EVAR Market: Challenges, Innovation and Growth

Endovascular aortic aneurysm repair procedures account for the majority of abdominal aortic aneurysm repairs performed in the US, and total worldwide revenues from aortic endograft systems now exceed $1 billion per year. Many believe that continuing improvements in endograft technology will drive EVAR penetration to 90% or beyond within the next five to 10 years. This article first appeared in the April issue of Medtech Insight, April 2011.

Mary Thompson

The field of endovascular aortic aneurysm repair (EVAR) has evolved considerably in the two decades since Juan Parodi, MD, and colleagues performed the first EVAR procedure in Argentina back in 1990. After a somewhat rocky start, exemplified by the well-publicized problems with early endograft designs, physicians and manufacturers have worked together diligently to address many of the considerable challenges inherent in placing and maintaining endovascular devices in the inconstant and often hostile aortic anatomy. As a result of this effort, EVAR has evolved into a procedure that is now considered the new standard of care for managing patients with abdominal aortic aneurysms (AAAs). Moreover, ongoing advances in endovascular technologies for repairing thoracic aortic aneurysms (TAAs), although a much smaller market than AAA repair, have created an important less-invasive alternative to risky open surgery in the technically challenging TAA patient population as well.

Today, EVAR procedures account for the majority (over 60%) of AAA repairs performed in the US, and total worldwide revenues from aortic endograft systems now exceed $1 billion per year. Many believe that continuing improvements in endograft technology will drive EVAR penetration to 90% or beyond within the next five to 10 years. However, before that milestone is reached, the field must address a number of lingering concerns about long-term endograft stability and viability, and endograft systems will need to evolve to encompass a wider range of patients with challenging anatomy, including small or tortuous access vessels, short or highly angulated aortic necks, and aneurysms that lie close to the renal arteries.

An Ongoing Evolution And A Growing Market

The ongoing evolution in endovascular therapy for aortic disease has fueled a growing device market, valued at over $1.2 billion worldwide in 2010 (for both AAA and TAA devices) and expected to grow to $1.7 billion by 2015. AAA devices account for the majority of this total, generating about $900 million in sales in 2010, the majority in the US. ( See Exhibit 1.)

Although physicians in the US and Europe currently implant most of these devices, procedure growth in the years ahead is likely to be highest in emerging markets, such as the BRIC countries (Brazil, Russia, India, and China) and the Asia-Pacific region, which are expected to see double-digit expansion as EVAR slowly makes its way into these underserved areas. As a result, many companies competing in this space are making efforts to bolster their presence in emerging markets outside the US (OUS). Japan is a particularly attractive target in the Asia-Pacific region. The country is on a high-growth trajectory already, with EVAR penetration growing from about 1% of AAA interventions in 2006 (when only one EVAR endograft was available) to 40% (about 6,000 EVAR procedures) in 2010, according to recent estimates. Four devices are currently available in Japan and more are on the way.

The US AAA market is projected to grow at a good clip as well – about 8 to 9% per year, a rate that outpaces many other medical device markets – increasing from about $578 million in revenues in 2010 to $877 million in 2015. ( See Exhibit 2.) AAAs affect an estimated 1.2 to 2 million Americans, although the majority go undetected. Each year, about 200,000 AAAs are diagnosed in the US, and AAA incidence is on the rise, driven by the aging population and an effort to expand screening among Medicare recipients. ( See Exhibit 3.) Not all diagnosed AAAs require repair; intervention is usually reserved for those at higher risk of rupture – typically aneurysms that are 5 cm or larger or smaller aneurysms that are expanding rapidly. In total, US physicians performed an estimated 60,000 to 70,000 AAA repairs in 2010, and industry participants estimate about 40,000 of those were EVAR procedures.

Over the past decade, as endograft choices have grown and physicians gained more experience with EVAR, there has been a steady expansion in the number and types of AAA patients considered suitable for endovascular repair. That trend has been most noticeable in the US, where EVAR penetration has climbed to about 60% of all AAA interventions. In Europe, penetration rates vary by country, but overall, the rate is much lower – about 35 to 40%, due to reimbursement differences and health care delivery models that favor open surgery.

The big challenge now is to figure out a way to safely expand the treatable patient population and bring EVAR to the 30+% of AAA patients who remain outside of the technology's current capabilities due to anatomical constraints. Manufacturers are working to meet this goal by developing an even wider variety of devices to address more challenging cases. And this effort could pay off in a big way in the years ahead.

Pushing The Envelope

The move by manufacturers to address more challenging anatomies is being spurred in large part by the physicians who perform these procedures – primarily endovascular surgeons in the US – who have been "pushing the EVAR envelope" for some time now in an attempt to provide the life-saving treatment to a wider range of patients. In response, manufacturers have been scrambling to introduce devices with greater flexibility, conformability, and deliverability in order to meet this need.

However, there has also been some recent concern that physicians are pushing the envelope a bit too far too fast. The case for EVAR versus open surgery rests largely on a handful of clinical studies that have shown clear advantages to EVAR, including a significantly lower perioperative mortality rate, a shorter length of hospital stay, and fewer rehospitalizations in the perioperative period. Large randomized trials – including EVAR-1, performed in the UK, and DREAM, performed in The Netherlands – demonstrated a roughly 3- to 3.5-fold decrease in perioperative mortality with EVAR, compared with open surgery.

But now that these early studies are approaching eight to 10 years of follow-up, physicians are getting their first look at longer-term outcomes, and the picture is not quite as positive. Analyses of 10-year follow-up from the EVAR-1 and EVAR-2 trials, published last year, are of particular interest. The data show that the early mortality benefits of EVAR were maintained for only about four years, after which the advantage gradually eroded due to late aneurysm-related mortality in the EVAR group. By year six, there was no difference in mortality between the EVAR and open surgery groups.

The study also revealed a three- to four-fold higher rate of graft-related complications and reintervention in the EVAR group, with new complications and reinterventions continuing up to eight years following endograft implantation. All told, EVAR complications resulted in a total average cost per patient that was about $4,500 higher in the EVAR group than in the open surgery group over the study period. These results were confirmed by a recently published two-center analysis of long-term outcomes with Medtronic PLC's Talent endograft, which showed a steady decline in primary clinical success (defined as clinical success without the need for a secondary procedure) out to seven years. ( See Exhibit 4.) Although freedom from AAA-related death over the seven-year follow-up was 92%, a "substantial amount" of reintervention was necessary to achieve these results, the authors said.

Meanwhile, a second EVAR trial analysis, published in the November 2010 issue of the Annals of Surgery, found that patients in the EVAR-1 and EVAR-2 trials who were treated with endovascular repair were much more likely to experience a graft rupture over 10 years than those treated with open repair, often due to sac growth, graft endoleaks, or migration/angulation of the graft. In fact, patients in the open surgery group had no graft ruptures over the 10-year period, which was surprising for many physicians. The study authors urged physicians to provide diligent patient follow-up after EVAR, including routine use of a predischarge computed tomography (CT) scan to uncover any problems that can be corrected immediately after implantation. They also pointed out the need for improvements in endograft technology to enable the grafts to better conform to the aorta.

In addition the authors admonished physicians to "respect suitability of the anatomy for EVAR," speculating that the accelerating trend to use EVAR outside of established anatomical indications could negatively impact long-term outcomes. That suspicion appears to be confirmed by another recent analysis, published in April 2011 in Circulation, which looked at over 10,000 EVAR patients from M2S Inc.'s core laboratory imaging database who were treated between 1999 and 2008. A large percentage of the patients fell outside of established indications for endovascular repair: nearly 60% had an aneurysm that fell below the 5.5 cm diameter threshold for intervention and over 30% had anatomical characteristics that fell outside the most liberal EVAR guidelines. And there were consequences. Sac enlargement at five years occurred in 41% of patients overall, but was significantly more common in those treated outside of established EVAR indications and in patients treated more recently (2004–2008).

Researchers are currently performing more detailed modeling of the EVAR-1 and EVAR-2 data to "assess whether endovascular repair is cost-effective for all patients or only for selected subgroups." In addition, work is ongoing to determine if specific complications that appear following EVAR can be used to identify patients at increased risk of endograft rupture and death.

It is important to note that all of the studies with long-term follow-up today began at least a decade ago and involved a good deal of older endograft technology. Presumably newer, more stable and durable systems, along with greater physician experience, could have a positive influence on future long-term results. However, there is as yet no evidence that newer endografts will perform better over the longer term, and a continuing list of unresolved problems, including Type II endoleak and late aneurysm growth, suggests that significant unmet needs still exist in the EVAR arena. ( See Exhibit 5.)

Although recently published long-term outcomes data could create a bit of pushback on physicians seeking to take on ever more challenging EVAR cases, the data are unlikely to have a significant impact on the endograft market, primarily because there are still compelling reasons to choose EVAR over open surgery for a large percentage of AAA patients. In fact, researchers have also uncovered data showing that EVAR, despite its flaws, has had a substantial positive influence on the treatment of AAA in the US.

According to an analysis by Kristina A. Giles, MD, and colleagues of the Beth Israel Deaconess Medical Center in Boston, which was published in 2009 in the Journal of Vascular Surgery, since the introduction of EVAR in the US, the annual number of deaths from AAAs has declined significantly, as physicians shifted from open repair of ruptured AAAs to elective EVAR for less-risky intact AAAs. The analysis uncovered a 42% drop in AAA repair-related deaths between 1993 and 2005, from a mean of 4,496 deaths per year in the pre-EVAR era (1993–1998) to a mean of 3,036 per year in the post-EVAR era (2001–2005) ( p < 0.0001). AAA-related deaths overall fell by 38% between 1993 and 2005 and hospital admissions for a ruptured AAA declined by 30%. ( See Exhibit 6.)

EVAR began to overtake open surgery in the US as the preferred AAA treatment method as far back as 2004. ( See Exhibit 7.) And it clearly has ushered in a paradigm change in the way AAA patients are treated. In light of the positive trends outlined in the study by Giles et al., as well as continuing patient preference for minimally invasive treatments, growth in this field is likely to remain strong going forward, with future technology improvements adding to the momentum.

Expanding The EVAR Toolbox

Endograft manufacturers are working on a number of device advances designed to improve EVAR performance in more challenging cases. These include more flexible, conformable, and stable endografts; lower-profile systems and delivery devices that provide more controlled, precise endograft deployment; and endografts with adjustable fenestrations (or holes) and side branches to enable EVAR in patients with juxtarenal AAAs (aneurysms at or near the renal arteries). In addition, there are a handful of technologies in development offering true out-of-the-box approaches to EVAR that go well beyond current design enhancements. Disruptive technologies such as these could one day permanently solve some of the lingering problems that continue to plague this field.

Endurant Posts Strong Growth

The past couple of years have already seen a sizeable increase in the number of new EVAR product introductions from the established players, as well as an influx of several new competitors into this space, some with novel technology solutions.

One company that has done particularly well with its new product launches lately is current EVAR market leader Medtronic, which has gained considerable market share in Europe since the mid-2008 launch of its latest-generation endograft, Endurant. Following on the device's US Food and Drug Administration (FDA) approval in December 2010, analysts expect to see Medtronic gain share in the US as well in 2011 and 2012. According to Hence Verhagen, MD, of Erasmus University Medical Center in the Netherlands, who spoke during a new products symposium at the 2011 Charing Cross International Symposium, held recently in London, Endurant has been used in some 26,000 EVAR cases worldwide over the past 2.5 years, and 2,000 cases were performed in the US just in the first 11 weeks following launch.

The primary features that appear to be driving sales of Endurant are its enhanced deliverability and its flexibility/conformability and short sealing zone, which improve performance in patients with short, angulated necks. Endurant's greater suitability for challenging anatomy makes the device a welcome addition to the arsenal as physicians seek to treat a growing number of these cases. At 18- to 20-French (F) outside diameter (OD), depending on the graft size, Endurant is currently the lowest profile EVAR system available in the US, and its ease of use expands the number and type of anatomies that can be treated.

According to the company, Endurant can treat necks as short as 10 mm, with angulation up to and including 60 degrees, which compares favorably with many of the other EVAR devices in development. ( See Exhibit 8.) Moreover, it is designed to conform to the natural tortuosity of the vessel without kinking, the firm says. The device's delivery system is also a plus, providing slow, step-wise proximal graft deployment with controlled release of the anchoring pins to ease delivery in angulated necks, and the graft tip can be recaptured to adjust graft placement, both proximally and distally, prior to full deployment. In addition to these features, Endurant has platinum-iridium radio-opaque markers to enhance fluoroscopy visualization during delivery, including a marker at the opening of the contralateral limb to facilitate cannulation of the gate.

Although it remains to be seen whether Endurant will perform better than competitive devices over the long term, the US Premarket Application (PMA) data are encouraging at 12 months, with no graft migrations, no confirmed Type I or III endoleaks, and 11.4% Type II endoleaks. Medtronic is conducting a real-world Endurant registry study in Europe (ENGAGE), which will follow patients out to five years, and so far, that data look similar to the US trial. One-year ENGAGE registry outcomes in the first 839 patients showed an all-cause mortality rate of 0.9%, a 4% rate of major adverse events, no graft migrations, and 9% Type II endoleaks, according to Vincent Riambau, MD, PhD, of the University of Barcelona, who presented an update on the registry study at the International Congress for Endovascular Specialists (iCON) meeting, held recently in Scottsdale, AZ.

In addition to its other features, Endurant also commands a premium price – as much as 15% higher than competitive products in some markets OUS. In Europe, the device has cannibalized much of the sales from Medtronic's older Talent endograft, but it has also taken considerable share from competitors, impacting both Cook Medical Inc./Cook Group Inc., whose Zenith graft competes directly in the suprarenal fixation segment of the market, and to a lesser extent, WL Gore & Associates Inc., according to recent market share estimates. Medtronic now holds an estimated 45 to 50% share of the AAA endograft market in Europe.

In the US, where the company has about a 35% market share, the situation is somewhat different, since there are only four competitors in the EVAR market – Medtronic, WL Gore, Cook Medical, and Endologix Inc. – and customer loyalty plays a larger role in purchasing decisions. However, most analysts expect Endurant to pick up share in the US as well. The US pivotal trial for the device completed enrollment two months ahead of schedule, which is indicative of strong physician interest. In addition, the device is approved for use in the US for the treatment of infrarenal or aortoiliac aneurysms, which is a broader indication than other endografts, the firm says.

Future AAA products in Medtronic's pipeline include longer limbs for Endurant as well as a next-generation low-profile (14-F) device, according to Verhagen. In addition to its AAA products, Medtronic is nearing an FDA submission for its Valiant TAA endograft. Last year, enrollment was completed in VALOR II, the pivotal Valiant IDE trial, and one-year results are expected to be presented in mid-2011. The Valiant TAA graft has been available OUS since 2005. The firm also has two trials underway testing Valiant on the Captivia Delivery System for the treatment of aortic dissection and thoracic aortic injury. Valiant Captivia was CE marked in October 2009. Medtronic's Talent Thoracic Endograft was FDA approved in May 2008.

Medtronic's Endovascular business achieved sales of $495 million worldwide in fiscal 2010 (ended in April 2010), an increase of 24% over the prior year, and the business posted strong growth in the company's latest quarter as well (3Q fiscal 2011; ended January 2011). Endovascular business sales in the third quarter grew 12% year/year to $132 million, driven, the firm said, by the US Endurant launch. Sales in the US grew 6% to $56 million, which increased Medtronic's market share by 400 basis points sequentially, company officials said in a February conference call. The firm also saw a 400 basis-point sequential share gain in Europe for the quarter in both the AAA and TAA markets, which it attributed to continued strength of both the Endurant device and the Valiant Captivia TAA System.

Gore And Cook Continue To Innovate

Medtronic's closest competitors in the US are two privately held firms, WL Gore and Cook Medical, both of which have also been strong innovators in this field. Gore has done well in the US market with its Excluder AAA endograft and currently holds an estimated 31% market share in the US and 16% in Europe.

The company has introduced several new product line extensions in the past few years to widen its reach, including more sizes for both the main graft and iliac extensions. In January 2011, Gore launched a new delivery system, the C3, in the US, which has been well received. The C3 enables physicians to reconstrain, rotate, and reposition the Excluder endograft to fine tune placement during delivery. In addition, company reps say the company's new DrySeal Sheath, released last year, has been receiving good feedback from physicians. The DrySeal has a unique pressurized self-sealing valve mechanism that minimizes blood loss during the passage of multiple EVAR guidewires and catheters.

In terms of future innovations, Gore continues to work on a lower-profile AAA endograft, although the firm declined to provide details on that device, which has yet to enter pivotal trials. And the company is likely working on fenestrated graft technology as well for both AAA and TAA applications.

Gore is also working to innovate in the thoracic aortic arena. The company was first to launch a TAA endograft in the US (TAG) in 2005, and is now nearing completion of three US trials with its new conformable C-TAG, addressing TAA, thoracic transection, and thoracic dissection. According to Gore, the C-TAG has a redesigned stent frame and fabric configuration that radically improves conformability, flexibility, and ease of use in angulated arches and other difficult anatomies. Company reps say the device provides a unique broad window for graft oversizing that enables physicians to choose more or less radial force depending upon a patient's individual need. Gore hopes to file for US approval and launch the C-TAG this year.

Cook, which holds an estimated 25% share of the AAA market in both the US and Europe, also has several new products in its pipeline. Last fall, the company launched its Zenith LP (low profile) Endograft in Europe and also completed enrollment in its pivotal US trial for the device. Cook expects to file for FDA approval of the Zenith LP before the end of 2011. The Zenith LP is constructed of a self-expanding nitinol Z-stent frame and a thin wall, densely woven polyester graft material and has a substantially lower profile than the current Zenith Flex device (18-F OD vs. 21- to 25-F OD).

Cook also has pioneered fenestrated AAA endograft technology, with its custom-made fenestrated AAA device, available outside the US for several years. The company recently completed a US trial of the device and plans to file for FDA approval within the next few months, according to David Biggs, Cook Medical's director of global products and market development. To date, over 3,000 of the custom endografts have been implanted worldwide. Cook is also making progress on an off-the-shelf fenestrated AAA endograft, and hopes to begin a clinical study with this device within the year. The off-the-shelf device is a three-piece design that is similar to the custom version, but has preconstructed, pivoting fenestrations and a preloaded wire and sheath to facilitate vessel access.

The company also offers the Zenith Renu Graft Repair System, introduced in 2006, for patients with existing AAA grafts that have migrated in vivo resulting in graft failure. According to Cook, the majority of cases treated with Renu in a US registry study were patients with migrated Medtronic AneuRx grafts. AneuRx is one of the first EVAR devices introduced and is now the oldest AAA endograft still available on the US market.

Other products in the pipeline for Cook include the Zenith Bifurcated Iliac Branch Graft, which is used for patients with aneurysms extending into the iliac arteries. This device is designed to maintain blood perfusion into the internal iliac to prevent ischemic complications. It is marketed in Europe and Australia and a pivotal US trial began in late 2010. In addition, Cook is developing a low-profile (16- to 20-F inside diameter [ID]) version of its TX2 TAA endograft, which is currently under investigation in a global clinical study. Cook currently markets the Zenith TX2 TAA Graft with the Pro-Form Delivery System, which utilizes a trigger wire mechanism to enable highly-controlled graft delivery. Physicians deploy the graft in segments; a process that Biggs says provides improved arch conformability to address a problem that has been the "Achilles' heel" of endovascular TAA procedures.

Endologix: Heavy Pipeline Could Drive Strong Growth Ahead

Fourth-place EVAR competitor Endologix has introduced a number of new sizes and enhancements over the past several years designed to improve the versatility and deliverability of its system, and the company also has one of the most active and interesting new product pipelines in this space.

Endologix entered the US AAA market in 2005 with the Powerlink device, currently the only AAA endovascular graft available that does not rely on proximal graft fixation with hooks or barbs. Instead, the Powerlink sits at the aortic bifurcation and relies primarily on anatomical fixation for graft stability. The device, which began as a one-piece system, is now placed in about 90% of cases as a two-piece device, comprising the main bifurcated graft and a proximal aortic extension, or cuff, that extends upwards to just below the renal arteries.

The aortic extensions come in both infrarenal and suprarenal configurations and were introduced in part to address angulated aortic necks, which require more proximal graft flexibility than Powerlink's main-body graft by itself can provide. The company also offers a wide range of iliac limb extensions that enable the device to treat patients with aneurysms that extend into the iliac artery, which occurs in about one-third of cases, according to Endologix president and CEO John McDermott.

For the past several years, Endologix has been on a mission to expand and improve its product line. In late 2008, the company launched its large diameter aortic extension ( Powerlink XL) to treat aortic necks up to 32 mm in diameter. That was followed in March 2009 by the second-generation IntuiTrak Delivery System, which features enhanced flexibility, a hydrophilic coating, and a lower delivery profile (21-F OD). More recently, in Q3 2010, the firm rolled out a wide range of additional Powerlink Graft sizes and configurations aimed at further broadening the number and type of AAA patients that can be treated with the Powerlink System. That launch included the new PowerFit Suprarenal Aortic Extension, an advance over the firm's previous aortic cuff that is designed to optimize sealing and provide better visibility on x-ray fluoroscopy.

With the addition of these new product line extensions, McDermott estimates that the Powerlink System can now address about 95% of all anatomies currently considered suitable for EVAR, up from about 80% previously. These new products not only broaden the range of addressable patients, he says, but they "optimize the anatomical fixation approach," enabling physicians to customize sizing for each case.

The third-quarter product line additions also are credited with helping drive sales growth well above the market rate in recent months. Endologix, which is a pure-play in this space, reported full-year 2010 revenue of $67.3 million, an increase of 28% from the previous year. US sales, which make up the majority (82% in 2010) of the firm's sales, increased 27%, while international revenue increased 35% for the year. In 2011, the company anticipates growth in the range of 16 to 27% and full-year revenues of $78 to $82 million, adding to the company's solid growth trajectory over the past several years. ( See Exhibit 9.)

A Robust Pipeline

Endologix also has considerable momentum in its pipeline, with several interesting new AAA products planned for launch over the next several years, including Ventana, an off-the-shelf fenestrated, side-branch endograft for juxtarenal aneurysms; and the Nellix Endograft, an out-of-the-box approach that has the potential to offer a significant step forward in terms of addressing many of the lingering concerns with EVAR.

PEVAR: Help Or Hype?

The company is also one of only a handful in the space actively pursuing percutaneous endograft delivery, and the only company currently engaged in a pivotal clinical trial aimed at gaining a specific percutaneous indication for its EVAR System. In April 2010, Endologix initiated a multicenter US randomized clinical trial investigating percutaneous delivery of the Powerlink Stent Graft in the IntuiTrak Delivery System and expects to complete enrollment this year, with FDA approval anticipated in 2012.

Percutaneous EVAR, or PEVAR, does not require a surgical cut-down of the femoral arteries (currently standard practice to enable vessel access for the relatively large EVAR delivery systems), and thus results in a faster, less painful recovery for patients. Endologix' foray into PEVAR follows the current trend in the industry toward increasingly lower-profile EVAR systems. However, while PEVAR has attracted a handful of surgeons who are dedicated to the approach, it has not gained much traction among the vast majority of endovascular surgeons who perform EVAR procedures, and some believe it is simply a marketing ploy.

Part of the reason for this slow adoption is that the EVAR field is still largely dominated by surgeons, who are comfortable with cut-down procedures and may perceive no clinical benefit to learning the percutaneous approach. Moreover, because even the smallest EVAR delivery systems are still relatively large and vessels must be expanded to accommodate the larger sheaths, percutaneous EVAR requires the use of closure devices to seal the puncture site, which adds cost to the procedure. That cost is not currently reimbursed, since there are as yet no closure devices with FDA approval for this use, so there is little incentive at the moment for physicians to change their current practice.

Although these drawbacks have kept most of the companies in this field from pursuing a percutaneous indication for their devices, McDermott says Endologix saw a need and is trying to fill it. Because the IntuiTrak Delivery System offers an integrated sheath and a 9-F percutaneous contralateral limb, some physicians began delivering the entire device percutaneously, using Abbott Vascular/Abbott Laboratories Inc.'s ProStar XL or ProGlide suture-based closure devices in a preclose technique – deploying the closure sutures in the vessel wall up front, before delivering the graft, and then simply tying off the sutures at the end of the procedure.

Other doctors then came to the company wishing to learn the technique, McDermott explains, but since these are off-label uses, neither Endologix nor Abbott is able to promote the percutaneous procedure or train interested physicians. So the two companies decided to partner in order to gain an FDA approved percutaneous indication for both the Powerlink and for Abbott's two suture-based closure systems, ProStar XL and ProGlide, both of which are being used in the ongoing PEVAR study. If all goes as planned, Abbott will use the data from the trial to gain an indication for large-hole closure, which it currently does not have, and Endologix will have the only EVAR device with a percutaneous indication.

McDermott acknowledges that some physicians may not be interested in performing EVAR percutaneously, but he believes many will over time, especially as EVAR devices continue to get smaller. Eventually, the company expects to have a percutaneous indication for its next-generation low-profile device, AFX, which is slated for US launch in the second half of this year. AFX will offer an even lower profile (19-F OD) delivery system for all aortic neck sizes, even those up to 32 mm, as well as improved delivery precision, according to McDermott, who characterizes AFX as a "significant upgrade" to the current IntuiTrak System.

Coming Soon: Off-The-Shelf Fenestrated Grafts

Although PEVAR could receive more attention from physicians as Endologix and Abbott Vascular move closer to US approval, the two technologies in Endologix' pipeline that are currently attracting the most interest are the Ventana and Nellix devices, both of which could significantly expand the treatable AAA patient population.

Ventana addresses an estimated 20% of AAA patients who cannot be treated with existing endografts because their aneurysm includes, or is too close to, the renal arteries. Today's off-the-shelf AAA endografts cannot be used in these patients because the grafts would cover the renal arteries and cut off blood flow to the kidneys. Thus, there is currently no way to treat these patients with EVAR outside of a custom-made fenestrated graft.

Some physicians have attempted to construct their own, home-made fenestrated grafts or use snorkel or chimney graft techniques to treat these patients, but the process is time consuming and complicated. In addition, Cook Medical, as mentioned earlier, offers a custom-made fenestrated AAA graft (constructed from a CT model of the patient's anatomy), which is sold in international markets and recently completed US clinical trials. This device could reach the US market before year's end; however, modeling, constructing, and shipping the custom graft is a two- to three-month process – time that many patients do not have – and it is expensive, costing up to $20,000 to $30,000 per graft, according to some sources.

As a result, several companies – including Endologix, Cook, Vascutek Ltd./Terumo Corp., and likely others as well – are developing off-the-shelf endografts containing adjustable fenestrations for use in these patients. Endologix' Ventana utilizes the main-body Powerlink Graft with the addition of two new components: a fenestrated aortic cuff containing moveable/adjustable fenestrations to accommodate a range of renal anatomy, and the company's new Xpand Balloon Expandable Covered Stents, which serve as the renal artery branches. Endologix is conducting clinical trials outside the US and plans to launch Ventana in Europe in 2012. In the US, the company expects to file for FDA IDE approval to conduct a US clinical trial of the device this year, which it hopes to begin in the second half of 2011. Assuming all goes well, that would put Ventana in line for US market approval sometime in 2014.

The closest competition appears to come from Cook, which plans to initiate a clinical study of its off-the-shelf device "within the year," according to company representatives. Since Cook already has a custom-made device on the European market, it is likely to have a relatively quick pathway to CE mark approval for the off-the-shelf version, which is based on the custom graft's design. Thus, if trials begin within the next few months, the device conceivably could reach the European market before the end of 2011.

At the Charing Cross conference, Andrew Holden, MD, of Auckland City Hospital in New Zealand, presented the first-in-man Ventana experience involving nine patients treated in New Zealand and Santiago, Chile. According to Holden, the technical success rate was 100%, with no major adverse events, 0% conversion to open repair, and 100% freedom from Type I or III endoleaks at one month as determined via CT scans in several patients.

Holden also provided additional details on the Ventana device, which he said has two 3-mm diameter renal fenestrations with preloaded renal sheaths. The fenestrations can be dilated up to 8 mm in diameter and moved up to 35 mm from their nominal locations. The device also has a 4-cm deep scallop to accommodate the celiac and superior mesenteric arteries. The device is fully constrained while cannulating the renal arteries, which Holden says improves ease of delivery.

The system does have some anatomic limitations, as eligible patients must have an infrasuperior mesenteric artery (SMA) neck length of at least 15 mm, the renal arteries must be within 30 mm of each other on either side, and no more than 35 mm from the SMA, and neck angulation must be less than 60 degrees, researchers say. However, the current configuration "accommodates a lot of anatomy" and has proven suitable for over 90% of patients with juxtarenal and suprarenal AAAs in the clinical experience thus far, according to Daniel Clair, MD, of the Cleveland Clinic, who presented on the technology at the iCON conference.

Is Nellix A Game Changer?

In addition to Ventana, the other big product in Endologix' pipeline is the Nellix AAA Endograft. Endologix obtained this device when it acquired privately held Nellix Endovascular Inc. late last year in a deal valued at up to $54 million ($15 million in stock up front and additional milestone stock payments of up to $39 million). [See Deal] As part of the agreement, Essex Woodlands Health Ventures, the majority shareholder of Nellix, agreed to provide a $15 million equity investment in Endologix.

The Nellix device offers a unique, out-of-the-box approach to addressing endograft and aneurysm stability, and if it proves safe and durable over the long-term, it could represent a true game-changer for this field. Instead of relying on active graft fixation with proximal barbs or hooks or on anatomical fixation at the bifurcation, the Nellix device seeks to permanently seal and exclude the aneurysm, while at the same time fixing and stabilizing the graft in the aorta.

The device is constructed of balloon-expandable stents with attached, inflatable endobags. Following deployment and expansion of the stents, the attached endobags, which run the length of the aneurysm, are filled with a biostable polymer and expand into the aneurismal sac, enabling the bags to conform closely to the AAA anatomy. The polymer filler cures over several minutes, permanently filling and sealing the aneurysm and excluding it from blood flow. Not only do the endobags seal the aneurysm, they also stabilize the graft, preventing any longitudinal migration or lateral movement within the sac that could cause endoleaks or other long-term durability issues.

Because the endobags conform to a wide range of anatomies, the company believes the Nellix device has the potential to expand EVAR treatment to patients who are currently outside the indications for existing technology, including those with very short aortic necks (5 mm or less), aortic neck diameters as large as 34 mm, and iliac arteries with diameters up to 35 mm.

Endologix also believes the technology has the potential to significantly reduce costly secondary interventions in EVAR patients, most of which are prompted by endoleaks, and perhaps even reduce or eliminate the need for long-term surveillance of these patients. Those goals remain to be proven in long-term clinical trials. However, results to date with the first 34 patients treated at four centers outside the US have been very encouraging, with 100% technical success, and no ruptures; no graft migration; no Type II, III, or IV endoleaks; and no sac expansion at one year. There were two Type I endoleaks, one of which resolved spontaneously and the other – caused by the lack of iliac extenders early in the clinical trial – was treated with a secondary procedure at 15 months. The latest findings from the study, including two-year CT follow-up in five patients, were published in the April 2011 issue of the European Journal of Vascular Surgery, showing no change in aneurysm size or endograft position and no new endoleaks.

These results have created quite a stir in the EVAR community, particularly the complete absence of Type II endoleak, something that has not been observed before with any other type of AAA endograft. Type II leaks are fairly common today, occurring in up to 25% of patients treated with existing EVAR endografts, and are caused by patent aortic branch vessels in the endograft area that provide retrograde blood flow through the aneurysm sac. While usually considered relatively benign, persistent Type II endoleaks may be indicative of an expanding aneurysm.

Endologix is currently working to finalize the design of the Nellix device and is completing bench testing on that now. The company is planning to run an international registry study with the final device and anticipates CE mark and European launch in the first half of 2012. The firm is also working to establish its own sales organization in Europe and expects to finish 2011with 12 to 15 of its own people in place. A US IDE-approved pivotal trial of Nellix is also expected to begin in 2012, with FDA PMA approval anticipated in 2015, assuming all goes well.

The technology looks very promising at the moment, but it is important to remember that clinical experience with Nellix is still limited and several questions about the technology remain to be addressed, including what secondary treatment options, when/if needed, will be available to patients who receive the device. Nellix also will require physicians to learn a new EVAR technique, which may lead to learning-curve issues. In addition, there could be some regulatory challenges with this device in the US, since it breaks new ground in the EVAR arena.

But barring any unforeseen circumstances, Endologix believes that its solid product pipeline, and particularly the combination of Ventana and Nellix, will drive strong growth in its AAA business in 2012 and beyond. In terms of expanding the treatable patient population, Nellix will open up EVAR to patients with infrarenal AAAs with short necks, perhaps as short as 5 mm, while Ventana will offer a treatment option for those cases with no-neck or extremely short-neck aneurysms, according to Dr. Holden, speaking during the company's October conference call. Interestingly, of the 34 patients treated to date in the Nellix trial, almost half would not have been able to receive EVAR with existing devices.

Exactly how much further this field will go remains to be determined. But McDermott believes that EVAR penetration rates in the US could be trending toward 90% within five years. "It's all technology driven," he says, "and we believe Nellix and Ventana will play a critical role in the treatment of more AAA patients in the years ahead. Nellix addresses many of the biggest limitations with currently available EVAR devices – there aren't any competitive devices that can do what it can do and offer the same kind of simplicity. And Ventana opens up a segment of the market that is not treatable today." That new segment – juxtarenal AAAs – is one that Endologix expects will contribute some $300 million to the worldwide EVAR market in 2015. ( See Exhibit 10.)

A Widening US Field

The competition in this space could heat up significantly in the future if other large cardiovascular players enter the market. St. Jude Medical Inc. and Cordis Corp./Johnson & Johnson already have established R&D programs in the field, and analysts speculate that Abbott Vascular – may be eyeing the opportunity as well.

St. Jude executives provided some details on the company's endovascular pipeline during a February investor conference call, telling analysts that the firm plans to develop endovascular stent-grafts for both the AAA and TAA markets. The technology will be leveraged from AGA Medical Holdings Inc.'s platform, which St. Jude gained when it acquired AGA Medical (a manufacturer of nitinol-based interventional occluders to treat structural heart defects) last November for $1.03 billion. [See Deal] St. Jude is focusing first on a TAA endograft because that is "easier to do" with the existing AGA technology, they said. The device will take advantage of AGA's expertise in nitinol/fabric configurations and will comprise a double-braid of nitinol with fabric sandwiched between the braids, a configuration designed to facilitate aneurysm healing. The company expects to begin a European feasibility trial with the device in the second half of 2011 and hopes to have CE mark approval before the end of 2012. An AAA endograft development program is planned to follow the TAA device, and St. Jude believes it can leverage the AGA Medical technology for a peripheral vascular graft as well.

Cordis/J&J has actually been working in the EVAR field for more than a decade, with a program to develop a low-profile device. The company's first attempt several years ago failed due to durability issues, but Cordis went back to the drawing board and has come up with what appears to be a successful design. Known as Incraft, the current device is an ultra low-profile (14-F OD), three-piece modular AAA system that features a customizable platform with the ability to adjust length up to 3 cm in situ.

In addition to these efforts, three companies that currently market endografts outside the US – Lombard Medical Inc., Vascutek, and Bolton Medical Inc. (part of the Werfen Group) – are hoping to enter the US market in the near future.

Lombard Medical is nearing completion of a pivotal US trial for its Aorfix AAA Endograft, a three-piece modular device that has a unique nitinol ring design that makes it highly flexible for use in tortuous anatomy, including highly angulated proximal necks. The Aorfix was CE marked in Europe in 2001, and in 2009 was the first AAA endograft in the world to receive a specific indication for treating neck angulation up to 90 degrees. The company hopes to have FDA approval for the Aorfix by the end of 2011, and if the FDA indication is the same, it could carve out a nice market niche for patients with highly angulated aortic necks, who are difficult to impossible to treat with existing endograft technology. Earlier this month, the company announced an equity financing to raise up to £25.3 million in two tranches, which will be used in part to fund US approval and launch of the device. ( See "Abingworth's Bet On Lombard: Best Of Both Worlds For VCs," this issue .)

Vascutek markets the Anaconda AAA Endograft in Europe and is conducting a pivotal US trial, which is expected to complete enrollment this summer. The Anaconda is a highly flexible device that can be reconstrained and repositioned during implantation. It also has a unique interlocking magnet system to simplify cannulation of the contralateral limb.

Bolton is focused first on the TAA market. The company has completed a pivotal US trial of its Relay TAA Endograft, which features a four-step delivery system that allows graft repositioning, and hopes to receive US FDA approval for the device in Q1 2012. Bolton is also gearing up for a US IDE trial of its new Treovance AAA Endograft with Navitel Delivery System, which it expects to begin in May or June of this year. The Treovance System features a low delivery profile (18- to 19-F OD, main body; 15-F, leg) with a detachable introducer sheath and proximal clasping system. The device also has both suprarenal and infrarenal barbs for improved fixation. A European trial of the Treovance System began in April. Bolton has marketed its Relay TAA device since 2005 in Europe, where it is currently fourth in that market.

Novel Emerging Systems

The AAA field now boasts a long list of competitors and devices in development, including several interesting and innovative start-up companies. ( See Exhibit 11.)

One new EVAR device that has generated a great deal of interest recently is the Ovation AAA Endograft from TriVascular Technologies Inc., a company that has traveled an interesting road to reach its current destination. ( See "Trivascular's Sequel Could Be a Blockbuster," IN VIVO, April 2010 (Also see "TriVascular's Sequel Could Be a Blockbuster" - In Vivo, 1 Apr, 2010.) .) TriVascular was a promising start-up developing a novel EVAR technology when it was acquired by Boston Scientific Corp. in 2005 for $65 million plus earn-outs. [See Deal] Following the acquisition, Boston Scientific invested millions into the TriVascular device, but then abruptly shut down the effort a year later as part of a larger restructuring plan when it became apparent that the device would require significant additional R&D investment to bring to market.

TriVascular's first product, the Enovous AAA Endograft, was a unibody endograft with a stentless main body supported by an injectable polymer sleeve. The device also had an injectable sealing ring at the proximal end and a suprarenal stent for proximal fixation. The stentless main body was designed to facilitate low-profile delivery, and the company was able to achieve a delivery profile of only 16-F OD. However, the design also resulted in uneven mechanical load on the graft, which led to metal fatigue and fractures of the suprarenal stent during clinical testing, according to Robert M. Bersin, MD, of Swedish Medical Center in Seattle, who wrote recently on the topic in Endovascular Today.

TriVascular's founders – a group of three engineers from Massachusetts Institute of Technology – were taken by surprise when Boston Scientific shelved the device, but they still believed in the idea behind the technology and in fact, the team had largely addressed the stent fracture issue and were moving forward with a new design when the ax came. Unwilling to give up, they began to seek out independent investor funding to enable them to take control of the technology, and in 2008 were finally successful, putting together a venture-backed coalition and raising $65 million from Delphi Ventures, Kearny Venture Partners, MPM Capital, and New Enterprise Associates to buy the business from Boston Scientific. [See Deal] The new TriVascular made a well-crafted deal that not only gave the company control of the TriVascular intellectual property (IP) but also gave it a broader IP platform previously held by Boston Scientific, along with the manufacturing facility that Boston had previously set up for the technology, designed and built specifically to manufacture the TriVascular endograft. Boston Scientific still holds a 6.75% stake in the company.

It was a risky proposition for the TriVascular team in a field well known for device failures, but fortunately for all the stakeholders, it looks like the company is headed for a happy ending. TriVascular received European CE mark approval for its current endograft, Ovation, in August 2010 and launched the device in Europe this January. In addition, in March the firm announced that it had completed enrollment in its 150-patient pivotal US IDE trial, conducted at 36 sites in three countries. The company is currently conducting 12-month follow-up for that study, which if all goes well, could put it in line for US approval in the latter half of 2012. TriVascular is also planning to eventually develop a TAA graft, but will focus initially on the AAA opportunity.

The Ovation device differs substantially from TriVascular's original Enovous Endograft. The team discarded most of the injectable polymer sleeve, retaining only a series of injectable polymer rings at the proximal end to facilitate graft sealing and conformation to the neck anatomy. Polymer is injected into the rings following graft deployment and cures fully within 20 minutes. Graft fixation is achieved with a new suprarenal stent design with fewer crowns and angulated hooks to minimize metal fatigue, and the legs of the device are supported by nitinol stents. The system has a delivery profile of 14-F OD, making it the lowest-profile commercially available AAA endograft.

Early results from the first 100 patients in the Ovation pivotal trial, presented at the iCON conference, showed a technical success rate of 100% and only one adverse event at 30 days, according to principal investigator Manish Mehta, MD, of Albany Medical College, New York, who said the device has key properties indicative of where the next-generation of EVAR will go. The bane of EVAR is the aortic neck, Mehta, said, and the Ovation device provides a sealing collar and ring that conforms to the neck even when the landing zone is very short. Moreover, the three-stage delivery and deployment mechanism is easy to use and adjustable, he said, and the device tracks like a catheter in the vessels.

Tackling Graft Fixation

A number of other novel AAA systems are in development, including a staple-fixation system from Aptus Endosystems Inc.; a series of liquid aneurysm stabilizing agents, under development by start-up [Vatrix Medical Inc.] ( See "Vatrix Medical Inc., START-UP , March 2010 (Also see "Vatrix Medical Inc." - Medtech Insight, 1 Mar, 2010.)); a 14-F (OD) EVAR device from start-up Altura Medical Inc., which will soon initiate a multicenter trial in Europe and South America ( See "Altura Medical Inc.," START-UP , April 2011 (Also see "Altura Medical Inc." - Medtech Insight, 1 Apr, 2011.) and "Advancing the Technological Frontier in AAA Repair, "START-UP, " April 2011 (Also see "Advancing The Technological Frontier In AAA Repair" - Medtech Insight, 1 Apr, 2011.)); and an active seal technology that can be applied to existing EVAR devices, under development by [Endoluminal Sciences Pty. Ltd.] (S ee "Start-Up News: Endoluminal Sciences: A New Twist on Endograft Sealing," Medtech Insight, April 2011 (Also see "Start-Up News" - Medtech Insight, 1 Apr, 2011.).)

Several of the new technologies in this field are aimed at improving graft fixation and thus long-term graft stability and durability. Furthest along in this effort is Aptus Endosystems, which received European CE mark approval in June 2010 for its low-profile EVAR system – consisting of a 16- and 18-F endograft and the separate EndoStaple fixation device. In the US, the firm has decided to initially pursue 510(k) clearance of the EndoStaple as a stand-alone product before seeking approval for the combined graft/stapling system and has filed for US clearance of the device. (Of note, Lombard Medical also was developing an endostapling device for AAA repair, but abandoned the effort in late 2008.)

As the name implies, the EndoStaple device delivers helical staples to fix the graft to the aortic wall, in a technique the company says replicates a surgical hand-sewn anastomosis and is designed to provide definitive long-term proximal seal integrity, even in challenging anatomy. The company believes the EndoStaple device may ultimately provide both a means to improve primary graft fixation, helping to avoid secondary interventions for newly placed grafts, as well as a way to repair existing endovascular grafts that have failed and require a secondary intervention to prevent aneurysm rupture.

The device is completely disposable and has two components: a steerable EndoGuide that guides and targets where the staple is to be deployed, and a staple applier that removes the staple from a cassette and drives it into the endograft and aortic wall. The physician chooses the number of staples to deliver, depending on specific patient need and situation, which generally ranges from four to six staples. The entire EndoStapling process takes about 15 minutes.

Initial limited sales of the Aptus EVAR system began this year and are focused in Germany and the Netherlands through distribution channels. The firm is also developing an endostapling system for TAA, which it expects to debut in 2012, as well as a fully stented endograft version to cater to physician preference.

The company's current success comes after the firm endured challenges in its initial US trial when a manufacturing discrepancy resulted in an unusually high rate of thromboembolic complications. The firm has since resolved the issue and hopes to file for FDA approval in 2012 to conduct a new cohort of the US IDE trial with the combined graft/stapler system. According to Aptus CEO Jeff Elkins, 12- and 24-month follow-up data from the original trial confirm high aneurysm regression rates along with few late secondary interventions relating to proximal seal/fixation failures.

Founded in 2002, Aptus has raised a total of $60 million in three rounds of financing to date (Series A, B and C), including $45 million from VC firms and a $15 million recapitalization from current investors that closed August 2010. [See Deal] [See Deal] [See Deal] The company plans on further fundraising later this year.