Coated stents: a new era Ulrich Sigwart MD Director, Cardiovascular Institute Royal Brompton Hospital London, United Kingdom Cindy Grines MD Director, Cardiac Catheterization Laboratory William Beaumont Hospital Royal Oak, Michigan, USA Patrick Serruys MD Director, Interventional Cardiology Laboratory Thoraxcenter Rotterdam, The Netherlands Spencer King III MD Clinical Professor of Medicine Emory University School of Medicine Atlanta, Georgia, USA

Coated stents A hot topic Local drug delivery using stents is a hot topic Morice M-C, et al. ESC 2001 Issues to be discussed thrombosis rapid initial endothelialization side effects

“There is some evidence that we can run into trouble with these drug-eluting stents.” Serruys Animal data suggest toxic levels with implications for the endothelium around doses of 70 g actinomycin Could there be more late thrombosis with drug-coated stents? ©2001 Conceptis Technologies Coated stents

Occlusions RAVEL no subacute occlusions despite 2 months of clopidogrel treatment Liistro and Colombo 1 case of late occlusion with paclitaxel-eluting stent Liistro F, Colombo A. Heart 2001;86(3): ASPECT subacute occlusion with cilostazol and aspirin “We have to read case by case.” Serruys Coated stents

Malapposition in RAVEL We are talking about IVUS at late follow-up Some incomplete apposition has been shown We cannot expect positive remodeling Serruys Group IVUS resultsControlTreated Malapposition4%20% Coated stents

Remodeling hypotheses Any thrombotic material in an unstable patient will not be colonized by smooth muscle cells migrating in the direction of the lumen Positive remodeling might occur, detaching the wall from the stent “It’s clear that it’s a very powerful biomechanical technology.” Serruys Coated stents

Self-expanding stents Self-expanding stents go with the development of the artery Sigwart Artery walls could become thinner if tissue behind the stent regresses There is the possibility of late aneurysm with self-expanding stents “I’d be a little concerned.” Grines Coated stents

Questions remain Is the coating protected once you have an endothelium on the cell? Could another wave of proliferation be initiated once the drug has been “eaten up” from the stent surface? Coated stents

Porcine models Studies in pigs show reduction of in-stent neointimal hyperplasia with sirolimus- coated stents Suzuki T, et al. Circulation 2001;104(10): There might be discrepancies between what the porcine model is showing and what is happening in humans 18-month follow-up looks very impressive Serruys Coated stents

How long does the FDA intend to follow these patients? Brachytherapy was approved despite incidents of late thrombosis; the benefit outweighed the potential downside “There’s no way that you can follow up patients as long as there are questions.” King Coated stents

Does the FDA require a 5-year follow-up? The FDA does not wait 5 years for approval, but is interested in postmarket surveillance King Analysts on Wall Street have estimated the incremental value of the drug-coated stent in 2005 to be $4 billion “If the FDA then unravels the problem again and…says ‘we missed some very important aspect in the long-term follow-up,’ that would be a catastrophe, wouldn’t it?” Sigwart Coated stents

RAVEL trial design 15/26 control patients had clinically driven target-lesion revascularizations “Probably 1/3 of the patients were treated for oculo-stenotic reflex.” Oculo-stenotic reflex prevented either with stringent intervention criteria or by double randomization, with an angiographic arm and a clinical arm Serruys Coated stents

Heparin A recent trial did not show any difference between a heparin-coated Jostent and an uncoated Jostent Wöhrle J, et al. Eur Heart J 2001;22(19): Should we forget about the focus on antithrombotic mechanisms? heparin in animal studies required high doses to reduce the proliferative response heparin on the stent was at a lower dose and was not eluted into the surrounding tissues Grines Coated stents

Could other coatings be effective? ASPECT: 4% restenosis with paclitaxel- coated stent Park S-J, et al. TCT 2001 Inclusion criteria differed from RAVEL diabetics included longer lesion lengths “It’s probably going to end up being comparable to the RAVEL results.” Grines Coated stents

ASPECT results 6-month QCA results Stent High-doseLow-doseBarep value Mean luminal diameter (mm) 2.53  0.86 <0.001 Late loss (mm) 0.29  0.83 <0.001 Mean diameter stenosis 1421%2325%3927% <0.001 Binary restenosis4%12%27%<0.001 Park S-J et al. TCT 2001 Coated stents

Is the clinical importance of therapies overestimated? A therapy reducing the late loss index by 100% might be equally effective as one reducing it by 50% in terms of clinical outcomes “When we have a very powerful agent…that can really block the proliferation, when we examine it with things like IVUS, it exaggerates the benefit.” King Coated stents

Softer coating Would you rather coat your stent with softer medication that has an anticipated 5% restenosis rate than with a harder but more effective material? “I would.” Grines “Yes, I think that all of us have felt that, if you ever got down really into single digits with interventions… there would not be an inhibition to doing it anymore.” King Coated stents

Treatment options Several treatment options anti-inflammatory drugs antiproliferatives drugs blocking the extracellular matrix Coated stents

The future “It’s the beginning of an era. I think there will be a very long battle to find a good compound.” Serruys “[This is] the first glance of what the future will bring. There will be lots of work to be done.” Sigwart Coated stents

Stent pricing Stents will be priced at about $3000, similar to the cost of brachytherapy Stents are user-friendly and are going to be much more widely adapted “We are going to have a lot of pressure from our patients to use a stent like this. Virtually every day a patient brings up a drug-coated stent to me.” Grines Coated stents

Stent pricing Cost of coated stents is a critical issue Because of the high cost of stents only highly culprit lesions are treated With 0% restenosis there will be increasing interest in “plaque sealing” “The cost could be quite exorbitant. It’s an important issue but I don’t think it ought to get in the way of the science and the therapy becoming available.” King Coated stents

Stent pricing Higher cost of eluting stents would be offset by the savings related to fewer cutting balloon and brachytherapy- treated patients returning with restenosis Stent costs should not exceed $1000 in Europe because beyond this, surgery could be more cost-effective “If the cost is too high, society will lose the benefit of having created something that is less invasive.” Serruys Coated stents

Stent pricing “In the beginning of a new era, everything is probably overpriced.” Competition will most likely lower the price Sigwart Coated stents

Potential problems People might too easily put a powerful drug on a stent Serruys There is always the danger of creating a new disease Sigwart Despite all problems, the enthusiasm about this technique is probably justified The SIRIUS trial will show its effectiveness for more complex lesions King Bx-stent platform Source: Cordis Coated stents

Angiographic results Angiographic results with sirolimus-eluting stent pre post 4 months1 year Source: Cordis Coated stents