In the short time since its approval, transcatheter heart valve implantation has become a widely accepted and adopted technique. It could also be used in patients who cannot be treated surgically. What is behind the unusual success of the technology? And how will this sector grow and change in the future? Elizabeth Cairns investigates

Five years ago, patients with diseased aortic or pulmonary heart valves could receive prosthetic replacements, but only at the price of open heart surgery. An incision would be made in the chest, the sternum split, the ribs spread, and the pericardium (the membrane surrounding the heart) cut into. The patient would then be placed on a cardiopulmonary bypass system – a heart-lung machine – and only then could the heart itself be opened, allowing manual excision of the diseased valve and its replacement with the artificial product.

Clinica 100: Clinica's Review and Analysis of the Medtech Industry 2010

Now, however, patients in Europe requiring a new aortic or pulmonary valve routinely undergo a minimally-invasive procedure instead, receiving one of the transcatheter valves that have been marketed in Europe since 2006. This option was extended to US patients with pulmonary valve disease in February this year. This procedure is faster and safer than the open heart surgery option (particularly in older and sicker patients), and has revolutionised the treatment of valve disease.

During the procedure, the valves are mounted on a catheter which is inserted into the body via one of two routes: through the femoral vein, starting in the groin (transfemoral delivery) or through the apex of the heart's left ventricle, starting in the chest (transapical delivery). The latter is most suited to aortic valve implantation.

The first transcatheter heart valve to reach market anywhere in the world was Medtronic's Melody pulmonary valve, CE marked by the Minneapolis company in October 2006. The second, Edwards Lifesciences' Sapien, an aortic valve, followed it in late 2007. Medtronic also won the race to the US market: the FDA approved Melody under a humanitarian device exemption (HDE) earlier this year there (www.clinica.co.uk, 2 February 2010).

A hopeful therapy

In fact, one of the most exciting times for this technique and the companies exploiting it is right now. In September, results from a large US trial of Sapien led cardiologists to state that transcatheter aortic valve implantation (TAVI) could become the standard of care in the US once the device is approved there (www.clinica.co.uk, 23 September 2010). The PARTNER trial showed that TAVI significantly reduced the risk of death compared with surgery, even in the sickest patients.

"Ten years ago, replacing a heart valve without open heart surgery was thought to be impossible," Michael Mussallem, chairman and CEO of Edwards, told Clinica. "Today, it’s a reality for many thousands of very sick patients each year. There are few medical therapies offering the prospect of a short, minimally-invasive procedure that can reduce patient mortality. Transcatheter valve replacement may be one of them."

The PARTNER data bring TAVI closer to acceptance in the US as they will be used to support Edwards' US approval application for Sapien. "We plan to submit this positive PARTNER data to the FDA later this year," Mr Mussallem said, adding that the firm anticipates approval of the valve in "late 2011".

Mr Mussallem said: "We feel very good about so many things with this trial, including the high bar of scientific rigour and the partnership created between surgeons and interventional cardiologists that many thought improbable. Most importantly, the technology has shown the potential to extend life for very ill patients."

The trial will not only benefit Edwards, however; other companies hoping to develop transcatheter aortic valves will also gain. First among these is Medtronic, whose transcatheter aortic device, CoreValve, has just entered a trial with an almost identical design to PARTNER (www.clinica.co.uk, 15 October 2010).

John Liddicoat, vice-president and general manager of Medtronic's structural heart division, told Clinica that the PARTNER data were "compelling", as "they demonstrated a true survival benefit for patients who were at a prohibitive risk for cardiac surgery".

Dr Liddicoat explained that the implications of the trial covered more than just Sapien itself. "It was a very important day for the therapy in the sense that the value was demonstrated in a prospective randomised clinical trial. In many ways they validated the value of the therapy overall."

He also pointed out that the technique has a value beyond its monetary worth. "Those of us who've been caring for these patients for years and years understand that this is a very lethal disease. When you are faced with having to tell the patients 'no', because they have comorbidities that mean that they're not candidates for the surgical correction of aortic stenosis, you know that that patient stands around a 50% chance of dying within the next 12 months. That's a pretty sad and grim conversation to have with the patient and their family. For the first time, physicians who manage these patients see a hopeful therapy with the transcatheter aortic valve replacement approach."

The international TAVI market is forecast to hit the $2bn mark by 2017, so the rewards are significant for the first company to reach market. Mr Mussallem said that Edwards wasn't sure how many patients it would be able to treat once Sapien gained FDA approval. "Research indicates the prevalence of calcific aortic stenosis is 2-4% of adults over the age of 65, and within the US, about 50,000 aortic valve replacements are performed for severe aortic stenosis each year."

However, Sapien's proven safety in sicker patients means it could reach more patients than this: "It is estimated that for every patient that receives a valve replacement, there is at least one other that does not for a variety of reasons – and it is these patients who today have a very poor quality of life and poor prognosis that may be able to look forward to a treatment alternative with transcatheter valve replacement."

Edwards is the first company to gain approval for a second-generation transcatheter valve. The firm CE marked Sapien XT for sale in Europe in March this year. It is smaller than the first-generation Sapien when loaded onto its delivery catheter, and has greater radial strength once deployed.

"Second-quarter [2010] global sales of transcatheter heart valves were $53.2m, with the Sapien XT valve making a strong contribution during what was its first full quarter of launch in Europe," Mr Mussallem said. "We believe we will achieve full-year transcatheter valve sales of $190-205m in 2010."

Once these products reach the US, Edwards estimates that they will bring in sales of around $125-250m for the first four quarters post-launch.

St Jude Medical is also making its first steps towards transcatheter valve implantation, and is investigating an aortic valve. In September, Frank Callaghan, president of St Jude's cardiovascular division, told Clinica: "We have an internal programme where we're developing a brand new technology where one can place aortic valves through a transcatheter method. You can access the femoral artery and thread the heart valve up into the aortic position and deploy it."

A European clinical trial of the unnamed aortic valve is expected to start in 2011 in patients with aortic stenosis. The study will assess both the transfemoral and the transapical delivery routes.

Pulmonary

The research on aortic valves has lit up the interventional cardiology world, but it is worth remembering that the only transcatheter heart valve currently on the US market is not aortic but pulmonary. Medtronic's Melody pulmonary (also called pulmonic) valve has been quite a success story, Dr Liddicoat said. "The value of Melody isn’t in the sheer number of patients that we are able to treat, but in the impact it has on patients' lives. Having said that, the number of patients we have treated has far exceeded our expectations."

He said that Melody tends to be used to treat congenital heart disease problems, and by nature those problems are rarer than the acquired diseases, like aortic stenosis and coronary artery disease, which tend to affect the aortic valve. However, patients with congenital conditions naturally require a lifetime of management. "With Melody, though the number of patients we serve isn't large, it's that lifetime of sequential care and follow-up that's so important." He added that more than 1,500 patients have received a Melody valve in the US so far.

Medtronic declined to state how much money it gains from sales of its valves. However, its structural heart division, which includes its transcatheter valve products, brought in revenues of $880m worldwide in fiscal year 2010.

And once again, Edwards is snapping at Medtronic's heels. It CE marked its pulmonary version of Sapien in May this year, and is gearing up for US approval. Mr Mussallem said: "We continue to work through the US regulatory process, with the goal of receiving an HDE from the FDA."

With transcatheter heart valves the focus of so much attention, it is inevitable that other companies are attempting to muscle in. One of the more successful recent start-ups in the area is Symetis, a Swiss company developing two transcatheter aortic valves. Called Acurate TA and Acurate TF, they are optimised for transapical and transfemoral implantation, respectively.

"Our most advanced product is the transapical valve," Jacques Essinger, Symetis's CEO, told Clinica. "We have now completed our 40-patient first-in-human trial."

Preliminary results from this trial have been largely positive; the Acurate TA valve was successfully implanted in 38 patients (95%), with one patient receiving a commercially-available transapical valve and one patient requiring surgical valve replacement. Five patients died within 30 days of the procedure (12.5%); three of these deaths were from non-valve-related respiratory complications.

The Lausanne, Switzerland-based company is, of course, planning further trials. "We will follow the standard path that goes from first-in-human to pilot to pivotal," Mr Essinger said. "We took an aggressive approach by taking the risk of going for a very large first-in-human study. It turned out to be a winning bet, because the results were superb and we'll be able to use this 40-patient data for our CE mark submission. The pilot study combined with the first-in-human study will provide the data we need for CE mark."

He said that as soon as the company obtained ethical committee approval it would initiate a pilot study of 50 patients – this is expected before the end of this year. Enrolment in this pilot trial is scheduled to be completed in the first half of next year. "That will give us the data to file for CE mark some time in 2011," he said.

"We then want to continue with the pivotal study, independently of the CE mark. A full pivotal study would be 200 patients, and obviously pan-European."

As for Acurate TF, "the transfemoral valve will be going into the clinic in about a year from today – we're planning Q4 2011," he said.

Assuming the firm successfully launches Acurate TA in Europe, it will then turn its attention to the US. The best route to gaining FDA approval, though, is not yet clear. "Will the FDA require similar large-scale randomised trials like they are now requesting Medtronic to fulfil with the CoreValve?" asked Mr Essinger. "Or will they, once [valves] have a little more visibility, be accepting non-inferiority studies? That is certainly a question. But today we are moving all our development and all our validation plans with the idea to meet the FDA requirements and filing an IDE in due time."

Mr Essinger is confident that Acurate TA will be a success once marketed, largely due to its transapical delivery route. "We do have the expectation that our Acurate product will, over time, gain some position in the market. When you're looking at competitors I think it’s very important to be looking at how the clinical market is segmented. CoreValve is only transfemoral – Sapien is both transfemoral and transapical. I think that the transfemoral field is going to be extremely crowded over time." He said that a number of smaller companies, including Sadra Medical (Los Gatos, California), Direct Flow Medical (Santa Rosa, California) and Jenavalve (Munich, Germany), are all developing transfemoral valves.

"If you look at the transapical field, the landscape is quite different. Medtronic is absolutely not in the transapical area – in fact, Edwards' Sapien is the only product in the transapical field. To that extent I do believe that our transapical Acurate has the potential to progressively gain market share in the transapical market sector."

Future developments

Future technological developments in the transcatheter valve sector appear likely to fall into one of two categories: incremental improvements to the current technology, and the application of transcatheter replacement to the other two valves in the human heart: the mitral and tricuspid valves.

Mr Essinger said that steady advancement of the technology is more or less inevitable. "I believe that overall, transcatheter valves are going to go through the same evolution as almost any medical device." He said that the first generation proved the concept, the second generation will be easier to implant, safer and more reliable, and the third generation would seek to decrease the incidence of leakage, which is seen "in quite a high percentage of cases, and could be a limitation for moving the technology to younger patients."

Mr Mussallem concurred. "As robust as medical technology is today, there is still room for meaningful improvement to address unmet patient needs." He said that Edwards would conduct future trials to evaluate the valve's use in other patient populations, and also intended to study "the technology’s application to other valve positions".

Edwards' second-generation Sapien XT is the exemplar of the incremental improvement strategy. Medtronic, naturally, is close behind. Dr Liddicoat said that it was working on updates of both Melody and CoreValve, though he said that the company might not keep the same branding. "We're working on a second-generation transcatheter aortic valve and a second-generation transcatheter pulmonic valve."

CoreValve in particular is, he said, "very amenable to improvements". Medtronic is keen to improve the delivery system which is critical within the interventional cardiology space, he explained, as ease of use is an important consideration for cardiologists when they are selecting a valve to implant. He said that the firm "continues to strive to meet broader clinical needs, and that is where we're targeting our second-generation device."

The inventor of CoreValve, however, has a different opinion. Prof Jacques Séguin, currently chairman of stent developer Stentys, is an entrepreneur and innovator partly responsible for the initial development of transcatheter valves. In 2002, he founded the company – also called CoreValve – that pioneered the development of the device. Medtronic bought CoreValve in April 2009; the device was then called the ReValving system (www.clinica.co.uk, 16 April 2009).

Prof Séguin is less enthusiastic about second-generation devices. "In terms of aortic valves, the two valves that are on the market – the Edwards valve and the CoreValve, now a Medtronic device – do not seem to be in danger of competition with any other devices. The so-called second-generation do not seem to be working well and do not seem to be bringing much to the table," he told Clinica.

The next big thing?

The other strategy for the future development of the transcatheter valve sector – applying the technology to other heart valves – may be a better bet.

"The other valve which seems to be creating a lot of buzz, and a lot of new companies, is the mitral," said Prof Séguin. There are two or three companies doing mitral valve replacement. [The products are] like CoreValve or Sapien, but for the mitral. I would think that mitral valve replacement could be the next big thing."

Medtronic's Dr Liddicoat concurred. "So far we've talked about pulmonic and we've talked about aortic, and we've talked about next-generation pulmonic and next-generation aortic, but we're very interested in next-generation transcatheter valves for repair and replacement in the mitral space."

He said: "This is an area that I've been following now for 11 years; it's a complex space but a space where there's a real clinical need. The scale of the problem of symptomatic mitral regurgitation, or heart failure caused by mitral regurgitation, is quite large." He said that Medtronic's catheter-based therapies for mitral valve replacement are "on the near horizon".

Of the 250,000 patients newly diagnosed with mitral regurgitation in the US each year, only about 20% are treated surgically. The rest are either too high-risk or not yet sick enough for surgery. It is this need that the companies aim to meet with transcatheter devices.

Edwards is interested in mitral valve development as well. "We’re aggressively investing in R&D, to the sum of nearly $200m this year," Mr Mussallem said. "We are making a significant investment in transcatheter heart valves and advanced technology, focused on structural heart disease. We believe in particular that there are substantial unmet patient needs in the area of mitral valve disease, and we are applying our resources to evaluate novel approaches."

The race to get a transcatheter mitral valve to the European market, however, has already been won. MitraClip was CE marked by its developer, Evalve, more than two years ago (www.clinica.co.uk, 4 April 2008). Evalve was subsequently acquired by Abbott (www.clinica.co.uk, 14 September 2009). MitraClip is not yet approved by the US FDA.

Transcatheter valve technology has become phenomenally successful in a short space of time. When the US market matures it is likely to take over from surgical valve replacement to become the standard of care. "The transcatheter heart valve sector has blossomed rapidly," said Mr Mussallem. "Adoption has been robust as clinicians see how they can help patients that previously didn’t have any real treatment options."

Increasing adoption of the technique means that more firms will move into this space. "So far it's been pretty much a two-horse race in terms of large companies," said Dr Liddicoat. "But there's a whole host of start-up companies, either in the transcatheter mitral space, the transcatheter aortic space or the transcatheter pulmonic space."

Transcatheter valve technology is definitely an area to watch in the future.