Next-generation drug-eluting stents tackle shortcomings of Cypher, Taxus

Shelley Wood

February 07, 2006

New York, NY - With several new drug-eluting stents (DES) already available in Europe and in pivotal clinical trials in the US, interventional cardiologists are starting to hope that the innovative newcomers will resolve many of their concerns or complaints about the Cypher (Cordis/Johnson & Johnson) and Taxus (Boston Scientific) devices.

Dr Mitchell Krucoff (Source: Duke University Medical Center)

"With any breakthrough technology that changes the landscape of medical therapeutics, the reality is, the first version is always the worst version," Dr Mitchell Krucoff (Duke Clinical Research Institute, Durham, NC) told heart wire . "In the case of first-generation DES, these are essentially bare-metal stents that have been spray-painted with plastic."

Liberté (Source: Boston Scientific)

While next-generation versions of both the Cypher and Taxus, known as the Cypher Select and Taxus Liberté, are already CE Mark approved and poised for US approval, both have focused primarily on easier deliverability, a major buzzword of the early DES era. Elsewhere, companies have tried to emulate or improve on the success of the Cypher by developing new macrolide immunosuppressive ("limus") drugs, such as biolimus A9 (Biosensors), everolimus (Guidant), tacrolimus (Sorin, Abbott), and zotarolimus (Abbott, Medtronic) for stent-based delivery. Likewise, innovation in stent composition and design continues, with many second-generation drug-eluting stents available outside North America doing away with stainless steel for the base stent, replacing it with alloys that maintain radiopacity and strength but permit thinner, more flexible struts. Indeed, Cordis/J&J has its own cobalt-chromium stent, the Cypher Neo, still several years away from US approval.

Cypher Select (Source: Cordis/J&J)

Perhaps the biggest and most contentious flurry of activity centers on the actual mechanics of drug-delivery and the need for a polymer coating. Polymers have been hailed by some as essential to controlled drug elution and maligned by others as a ticking time bomb: the potential cause of increased late thrombosis and other adverse tissue responses. The polymer has also been blamed for stent-delivery glitches; in particular, the increased friction, or "stickiness," between the delivery balloon and the stent itself. Although the original Taxus and Cypher stents both have polymer coatings, other DES developed at the same time, such Cook Inc's drug-eluting stent program, did not make it through clinical testing, having failed to demonstrate superiority over bare-metal stents—a fault blamed largely on the inability to regulate elution of the drug.

Puzzling over polymers

Dr Marie-Claude Morice

New stents, however, are revisiting the concept of polymer-free stents or at least trying to develop polymers that will disappear over time. As Dr Marie-Claude Morice (Institut Cardiovasculaire Paris Sud, Massy, France) emphasized to heart wire , operators have enough years of experience with bare-metal stents to feel confident that a metal stent can remain in the coronary system without causing late adverse effects. The same cannot be said for the polymer.

"It's a very important issue," Morice said. "The polymer coatings currently used reflect the early phase of DES development. The long-term outcome of bare stents is well known, whereas that of polymer coatings is not."

Dr Adnan Kastrati (Deutsches Herzzentrum, Munich, Germany) agrees: "Why would you have something on the stent that you don't need? There are not enough data to show that polymers are risky over the long term, but there are still some concerns," Kastrati said.

Dr Adnan Kastrati

Those concerns stem from a number of sources, experts say. For one, says Krucoff, even a polymer that is not loaded with drug can cause localized reactions in the artery.

"In the preclinical work with the Cypher stent in pigs, for instance, it was very dramatic that once the sirolimus had eluted, there was an intense subsequent inflammatory response at the cellular level that generated profound late in-stent restenosis," Krucoff explained. "Now, it's very clear we're not seeing that in humans, but on the other hand, this does give us an animal model that alerts us to the fact that, once the drug has eluted, if the polymers persist, these are not inert substances."

Scanning electron microscope studies also indicate that polymer integrity can become damaged during stent delivery, cracking or peeling away from the stent struts, but the extent of the problem and its clinical impact are unknown.

"We can never really be sure what the true denominator is that we're dealing with," Krucoff told heart wire . "For instance, if you're concerned that in high-pressure balloon delivery you could potentially fragment or cause the polymer to flake—well, how many thousand times does that have to happen for any one time you have late stent thrombosis?"

Krucoff points out that the potential problems associated with polymer integrity may depend on type of drug, dose, and properties of the polymer itself. For example, he says, studies of the Taxus stent indicate that only 20% of the paclitaxel embedded in the polymer actually elutes during the healing process, but that amount, as shown in the pivotal trials, is clearly enough to substantially reduce the risk of restenosis.

"But what about the rare occasion when something else happens?" Krucoff asked. "The coronary artery constricts, or you overlap the stents and create more fragmented polymer when the stents are dilated with a high-pressure balloon where they've overlapped, and you create unusual contortion, and more drug is eluted from the polymer—what happens then? No polymer is inert, and whether or not it is still eluting drug, or if it is just how the tissue responds to the polymer—all of those things get back to our concerns."

Getting away from the polymer

The Translumina stent-coating system

Kastrati's group recently became the first to show that it may be possible to get away without using a polymer coating, at least for relatively simple lesions. As reported by heart wire , Kastrati et al's ISAR-TEST trial used an in-house system for applying sirolimus to a "rough" bare-metal stent. The ISAR-TEST results, first presented at the 2005 TCT meeting, were recently published as a rapid-access publication online in Circulation[1], proving that a nonpolymer approach to drug-eluting stents can work in a field where other nonpolymerized stents have repeatedly met with failure.

The economic benefits of a coat-it-yourself stent were one of the rationales behind ISAR-TEST, but Kastrati insists that the most important factor was the drive to create a stent that does not have a permanent polymer coating.

 
The long-term outcome of bare stents is well known, whereas that of polymer coatings is not.
 

"The most important factor is that we don't want to have polymers permanently on the stent, so we can be sure that, after six months, we have a bare-metal stent like those for which for many years we had no concerns about long-term efficacy," Kastrati said.

For her part, Morice told heart wire that coating stents in-house is "a good temporary solution," comparable to the manual crimping of bare-metal stents in years past, and may play a role until the cost of DES declines. In the long run, however, "I do not think that 'coat-it-yourself' stents will have a major role," she says. "They will never compete with industrially engineered stents."

Morice has, herself, been involved in research examining polymer-free stents, most recently the JUPITER trial, testing the Janus Carbostent, a nonpolymerized stent coated with tacrolimus. The Janus is available in Europe, but not the US. As previously reported by heart wire , the JUPITER trial disappointed investigators by failing to show a difference between the tacrolimus-coated Janus stent, with its unique reservoir design, and the bare-metal Tecnic carbostent. When Morice first presented the results at the TCT 2005 meeting, she told heart wire she still believes the Janus stent has potential, an opinion she now says has not changed.

"The bare-stent version is associated with an excellent outcome in terms of late loss and restenosis, and the reservoir concept is a good idea," Morice said in a recent interview. "However, the drug effect is minimal or nonexistent, although tacrolimus is probably a very good antirestenotic drug. The drug dosage is perhaps insufficient or the release profile should be improved."

Second-generation stents

Other companies are working to get around the problem of polymer tackiness and tissue reactions by using them only on the abluminal surface of the stent. The idea is to direct drug at the vessel wall, and not the bloodstream; indeed, even Biosensor's nonpolymerized paclitaxel-coated Axxion stent is coated with drug on its outer (abluminal) side only. Likewise, the Janus stent's reservoir design releases drug only on the outer aspect of the stent.

Drug reservoir on the Janus stent (Source: Sorin)

In fact, the Janus, like another much-talked-about up-and-comer, the CoStar stent (Conor Medsystem), was perhaps one of the first stents designed specifically for drug elution. Both stents employ reservoirs where drug can be loaded, rather than plastered over the entire outer and inner surface area of the stent, as was done with the first-generation stents Cypher and Taxus. The Janus is designed for abluminal elution, while the Costar has different wells on both the luminal and abluminal sides of the vessel, such that antiplatelet drug could potentially be released in one direction and antiproliferative drugs in another.

CoStar (Source: Conor)

While the Janus uses no polymer at all, the CoStar uses poly(lactic-co-glycolic acid) (PLGA), a proprietary bioresorbable polymer, but only within the small wells embedded in the stent where the drug is loaded, leaving the actual surface of the stent polymer-free. As Krucoff, who is the principal investigator for the US trial of the CoStar stent (COSTAR II), explained to heart wire , using the CoStar "feels like you've gone back to bare-metal stent delivery," doing away with "stent stickiness," a charge that has been leveled at the Cypher and Taxus and believed to be linked to problems deflating or removing the balloon during stent deployment.

"The most immediately noticeable difference is that, with all the polymer down in these wells, the surface of the stents themselves is polished cobalt chromium, so there's no sticky, tacky plastic on the surface," Krucoff said. "These stents just fly into the coronary arteries, compared with polymer-coated stents."

Innovation in next-generation DES

Manufacturer Name Drug Stent material Polymer Status
Abbott ZoMaxx Zotarolimus Tantalum/stainless steel Durable
Biosensors Axxion Paclitaxel Stainless steel None CE Mark
Biosensors BioMatrix Biolimus-A9 Stainless steel Bioabsorbable
Boston Scientific Taxus Liberté Paclitaxel Stainless steel Durable CE Mark
Conor CoStar Paclitaxel Cobalt chromium Bioabsorbable
Cordis/J&J Cypher Select Sirolimus Stainless steel Durable CE Mark
Cordis/J&J Cypher Neo Sirolimus Cobalt chromium Durable
Guidant Champion Everolimus Stainless steel Bioabsorbable
Guidant Xience V Everolimus Cobalt chromium Durable CE Mark
Medtronic Endeavor Zotarolimus Cobalt chromium Durable CE Mark
Sorin Janus Tacrolimus Stainless steel None CE Mark
SMT Infinnium Paclitaxel Stainless steel Bioabsorbable CE Mark
Terumo Nobori Biolimus-A9 Stainless steel Bioabsorbable

Now you need it, now you don't

BioMatrix (Source: Biosensors)

While not everyone agrees on the absolute need for a polymer, most concede that the best-of-both-worlds strategy would be to have a polymer that disappears after it has done its job. Sahajanand Medical Technologies' (SMT) Infinnium stent elutes paclitaxel via a proprietary biodegradable polymer, while Conor Medsystem's has its own PLGA bioabsorbable polymer that it is testing on its CoStar stent. Other front-runners in the field are Guidant, Biosensors, and Terumo, whose Champion, BioMatrix, and Nobori stent programs, respectively, all use Biosensor's proprietary bioresorbable polymer. Last year, however, Guidant announced that it would first be moving forward with its Xience (previously known as the Vision) DES program, which uses a durable polymer, instead of its Champion stent program, as a result of "link fractures" seen in the Champion's stent platform during testing.

Reva (Source: Reva Medical)

Still, as Krucoff pointed out to heart wire , second-generation stent manufacturers focusing on bioresorbable polymers are for the most part basing their technologies on elements that are already well established in the coronary stent world: antiproliferative drugs delivered via metal stents. Beyond these are the devices he believes are best described as "third-generation" devices, namely fully bioresorbable stents, made completely out of dissolving polymers or magnesium. Companies like Reva, Endovasc/TissueGen, and Igaki-Tamai have all presented or published data in recent years on stents made completely out of biodegradable polymers that elute drug as they dissolve. Taking another tactic, Biotronik is working away on a drug-eluting magnesium-based alloy that degrades over the course of approximately two months and, in 2004, signed an agreement with Conor to develop a fully absorbable magnesium-based DES.

 
Maybe it's enough to have a bare-metal stent with a good drug on it.
 

This is "an entirely new domain," Krucoff says. "There are some totally novel questions that will have to be answered to make these fully bioresorbable stents usable and government approved in the US," he says. "What is the difference between the rate in which you deliver drug and the rate at which the stent ultimately loses its physical properties that are a part of the scaffolding? And is that different if that is a metal scaffolding vs a plastic scaffolding? The answers to all of these questions really have to be worked out. The second-generation stents, like the Conor stent, can come forward very quickly because the components they are using are all very well known. Third-generation, fully bioabsorbable stents, will enter a new domain in such fundamental ways that they're certainly going to have to do a lot more work."

Kastrati, likewise, called the whole field of bioabsorbable platforms "an interesting idea" but pointed out that it is one that has been around from the dawn of bare-metal stents, when people were first concerned about leaving bare metal in coronary arteries. Those fears, he points out, have largely disappeared. If the polymer problems can be solved and the stent design doesn't pose late hazards, having the stent disappear altogether might not be necessary. "If we can get a good drug," says Kastrati, "maybe it's enough to have a bare-metal stent with a good drug on it."

Asked what sort of innovations they hoped to see in the next few years, experts pointed to alterations related to safety and deliverability, many of which are already well into clinical testing. Leading the way are dedicated bifurcated DES, such as the conical-shaped Axxess-Plus stent (Devax Inc), or systems and techniques that would facilitate the placement of main and side-branch DESs. Elsewhere, companies are working on dedicated left main stents, while still others are looking at ways to combine different drugs on a single stent with the aim of inhibiting smooth-muscle-cell proliferation, reducing thrombogenicity, and boosting reendothelialization.

At least one company, Xtent Inc, is focusing on the problem of how to avoid the need for overlapping stents by having the capacity to deliver longer stents, at customizable lengths, and multiple stents within a single catheterization. The Cypher stent was recently awarded FDA permission to change its labeling to explicitly permit overlapping stents, but operators have raised concerns about the effects of overlapping for the Taxus and, more recently, the Cypher stents. Investigators for the TAXUS V trial noted an increase in non-Q-wave MIs in patients with overlapping stents, potentially due to a double dose in the areas of overlap, while a recent study of the Cypher stent found focal restenosis in overlapped segments[2].

Xtent has developed a system that permits an operator to first deliver a stent, detach the length desired, expand it, then move on to stent separate lesions in the same vessel or in a different vessel, without needing to retract and reintroduce the catheter. Currently, the system can deliver up to 60 mm of stent. The Xtent system also uses a bioabsorbable polymer and Biolimus-A9, licensed from Biosensors.

-SW

Other nitpicks, other solutions

Axxess-Plus (Source: Devax)

Xtent (Source: Xtent Inc)

 

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