CD&D Washington Editor

WASHINGTON – This year's edition of the Transcatheter Cardiovascular Therapeutics conference – TCT 2008, for short – marked the 20th anniversary of the gathering, and the agenda for opening day at the Washington Convention Center in mid-October showed very clearly that the drug-eluting stent (DES) is still a newsmaker despite the slowdown in sales seen over the past two years.

On the other hand, markets outside the industrialized West are opening up, even if native industry is taking up a lion's share of the largest of those markets, namely China.

Martin Leon, MD, the founder and chairman emeritus of the sponsor of the TCT series, the Cardiovascular Research Foundation (New York), led off the DES summit with a brief discussion titled "The Changing Landscape of DES: Finally Stabilizing or Still in Transition?"

He said, "Things have essentially stabilized … but we have not fully rebounded" to the DES usage numbers seen in 2006. According to Leon, the numbers indicate a reduction of roughly 10% in PCI procedures from 2006, although "we've seen an increase in PCI procedures year to year" since then.

Cardiologists implanted about 15% more DES units as of August 2007 than in 2006, he said, adding that the numbers indicate that DES use rose by another 7% as of this past August.

Leon said European patients were implanted with about 4.5% more coated stents last year than in 2006, but that there was no increase in Japan. He was pointing out the obvious in remarking that compared to other parts of the world, the market in "the U.S. has been the most subject to change."

Christian Spaulding, MD, of Rene Descartes University (Paris), gave attendees a look at how doctors in Europe deal with the large number of coated stents that have earned a CE mark. The first thing he pointed out was that a CE mark is not the same as a place in the catheter lab arsenal.

"Stents have to go through different hurdles before they end up on the shelf of a cath lab," let alone in someone's chest, he said. He reminded attendees that Europe "is a patchwork of countries" and a CE mark means "you can put the device on the market," but "there are a lot of notified bodies and there is no uniform process in analyzing manufacturing process or clinical data," which are the steps needed to obtain reimbursement.

"Several countries, such as France and Belgium, have several additional hurdles," Spaulding said, noting that in his home nation, "we currently have only four or five reimbursed stents" and they "can only be implanted in some specific indications." Among the indications are patients with new lesions, those with lesions of 3mm in diameter or less, and lesions of 15mm or less in length.

"Things are changing in France," he said, noting that the government "will ask for large trial registries and … for one-year data" on a range of scores and outcomes. This will slow adoption, he said, "but will be good for safety."

France has a fixed price it pays for stents, Spaulding noted, but hospitals and hospital groups can negotiate prices down. He echoed Leon's remarks about the relative volatility of the European market as a whole, but reminded attendees that there are substantial variations within Europe in terms of reimbursement and market penetration.

Junbo Ge, MD, director of cardiology at Zhongshan Hospital (Shanghai, China), gave attendees a quick look at how the DES is making an impact on care and on the bare-metal stent (BMS) in the world's most populous nation.

He said that the first PCI to be performed in China was in 1982 and from that point, "development was very slow." However, for the past few years, "the interventional market is up 30% each year."

As might be expected, most of this activity is along the heavily urbanized east coast. China has only about 150 medical centers that are authorized to perform percutaneous interventions, Ge said, but Beijing wants to expand that number into the nation's interior.

As for market penetration, the Firebird, a sirolimus-coated stent based on a stainless steel frame, currently holds 30% of the Chinese market. The Firebird is made by Microport (Shanghai), and its biggest competitor, the Partner DES, is manufactured by Lepu (Beijing) and accounts for another 23% of the market.

Perhaps not surprisingly, at least one of China's bigger players is run by a physician who cut his teeth in the U.S. According to the web site for Lepu, the company "was founded in 1999 by Dr. Zhongjie Pu, a Chinese returnee with U.S. post-graduate education in material science and years of research and development experience" with Cordis (Miami Lakes, Florida.)

According to Ge, the first iteration of the Firebird used a strut with a thickness of about .004", but the Firebird 2 is built on struts only .0034". The supporting data is not necessarily easy to come by despite the huge numbers of China's population. "In China, it's very difficult to do a randomized study" because of follow-up issues, he said, so much of the supporting data for the Firebird stents is registry data.

The pivotal study for the Firebird, the FIREMAN (FIREbird sirolimus-eluting stent In coMplex coronAry lesioNs) study placed no limits on the number of stents that could be implanted, and dealt with complex lesions. Ge said the rate of major adverse cardiac events at 12 months was 4.1%, and the target lesion revascularization rate was 2.1%.

Patients in this study were on 100 mg of aspirin and 75 mg of clopidogrel for at least eight months. Roughly 27% of the patients got only one Firebird, but the largest group, at almost 42%, got two stents. Patients with three stents accounted for almost 20%, and there were patients who received more than seven. The total number of patients who were subject to thrombosis at one year was nine out of 1,078.

Bare-metal stents now competing with DES

Just when doctors thought it was safe to go back into the deep waters of the drug-eluting stent (DES) market and leave the shallow end of the stent pool – the part occupied by the bare-metal stent (BMS) – someone with imagination, pluck and a lot of drive makes the shallow end look a lot deeper.

In fact, it's a lot more than just one person filling out the BMS end of the pool, as one of the TCT sessions clearly demonstrated. And while it seems unlikely that the DES is destined for oblivion as a result, it is quite clear that researchers think there is a lot of mileage left in the BMS.

Speaking on the subject of one such technology was Alexandre Abizaid, MD, chief of coronary interventions at the Dante Pazzanese Institute of Cardiology (Sao Paulo, Brazil), who offered some early returns on the Nuloy BMS, made by Icon Interventional (Atlanta). Regarding the characteristics of the device, Abizaid said the Nuloy stent improves "deliverability, radiopacity, radial strength and recoil." Much of the real advantage of the Nuloy, however, is based on the stent's skinny but sturdy struts.

Abizaid said that animal model studies have produced no difference in outcomes between stainless steel and Nuloy foils, "indicating no adverse biological reactions."

However, the Nuloy is a lot thinner than much of the competition. Abizaid said the Nuloy's struck thickness is a mere 64 mm wide, a slim item compared to the heftier Cypher, made by Cordis, which he said is 140 mm wide.

Without citing specific references, Abizaid said "the clinical value of thin struts have been shown in several studies," and he added that the Nuloy exhibited a 20% lower device profile inside the vessel compared to the Cypher. He said that among the next steps for the device are a CE mark study and a PMA study.

Despite the enthusiasm for a non-DES product, the early success of this naked stent has not deterred Icon from eyeing the DES market. Abizaid told the audience that the company has taken out a license with Ariad Pharmaceuticals (Cambridge, Massachusetts) to use that company's rapamycin analogue, deforolimus, as an antiproliferative (Medical Device Daily, Oct. 15, 2007) for future DES development.

Mark Bates, MD, professor of medicine and surgery at West Virginia University (Charlestown, West Virginia) and the CEO of Nexeon MedSystems (also Charlestown) discussed his company's Protex cobalt alloy stent. The stent does not elute drugs, but is nonetheless, as one might gather, not precisely a bare-metal device inasmuch as it comes with a "pro-healing" coating.

Bates described the stent as "a marriage of two technologies." Based on the company's Riviera cobalt stent and coated with a substance called Finale, made by Surmodics (Eden Prairie, Minnesota), the device is designed to prop open the artery and to speed the healing of that artery.

Bates said the company's inversion point technology "is a cobalt alloy technology that uses a simple concept" involving crimping of the stent's struts. He said the Protex comes in at about 77 mm. This skinny strut does not disappear during radiological examinations, Bates said. "We found that in a pig model, it had equivalent visibility to cobalt alloys." The hoped-for benefit of the Finale coating, which Bates described as a protein layer that attracts "endothelial progenitor cells," is faster healing and perhaps less antiplatelet therapy.

"When you put this stent in endothelial cell culture, you'll see attachment of cells within 30 minutes," Bates said, and a 14-day rabbit model indicated "complete coverage" of the stent.

"We're taking the opposite approach to that of DES, trying to repopulate the" blood vessel lining, Bates said, adding that the first case coming back from the Protex I trial is encouraging. "Basically we see excellent stent behavior and performance," he said. As for antiplatelet therapy, the company's web site says, "only a short one-month antiplatelet therapy regimen is expected to be required."

For the interventionist who is concerned about how well the end of a stent seats at the juncture of the aorta and one of the main coronary arteries, there is almost a new industry to help. One of the presentations at the meeting was by Tim Fischell, MD, chief scientific officer at Ostial Solutions (Kalamazoo, Michigan), who discussed the company's Ostial Pro stent-positioning system.

Fischell described the Ostial Pro as "a new tool to help you position a stent at the aortal-ostial opening" with much more certainty and precision than is currently possible. He said, "the rationale [behind the device's development] is that angiographic landmarks are often ambiguous or misleading," which too often leads to misplaced stents. "The need to correctly position a stent is even more critical in the era of the DES," he said, adding that a positioning device "should be simple and nearly foolproof."

The company believes it is onto a substantial opportunity. Fischell said the market in 2008 is about 290,000 procedures worldwide. "This is not a trivial market or problem," he said.

The Ostial Pro is a four-prong guide that expands to the side when pushed past the end of the catheter and deploys against the aorta around the entry into the affected artery. The idea is to help the interventionist position the end of the stent so that the balloon can flatten out the end of the stent securely against the geometry of the coronary artery where the artery opens into the aorta. Fischell said with proper use, an interventionist can "get a flush, perfect alignment," and said the company's device has been used for dozens of cardiac and renal placements. He said the device is now being marketed after obtaining a PMA in June 2007 and is approved for coronary and other applications.

As for the device's pivotal PMA trial, Fischell said "the miss rate in the 30 control cases was 30%," but there were none in the study group. "This is a simple tool that is compatible with contemporary guiding catheters and stents," he said.

New stent trials now must follow patients for 1.5 years

The lead-up to the DES guidance published by FDA in March probably triggered at least a fair amount of anxiety among firms working on new DES products, a fact that was not lost on TCT's organizers. One of the "hot topic" sessions at this year's conference, was titled, "New DES Guidance: Does Preserving Safety Blunt Innovation?"

Leading off the discussion was Ashley Boam, chief of the interventional cardiology devices branch at FDA's Center for Devices and Radiological Health (CDRH). Boam quickly recapped the essentials of any clinical study of a new stent, reminding industry that stent thrombosis "will continue to be an important secondary safety endpoint." She also reiterated the agency's standing invitation to industry to "come early, come often" to discuss the particulars of an application. "We're open to a global approach," she said in reference to the possibility of using data from outside the U.S. (OUS) to support a PMA.

Elizabeth Hillebrenner, a scientific reviewer at CDRH, said the agency "received many excellent comments" after the publication of the guidance, "and now we're at the editing phase," adding that there are more changes to come.

"The area you'll see the most change is the engineering section," Hillebrenner said. On the topic of coating integrity, she said a baseline test would consist of expanding the stent to its nominal diameter in air. To simulate deployment, sponsors should use a mock blood vessel in an aqueous solution and dilate a single stent to its maximum-labeled diameter after maneuvering the stent through "a tortuous path."

Particulate matter testing is a concern and "we want to make sure there is no embolic risk from downstream particles," Hillebrenner said. For baseline testing, FDA will require expansion of a single stent to the maximum-labeled diameter in an aqueous solution and in an unconstrained environment to test for such precipitates.

The requirements for simulated deployment are a bit more rigorous. Hillebrenner stated that "for simulated deployment for particulate matter tests," sponsors will have to track multiple stents through a tortuous path and expand the stents to the maximum diameter "in an overlapped configuration in a mock vessel bent to a clinically relevant radius of curvature," again in an aqueous solution.

Hillebrenner said there was something for industry in this first round of edits. "I think everyone will be happy to see that the revision eliminates the need for long-stent studies in animals," but this is the point at which she dropped the news that half of patients enrolled in the pivotal study have to have made it to 18 months at the time of submission of a PMA. "Please keep in mind that our recommendations for this or any other study" may change given the dual antiplatelet study that industry and FDA will collaborate on in the coming months (see sidebar).

The agency does not have a fully fleshed out set of amendments to the guidance, but Hillebrenner said "we hope to have the modified document posted in four to six months." She also said "we will issue a Federal Register notice to announce its availability."

Also on the dais was Campbell Rogers, the chief technology officer at stent maker Cordis, whose reaction to the news of an 18-month requirement was not at all negative. He said "the pace of approvals for stents in the pre-DES and DES era" shows a significant slowdown, but this slow-down parallels the rise of technologically challenging stents.

Rogers said the discussions on the guidance between the agency and industry "have been extremely productive and timely," and said he is of the opinion that some of the requirements "get to be extremely enabling because it becomes a very clear and specific roadmap," the value of which "cannot be overstated."

In the modern medical device world, resource allocation "is overwhelmingly tipped toward development, not creation," Rogers stated, which means "eliminating options early" and investing in the more promising early contenders. The chief question posed by the guidance, Rogers said, is whether "the clinical benefits of possible incremental safety … outweigh the opportunity costs" of improved therapeutics.

Donald Cutlip, MD, chief of interventional cardiology at Beth Israel Deaconess Medical Center (Boston), posed the question: "Will it become more difficult to bring a new DES to market?"

Cutlip said the answer is a flat "yes" because of the longer duration of trials and the larger number of patients. Safety is still the crux of the matter, he said, adding, "even a similar risk is important if it occurs without a significant benefit" that exceeds the current state of the art. He said even though stent thrombosis "is a low-frequency event," it is as the factor that prompted the discussions over DES safety.

Mitchell Krucoff, MD, professor of medicine at Duke University Medical Center (Durham, North Carolina), said the post-approval study is based on "the notion that we would not be pursuing pre-market issues in a post-market study," but he said this is difficult to take verbatim if only because adverse events that occur at low rates will not show up in a PMA study.

"What we all agree is [a] reasonable [assurance of safety and efficacy] becomes the tipping point" between PMA studies and post-approval studies, Krucoff said. He asked: "What is the difference between 12 months and 18 months?"

"This is millions of human beings and billions of dollars, and delaying it for six months is a huge reallocation of resources" for industry, Krucoff said, but these stents will go into a lot of patients.

Boam responded that "the initial recommendation was to have a substantial number of patients out to 24 months" because a lot of patients drop their anti-platelet therapy at 12 months. "We wanted to see some sort of reassurance" that "people didn't fall of the cliff after 12 months." She said industry was okay with 18 months, but also said FDA is aware of the burden on industry. "I agree with Dr. Cutlip's comments that we don't see 18 months as an undue burden given the levels of enrollment."

Some procedures encroaching on thoracotomy

Bad heart valves are likely to eat up a lot more of the Medicare dollar in times to come, so there is no lack of interest in this area of cardiology among researchers, as was made clear during one of the TCT sessions.

This session included an overview of two of the stronger candidates for a pre-market approval application (PMA) for sutureless valve, but another presenter indicated that while minimally invasive procedures for repair and replacement of heart valves have a lot going for them, they are still not at a stage of full maturity.

Discussing minimally invasive approaches to aortic valve disease, Lars Svensson, MD, director of the Center for Aortic Surgery at the Cleveland Clinic, opened by hinting at the fact that minimally invasive procedures have not quite yet come of age. "For the more complex cases, we're still doing partial sternotomy," he said.

One of the obvious apparent benefits of cutting down on the cutting up is that blood transfusions for minimally invasive approaches are "a lot less" in terms of quantity than for conventional surgical procedures, Svensson said.

One approach that induces less trauma than a full-blown open-heart surgery would commence from the patient's right side at the second, third and fourth intercostal space, which are points on the rib cage that flank the sternum. However, this approach could damage the patient's mammary artery because this artery runs down the side of the sternum right behind the ribs.

He said that using this access point "is doable," but added that it "is not a fun operation for the patient," even if it is not as traumatic as the traditional opening of the entire chest cavity.

However, Svensson also cautioned that a surgeon who cannot reliably get in and out in an hour when doing a percutaneous valve procedure should consider employing a more conventional approach due to the risk of damage to the native valve. While he didn't say it, any manufacturer that comes up with a device that can help address some of these concerns might have quite a market to fill.

"Patients are increasingly looking for a minimally invasive approach," Svensson said, but very often react negatively to the word "percutaneous," which might be the pop-culture fallout from the drug-eluting stent flap of 2006.

Svensson said an analysis of almost 2,000 patients undergoing various procedures for aortic valve repair showed substantial improvements for those undergoing minimally invasive procedures.

Survival, however, did not seem significantly enhanced because, while the raw data indicated that long-term survival is better for all patients who underwent minimally invasive procedures compared to all who had more traumatic operations, an analysis that matched sub-populations for various characteristics drove the survival score lines closer together.

Pain scores, on the other hand, are vastly different. "The majority [of patients getting minimally invasive surgery] have a significant amount of pain initially," but most of the problem disappears after a week, he said, adding that this group experienced less pain overall than controls.

As for measurements of lung output via spirometry, Svensson said patients who were put through minimally invasive surgical procedures "had significantly better function," although he could only speculate that this is because it does less damage to the chest wall and the diaphragm than a procedure that cracks open the entire rib cage.

Predictably, less-invasive procedures generated less blood loss and hence incurred less use of blood and plasma. "Length of stay [in critical-care rooms] was shorter, as was overall hospital stay," he said. In conclusion, he said minimally invasive aortic valve surgeries "had better pulmonary function, better pain scores, less product usage."

Svensson also recommended that practitioners rethink patient selection standards. "As you face more and more of these [high-risk, morbidly obese] patients, I would urge minimally invasive procedures" be used in patients who might otherwise be rejected for any sort of non-pharmacological care.

He brought this up in a discussion of the case of a 52-year-old man who was on six liters of oxygen a day and was morbidly obese and dying on admission. Svensson said he repaired the patient's aortic valve and reduced his oxygen need by two-thirds, and although the patient was not exactly hale and hearty upon discharge, he at least had a fighting chance to recover and lead a somewhat normal existence.

James Cox, MD, the inventor of the Maze-Cox procedure – which was the first surgical procedure to deal effectively with defibrillation – and medical director of ATS Medical (Minneapolis), presented an update on the company's Enable sutureless aortic valve replacement. He led his presentation by commenting: "In our haste to make operations less invasive, we need to keep our eye on the ball of the quality of the valves we're implanting."

He said the ATS 3F Enable valve "has been in development for 20 years," is built on a nitinol frame, and is made with bovine cardiac tissue. "This valve is based on a tubular structure" and the maximum stress "occurs exactly where it should," where the valve seats into the heart, which is fixed in part by a single circumferential stitch. The company announced the first implant of the valve in a patient in North America, into a Canadian patient, in April.

Many commercially available tissue valves suffer from stress at the other main attachment points, known s the commissural posts, but the Enable attaches to the inside of the aortic wall by means of three commissural tabs that attach with mattress sutures, Cox said, and tests indicate that "the flow pattern across these valves" indicate "no more [turbulence] than normal valves." Since turbulence is thought to be the cause of calcification, ATS feels it can avoid the use of anti-calcification agents in the Enable.

He said the design of the Enable helps preserve the aortic sinus by allowing the blood to fill in behind the valves, just as the normal heart does. Failure to allow this backfill feature creates more turbulence in the blood flow through the valve area.

Cox said that another of the unusual features of this valve is that "because the valve closes from below up, it takes the pressure off the commissure."

The nitinol frame can be folded for delivery into the body without damaging the device, he said, which is one of reasons he said "the big advantage of a valve like this is going to be in tiny roots," which are found in small patients, a group that is often left behind where new cardiovascular devices are concerned.

"The main things you're concerned about is will it migrate," Cox said, adding that out of 101 implants in Europe, there have been no cases of migration. "Two became slightly tilted, and one had to be explanted. "We don't know what the durability is," but wear testing and the optimal flow characteristic should make "durability optimal." Next up at ATS, he said, is a percutaneously introduced valve.