BB&T

PARIS – Transcatheter aortic valve implants (TAVI) have experienced a rapid take-up in Europe since the procedure was introduced in 2007.

At EuroPCR, the annual congress for interventional cardiologists that this year attracted 12,000 participants, CoreValve/Medtronic (Minneapolis) reported it had passed the 10,000 patient milestone.

Meanwhile, Helene Eltchaninoff, MD, who pioneered the procedure in 2002, predicted that later this year procedures will cross the 17,000 patient threshold using either the valve system from Edwards Life Sciences (Irvine, California) or CoreValve.

More significantly, this year at EuroPCR patient registries recording one-year mortality and other clinical outcomes from TAVI procedures were first reported.

The chairman for the session “TAVI Facts, Figures and National Registries“, Gérard Fournial, MD, noted that with a cumulated total of from more than 3,000 patients in the registries the results were strikingly consistent with a survival rate of 80% and procedural success of 97%.

“Perhaps it is time to extend this procedure to less sick patients,“ he suggested to colleagues.

It is important to note that TAVI is indicated only for patients who can not undergo traditional open surgery to replace a failing heart valve.

Patients tend to be over 80 years of age and are fragile often presenting with complex co-morbidities.

In other words TAVI is the only hope for this population, half of whom have a life expectancy of less than one year, so that a mortality rate of one-patient in five, which would be unacceptable and even scandalous for other medical acts, is considered a triumph.

The headline presentation was the long-awaited results from the 1,038-patient SOURCE registry compiled by Edwards across 32 European centers from November 2007 to January 2009.

SOURCE demonstrates a one-year survival rate of 81.1% in transfemoral procedures where the heart valve is delivered by catheter via the femoral artery, and 72.1% in transapical procedures where the valve delivered via a small incision through the ribs.

The 463 transfemoral (TF) patients presented with an average Euroscore of 25.8indicating the severity of the condition while the 575 transapical patients presented as far more severe with Euroscores of 29, and had the further complication of blocked and torturous arteries that excluded the TF approach.

“The encouraging outcomes add to the evolving body of clinical evidence that demonstrates transcatheter aortic valve implantation is a viable option for this high-risk patient population in need of alternative therapies to traditional open-heart surgery,“ said Martyn Thomas, MD, from Guys and St. Thomas' NHS Foundation Trust (London), who presented the SOURCE data.

Larry Biegelsen, Senior Analyst with Wells Fargo Securities (New York) explained that SOURCE data is significant because it is the closest dataset to the pivotal PARTNER trial Edwards is conducting as part of its application for approval by the FDA.

“We would view a one-year mortality rate in the low 20s as positive because it would increase the likelihood that Edward's Sapien valve will show a mortality benefit over medical management in Cohort B of PARTNER in September,“ he wrote recently.

In the Cohort B, the TAVI procedure will go head-to-head with outcomes from traditional open surgery procedures.

CoreValve scores high with 2,000 patients

CoreValve presented data from five European national clinical registries at EuroPCR demonstrating sustained positive patient outcomes at six months and one year.

The registries were not consolidated by a single methodology resulting in differences in the reporting, though all shared the same sharp focus on mortality rates with the average survival rates hovering between 80% to 85% for TF and 75% for TA.

The registries also provided side-by-side comparisons of Edwards and CoreValve implantations with surprising insights.

In the UK registry of 862 cases, 420 patients received the CoreValve and 402 patients received the Edwards Sapien.

Less even was the FRench Aortic National Corevalve and Edwards (FRANCE) registry reporting results on 244 patients with 68% receiving the Edward's Sapien while in Germany the heart centers overwhelmingly favored the CoreValve system for 84.5% of the 666 patients reported in its registry.

In the FRANCE registry general anesthesia was used on 84% of patients while in Italy 67% of patients underwent the procedure on local anesthesia.

Another significant variation was the need for an implanted pacemaker following the procedure for the CoreValve patients.

The incidence of these placement varied wildly with 38% of German CoreValve patients receiving the device, 18% in Italy and 25% in the UK.

This compares with a rate of 5% to 8% for Edwards Sapien valve patients reported in the registries.

Edwards confident, CoreValve challenged on TAVI

Clinical acceptance of transcatheter aortic valve implants (TAVI) is driving powerful growth in the structural heart segment of the cardiac market, exclusively in Europe for the moment where the procedure is approved and reimbursement is progressively arriving.

The success in this fragmented and conservative region begs the question of what kind of growth awaits the market leaders Edwards Lifesciences (Irvine, California) and CoreValve/Medtronic (Minneapolis) when they are able to enter the world's largest single market for medical technology, the U.S.

Edwards is hoping to win approval from the FDA and begin selling its Sapien heart valve toward the end of 2011.

Edwards is expected to hold this first-to-market advantage for three or four years before CoreValve arrives.

In interviews with BB&T at EuroPCR 2010, Edwards CEO Mike Mussallem, and the general manager of the Structural Heart division of the CardioVascular business at Medtronic, John Liddicoat, MD, discussed the opportunities and challenges ahead.

Edwards enjoys a stable product platform and promising clinical outlook with a growing support of clinical evidence.

Edwards also has introduced a second valve in Europe, the Sapien XT, which challenges CoreValve's leading position in transfermoral (TF) delivery, that it hopes to bring to the U.S. by 2014 when CoreValve is expected to enter the market.

While CoreValve presents equally strong clinical evidence and holds a powerful advantage in the TF access, the company's device is suspected of contributing to a troublesome disruption in the conductivity of the heart's electrical pulses that leads to abnormal heart rhythms and that require the implantation of a pacemaker.

The incidence of pacemaker implantation varies wildly in the registries of European nations from 38% in Germany to 18% in Italy, which compares with a similar requirement for the Edwards device of between 8% to 5%.

In the interview with BB&T, Liddicoat discussed this issue that Medtronic inherited when it acquired CoreValve one year ago and the steps the company is taking to address the challenge.

Edwards sees $1 billion opportunity by 2013

Edward's CEO Mussallem exudes a confidence in the Sapien product line and is sharply focused on regulatory milestones as Edwards begins its approach to the U.S.

“The PARTNER trial is fully enrolled and we expect results to be reported in the third quarter of this year with documentation going to the FDA in the fourth quarter,“ he said.

“Typically it takes 500 days for a premarket approval but we are estimating it could be closer to a year and we look to an approval in late 2011,“ he said.

At the same time, Mussallem said, Edwards is submitting the next-generation Sapien XT device and delivery systems for approval, “and we would love to be able to start that trial very soon.“

Sapien XT received the CE mark in March, as well as for the NovaFlex and Ascendra 2 delivery systems for the new valve.

“Depending on how things go it looks like we could be bringing XT to the U.S. market at the same moment we will see our first competitor arriving,“ he said.

Medtronic has not yet begun its trial for CoreValve in the U.S., he explained “so you can figure out how long it takes for them to enroll that trial, he said.

“The process may go a little faster than ours, but it is going to take them some time because Medtronic will likely conduct a trial the size of PARTNER,“ he said.

The PARTNER trial is a multicenter randomized trial with 1,040 patients that addresses both operable and non-operable patients in two cohorts, including a head-to-head comparison with outcomes from traditional open heart surgery for valve repair, a vital segment for Edwards as well.

Mussallem estimates the first full year in the U.S. will generate from $125 million to a high of $250 million in sales, depending on the number of centers and the number of procedures performed per center.

At an investor conference in 2009 Edwards showed that earning $30,000 per case at 200 sites performing three cases per quarter would yield $125 million.

Publicly traded and breaking out TAVI sales, Edwards provides a transparent view into the emerging opportunities for aortic heart valve growth.

Larry Biegelsen, senior analyst with Wells Fargo Securities (New York) closely follows the company and reports the company has seen a surge in revenues for this segment from $2 million in 2007 to $112 million in 2009 and is expected to generate $182 million this year.

In 2009 the segment accounted for 15% of Edwards heart valve business and 8% of the company's overall revenues of $1.3 billion.

Edwards is expected to crest the $1 billion milestone for TAVI revenues in 2013, according to Biegelsen.

He estimates U.S. sales will approach Europe's contribution by 2012 with $263 million and $289 million respectively, and U.S. TAVI revenues will surge after that growing to 70% of the segment revenues by 2014.

Edwards is already looking beyond western markets and has begun enrolling patients in Japan's first clinical trial of transcatheter aortic valves using the new Sapien XT valve.

If all goes as planned, the company expects Japanese approval in 2013.

Medtronic treads carefully toward TAVI market

Dwarfing Edwards with $14.6 billion in revenues in 2009, Medtronic has spent more than $2 billion to muscle up its cardiovascular division over the past 18 months.

The $700 million acquisition of CoreValve in February 2009 coincided with a $325 million purchase of Ventor Technologies (Netanya, Israel) that makes transcatheter delivery systems.

More recently, Medtronic spent an additional $370 million to acquire Minneapolis neighbor ATS Medical, which includes in its portfolio key technologies for valves.

Heading up the Structural Heart division, John Liddicoat faces the task of integrating these diverse resources and advancing the opportunities for Medtronic as it enters the TAVI market.

The ATS acquisition particularly adds new strengths, he said.

“It gives us three important advantages that include a mechanical valve that will be important for Medtronic in emerging markets, a tissue valve technology that presents intriguing possibilities with a stentless tissue valve and a sutureless valve for minimally invasive cardiac surgery,“ he said.

“And it brings us a cryoablation product which rounds out the product portfolio and gives us a full offering to complement other technologies such as radio frequency ablation and open surgery cryo procedures,“ he said.

A cardiac surgeon, Liddicoat responded to a statement that the clinical case for TAVI is already made saying “We are excited and encouraged by the clinical evidence, but also caution that these are very specific patient populations and the results can not be extrapolated to other populations.“

“Both Corevalve and Edwards have been very careful, very focused and methodic in working with these fragile patients,“ he said.

He acknowledged that having established safety and efficacy for the CoreValve device among the sickest of patient populations, the company is now exploring the possibility to extending the procedure to a wider population.

“We are now in the planning stages for a new randomized, controlled study using Medtronic CoreValve called SURTAVI that will enroll a more moderate risk population,“ he told BB&T.

While the protocol and timing are still undetermined, Liddicoat said, “We expect this study will help to place the role for TAVI within the context of wider treatment options for this population that includes open surgery, minimally invasive interventions, pharmaceutical therapies to address aortic stenosis.

In a follow up communication, a company spokesman confirmed the planning of SURTAVI and said, “This additional clinical and health economic evidence may enable Medtronic to expand indications, enter new geographies and help more patients worldwide.“

With the clinical evidence for CoreValve coming out of Europe, where the device is well-established in major markets, Liddicoat said he is finding “a lot of excitement, a lot of passion and discussion with cardiologists and with cardiac surgeons in the U.S. who want to be part of the introduction of the procedure.

“The number of centers interested in CoreValve is unbelievable,“ he said, adding that where some had earlier expressed a doubt as to whether the patients would be there for the specialized TAVI procedure, “now these surgical teams are seeing the size of the opportunity for application to a wider patient population.“

“Coming second to the U.S. market simply means that if we cannot be the first, then we need to be the best,“ he said.

“Edwards will be doing a lot of the heavy lifting introducing TAVI, and Medtronic will find some benefit in the regulatory approval process and with acceptance among clinicians,“ he said.

Liddicoat estimated that Medtronic's first year with TAVI in the U.S. will go slowly but agreed the company would match the Edward's year-one performance in the range of $120 million to $200 million.

“That estimate is in line with our own expectations, but by that point Edwards will have a larger revenue share,“ he said.

“Still, we are going to take market share,“ he said.

CoreValve challenged by rhythm disruptions

The legacy of the CoreValve acquisition brings powerful clinical evidence and a strong preference among interventionalists for the device and its delivery system.

But these advantages are mitigated by a problem with device placement that is emerging in European registries.

Liddicoat said there is not an issue with the device design but its placement.

“I could not be more pleased with the valve implant device because it is the most deliverable, the easiest to use, the most forgiving and results in fantastic patient outcomes,“ he said.

The evidence supports these claims in the procedure success rates of 98%, he said.

“I am confident the pacemaker implant issue will be resolved because I see the evidence in the range of the registries,“ he said.

The range of incidence are wide and hugely disparate, he said.

In 2009, he said the incidence of pacemaker implants after Corevalve TAVI procedures ran as high as 40% in some geographies, “then fell to 20% in 2010 and by 2011 we will expect to see 15% incidence,“ he said.

“The Italian registry with over 700 patients, which is an adjudicated registry, provides perhaps the best evidence of the variation in clinical experiences,“ he said.

The incidence of pacemaker was 18% on average, he said, yet ranged from 3% reported at some centers and 30% in others.

“We have determined the issue emerges when the cardiologist places the stent too deeply so that it sits below the valve and disrupts the conductivity,“ he said.

“We have also found that in 50% of the cases where we have seen a conductivity abnormality, a specific balloon was used for the valvuoplasty,“ he said.

Liddicoat explained that CoreValve does not utilize balloon inflation to seat the valve, which is perceived as an advantage among cardiac interventionalists as the valve placement is more flexible and forgiving than with the Edwards technique.

Yet a balloon is employed to dilate the valve opening prior to placement of the prosthesis in a procedure surgeons refer to as “preparing the landing zone,“ he said.

CoreValve specified a dumbbell-shaped balloon for the valvuoplasty due to its advantage of conforming to the anatomical structure and providing greater stability in the beating heart than the cylinder-shaped balloon used by Edwards.

“The downside of this balloon is that it is placing a pressure on the conductivity system in the left ventricle during dilatation,“ said Liddicoat.

“We are now looking at different balloons at different sizes to determine the optimum effect for the procedure,“ he said.

Medtronic is also assessing a different approach to preparing the landing zone and on techniques for improving the accuracy of the implantation of the valve stent, he said.

“We will set standards around the new protocol and then teach these standards,“ he said.

Post-buy, Medtronic seeks to integrate Invatec

During its $2.5 billion shopping spree of cardiovascular companies over the past 18 months, Medtronic (Minneapolis) picked up a gem in April when it acquired the innovative Italian firm Invatec (Roncadelle, Italy) for $350 million.

The two organizations have made an odd couple from the start, and Ross Allen hopes to keep things that way.

A 19-year veteran of Medtronic who has led two previous acquisition-integration efforts, Allen said he specifically needs the uniquely European imprint of Invatec's culture to influence the giant from Minnesota, and not the other way around.

A specialist in drug eluting balloons (DEB), Invatec has quickly created new treatment opportunities for peripheral arteries that have won the attention of clinicians and has created an emerging and fast-growing new branch of cardiovascular medicine.

“Both the products and the organization create new opportunities for Medtronic for entering the peripheral space, which encompasses a series of procedures for below-the-knee (BTK) vasculature, superficial femoral artery (SFA), femoro-popliteal and carotid arteries,“ said Allen.

“We are committed to developing this segment, frankly because it is early in development,“ he said.

Going into the acquisition, Medtronic said it saw a $1.8 billion market growing from 6% to 8% annually.

“As we have gotten deeper into the space, Invatec has shown us further areas that can be important that we had not considered that suggests the opportunity is even bigger than we had realized“ said Allen.

“We are now making a thorough assessment to evaluate these opportunities, to decide which will be the most meaningful,“ he said.

“We have not determined what the unique position for Medtronic-Invatec will be,“ he said.

“Invatec is known for specialized long, thin balloons that allow them to get down into the ankle, and these physicians are telling us BTK is the focus to help solve critical limb ischemia,“ he said.

“Others are telling us to focus on the SFA because if they can open this artery then they solve the issues with the lower leg,“ he said.

In a very European spirit, Allen said the discussion are continuing and the decisions will be taken in due course.

“We want to maintain Invatec's drive for innovation that includes a unique model of collaboration with physicians, something that we like to think Medtronic does as well,“ he said.

“Yet it has been intriguing to see how Invatec achieves this through personal relationships with physicians that allows them to be very fast to market,“ said Allen.

A key challenge in the peripheral artery space, he said, is a lack of clinical evidence.

“Last year at EuroPCR Invatec reported early data, and we are delivering further reports, but these remain early stage results,“ he said.

“Frankly it is challenging because there are so many diverse elements unlike in the coronary field where we know what to measure, what to monitor and what the comparatives are,“ he said

“In the peripheral segment this framework still needs to be defined, which is one of the reasons Medtronic was motivated to enter this developing area because of the opportunity to develop evidence that will meet with the rigor required as the field develops,“ he said.

“There is a lot of activity and discussion right now in the physician community over DEB and there is an opportunity help physicians identify and define clinical criteria and especially the critical endpoints for any trials we will conduct,“ he said.

“There are also discussions with the Food & Drug Administration to better define appropriate standards for the patient population and determine what are the right measurements will be, and then how to measure them,“ said Allen.

“Medtronic has demonstrated it has the experience for delivering dramatic clinical evidence, and we will bring that capability to the Invatec organization,“ he said.

In terms of integrating the two organizations, Allen said a critical element is staying close to the company's original management.

Invatec's founders have agreed to stay with the new business in senior leadership positions with Andrea Venturelli as VP of research and development and chief technology officer; and Stefan Widensohler as VP of global sales.

As a private company Invatec kept a focus on certain markets, primarily Germany, Italy and Switzerland, Allen said.

“We have dramatically expand that presence very quickly by investing aggressively in our sales organization,“ he said, adding that he is adding 50 people worldwide into the sales channel as well as leveraging the established Medtronic sales organizations in local markets.

In the U.S. he is adding 25 people to bring the group up to 35.

In Europe Medtronic-Invatec is now selling direct in the UK and France, while in Australia five new people are selling direct.

Allen said he intends to expand, and not trim, the extensive Invatec portfolio of products with a focus on filling gaps in the peripheral artery devices.

In the coronary products area, however, there are overlaps with the Medtronic line that is being addressed.

“The first thing to say here is that we want to encourage, and not discourage, the physician collaboration that has resulted in unique and differentiating products in coronary DEB,“ Allen said.

“DEB in coronary can be an adjunct and in several areas it makes a lot of sense to add to the Medtronic offering, for example for treatment of in-stent restenosis, for treatment of side branches in bifurcations, and also for small, long lesions as an alternative treatment to the full metal jacket approach with a long stent,“ he said.

The rest needs to be sorted out in the context of Medtronic's $1 .5 billion coronary business identifying the opportunities to marry products and procedures that complement the existing offering.