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J Palmaz article...

This article was just released today:

http://www.theheart.org/article/1015869.do

Stent pioneer Julio Palmaz urges DES makers to "learn from mistakes of the past"
October 27, 2009 | Shelley Wood

Bologna, Italy - The man who invented the first balloon-expandable coronary stent believes the future of stenting lies in a return to the pure bare-metal stent and says he has "always been against" drug-eluting stents (DES).

A plenary speaker during the XXX Congresso Nazionale Della Societa Italiana Di Cardiologia Invasiva (GISE), Dr Julio Palmaz (University of Texas Health Science Center, San Antonio) predicted that coatings "of any kind" will prove to be the downfall of drug-eluting stents—even the bioerodable polymers or the coatings used on fully bioerodable stents that today represent the next great hope in DES technology. Pointing to the failure of gold-coated stents back in 2000, Palmaz called on stent manufacturers to "learn from the mistakes of the past."

"Any coating, of any kind, will have the potential to [produce] nonspecific inflammatory changes," he predicted.

Palmaz is credited with coming up with the idea for the first balloon-expandable coronary stent, ultimately patenting his idea with Dr Richard Schatz in 1988. Palmaz later cofounded and is chief scientist at Palmaz Scientific, a company developing "advanced metallurgical surface nanotechnologies" for use in implantable medical devices. Speaking with heartwire, Palmaz was frank about his personal stake in the theories he was espousing but also passionate about how he thinks stent development is evolving in the wrong direction.

Coatings and impaired healing

During his presentation, Palmaz proposed that the reason bare-metal stents first proved safe and efficacious was due to the fact that the stent surfaces were smooth and the material in contact with human tissue was conductive metal.

"When we have a metal implant, essentially all of the positive charges of the metal are countered by ions that are surrounding it, most likely oxygen in the form of oxide: this is actually a good thing because these oxides [promote] healing," he explained. "But when we put a polymer on top of a stent, essentially we are insulating all those charges."

This wouldn't be a problem if the metal stent could be "perfectly" coated, he continued. But due to the stress placed on the device during expansion, fissures in this coating inevitably form, disrupting the oxide layer.

"Cracks will lead to an accumulation of charges at sites where the metal is exposed and invariably create dissimilar charges when different parts of the stent allow the flow of electrons from one direction to another, with a larger amount of charges actually resulting in erosion of that area and recruitment of inflammatory cells. . . . Once you do that, you set up the conditions for impaired healing," he said.

Bioerodable innovations face same problems

Asked whether he believed coatings are a problem just for the kinds of permanent polymers used on currently approved DES, Palmaz said his theory would also apply to bioerodable polymers and even to polymer-free stents designed to minimize the interface between polymers and tissue/blood. "We know that, for example, some of the biobsorbable stents involve several layers of primers before you even apply [the polymer], and primers may act like a coating, so that eventually we will have the same end result. Short of a perfectly pure, homogenous, metal surface, everything else has the potential for having problems like this."

Acknowledging that some companies are already exploring the use of little wells, or reservoirs on the abluminal surface of the stent, loaded with polymer and drug, leaving the surface more or less bare (such as the Nevo stent [Cordis/Johnson & Johnson]), or applying drug directly to porous metal stents (such as the ISAR polymer-free, stainless-steel stent), Palmaz cautioned that both of these approaches will create a different set of problems.

"Implantable devices in general need to be open faced, so that the interface between living cells and the stent material is clean-cut and single-face," he told heartwire. Pores or "crevices," he explained, create an "unhappy" environment of impaired oxygen and electrolyte exchange for circulating cells.

"The minute that happens, the cells will be producing materials that will be actual promoters of corrosion, such as superoxide radicals."

In search of the perfect solution

Commenting on Palmaz's theory, Dr Adnan Kastrati (Deutsches Herzzentrum, Munich, Germany), who presented long-term safety and efficacy data on DES during the GISE meeting—and whose group is developing the ISAR polymer-free stent—said he had "great respect for Dr Palmaz.

"Without his work, it would have been much less probable for us to even talk together about stents," Kastrati said. "The fact that he is not completely happy with a new technology is an inherent feature of great innovators, who are always in search of the perfect solution."

That said, continued Kastrati, "We have sufficient clinical evidence from a specifically designed, randomized study that the microporous stent surface is at least as safe and effective as the polished one. In addition, we have used this kind of stent in thousands of patients with or without drug on it, and no safety concerns have emerged over years."

Likewise, Dr Marco Valgimigli (University of Ferrara, Italy) told heartwire that he agrees with Palmaz's concerns "that the polymer, acting as a barrier between the stent and the blood, may cause late adverse events. This is what we are all concerned about."

But, Valgimigli continued, "I am not so convinced that any type of coating that would provide a barrier between the metal and the patient may be deleterious in the long run. I am more convinced that the type of barrier matters."

For example, he said, "There are barriers that may actually improve endothelialization and/or prevent thrombus deposition on the stent and, at least in vitro and in the animal models, seem to work quite nicely."

That said, Valgimigli agreed that some polymers used on current-generation DES "may trigger immune reaction and induce chronic inflammation, which may explain at least partially some late events that are connected with positive remodeling—ie, progressive dilatation of the lumen of the vessel."

Speaking with heartwire, Palmaz emphasized that he is persuaded by the totality of evidence—summarized by Kastrati during his presentation—that the risk of stent thrombosis is very low and likely similar for DES and bare-metal stents. In his opinion, the downfall for DES will likely end up being a late-catch-up restenosis, potentially related to the inflammatory response triggered by nonmetallic coatings.

Time will tell

Valgimigli, however, disagreed: "I still remain convinced that the true issue is very late stent thrombosis, much more than late restenosis," he told heartwire. "So far, we have not seen true clinical late catch-up in any randomized controlled trials with follow-up even greater than four or five years, whereas we have definitively seen, unfortunately, patients coming back with sudden stent occlusion even four to five years after PCI and even despite ongoing antiplatelet medication. As [long] as late restenosis is not sudden but a progressive narrowing of the vessel, then it will not cause reinfarction but may only require reintervention."

As for whether the stent of the future will be bare metal, Kastrati remained unconvinced. "A good bare-metal stent is certainly welcome, but I am afraid that there is little room for further improvement of this technology in terms of risk of thrombosis and restenosis. I strongly believe that local drug elution, through permanent or temporary devices—let's say balloons or biodegradable stents—will remain the winning technology in the years to come."