Medical Device Daily Contributing Writer

SEATTLE – Last week's Transcatheter Valve Therapies (TVT) conference, sponsored by the Cardiovascular Research Foundation (New York) and held here, was very well-attended and provided the most current information on this very dynamic and embryonic market.

It was just a little over seven years that Alain Cribier, MD, an interventional cardiologist from University Hospital Charles Nicolle (Rouen, France), performed the first percutaneous aortic valve replacement (PAVR) procedure. As is often the case in pioneering technologies, this watershed event was greeted with tremendous skepticism, especially in the cardiac surgical community, which for over 40 years has dominated the heart valve market.

From its modest beginning and despite some vociferous protestations from the early naysayers, in recent years PAVR has become perhaps the hottest market in medical devices.

Stunning evidence of the ascension of the TVT market is amply evidenced by the recent purchases of two privately held, venture-capital (VC) backed PAVR companies, CoreValve (Irvine California) and Ventor Technologies (Netanya, Israel) by medical device juggernaut Medtronic (Minneapolis).

The acquisition exceeded $1 billion, a massive premium relative to the sales level of the two companies, which in calendar year 2008 is estimated at $30 million to $40 million.

Additionally, the ebullience in the VC for minimally invasive valve procedures was demonstrated by recent financing announcements for emerging companies in this space.

Sadra Medical (Campbell, California) raised $30 million in its Series C preferred round to fund its Lotus Valve System toward a CE mark. The company has previously raised $26 million to develop its PAVR device.

Embrella Cardiovascular (Malvern, Pennsylvania) closed its Series B financing round, raising about $5.1 million to fund its human clinical trials outside the U.S. Notably, PAVR market leader Edwards Lifesciences (Irvine, California) participated in this round.

Whereas virtually all previous PAVR financings were for valve development, Embrella is developing an embolic protection device that could reduce the procedural risk of an embolic stroke.

Several speakers during the conference commented that while the stroke rate has dropped significantly as operators have gained more experience, it is still a concern because it occurs in 2% to 3% of cases.

Michael Mack, MD, a cardiac surgeon from Medical City Dallas Hospital (Dallas) and a luminary in this fledgling field, noted that "we will need embolic protection ... to mitigate stroke risk."

Both Edwards and CoreValve are actively commercializing their devices in Europe, the former received a CE mark in September 2007, while CoreValve received its CE mark in May 2007.

Despite a very methodical commercial rollout and painstaking training programs, both companies have been enjoying remarkable commercial success. Medtronic recently announced that the CoreValve device has been implanted in 4000 patients since CE mark clearance, while Edwards reported revenue from Europe in calendar 2008 at $48 million, significantly above its earlier expectations.

According to a report this week from medical device analyst Larry Biegelsen of Wachovia Capital Markets (New York), Medtronic and Edwards each implanted about 850 valves in 1Q09 and Biegelsen estimates that the penetration rate of PAVR is an "impressive" 9% in Europe in 1Q. He further believes that Edwards will sell 935 implants in Europe in 2Q09, generating revenue of over $26 million.

What makes this performance all the more noteworthy is that European reimbursement is virtually non-existent and that these devices are still considered investigational by governmental authorities.

Course co-director, Martin Leon, MD, a renowned interventional cardiologist and associate director of the Center for Interventional Vascular Therapy at Columbia University Medical Center (New York) gave a comprehensive review of the latest clinical results, lamenting that "our biggest challenge is that there is still so little reliable data available."

He further noted that amongst the several clinic trials, "the endpoints are not properly defined," specifically there are inadequate definitions of complications. Moreover, since transcatheter valves are being implanted in the "sickest of the sick," he indicated that it is very hard to get consistent follow-up with these patients and therefore the data is incomplete.

According to Leon, the most valid PAVR data seen so far is from the SOURCE registry, which followed a total of 1,038 patients treated at 32 European centers, of which about 45% were treated with a trans-femoral (TF) approach. The balance were implanted via a trans-apical entry.

The acute procedural success was achieved with the TF approach in nearly 96% of patients, with vascular complications, which have been a major issue, no longer a significant mortality risk. At 30-day follow-up, the mortality incidence was 6.3%.

These results, which were initially reported at EuroPCR by Martyn Thomas, MD, of St. Thomas' Hospital (London, UK) (MDD, May 29, 2009) were significant for two reasons. First, in Leon's words, "the data is legitimate," and second, they show that with better patient selection and improving physician skills, the clinical outcomes are improving.

It is very clear from the many presentations at this meeting that the enthusiasm for these devices is enormous, that there has been substantial progress in "second generation" valve designs and delivery systems and yet, there is huge room for further improvement.

Adverse events and mortality are still unacceptably high. For example, the design of the Medtronic system ensures secure placement but places pressure on the heart. This interferes with the body's ability to transmit electrical impulses, causing the two ventricles of the heart to no longer receive electrical impulses simultaneously.

The solution to this condition is that these patients must be implanted with a pacemaker. The Medtronic device is particularly vulnerable, with multi-center results showing average post-procedural pacing rates of 23%. This is about four times the rate seen with Edwards' device and may prove to be a competitive disadvantage if Medtronic cannot solve this problem.

As one physician wryly said "this may be good for Medtronic's pacer business, but it is not good for the patients!"

Several physicians provided their "wish list" for the ideal PAVR device, with lower profile (18Fr or less), improved deliverability and a retrievable/repositionable option heading up their list.

The list (see table, p. 6) details the ideal device, which was presented by Peter Block, MD, professor of internal medicine at Emory University Hospital (Atlanta).

The pace of innovation in this field is furious as both the established companies and many startups race to develop and market improved products. The promise is huge and according to Leon, "in five to ten years, the majority of patients with severe aortic valve disease will receive a percutaneous device."