CDU Associate Managing Editor

PARIS The controversy began early at the 2005 EuroPCR meeting at the Palais de Congr s. In the opening symposium at the conference, physicians on a panel covering the use of percutaneous coronary intervention (PCI) in "challenging" patients discussed how far they could take such technology, in essence further invading the already dwindling turf of the cardiac surgeon.

First up, and presenting a more conservative approach to the limits of PCI and the continuing merits of surgery, was William Wijns, co-director of the Cardiovascular Center at OLV Ziekenhuis (Aalst, Belgium).

Looking at bare-metal stents, he noted that based on a composite of studies comparing key endpoints death, myocardial infarction, stroke and hospitalization with use of those devices vs. coronary artery bypass surgery (CABG), "there is basically no difference between the two approaches in those patients who are deemed treatable by either one [cardiac interventionalist] or the other [cardiac surgery]."

The differences between the two approaches are only highlighted when the need for target vessel revascularization (TVR) is observed, Wijns said. In almost all cases, he said, it appears that the stent has the edge, with, perhaps, the notable exception of the diabetic patient.

Even with the notable improvements that have come with the drug-eluting stent (DES), he said that CABG is the benchmark by which most coronary interventional procedures should be measured.

"CABG provides durable results," Wijns said, adding that it has "a well-defined and well-known safety profile," one that he said PCI is still in the process of establishing, particularly in regard to the wildly successful, thus far, use of DES.

Painting a much more all-encompassing view of the value of PCI was Antonio Colombo, MD, of Centro Guore Columbus (Milan, Italy)

Colombo, who has almost never met a vessel he couldn't stent, outlined several areas that he said PCI can benefit in his presentation titled, "There are no limits: any anatomy, any patient."

The primary problem he mentioned was that of the chronic total occlusion (CTO). "Chronic total occlusion is a major limitation of angioplasty and a major limitation of stents, even drug-eluting stents," he said.

That being said, Colombo discussed several CTO treatment options using DES, including one at his center in which six Cypher sirolimus-eluting stents were implanted in one patient, with no major adverse events evidenced after one year of follow-up.

He also described its use in patients with multi-vessel disease, including one clinical example from his center of triple-vessel disease in which an astounding total of nine Cypher DES were implanted.

"When you see a patient like this with multiple lesions on the left coronary and on the right coronary, you can convert these vessels into a well-functioning conduit," Colombo said. However, he cautioned that one still has to be careful to protect the coronary branches. "You cannot just implant one stent after the other, it's not like eating M&Ms."

Colombo also mentioned the use of PCI in left main artery disease and in treating bifurcations.

Presenting the cardiac surgeons' point of view was Gianni Angelini, MD, of Bristol Heart Institute at Bristol Royal Infirmary (Bristol, UK).

He noted that in the wake of DES, his profession may be down, but he joked that it is certainly not an extinct species yet.

He said that much of the traditional surgeon's territory that interventionalists are starting to move in to is very much pioneering work, and that surgeons are adapting new techniques of their own to try to preserve their turf, and perhaps expand it.

Emphasizing that interventionalists are treading on new ground, he cited the example of Colombo: "I heard with interest the presentation of Dr. Colombo, who obviously is an extremely skilled individual but also very brave."

Angelini noted that if, as Wijn stated in his address, surgery is the "gold standard," "I guess you will agree with me that PTCA [percutaneous transluminal coronary angioplasty] has got some limitations. You need to redo some more PTCA and you need occasionally [to do] surgical revascularization."

He said the numbers thus far for DES trials have included only about 5% or 10% of the recruitable population. From the surgeons' point of view and quoting former British Prime Minister Margaret Thatcher, he noted: "Perhaps you've been a little bit economical with the truth."

As a conservative estimate, he said that at least 60% of patients being treated every day by interventional cardiologists are receiving that treatment not based on solid clinical evidence from well-constructed randomized trials.

"What I think is happening here is that while we are all dealing with the same 'apples,' I think we are going to have to deal with the bad apples because you've taken the best already away from us," Angelini said.

That isn't to say that the surgeon isn't to blame, he acknowledged, adding that surgeons are generally in a state of denial. "Denial means 'What we are doing or what we have been doing for 40 years is great, why do we have to change?'"

The question the cardiac surgeon ultimately has to ask, said Angelini, is "What is the future leaving to us?" since the interventional cardiologist has become the "gatekeeper" to cardiovascular medicine.

With the "big key," he said, one can do big things, such as open very difficult and worthwhile areas of medicine, or "we can have a different approach, which is evidence-based clinical medicine."

Angelini said that he believes the cardiology field needs a referee, "who is going to provide our patients with information even before they have an angiogram."

Ultimately, however, he said the next 10 years could see the demise of not only the cardiac surgeon but also PTCA, because of better pharmaceuticals and the rise of gene therapy, among other things. "Probably in 10 or 20 years, people will be laughing at what we do now, which will give me enough time to get to my retirement."

Stent improvements still needed

While many clinicians, industry officials, analysts and the media have extolled the virtues of DES devices, not enough has been said about the challenges, and indeed, problems associated with making these simple-looking but complex devices work properly in the clinical setting. To that end, a symposium, sponsored by Guidant (Indianapolis) was convened at the EuroPCR meeting to discuss the challenges for the DES in 2005 and beyond.

Giving a "big picture" overview was Jean Marco, MD, of the interventional cardiology unit at Clinique Pasteur (Toulouse, France). He broke the devices down into their four basic elements: the stent, the polymer, the drug and the delivery system.

"Increasing the patient complexity, we know that we increase the chance of early- or late-stent complications or latent thrombosis," he said, adding that increasing patient complexity and treating more complex lesions "increases the risk of failure of the stent."

The objectives of the symposium, Marco said, were to discover the main risks to these increasingly complex patient and lesion subsets; to discover what possible solutions are needed to improve the efficacy of the DES; and to determine which drugs work best on the devices.

Campell Rogers, MD, director of the cardiac catheterization laboratory at Brigham & Women's Hospital (Boston), addressed the complexity issues for a DES program from the perspective of someone who runs a large cath lab in which DES utilization already exceeds 93%.

He characterized his hospital's use of the devices as "very broad," saying that they already use DES in very complex patients, including bifurcation, total occlusions and thrombotic lesions, "lesions in which efficacy has really not been studied in any sort of well-controlled or randomized trials."

In the bare-metal stent era, Rogers noted, there were very few randomized or controlled trials comparing the different companies' devices. "In the DES era, there are increasingly comparative trials looking at efficacy and safety measures."

He evaluated how the available data on the more complex patients and lesions may be helping to "tease out" data that could help to discern the differences between the various DES "with an eye towards optimizing DES in the future not so much for standard workhorse lesions but for much more complex patients and much more complex lesions."

One area Rogers looked at was that of diabetic patients, an area in which he said that the data comparing current devices, such as it exists, is small.

While he said that some preliminary data appear to give the edge to the Cypher stent from Johnson & Johnson's (New Brunswick, New Jersey) Cordis (Miami Lakes, Florida) for that population over the Boston Scientific (Natick, Massachusetts) Taxus Express2 stent, he said that registry data, such as that coming out of the e-Cypher registry looking at DES outcomes in diabetic vs. non-diabetic patients, shows that while there is little doubt that drug-eluting stents are better in diabetic patients than bare-metal stents, "DES in diabetic patients are not as good as DES in non-diabetic patients."

This means there still is a lot of room for understanding how to improve upon the devices and how to possibly tailor them for patients with diabetes, Rogers said.

He said better animal models are now being developed to study how diabetes affects lesion size.

A second challenging area cited by Rogers was that of long, diffuse lesions and the need for overlapping stents in these patients.

A clinical concern arises, he said, when data from such trials as Boston Sci's TAXUS V demonstrates higher major adverse cardiac event (MACE) rates in those patients receiving multiple, and in most cases, overlapping stents.

Drug retention on the stents may be one factor that causes problems within vessel walls, according to Rogers, and that appears to be borne out by the wildly varying rates at which various drugs are eluted from the different devices.

In the area of stent thrombosis, he said that very little has been done to look at the delivery of drugs specifically into thrombotic lesions.

Rogers noted that data from the head-to-head REALITY trial shows that all 29 of the patients who had stent thrombosis, regardless of whether they were treated with the Cypher or Taxus stent, either died or had a heart attack.

Renu Virmani, MD, chair of the department of cardiovascular pathology at the Armed Forces Institute of Pathology (Washington), discussed how polymer coatings can make a big difference in the success or failure of a DES.

She noted that the individual polymer coating's mechanism of action is influenced by several unique physical characteristics that all work together to control the release of a drug from the stent. These include polymer thickness, flexibility, drug-eluting capacity, mechanical integrity, how it adheres to the stent, biocompatibility, thrombogenicity, inflammation, historical use and the ability to release drugs in a controlled fashion.

As an example of a coating she has helped develop that addresses many of the aforementioned characteristics, Virmani cited Guidant's Xience V polymer, the backbone of that company's cobalt chromium Vision stent.

"The polymer has excellent drug-loading capabilities and minimal coating thickness is needed, only five to six microns in thickness," Virmani said.

She added that the Xience also has a good physical coating, with superior adhesion to metal, as well as possessing good conductibility as well as flexibility.

Additionally, the polymer is coated on a well-known stent platform, Guidant's Multi-Link Vision stent, with everolimus as the pharmaceutical compound.

While Virmani said the Xience showed good coverage results, particularly in the case of overlapping stents at 90 days better in fact than the Cypher or Taxus DES she noted that stent thrombosis is a problem.

She said that real-world data from 2,229 patients that were implanted with either a Cypher or Taxus DES in the REALITY trial revealed that 29 patients (9.3%) had stent thrombosis. "Of the 29 patients with thrombosis, 13 of them died." This, she noted, "gives us a mortality rate of 45%."

The current generation of stents, especially Taxus stents, she said, show greater fibrin disposition (delayed healing) and endothelialization in animal models.

In real-world patients, she said the current generation of DES also have a greater tendency for thrombosis, especially the Taxus.

"We believe a newer generation of polymer and drugs for the prevention of restensosis are needed," she said, adding that the devices such as the Xience V stent have shown promise in preclinical studies with greater endothelialization while maintaining low profile, good deployment characteristics and minimal neointimal formation in animal models.

In closing the symposium, Marco said that it appears that the primary cause of DES failure is inadequate release of antiproliferative agent into the vessel wall and polymer, and he noted that an improved drug/stent platform is needed, with two intriguing solutions being the combination of biologically inert polymers with nontoxic drugs and the successful development of a bioabsorbable DES.

Valve talks keep stents from stealing the show

While the lion's share of the focus at the EuroPCR meeting was on the drug-eluting stent market, other interesting areas in the interventional cardiology field also were discussed, including the up-and-coming valve replacement and repair sector.

Speaking on the many new innovations in this potentially lucrative sector was Carlos Ruiz, MD, PhD, professor and director of the division of pediatric cardiology at the University of Illinois at Chicago.

He acknowledged that this sector traditionally has been the turf of the cardiovascular surgeon but said that ultimately, as has already been seen in other areas, interventional cardiologists "almost certainly" will win out when furnished with the needed technological advances.

"It's obvious to every one of us who are here that the less-invasive procedure will always be preferred for as long as there is an equivalent safety and efficacy in that procedure and patients will always like that," he said.

Adding to that assertion Ruiz hypothesized that "if transcatheter valve replacement and repair can be done safer than surgery with an equivalent efficiency, it may supplant, not all, but some of the current surgical methods for the current options."

Better yet, he noted that patients who currently are considered bad candidates for surgery and are being managed with medication could have "better outcomes and better possibilities" with new minimally invasive valve technology.

Ruiz described some of the latest developments for transcatheter valve repair. He noted that many of the described devices are still in the animal model stage, but a few have had limited clinical trials. He noted that the valves are either mechanical or biological, with most of the work being done in biologicals.

One exciting new mechanical valve he mentioned involves nanotechnology. Using vacuum deposition, Steve Bailey, MD, of the Janey Briscoe Center for Cardiovascular Research at the University of Texas Health Sciences Center (San Antonio, Texas), reported producing 4 micron-thin nitinol to make the Nitinol Membrane PercValve. This device has been used in a small series of animal models.

On the biological side, there are a number of entries. Edwards Lifesciences (Irvine, California) has, according to Ruiz, made a major leap with the PVT valve. There is an ongoing human trial. "This valve is constructed from equine pericardium on a very strong stent and results have been spectacular," he said. Edwards acquired Percutaneous Valve Technologies (PVT; Fort Lee, New Jersey) early in 2004.

Also on the biological side, he described the Paniagua valve, developed by David Paniagua of the Texas Heart Institute (Houston). He said that device wasn't exciting so much for the valve itself but rather for the tissue, which he described as a composition of porcine pericardium. "After eight months of implant in the sheep model . . . those pericardial valves have not developed any calcifications," he said.

Another interesting valve Ruiz mentioned is the CoreValve, from CoreValve (Irvine, California), a bovine pericardial device being developed with a self-expandable, high radial-force nitinol stent. This valve already has been used in several patients with excellent results, he said, though adding that better imaging techniques are needed to utilize the potential of the technology.

Other biological valves he cited include the NuMED Valve from NuMED (Hopkinton, New York) and the Cook SIS valve from Cook Biotech (West Lafayette, Indiana). Using submucosa from pig intestine, the SIS collagen base material includes growth factors. Pig studies show a remodeling process that occurs long-term.

While he said that progress has been made, Ruiz noted that the "ideal transcatheter valve" is not yet available. He said the requirements for the ideal valve include issues of delivery, scaffold, material and design. For delivery, the valve needs to be low profile, reliable for orientation and easily placed. "The scaffold of the valve must be flexible, and stentless is better," Ruiz said. As to material for the valve, it must be nonthrombogenic, noninflammatory and would be best if it could sustain somatic growth. It should also be readily available off the shelf, with no preparation needed.

Ruiz also described another valvular problem area: mitral valve regurgitation. This occurs when the mitral valve doesn't hold a good seal. Ruiz said that interventional cardiologists have invented a number of potential devices to treat this problem with transcatheter approaches.

One company attempting to fix this problem is Evalve (Redwood City, California). The company's technique involves threading a dime-sized clip into the heart via a catheter. The catheter is guided by a small echocardiography probe in the patient's throat, as well as an ordinary echocardiography transducer placed on the chest.

Edwards Lifesciences has developed the Milano II LifeStitch, a device using stitches that are applied to the valve, and a nitinol anchor used to tighten the knots.

Cardiac Dimensions (Seattle) is developing an implant using the superior vena cava as its entry point. Guided by echocardiogram, traction is placed on the valve leaflets.

A device from Viacor (Wilmington, Massachusetts) uses nitinol covered with surgical-grade Teflon. The device uses radio frequency to create burns on top of the mitral annulus that cause constriction of the mitral annulus at the selected target.

Another company trying to solve the regurgitation problem mentioned by Ruiz is Mitralign (Salem, New Hampshire). Combining surgical precision with interventional therapy, the company is developing a catheter-based mitral valve repair system.

The Mitralign system resembles surgical annuloplasty, during which a dysfunctional, dilated mitral valve opening is reduced or cinched down to a functional size.

Catheters are percutaneously guided to the mitral valve using the company's MitraLock Guidance System. Once positioned in the left ventricle, the physician performs an annuloplasty via the catheters utilizing standard imaging techniques.

Ruiz noted: "No one single device will fix all the varieties of valvular disease, and I wonder how the regulatory agencies will compare the products to traditional surgery."

Speaking about the valve repair and replacement field, he was unabashedly enthusiastic. "I think it is definitely one of the most exciting fields today in intervention and we'll see that this is going to be quite explosive."

That being said, Ruiz cautioned that perhaps one of the only real handicaps to further advancing interventional technology in this field is a lack of good imaging techniques. "We don't have a good, reliable online imaging that allows us to do safely many of these procedures," he said.

To that end, Ruiz challenged the device industry to come up with solutions. "I think the imaging companies need to step up to the plate and help us to employ and use those devices in a safe[r] manner."

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