcatheter valves, is as durable as a surgical valve, and operates more like … well, a healthy human aortic valve. Such a valve would open the door to TAVI’s use in the hundreds of thousands of lower-risk (and generally younger) AS patients whose only current option is a surgically implanted valve, and who would rather not have their chest opened.

Now, a man who has dedicated his professional career to studying the aortic valve has invented a new artificial valve design that he says will revolutionize TAVI. And if everything goes according to plan, his TAV will reach European patients in 2015 and U.S. patients soon after. How did he and his startup company design such technology? By reverse engineering the aortic valve.

The Man Behind The Valve

Mano Thubrikar

Mano Thubrikar

 

 

 

Mano Thubrikar, quite literally wrote the book on heart valves and heart disease — two of them, in fact. His The Aortic Valve (1989) and Vascular Mechanics and Pathology (2007) are leading textbooks in cardiovascular studies, and the former is widely used as a guide in the design of bioprosthetic heart valves.

After earning an undergraduate degree in metallurgy, a master’s in materials science, and a Ph.D. in biomedical engineering, Dr. Thubrikar spent the first 30 years of his career exclusively in academic research. He studied the aortic valve and bioprostheses from almost every conceivable angle while working at the University of Virginia (UVA) and at the Carolinas Medical Center and the University of North Carolina (UNC) at Charlotte.

But in 2003, Dr. Thubrikar received a phone call that would change the trajectory of his career and set him on the path to develop a novel TAV technology. A woman contacted him to discuss her son, a 35-year-old athlete with a calcified aortic valve. The condition was the result of a bicuspid valve, a congenital condition where the aortic valve has two cusps, rather than the customary three. The man needed a valve replacement, and his only choice was to have a mechanical heart valve surgically implanted. However, the surgical valve meant he would have to stay on anticoagulants for the rest of his life, effectively ending his athletic pursuits. Dr. Thubrikar informed the mother that there just weren’t any treatments available that would allow her son to continue his active lifestyle.

“Didn’t you write the book on the aortic valve?” she asked. “Why didn’t you make a valve that my son could use?”

The conversation and question deeply affected the researcher. “I went home and was so disturbed,” he told me during a recent visit to his office. “I talked to my wife and said, “You know what? Years of research, writing papers, and giving presentations — that’s done. I now need to make a heart valve.”

Soon after, Dr. Thubrikar left Carolinas Medical Center to embark on his new mission. He joined artificial heart valve pioneer Edwards Lifesciences as a Distinguished Scientist, but left after it became clear that the company’s plans for him didn’t align with his own.

So in 2007 — coincidentally, the same year Edwards launched the first commercially available TAV device — Dr. Thubrikar returned to academia, joining the staff at the South Dakota School of Mines & Technology. There he spent the next three years working on a new artificial valve design — one based on decades of research on the physics behind the human aortic valve.

Looking To The Human Body For Design Output
According to Dr. Thubrikar’s research, the natural aortic valve follows four strong design principles for maximum longevity and optimal hemodynamic performance. Those criteria are:

1. A specific coaptation height — When the valve’s three leaflets come together to close the valve, there is some surface-to-surface contact between the leaflets, rather than an edge-to-edge seal. This safety margin helps prevent against blood leakage back into the left ventricle.

2. No folds in the leaflets — Natural aortic valve cusps flex without folding. Folds would crease the tissue and cause unwanted stress on the leaflets, negatively impacting durability.

3. Minimum overall height — Extra height would produce dead space, which can lead to a variety of issues.

4. Minimum leaflet flexion — The human aortic valve manages to open completely with the leaflets moving only 70 degrees, not the 90 degrees you might expect. Again, this improves the valve’s longevity.

“You almost need to be a solid geometry design engineer to understand the math and the equations behind these principles,” he explained. “With these criteria, however, you have design parameters for the aortic valve. The mathematical equations give you the output of how an artificial valve should be designed.”

Dimensions of the natural aortic valve

Dimensions of the natural aortic valve

Dimensions of the natural aortic valve

 

 

Based on these four principles, Dr. Thubrikar reverse engineered the aortic heart valve, developing a new artificial valve design that mimics the aortic valve’s precise geometry. In October 2010, he launched a startup company called Thubrikar Aortic Valve, Inc. to commercialize his new creation, which he calls Optimum TAV and touts as “nature’s valve by design.”

“When someone asks me, ‘How does your valve compare with Edwards’?’ or ‘How does your valve compare with Medtronic’s?’, I say ‘We don’t compare our valve to them,'” Dr. Thubrikar told me. “We compare our valve with the natural aortic valve.”

On the surface, Optimum TAV looks similar to other artificial heart valves on the market, with three leaflets of bovine pericardium tissue mounted on a metal stent-frame. (In fact, the design is often mistaken for another widely used surgical valve.) But according to Dr. Thubrikar, it has a unique combination of features that will help it overcome the major design limitations of current-generation TAVs (if we’re going to compare). Those design limitations include:

  • Suture holes in the leaflet body — While all TAVs (including Optimum TAV) are constructed by sewing animal tissue to a metal frame, piercing the flexion zone of the leaflets leads to potential wear. Optimum TAV does not have a single suture hole in the working portion of the leaflet body.
  • Blood flow through frame — Some TAV frames are as tall as 5 cm in height, extending up into the aorta once implanted. As a result, blood must pass through the frame to enter the coronary arteries. Proteins in the blood will accumulate on the frame, and can eventually break loose and cause thromboembolisms (blood clots).  Optimum TAV is only 2 cm in height. (Related, the low height of the Thubrikar valve also makes it less likely to require a pacemaker.)
  • Thick outer frame — The thicker the frame, the smaller the valve opening will be, allowing less blood to pass through. This opening is referred to as the valve’s EOA, or effective orifice area. The average EOA of a surgical valve is around 1.9 cm2, and some TAVs have EOAs as small as 1.5 cm2(technically, a mild form of stenosis). In bench tests, Optimum TAV’s EOA was 2.3 to 2.4 cm2. (A healthy aortic valve has an EOA of approximately 2.7 cm2.)
  • Clipped calcified leaflets — Some current TAVs are anchored to the patient’s original valve using a paper-clip like mechanism. In this design, there is the potential that the TAVs leaflets will come into contact with the old, calcified leaflets during the operation, causing wear. Optimum TAV’s design eliminates the possibility of contact between the leaflets and native valve.
  • Paravalvular leakage — In some cases, a space forms between the outside of a TAV and the surrounding heart tissue, and blood can leak through. Optimum TAV has a high skirt to prevent this type of gap from developing. In addition, Optimum TAV’s novel frame architecture allows it to conform to and seal off either a round or elliptical annulus (the ring-shaped base of the original valve). This is particularly helpful in minimizing or eliminating leakage in bicuspid patients, who often have an irregularly shaped annulus.
  • Balloon expansion — TAV frames made of stainless steel must be forced open by a balloon. The TAV’s tissue can get caught between the balloon and the frame and potentially tear. Optimum TAV’s frame is made of nitinol, which automatically expands once deployed from the catheter.

 

optimum TAV

optimum TAV

 

 

Optimum TAV

“Other technologies have built-in issues,” Dr. Thubrikar said. “To be able to avoid those problems in a comprehensive fashion is no small feat.”

Trial By Fire
During the two and a half years following the establishment of Thubrikar Aortic Valve, Optimum TAV seemed to be moving steadily toward market. The company raised enough funding to get started, primarily from friends, family, physicians, entrepreneurs, and technology industry executives. Patent applications were filed, suppliers were selected, valves were painstakingly produced (by hand, over one-and-a-half to two days each), and preclinical testing began.

Members of the Thubrikar Aortic Valve team

Members of the Thubrikar Aortic Valve team

 

 

Members of the Thubrikar Aortic Valve team (left to right): Deodatt Wadke, member of the board of directors and cofounder; Samir Wadke, executive director of business development and cofounder; Dr. Mano Thubrikar, president and founder; Samuel Evans, research engineer II; and Nikhil Heble, counsel, secretary, and cofounder

But the fledgling company was dealt a major setback in April 2013, when a fire destroyed the Horsham, Pa. office building to which the Thubrikar Aortic Valve laboratory had recently relocated (from South Dakota). All of its equipment was destroyed and needed to be replaced. The company had to relocate to nearby Norristown, Pa. Not an ideal scenario for a startup trying to make the most of extremely limited resources.

The company was undeterred by the fire, and the last year has been a successful one for Thubrikar. The company completed most of its preclinical testing (including implants in 12 animals and two diseased human cadaver hearts), reached design freeze on Optimum TAV, filed a provisional patent application for its proprietary delivery catheter, and achieved almost $2 million in total funding. Perhaps the biggest milestone came in August 2013, when Optimum TAV met the International Organization for Standardization’s (ISO’s) durability requirements by surpassing 200 million cycles in a third-party ISO certified laboratory.

The durability testing has continued, and Optimum TAV continues to function beyond 390 million cycles, which approximates 11 years in vivo. Surgical valves typically last anywhere from 12 to 18 years, and Thubrikar expects his valve to last at least that long.

“I would not be surprised if it surpasses the longevity of even the surgical valve,” he said.

The company also received its first institutional investment, from Delaware Crossing Investor Group (DCIG), in 2014. The primary DCIG investor, Marv Woodall, led the commercialization of the world’s first stents as president of Johnson & Johnson Interventional Systems (now Cordis) and was on the board of director of the first TAV company, Percutaneous Valve Technologies (PVT, now part of Edwards Lifesciences). Thubrikar has recruited him as its business advisor.

What Lies Ahead
Like many other developers of novel medical devices, Thubrikar Aortic Valve has decided to take its product to market through Europe initially, given European regulators’ comfort level with TAV and the FDA’s steep requirement for clinical trials. “We have spoken to the FDA and will continue to do so on a regular basis,” according to Dr. Thubrikar. “But they asked for a lot more preclinical testing than the European Notified Bodies to start a clinical trial.”

The company is now working to raise an additional $2 million to $10 million, and expects the granting of its patent for Optimum TAV in 2014. The finances will enable Thubrikar to not only conduct a first-in-human (FIH) feasibility study in up to 15 patients this year, but also to expand to a full European clinical trial of about 65 additional patients in 2015. If all goes well, a 2015 CE Mark for Optimum TAV isn’t out of the question.

However, trial success is vital, since today’s investors — and large companies in search of technology acquisitions — wait for significant clinical data to accumulate before backing a medical device. “We realize that until we actually implant the valve in a patient, other companies will think, ‘You don’t know what can go wrong,'” Dr. Thubrikar explained. “We had one big company say, ‘We will pay you four times as much once the product is in a patient.’ They want you to de-risk everything, to work out all the bugs yourself on your own dime.”

Yet Dr. Thubrikar thinks its only a matter of time until his life’s work finally arrives in the hands of interventional cardiologists, who he said have been “knocking at his door” since he first presented a paper on the technology in 2012. Since then, he has spoken at several of the largest interventional cardiology conferences, and word continues to spread about Optimum TAV. Like many other researchers-turned-entreprenuers, he steadfastly believes that his invention will eventually reach the market, where it can begin helping patients — like the one whose mother contacted him a decade ago.

“If hell freezes over, if we don’t get any money, I don’t care,” he said. “I don’t care how it happens. We are going to make a heart valve. That’s the only mission in my life.”

For more information on Thubrikar Aortic Valve and Optimum TAV, visit http://tavi.us/.

 

 

 

 

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Updated Transcatheter Aortic Valve Implantation (TAVI): risk for stroke and suitability for surgery

Reporter: Aviva Lev-Ari, PhD,RN

 

UPDATED on 5/27/2014

Survival After TAVI: Longest Follow-up Data Yet Yield Some Surprises

May 23, 2014

PARIS, FRANCE — Some of the longest follow-up for the first transcatheter aortic-valve implantations (TAVI) ever performed confirm earlier observations that the biggest threat to survival in TAVI-implanted patients remains their comorbidities and not problems related to their valves, regardless of valve type. More surprising, some of the procedural issues that preoccupy interventionalists and surgeons today did not emerge as important in this longer-term follow-up.

Presenting three- and five-year data from the UK TAVI registry in a press conference here at EuroPCR 2014 , Dr Neil Moat (Royal Brompton Hospital, London, UK) pointed to what he called “biphasic” survival curves. In the first few months after valve implantation, there is a steep drop in survival, he noted. Thereafter, the curve becomes significantly less steep, mirroring the survival curves typically seen in older patients who have undergone surgical valve replacement.

“In the first six months, you have quite a dramatic attrition of patients, then mortality falls to about 6% of patients per year,” he said. “What this is telling us is that patients undergoing TAVI are not dying of TAVI-related factors.”

The UK TAVI registry contains prospectively collected data from 100% of all consecutive transcatheter aortic-valve replacement (TAVR) patients treated since January 1, 2007. The current analysis includes 870 early patients whose mortality status was ascertained in July 2013.

In all, 62% of TAVR-treated patients were alive at three years, while just under half—48.4%—were still alive at five years.

Dr Neil Moat [Source: EuroPCR]

In multivariable analyses, the strongest baseline predictor of mortality at three years was

  • creatinine >200 µg/mmol, followed by
  • presence of atrial fibrillation,
  • chronic obstructive pulmonary disease (COPD), or a
  • high EuroSCORE (>18.5).

Of note, device- or procedure-related characteristics that typically get a lot of attention at interventional meetings were not significant predictors of late survival. For example,

  • 12.7% of patients still alive at three years had had moderate/severe aortic regurgitation at the time of their procedure, compared with
  • 14.9% of patients who’d died, but the difference was not statistically significant. Likewise,
  • permanent pacemaker implantation had been performed in 16.2% of patients still alive at follow-up and in
  • 19.3% of patients who died, again a nonsignificant difference.

Not surprisingly,

  • more transfemorally treated patients were alive at three years than
  • patients treated via a nontransfemoral procedure (64.3% vs 55.7%, p=0.017).

Roughly the same number of patients received the

  • Edwards Sapien device in the early days of the TAVI registry (410) as received the
  • Medtronic CoreValve (452).

By three years,

  • 40.7% of Sapien-treated patients had died, compared with
  • 35.4% of CoreValve-treated patients (p=0.078).
“CoreValve had a trend toward better survival, but I wouldn’t want to overinterpret that,” Moat cautioned. These are preliminary data, he stressed, but added, “There is a trend there that needs looking at” when the registry has more patients, with more follow-up.

One of the theories put forward in other sessions at EuroPCR is that the higher pacemaker-implantation rate with CoreValve might, in fact, help bump up survival rates with this device.

“It’s an interesting hypothesis,” Moat said. “But I don’t think we have any data to support that hypothesis, either here or in any other study. I think if there were an effect of early pacemaker implantation it would be in this first [six-month] phase. Some people are concerned that the early attrition is sudden death because of late heart block occurring two, three, or four months after the procedure. So if you are having pacemakers implanted more frequently, you are being protected from that, but I think our data strongly suggest that pacemaker implant does not affect long-term survival.”

Moat disclosed being a consultant for Medtronic.

 

UPDATED on 2/9/2014

Transcatheter Technologies Completes Durability Testing of Its Prosthetic Aortic Heart Valve, Intrinsic to World’s First ‘Truly Repositionable’ TAVI Device, TRINITY

January 28, 2014 6:29 AM 

Business Wire

“This 3rd-generation TRINITY technology could be a game-changer for TAVI.” Prof. Dr. Christian Hengstenberg, MD, German Heart Center, Munich (Note: Prof. Dr. med Hengstenberg has no financial ties to Transcatheter Technologies.)

REGENSBURG, Germany–(BUSINESS WIRE)–January 28, 2014–

Transcatheter Technologies GmbH, an emerging medical device company that is developing a third-generation transcatheter aortic valve implantation (TAVI) system-TRINITY-announced today that an independent laboratory has completed ‘advanced wear testing’ (AWT) of the company’s TRINITY valve prosthesis, far exceeding minimum testing standards. Indeed, AWT of the TRINITY heart valve has already completed 600 million cycles, or an estimated 15 years of durability testing.

Transcatheter Technologies has previously announced the successful 30-day follow-up results of a pilot study of its TRINITY TAVI system that is designed to be the world’s first ‘truly repositionable’ and, therefore, best TAVI system.

“Unlike second-generation TAVI systems, the Trinity aortic valve is designed to be positioned precisely or repositioned, even after full implantation, in a safe and simple manner,” said principal investigator Prof. Dr. Christian Hengstenberg, a cardiologist at the German Heart Center, Munich, Germany, with no financial interest or arrangement or affiliation with Transcatheter Technologies. “In our study, Trinity’s novel sealing cuff continues to provide outstanding follow-up results without PVL (paravalvular leak), a frequent complication of TAVI. Equally important, the TRINITY aortic valve is designed to reduce the risk of atrio-ventricular (AV) block significantly through supra-annular positioning of the TRINITY valve.”

“We are extremely pleased that our TRINITY valve has already demonstrated three times the minimum standard for advanced wear testing of a tissue heart valve,” said Wolfgang Goetz, M.D., Ph.D., CEO, a cardiac surgeon by training. We also are extremely pleased with the continuing excellent results of our third-generation TRINITY System in the follow-up of our first patient.

“The big issue with the second-generation TAVI systems is that they cannot be truly repositioned once fully implanted. TRINITY, however, is designed to solve this critically important issue and thereby potentially reduce the undesirable side consequences of PVL,” added Dr. Goetz. “With TRINITY, once our valve is completely expanded and anchored above the annulus, a cardiologist can fully evaluate the valve’s function to determine whether it needs to be repositioned, retrieved, or kept in the same position. This feature and its supra-annular anchoring are absolutely unique to TRINITY, which is why we have positioned TRINITY as a Third-Generation TAVI System.”

CAUTION: TRINITY is not approved for use in the United States

Ronald Trahan Associates Inc.
Ronald Trahan, APR, +1-508-359-4005, x108

SOURCE

Transcatheter aortic valve implantation (TAVI): risk for stroke and suitability for surgery

For additional discussion go to 

Transcatheter Aortic Valve Implantation (TAVI): Risky and Costly

https://pharmaceuticalintelligence.com/2012/08/02/transcatheter-aortic-valve-implantation-tavi-risky-and-costly/

BMJ 2012; 345 doi: 10.1136/bmj.e4710 (Published 31 July 2012) Cite this as: BMJ 2012;345:e4710

Evidence for TAVI Questioned

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: July 31, 2012

The tens of thousands of transcatheter aortic valve implantations (TAVI) performed worldwide may not have solid evidence behind them, European researchers suggested.

To begin with, a health technology assessment commissioned by the Belgian government suggested that only patients who are “deemed inoperable for technical reasons such as a series of previous operations or irradiation of the chest wall” be reimbursed for TAVI, according to Mattias Neyt, PhD, of the Belgian Health Care Knowledge Centre in Brussels, and colleagues.

That’s about 10% of patients currently being considered for the procedure, they wrote online in an analysis article in BMJ.

Why is there such a big disconnect between the growing number of patients undergoing TAVI and the findings of the Belgian technology assessment? Neyt and colleagues said there are several factors that have resulted in more enthusiasm than evidence for TAVI.

One of those factors is the process by which medical devices receive marketing approval in the E.U., which, they said, puts medical devices “on the same footing as domestic appliances such as toasters.”

As a consequence of what the authors referred to as “Europe’s lax licensing laws,” the two TAVI devices in common use today – Medtronic’s CoreValve and Edward Lifescience’s Sapien – were approved in 2007, “long before any substantial clinical trial evidence was available.”

Even the U.K.’s National Institute for Health and Clinical Excellence (NICE) concluded that the evidence was “adequate from a clinical point of view” for the use of TAVI in those unsuitable for surgery, but when surgery is an option — even a high-risk one — the evidence for TAVI was inadequate.

However, the British analysis did not consider costs associated with the procedure, Neyt and colleagues pointed out.

In the U.S., the FDA approval process is more rigorous than that of the E.U., but Neyt and colleagues were “far from convinced” that the results from the PARTNER trials (Cohort A andCohort B) were adequate to justify approval of the Sapien valve.

Although the cost-effectiveness of TAVI for inoperable patients (cohort B) is “equivocal,” they wrote, the clinical evidence seems to suggest that TAVI can be justified. However, they pointed out some problems that they said were not considered within the overall evidence, such as a higher rate of comorbidities and a higher rate of previous MIs among the inoperable control patients.

In PARTNER cohort A, where TAVI was compared with high-risk surgical patients, the authors noted a concern for a higher rate of stroke or transient ischemic attack among the TAVI patients.

Nevertheless, an FDA panel in June recommended expanding the indication for the Sapien valve to include high-risk surgical candidates. One of the panelists said that stroke is “just an accepted risk of the procedure.”

But Neyt and colleagues don’t accept that. They concluded that based on the evidence, as well as the concern for efficient use of limited resources, “it is difficult to see how healthcare payers can justify reimbursing TAVI for patients suitable for surgery, given that the risk of stroke is twice as high after TAVI.”

Another issue that could undermine the integrity of the evidence, Neyt and colleagues said, was the absence of full disclosure on the part of principal investigator Martin B. Leon, MD, from Columbia University.

According to the Belgian researchers, part of the deal involving the sale of Leon’s valve company to Edwards included future payments from Edwards “on the achievement of three milestones: successful treatment of 50 patients, regulatory approval in Europe, and limited approval in the U.S.”

These three milestones were not disclosed in the original paper published in the New England Journal of Medicinethey said.

Neyt and colleagues also complained that the FDA and Edwards Lifesciences are holding on to negative findings from an FDA-authorized follow-on study of 90 inoperable patients. Some of the data released at an FDA meeting in 2011 showed a higher 1-year mortality rate among those receiving TAVI (34.3% versus 21.6%), they said, but efforts to obtain any of those data have been rebuffed by both the FDA and Edwards.

They brought this concern to the editors of the NEJM, but the editors didn’t think the concern invalidated the overall PARTNER findings.

Tying all this together, Neyt and colleagues called for “a major improvement in transparency of information” that would “allow clinicians to practice evidence-based medicine, patients to make informed decisions, and health technology assessment agencies to make the right judgments.”

The authors reported they had no relationships to disclose.

Primary source: BMJ

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Transcatheter Aortic Valve Implantation (TAVI): FDA approves expanded indication for two transcatheter heart valves for patients at intermediate risk for death or complications associated with open-heart surgery

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED ON 8/23/2016

FDA approves expanded indication for two transcatheter heart valves for patients at intermediate risk for death or complications associated with open-heart surgery

about a third of patients referred for open-heart surgery for aortic-valve replacement fall into the intermediate-risk category, defined as having at least a 3% risk of death within 30 days of surgery.

http://www.medscape.com/viewarticle/867656?nlid=109007_3866&src=WNL_mdplsfeat_160823_mscpedit_card&uac=93761AJ&spon=2&impID=1183827&faf=1

 

For Immediate Release

August 18, 2016

Release

The U.S. Food and Drug Administration today approved an expanded indication for the Sapien XT and Sapien 3 transcatheter heart valves for patients with aortic valve stenosis who are at intermediate risk for death or complications associated with open-heart surgery. These devices were previously approved only in patients at high or greater risk for death or complications during surgery.

“This is the first time in the U.S. that a transcatheter aortic valve has been approved for use in intermediate risk patients,” said Bram Zuckerman, M.D., director of the division of cardiovascular devices at the FDA’s Center for Devices and Radiological Health. “This new approval significantly expands the number of patients indicated for this less invasive procedure for aortic valve replacement.”

Aortic valve stenosis increases with age as the aortic valve becomes narrow, causing the heart to work harder to pump enough blood through a smaller opening. It occurs in about three percent of Americans over age 75 and can cause fainting, chest pain, heart failure, irregular heart rhythms (arrhythmias), cardiac arrest or death. Patients with severe aortic valve stenosis generally need to have a heart valve replacement to improve blood flow through their aortic valve.

Traditionally, open-heart surgery has been the gold standard for aortic valve replacement in intermediate risk patients, but it involves a larger incision and longer recovery time than the minimally invasive procedure used to insert the transcatheter heart valve. About one-third of patients referred for open-heart surgery for aortic valve replacement fall into the “intermediate risk” category, which is defined as having a greater than three percent risk of dying within 30 days following surgery.

In a clinical study to evaluate safety and effectiveness, 1,011 aortic stenosis patients at intermediate risk for surgical complications were randomly selected to have a transcatheter aortic valve replacement procedure using the Sapien XT valve and 1,021 were randomly selected to have a traditional aortic valve replacement during open-heart surgery using a surgical tissue valve. In a second study, 1,078 intermediate risk patients were implanted with the Sapien 3 valve; and outcomes in these patients were compared to the same group of 1,021 surgical control patients in the first study. The two studies demonstrated a reasonable assurance of safety and effectiveness of the Sapien XT and Sapien 3 devices in intermediate risk patients.

Patients who receive either the Sapien XT or the Sapien 3 valve face a potential risk of serious complications from the device or implantation procedure, such as death, stroke, acute kidney injury, heart attack, bleeding, and the need for a permanent pacemaker.

The devices are contraindicated for patients who cannot tolerate blood thinning medication. They are also contraindicated for those who are currently being treated for a bacterial or other infection.

As part of the approval of these devices, the FDA is requiring the manufacturer to conduct a post-approval study to follow the patients treated with either device in the first and second clinical studies for 10 years to further monitor safety and effectiveness.

Sapien XT and Sapien 3 are manufactured by Edwards Lifesciences, LLC, based in Irvine, California.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

 
8/2/2012

Transcatheter Aortic Valve Implantation (TAVI): Risky  and Costly

On this Scientific Web Site, Frontiers in Cardiology and Cardiac Repair are reported as discovered and debated in the literature. Our address of the innovations involving the development of TAVI are reported as follows:

June 4, 2012 Investigational Devices: Edwards Sapien Transcatheter Aortic Valve Transapical Deployment https://pharmaceuticalintelligence.com/2012/06/04/investigational-devices-edwards-sapien-transcatheter-heart-valve/

June 10, 2012Investigational Devices: Edwards Sapien Transcatheter Aortic Heart Valve Replacement Transfemoral Deployment https://pharmaceuticalintelligence.com/2012/06/10/investigational-devices-edwards-sapien-transcatheter-aortic-heart-valve-replacement-transfemoral-deployment/

June 19, 2012 — Executive Compensation and Comparator Group Definition in the Cardiac and Vascular Medical Devices Sector: A Bright Future for Edwards Lifesciences Corporation in the Transcatheter Heart Valve Replacement Market https://pharmaceuticalintelligence.com/2012/06/19/executive-compensation-and-comparator-group-definition-in-the-cardiac-and-vascular-medical-devices-sector-a-bright-future-for-edwards-lifesciences-corporation-in-the-transcatheter-heart-valve-replace/

Our reporting on Regulatory Affairs for Medical Devices was reported on 7/31/2012.

July 31, 2012 Gaps, Tensions, and Conflicts in the FDA Approval Process: Implications for Clinical Practice https://pharmaceuticalintelligence.com/2012/07/31/gaps-tensions-and-conflicts-in-the-fda-approval-process-implications-for-clinical-practice/

 

On August 1, 2012, in BJM researchers at  KCE, Belgian Health Care Knowledge Centre, Administratief Centrum Kruidtuin, Kruidtuinlaan 55, 1000 Brussels, Belgium; 2CEBAM, Belgian Centre for Evidence-Based Medicine and Branch of the Dutch Cochrane Centre, Leuven, Belgium — reported research results which are examining why the practice of TAVI has gone beyond the evidence.

Edwards Lifesciences shares closed down more than 2% yesterday after the British Medical Journal said many procedures using its Sapien heart valve “cannot be justified on medical or cost-effectiveness grounds.”

On August 1, 2012 — Shares of Edwards Lifesciences (NYSE:EW) slid 2.2% yesterday after an analysis published in the British Medical Journal claimed that “many” of the heart valve replacements using its flagship Sapien heart valve “cannot be justified” and leveled accusations of conflict of interest and unethical conduct against Edwards and Sapien inventor Dr. Martin Leon.

http://www.massdevice.com/news/edwards-lifesciences-slides-rebounds-negative-heart-valve-study

A trio of Belgian researchers said their “rigorous analysis of all the available data, in combination with a study of real world [transcatheter aortic valve implant] practice in Europe, led us to conclude that the arguments supporting the widespread use of TAVI do not stand up to scrutiny.”

“In addition, the Partner trial seems to have important problems, the most relevant being publication bias and lack of data transparency, unbalanced patient characteristics, and incompletely declared conflicts of interest,” wrote Hans Van Brabandt, Mattias Neyt and Frank Hulstaert, who were commissioned by the Belgian government to run the analysis.

Edwards shares closed on 8/1/2012 at $101.20, down 2.2%, 

On 8/2/2012 it closed at 99.30 (0.75 below yesterday)

52wk Range: 61.59 – 106.94

The BMJ researchers wrote that Belgian health authorities should pay for only about 10% of the patients now considered for trancatheter aortic valve replacements in the lowland country – procedures using the Sapien heart valve and a competing device, Medtronic‘s (NYSE:MDT) CoreValve implant, should be limited to patients who aren’t good candidates for traditional open heart surgery. The CoreValve device is not yet approved for the U.S. market.

Edwards’ Partner trial for the Sapien valve was flawed due to potential bias on the part of Leon, according to the researchers. Leon founded a company to develop the implant that Edwards acquired in 2004, triggering a $6.9 million payout that was disclosed. But other milestone payments due to Leon were not disclosed, they wrote, creating “substantial financial interests that we do not believe were fully disclosed.””We believe Dr. Marty Leon has conducted himself throughout the Partner trial in accordance with the highest ethical standards. In his role as co-principal investigator of the trial, he has only been reimbursed for travel-related expenses,” an Edwards spokeswoman told MassDevice.com in an email today. “Dr. Leon also has – throughout the Partner trial – remained in compliance with the strict conflict-of-interest standards of both the FDA and Columbia University. As previously reported, the sale of PVT to Edwards took place in 2004 and the single milestone payment (that Dr. Leon donated to charity) was made in 2006, well before the beginning of the pivotal trial.”The Partner study was also biased by imbalance between the treatment and control groups in the TAVI cohort that favored Sapien, they wrote.Brabandt, Neyt and Hulstaert also claimed that repeated requests to Edwards and Leon for access to data from an FDA-ordered follow-on study of the Sapien device “went unanswered.”

“In our view, this behaviour is both ethically and scientifically unacceptable and should be legally regulated in
future [sic],” they wrote. “Study sponsors should be obliged to make the results of a negative trial public so that policy makers can reach rational and balanced decisions.”

Some of that data, from a 90-patient study of inoperable candidates, was presented at an FDA meeting in July 2011, according to the Belgian researchers. Those results demonstrated a higher risk of mortality after a year among the cohort treated with the Sapien valve (34.3% vs. 21.6%, they wrote).

The researchers also took a shot at the New England Journal of Medicine, which they approached after being rebuffed by Edwards and Leon. The NEJM editors passed the researchers’ “objections” on to the investigators, but the response convinced the editors that “while each of the points we raised deserved a thoughtful review, they did not, either individually or together, fundamentally place the findings of the Partner trial in serious doubt.”

 “NEJM has, however, published 2-year follow-up results that essentially confirmed the one year data. However, it did so without demanding that the study sponsor publish or discuss the negative results of the follow-on trial. It is difficult to understand this decision,” the Belgian researchers wrote.

“Based on current evidence, and considering efficient use of limited resources, it is difficult to see how healthcare payers can justify reimbursing TAVI for patients suitable for surgery, given that the risk of stroke is twice as high after TAVI,” the researches concluded. “In addition, TAVI is much more expensive, on average about €20,000 more per patient in our analysis of Belgian data. Based on observational data, the costs during the initial hospital admission, inclusive of an Edwards Sapien valve of €18,000, are on average €43,600 for TAVI versus €23,700 for surgical valve replacement.”

Transcatheter aortic valve implantation (TAVI): risky and costly

Many of the 40 000 transcatheter procedures so far carried out cannot be justified on medical or cost effectiveness grounds. Hans Van Brabandt, Mattias Neyt, and Frank Hulstaert examine why practice has gone beyond the evidence. The three researchers are:

Hans Van Brabandt researcher 1 2, Mattias Neyt researcher 1, Frank Hulstaert researcher 1

1KCE, Belgian Health Care Knowledge Centre, Administratief Centrum Kruidtuin, Kruidtuinlaan 55, 1000 Brussels, Belgium; 2CEBAM, Belgian Centre for Evidence-Based Medicine and Branch of the Dutch Cochrane Centre, Leuven, Belgium

Correspondence to: M Neyt mattias.neyt@kce.fgov.be

BMJ 2012;345:e4710 doi: 10.1136/bmj.e4710 (Published 31 July 2012) Page 1 of 5

Analysis

Around the world, tens of thousands of people have been treated for a life threatening heart condition using a minimally invasive technique that many see as the wave of the future. Transcatheter aortic valve implantation (TAVI) offers hope to patients too old or too ill for conventional aortic valve replacement operations, and since its introduction 10 years ago it has spread swiftly—by the end of 2011, an estimated 40 000 transcatheter implantations had been done.1 But serious unanswered questions remain over the clinical outcomes and the cost effectiveness of TAVI, as well as the regulatory process that enabled it to gain such a large market so rapidly, particularly in Europe.

Aortic stenosis, the progressive failure of the aortic valve to open fully, is the commonest type of valve disease in elderly people. It is usually treated by valve replacement surgery, but around a third of those who might benefit are turned down because the risks of surgery are too high or because problems such as a calcified aorta or scarring from previous surgery make them unsuitable for surgery.2 Untreated, most will die within five years.3 TAVI offers an alternative, in which a replacement valve is introduced through an artery via a small incision (usually the femoral artery) or, less often, surgically with an incision into the chest and then into the left ventricular apex—the transapical approach.

The numbers who could potentially benefit from TAVI are verylarge.4 Almost 3% of people over 75 have aortic valve disease,5which means that in England alone there are more than 100 000patients in whom aortic valve surgery might at a given moment be contemplated. But only around 1200 aortic valve replacements are carried out in this age group in England each year. This helps explain the enthusiasm with which TAVI has been taken up, and the large potential market. In April 2011, a New York securities analyst for the financial services company Wells Fargo estimated that TAVI could generate more than $2.4bn (£1.5bn; €2bn) in sales in the US and account for more than a third of aortic valve replacements by 2015.6 Cardiologists in the US also expect growing demand from patients who are suitable for conventional surgery but who prefer the quicker and less painful transcatheter option. Data reported at the European Society of Cardiology (EuroPCR) meeting in Paris in May7 suggested that transcatheter procedures have more than tripled in Europe since 2009, rising to 18 372 in 2011. Germany is far ahead of other European nations, being responsible for 43% of all TAVIs, followed by France (13%), Italy (10%), and the UK and Ireland (7%).1

Approval processes

Given the enthusiasm with which the procedure has been adopted, we might expect the evidence for its efficacy to be solid. But a health technology assessment we carried out, commissioned by the Belgian government, concluded that the Belgian health authorities should pay for TAVI in only a minority of patients (10%) of those currently considered for treatment—those who are deemed inoperable for technical reasons such as a series of previous operations or irradiation of the chest wall.8 The United Kingdom’s National Institute for Health and Clinical Excellence (NICE) guidance issued in March this year said that for patients considered unsuitable for surgery, the evidence for TAVI was adequate from a clinical point of view but it did not take costs into account.9 But NICE said that for patients for whom surgery is suitable, albeit risky, the evidence for using TAVI was inadequate, and it should be used in these circumstances only when special arrangements for clinical governance, consent, and data collection or research were in place.9

In the European Union, medical devices fall outside the scope of the European Medicines Agency and need only a simple quality certificate (CE mark) to gain access to the market, putting them on the same footing as domestic appliances such as toasters. Two different valves for transcatheter implantation gained their CE marks in 2007, long before any substantial clinical trial evidence was available: the Edwards Sapien valve and the Medtronics CoreValve. In the US the law demands evidence of efficacy in a randomised trial before the Food and Drug Administration can license any innovative device. Thus TAVI was in use in Europe four years before the FDA licensed the Sapien valve in November 2011, and—in contrast to Europe—only for the transfemoral approach and for patients considered unsuitable for standard valve surgery.10 The transapical route was not approved. In June 2012, a panel of expert advisers recommended that the FDA approved the Sapien valve for high risk operable patients, including a transapical delivery option.11 The advisory panel does not take economic considerations into account.

The European system for approving medical devices has already come in for criticism over breast and hip implants, with the new executive director of the EMA, Guido Rasi, acknowledging in January that there is an urgent need to regulate devices with the same care as medicines. “I think, at the end of the day, we will see everyone moving to increasing use of comparative trials,” Rasi said in an interview with Reuters.12 He expected that concerns about the now defunct French breast implant company Poly Implant Prosthese might help to speed the process. But while the evidence demanded by the FDA exceeded that required in Europe, we remain far from convinced that it is adequate. The Sapien valve was approved on the basis of a trial called PARTNER (Placement of Aortic Transcatheter Valve).

We reviewed the conduct and results of the trial through papers published in peer reviewed journals, proceedings from congresses, press releases, and direct contacts with the manufacturer, the FDA, the New England Journal of Medicine (NEJM) (where it was published), and the principal investigators.

Our rigorous analysis of all the available data, in combination with a study of real world TAVI practice in Europe, led us to conclude that the arguments supporting the widespread use of TAVI do not stand up to scrutiny. In addition, the PARTNER trial seems to have important problems, the most relevant being publication bias and lack of data transparency, unbalanced patient characteristics, and incompletely declared conflicts of interest.

What the evidence shows

PARTNER was a randomised controlled trial in 26 sites, most of them in the US. It allocated patients with severe aortic valve stenosis to two groups: those at very high risk from surgery (cohort A)13 and those deemed inoperable (cohort B).14 The 699 patients in cohort A were randomised either to TAVI or to surgical valve replacement, and the 358 in cohort B were randomised to TAVI or standard therapy, which was balloon aortic valvuloplasty in most cases, combined with medical supportive treatment.

The results showed that in the high risk operable patients, mortality at one year was similar for TAVI and surgical insertion (24.2% v 26.8%, P=0.44) (table⇓). PARTNER was designed as a non-inferiority trial, with a difference of 7.5 percentage points in survival set as the margin, so TAVI met this target. But strokes and transient ischaemic attacks were significantly commoner in the TAVI group at one year (8.3% v 4.3%, P=0.04) and major vascular complications significantly commoner at 30 days (11.0% v 3.2%, P=0.001). Major bleeding and new onset atrial fibrillation were significantly higher in the surgical group. At one year, symptoms were about the same in both groups.13

In the patients deemed inoperable, results were relatively better. Mortality at one year was significantly lower for TAVI (30.7% v 50.7%, P<0.001). Again, however, there was a higher incidence of stroke and major vascular events in the TAVI group (10.6% v 4.5%, P=0.04).14 Taken together, these results suggest that TAVI can be justified for inoperable patients on clinical grounds, though cost effectiveness calculations are more equivocal. But even this conclusion is thrown into doubt by a follow-up study authorised by the FDA, in which 41 inoperable patients were randomised to TAVI and 49 to standard therapy. This study remains unpublished, and our attempts to gain access to further details have been rebuffed by the FDA and the study sponsor. But the data presented at an FDA meeting on 20 July 2011 showed that the TAVI patients fared worse than those given standard therapy (one year mortality 34.3% v 21.6%).15

We have repeatedly sought access to further details of this follow-on trial, carried out under FDA auspices as a formally approved “continued access study,” the purpose of which is to enable sponsors of clinical investigations to continue to enroll patients while a market application is being sought. The FDA responded that any further data analysis of a premarket application is proprietary information and that it was up to the sponsor to release it, if so inclined. But our requests to the sponsor (Edwards) and the principal investigator went unanswered. In our view, this behaviour is both ethically and scientifically unacceptable and should be legally regulated in future. Study sponsors should be obliged to make the results of a negative trial public so that policy makers can reach rational and balanced decisions.

Given our failure to make progress with the FDA or the sponsor, we approached the NEJM which had published the PARTNER trial. We put our objections to the NEJM, which passed them on to the investigators. Their response convinced the NEJM editors that “while each of the points we raised deserved a thoughtful review, they did not, either individually or together, fundamentally place the findings of the PARTNER trial in serious doubt.” Asked what the responses of the investigators had been, NEJM responded that it had not requested permission from them to pass them on, since they were intended for its own confidential evaluation. We were recommended to request this information directly from the study sponsor, which we did, to no avail.

NEJM has, however, published two year follow-up results that essentially confirmed the one year data.16 17 However, it did so without demanding that the study sponsor publish or discuss the negative results of the follow-on trial. It is difficult to understand this decision. Our concerns about the PARTNER trial go further than this, however. Published data on the inoperable patients, who had the most convincing results, show that the treatment and control groups are unbalanced in a way that would favour TAVI. The control group contained more patients with comorbidities, more who had had a previous heart attack, and more who were classified as frail than the TAVI group. There were fewer patients with an extensively calcified aorta. All these differences could have arisen from a flawed randomisation or by chance; but since they favour TAVI, an analysis that adjusted for prognosis at baseline would have produced a more realistic estimate of the effect size.

Disclosure of interests

BMJ 2012;345:e4710 doi: 10.1136/bmj.e4710 (Published 31 July 2012) Page 1 of 5

Practice beyond the evidence

What concerns us most is that in Europe the use of TAVI in the transapical route far exceeds what is justified by the clinical evidence. The PARTNER trial does not provide clear evidence on this route. A subgroup analysis suggests that the transapical approach is not inferior to surgery but has double the risk of stroke. Although the FDA proposed it,19 the trial sponsor declined to include a transapical arm in inoperable patients. But despite this dearth of evidence, TAVI is widely used transapically in Europe.

The UK TAVI registry, for example, shows that 409 of 1620 TAVI patients (25%) were treated transapically, with a one year mortality of 25.5%.20 The FRANCE-2 registry shows that of 2430 patients treated in 2010 and 2011, 20% had transapical TAVI, with a six month mortality of 20.2%.21 We cannot know, of course, what the survival rate of these patients would have been if they had been treated medically or by standard surgery. A position statement by the British Cardiovascular Intervention Society and the Society of Cardiothoracic Surgeons does not distinguish between the transfemoral and transapical approaches despite the different evidence bases.22 It states that TAVI should currently be reserved for patients in whom “the risk/benefit ratio of open heart surgery versus TAVI favours TAVI.” It calls for randomised trials, but only when centres in the UK have got “beyond their learning curve.” Patients may be surprised to hear that trials are being delayed to allow cardiologists and surgeons time to learn the technique.

Concerns about transapical TAVI were heightened by the early termination of a Danish trial called STACCATO,23 which compared transapical TAVI against conventional surgery. Five of 34 TAVI patients and only one of 36 surgically treated patients had either died or had a major stroke or renal failure within 30 days, prompting the data safety monitoring board to call a halt. This discouraging result was reported at the 2011 transcatheter cardiovascular therapeutics conference in San Francisco and drew criticism from Michael Mack, of the University of Texas at Dallas, who said the study was poorly designed and poorly executed.24 Mack, an investigator in the PARTNER trial, said: “I think there is some misinformation here, based on an invalid trial design, that is likely to hurt the field.”

Leif Thuesen, of Aarhus University Hospital in Denmark, who presented the STACCATO results, was more concerned with patients than with the field. “There is no doubt that there are patients who can’t be operated on, and they should be treated with TAVI” he told heartwire. “But the patient who can be operated on—here, we should be very, very cautious. It’s the operable patients, the low-risk patients, they should not have the TAVI procedures, but that’s what is happening. We had one patient, for instance, who did not want the conventional operation, so he had the TAVI procedure in Canada. That’s how it is. Indications are slipping.”24 In contrast to the current situation in Europe, we recommend that marketing approval for a high risk device should be granted for specific indications only. Each of these indications should be supported by clinical evidence from high quality randomised trials. Patients may be at risk if the high risk device is routinely used outside those indications. Payers may have an interest in limiting reimbursement of such high risk devices only to those indications for which there is a high level of evidence of efficacy and cost effectiveness.25

Based on current evidence, and considering efficient use of limited resources, it is difficult to see how healthcare payers can justify reimbursing TAVI for patients suitable for surgery, given that the risk of stroke is twice as high after TAVI. In addition, TAVI is much more expensive, on average about €20,000 more per patient in our analysis of Belgian data. Based on observational data, the costs during the initial hospital admission, inclusive of an Edwards Sapien valve of €18 000, are on average €43 600 for TAVI versus €23 700 for surgical valve replacement. The average cost of transapical TAVI is higher than for the transfemoral approach (€49 800 v €40 900).26 The NICE guidance did not include a cost-benefit analysis, but these costs should be taken into account by local NHS commissioners in decisions about whether to fund the procedure. If policy makers are willing to pay for TAVI, they should give priority to anatomically inoperable patients.8 26 Europe’s lax licensing laws set up in an era where medical devices typically comprised hearing aids, walking frames, and spectacles are not appropriate for implantable devices. It should require high quality randomised trials to show clinical efficacy and safety before granting marketing approval to innovative, high risk medical devices. And a major improvement in transparency of information is also needed to allow clinicians to practise evidence based medicine, patients to make informed decisions, and health technology assessment agencies to make the right judgments.

REFERENCE

1 Nainggolan L. Germany tops TAVI table, but room for growth remains, 1 November, 2011. www.theheart.org/coverages.do.

2 Iung B, Cachier A, Baron G, Messika-Zeitoun D, Delahaye F, Tornos P, et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005;26:2714-20.

3 Varadarajan P, Kapoor N, Bansal RC, Pai RG. Survival in elderly patients with severe aortic stenosis is dramatically improved by aortic valve replacement: results from a cohort of 277 patients aged ≥80 years. Eur J Cardiothorac Surg 2006;30:722-7.

4 Ray S. Estimated population need for TAVI, data presented at a consensus meeting, 16 December 2008. www.ucl.ac.uk/nicor/audits/tavi/pdfs/estimated.

5 Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 1997;29:630-4.

6 Cortez M. Edwards valve study may spur patient demand doctors aren’t ready to meet Bloomberg News 2011 Apr 4. www.bloomberg.com/news/2011-04-04/edwards-valvestudy- may-spur-patient-demand-doctors-aren-t-ready-to-meet.html.

7 TAVI numbers rise in Europe as reimbursement, expertise expands. Heartwire 2012 May 17. www.theheart.org/article/1401795.do.

8 Neyt M, Van Brabandt H, Van de Sande S, Devriese S. Transcatheter aortic valve implantation (TAVI): a health technology assessment update. KCE reports 163C. Belgian Health Care Knowledge Centre (KCE), 2011.

9 NICE. Transcatheter aortic valve implantation for aortic stenosis. NICE interventional procedure guidance 421. NICE, 2012.

10 FDA. Edwards SAPIENTM transcatheter heart valve, model 9000TFX, sizes 23mm and 26mm and accessories. www.accessdata.fda.gov/cdrh_docs/pdf10/p100041a.pdf.

11 Wood S. Approve Sapien TAVR for high-risk operable patients, FDA advisors say. Heartwire 2012 Jun 14. www.theheart.org/article/1414539.do.

12 Hirschler B. EU medicines head urges tougher implant rules. 2012 www.reuters.com/ article/2012/01/06/us-breastimplants-ema-idUSTRE8050VL20120106.

13 Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187-98.

14 Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. Engl J Med 2010;363:1597-607.

15 FDA. SAPIEN THV briefing document—advisory committee meeting. FDA, 2011:301.

16 Makkar RR, Fontana GP, Jilaihawi H, Kapadia S, Pichard AD, Douglas PS, et al. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 2012;366:1696-704.

17 Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686-95.

18 Medicine in conflict. Businessweek 2006 Oct 23. www.businessweek.com/magazine/ content/06_43/b4006081.htm.

19 FDA. FDA executive summary: Edwards SAPIEN THV. FDA, 2011.

20 Blackman D. Outcome of TAVI by valve type and access route: UK TAVI registry. 2011. www.pcronline.com/Lectures/2011/Outcome-of-TAVI-by-valve-type-and-access-route.- UK-TAVI-registry.

21 Gilard M. FRANCE II—French aortic national core valve and Edwards registry. EuroPCR conference, Paris, 17-20 May 2011.

22 British Cardiovascular Intervention Society, Society of Cardiothoracic Surgeons. Transcatheter aortic valve implantation (TAVI): a position statement. www.ucl.ac.uk/nicor/ audits/tavi/pdfs/bcisposition.

23 Nielsen HH, Klaaborg KE, Nissen H, Terp K, Mortensen PE, Kjeldsen BJ, et al. A prospective, randomised trial of transapical transcatheter aortic valve implantation vs. surgical aortic valve replacement in operable elderly patients with aortic stenosis: the STACCATO trial. EuroIntervention 2012. May 14. [Epub ahead of print].

24 O’Riordan M. STACCATO; transapical TAVI in surgery-eligible patients stopped due to adverse events. Heartwire 2011 Nov 10. www.theheart.org/article/1307437.do.

25 Hulstaert F, Neyt M, Vinck I, Stordeur S, Huić M, Sauerland S, et al. The pre-market clinical evaluation of innovative high-risk medical devices. KCE Report 158C. D/2011/10.273/31. Belgian Health Care Knowledge Centre, 2011.

26 Neyt M, Van Brabandt H, Devriese S, Van De Sande S. A cost-utility analysis of transcatheter aortic valve implantation in Belgium: focusing on a well-defined and identifiable population. BMJ Open 2012;2:e001032.

 

Table

Table 1| One year mortality and stroke rate in the PARTNER trial13 14 15

Inoperable patients

High risk patients* Pivotal trial† Continued access study‡

TAVI AVR P value TAVI Control P value TAVI Control

No of patients 348 351 179 179 41 49

1 year all cause mortality (% (No of events))§ 24.2 (84) 26.8 (89) 0.44 30.7 (55) 50.7 (89) <0.001 34.3 (13) 21.6 (10)

1 year stroke rate (% (No of events))¶ 8.3 (27) 4.3 (13) 0.04 10.6 (19) 4.5 (8) 0.04 2.4 (1) 0 (0)

TAVI= transcatheter aortic valve implantation, AVR=surgical aortic valve replacement.

*Hazard ratio with TAVI in high risk patients: 0.93 (95% CI 0.71 to 1.22; P=0.62)

†Hazard ratio with TAVI in inoperable patients (pivotal trial): 0.55 (95% CI 0.40 to 0.74; P<0.001);

‡No P value or hazard ratio was published for the continued access study.

§ Kaplan-Meier estimates.

¶ Includes any stroke and transient ischaemic attack; stroke rate in continued access study includes “major stroke” only.

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