Coated stents: a new eraUlrich Sigwart MD

Director, Cardiovascular InstituteRoyal Brompton HospitalLondon, United Kingdom

Cindy Grines MDDirector, Cardiac Catheterization LaboratoryWilliam Beaumont HospitalRoyal Oak, Michigan, USA

Patrick Serruys MDDirector, Interventional Cardiology LaboratoryThoraxcenterRotterdam, The Netherlands

Spencer King III MDClinical Professor of MedicineEmory University School of MedicineAtlanta, 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 thrombosiswith drug-coated stents?

©2001Conceptis 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):262-264

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 remodelingSerruys

Group

IVUS results Control Treated

Malapposition 4% 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. Circulation2001;104(10):1188-1193

There might be discrepancies between what the porcine model is showing and what is happening in humans

18-month follow-up looks very impressiveSerruys

Coated stents

How long does the FDA intendto 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 J2001;22(19):1808-1816

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-monthQCA results

Stent

High-dose Low-dose Bare p value

Mean luminal diameter (mm)

2.530.72 2.280.83

1.790.86

<0.001

Late loss (mm) 0.290.72 0.570.71

1.040.83

<0.001

Mean diameter stenosis

1421% 2325% 3927% <0.001

Binary restenosis 4% 12% 27% <0.001

Park S-J et al. TCT 2001

Coated stents

Is the clinical importanceof 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 ofa new era, everythingis probably overpriced.”

Competition will mostlikely 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 platformSource: Cordis

Coated stents

Angiographic results

Angiographic results with sirolimus-eluting stentpre post

4 months 1 year

Source: Cordis

Coated stents