Medical Device Daily Associate
ARIS – While many in the medical field, healthcare industry, analysts and the media have extolled the virtues of the drug-eluting stent (DES), 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 during the EuroPCR meeting here last week 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 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 increasingly are comparative trials looking at efficacy and safety measures.”
In his talk, 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 ever-olimus 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 pre-clinical 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.