Patrick W. Serruys, M.D., F.A.C.C.; C. Richard Conti, M.D., M.A.C.C.

Cardiosource.  2007; ©2007 American College of Cardiology

Introduction

Drug-eluting stents (DES) dramatically reduce restenosis rates after percutaneous coronary intervention. However, the permanent metallic implants may impair coronary imaging with MRI or CT, can hinder surgical revascularization, prevent positive remodeling, and predispose the vessel to late stent thrombosis.

Recent reports also have indicated that there may be an increased risk of late stent thrombosis with DES compared with bare-metal stents (BMS). In a meta-analysis of 14 clinical trials that randomized 6,675 patients to paclitaxel- or sirolimus-eluting stents versus BMS, there was a significant increase in the incidence of very late thrombosis (>1 year following the index procedure) associated with DES use compared to BMS placement.^[1]

Stents are in development to address these problems; some stents contain newer drug-eluting agents while others feature new designs and new stent material. At the ACC 2007 i2 Summit, Serruys and colleagues reported a first-in-man study assessing the safety and overall performance of a bioabsorbable stent that, if effective, could eliminate several of the problems associated with metallic stents.

The ABSORB trial evaluated the Bioabsorbable Everolimus-Eluting Coronary Stent System, placed in a single de novo coronary artery lesion. Researchers evaluated device efficacy, procedural success in terms of ease of deployment and safety, major adverse cardiac events (MACE), and stent thrombosis at 30 and 180 days.

At 30 days in the ABSORB trial, device and procedural success was very high – 93.5% device success and 100% procedural success – and no patients experienced MACE or stent thrombosis. At 6 months, rates of MACE continued to be low (3.3%, one patient with non-Q wave MI at 46 days postprocedure) and still no stent thrombosis. Ninety-day results, presented May 22, 2007 at EuroPCR, showed no additional MACE nor stent thrombosis.

Bioabsorbable Stents

The bioabsorbable stent is composed of a poly-L-lactic acid backbone, coated with a bioabsorbable polymer containing the antiproliferative drug everolimus (Figure 1). Polylactic acid is a proven biocompatible material commonly used in medical implants such as dissolvable sutures. The stent is designed to be slowly metabolized by the body and completely absorbed over time.

Figure 1. 

Abbott's Bioabsorbable Everolimus Eluting Stent

     

According to principal investigator Dr. Patrick Serruys, the scaffolding effect of any stent is needed for only 3-6 months to prevent constrictive vascular remodeling postdilatation. But the traditional metal cage, which is how he describes metal stents, remains long after this period.

The newer coating may minimize chronic inflammation seen with current agents and may reduce the need for long-term dual antiplatelet therapy. Also, the bioabsorptive properties of the new stent may allow late expansive luminal and vessel remodeling that is not hindered as it is now with metal stents. However, because the stent is made from polymer, it might have more acute recoil than metallic stents in vivo.

ABSORB patients will continue to be followed for longer-term safety and efficacy results. Plus, the next group of patients to be studied will receive an updated version of the stent system designed to deliver additional support to the arterial wall, potentially reducing late lumen loss even further.

In June 2007, results were published in Lancet from the PROGRESS-AMS study assessing the efficacy and safety of an absorbable magnesium alloy stent.^[2] Histology and spectroscopy in animal studies had shown that magnesium disappears within 2 months and is replaced by calcium, accompanied by a phosphorous compound. It was hypothesized that a metallic biodegradable stent would reduce immediate recoil due to greater intrinsic strength compared to a polymer stent like that used in the ABSORB trial.

Investigators enrolled 63 patients who received a total of 71 stents, 10-15 mm in length and 3.0-3.5 mm in diameter. While initial success was good (diameter stenosis reduced from 61.5% to 12.6% and an acute gain of 1.41 mm), in-stent late loss was 1.08 mm.

The ischaemia-driven target lesion revascularization (TLR) rate in PROGRESS-AMS was 23.8% after 4 months and the overall TLR rate was 45% after 1 year. Neointimal growth and negative remodeling were the main operating mechanisms of restenosis.

In this interview, Dr. Serruys discusses why a fully bioabsorbable DES might be preferable to “a full metal jacket' stent and reviews the angiographic and IVUS results of the ABSORB study that were presented at ACC '07.

Dr. Conti:
I'm Richard Conti with Patrick Serruys, professor of medicine and interventional cardiology at Erasmus University in the Thorax Center in Rotterdam, The Netherlands. We're going to talk about the ABSORB trial: Six-Month Angiographic and IVUS Results from a First-in-Man Evaluation of a Fully Bioabsorbable Everolimus-Eluting Coronary Stent. Patrick, why bioabsorbable stents? What's the rationale?

Dr. Serruys:
We should think back to the early days of the metallic stent in 1986. Cardiologists may not think about it today, but when I first started to push a piece of metal into the coronary artery, I had a strange feeling of guilt. It is against nature.

Stents work; they are good scaffolding devices. But, it's clear that the scaffolding is only necessary for a short period of time, probably 4 to 6 months. Once the healing process has taken place, ideally this piece of metal should disappear. It has been a long dream of mine to have a scaffolding device that disappears after having performed its function.

Dr. Conti:
Why should we want the stent to disappear?

Dr. Serruys:
There are a number of reasons (Figure 2). We don't want to have this metallic cage in the coronary artery. It has a critical transient function, but over the long term the metallic cage prohibits expansive luminal and vessel remodeling. Later, if a surgeon wants to do a bypass he has to cut through the metal. Also, if vasomotion is important in the cold weather and during exercise, there is no vasomotion at the stent site. So, there is plenty of reason why a stent should be something transient and not a permanent fixture in the coronary arteries.

Figure 2. 

Why a Bioabsorbable Stent?

     

Dr. Conti:
Tell us about the bioabsorbable stent.

Dr. Serruys:
The stent is made of a polymer of polylactic acid, which has been used in medicine for the last 40 years. It's very simple: the molecules of lactic acid break down over time into CO^[2] and water and that's it. As long as the absorption occurs very slowly over a period of months, you can fool Mother Nature; you will not have all the cellular reaction against a foreign body that would naturally occur. It took us almost 20 years to get a bioabsorbable stent, but we seem to finally be there.

Dr. Conti:
What are the data demonstrating that the bioabsorbable stent is bioabsorbed in 6 months?

Dr. Serruys:
Very good question. All the data we had originally, of course, were in healthy animals, and the variables that affected absorption included age, whether it was an atherosclerotic vessel, plus other biological variables including the presence of other enzymes.

We now have data on 30 patients, including angiographic and IVUS data; that's what we are reporting at this meeting. We also will be doing optical coherence tomography to look at the struts with multislice CT scan palpography – virtual histology – using backscattering of the radiofrequency, but that will take place at 18 months to 2 years or even later.

Dr. Conti:
What have you found at 6 months?

Dr. Serruys:
All the patients are doing well and there has been no subacute occlusion. I started my career reporting a 20% subacute occlusion rate in a New England Journal of Medicine article in '91.^[3] We certainly have made progress over the years in terms of reducing the risk of subacute occlusion.

In these first 30 patients, the angiographic results are promising (Figure 3). Nobody has required reintervention of the stented segment. What we have observed with angiography when looking at a bare-metal stent is evidence of late loss; typically, a late loss of about 0.8 mm. With the drug-eluting Cypher stent late loss is usually around 0.1 to 0.2 mm; with the Taxus stent it's between 0.3 and 0.4 mm. To our surprise, we saw a late loss of 0.44 mm with our bioabsorbable stent, which is in-between the bare-metal stents and a good drug-eluting stent. We were very pleased.

Figure 3. 

ABSORB: Angiographic Results (Per-Treatment Evaluable Patients)

     

Dr. Conti:
Those were your angiographic results; what about IVUS results?

Dr. Serruys:
The IVUS gives us all the cross-sections of the vessels, the external elastic membrane, the stent itself, and what is growing inside the stent. As for the neointimal hyperplasia inside the stent, it has been very small: 0.3 mm^[2], which is even less than a good drug-eluting stent.

The critical observation is that by watching the ring of the struts we show a reduction of the stent area. You can call that late shrinking or late recoil at the beginning of the bioactive remodeling. It amounted to an 11.6% reduction of the stent area, for a late-loss of 0.44 mm. This is not due to neointimal hyperplasia; it's mainly the late-recoil of 11.6% of the struts itself.

Dr. Conti:
What about the lesions? Can you describe the lesions you were stenting?

Dr. Serruys:
The research is still in its infancy, so we were limited to treating very short lesions. The stent is 12 mm long, so we had to find lesions of 8.5 mm to cover it properly. And these lesions were in 30 patients at six institutions. We were very proud that in Rotterdam we found 16 of these patients.

Dr. Conti:
Is it easy to deploy or is it difficult?

Dr. Serruys:
No special challenge at all. What is amazing is the acute recoil, which is being published in CCI: it was 0.20 mm.^[4] Acute percent recoil was 6.4% with the bioabsorbable stent compared to 4.2% with an everolimus-eluting metal stent. So, we were very happy about the way they have processed this polymer to achieve almost the radial force and the scaffolding properties of the metal stent. This is a great achievement.

Dr. Conti:
And this is a first-generation stent you have; so, there is a lot of promise of even greater things to come.

Dr. Serruys:
A second version of this stent is ready for study. This iteration is much stronger in terms of radial force and scaffolding properties, so it may further reduce late recoil of the stent.

Dr. Conti:
This is fascinating. Everybody is talking about the risk of late stent thrombosis with drug-eluting stents. What do we know about endothelialization following implantation of these bioabsorbable stents? Is there any evidence for thrombosis in any of these patients?

Dr. Serruys:
No evidence of thrombosis. I can tell you Renu Virmani likes it. (Editor's note: Dr. Virmani was one of the first to express concerns about the risk of late thrombosis with drug-eluting stents.^[5,6]) We don't expect any problem, because the stent slowly dissolves into CO₂ and water. Certainly, the body is used to seeing some lactic acid, so Dr. Virmani liked the concept, but we have to prove this with clinical trials and show that you will not run into trouble early or late. That's the whole beauty as well as the great responsibility of these kinds of trials where you test something in uncharted fields.

Dr. Conti:
Are you yourself going to continue working in this area?

Dr. Serruys:
Oh, yeah. My wife said the world has entered a new cycle where a lot of products are biodegradable. Now, we're entering an era of biodegradable stents.

Dr. Conti:
We look forward to hearing more in the future. I think this is wonderful news. If we go back to 2003 when Renu Virmani said, “I think it's time to think about biodegradable materials,' we're here.

Dr. Serruys:
You have to listen to this lady. That's for sure.

Dr. Conti:
Patrick, I want to thank you very much for coming to ACCEL.

Dr. Serruys:
Thank you very much.

Bavry AA, Kumbhani DJ, Helton TJ, et al. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med 2006;119:1056-61. Erbel R, Di Mario C, Bartunek J, et al. Temporary scaffolding of coronary arteries with bioabsorbable magnesium stents: a prospective, non-randomised multicentre trial. Lancet 2007;369:1869-75. Serruys PW, Strauss BH, Beatt KJ, et al. Angiographic follow-up after placement of a self-expanding coronary-artery stent. N Engl J Med 1991;324:13-7. Tanimoto S, Serruys PW, Thuesen L, et al. Comparison of in vivo acute stent recoil between the bioabsorbable everolimus-eluting coronary stent and the everolimus-eluting cobalt chromium coronary stent: Insights from the ABSORB and SPIRIT trials. Catheter Cardiovasc Interv 2007 May 14; [Epub ahead of print] Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation 2004;109:701-5. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202.

Sidebar: Learning Objective

Upon completion of this activity, the reader should be able to list potential advantages of a bioabsorbable stent and summarize the results of new studies evaluating these new stents.

Reprint Address

Patrick W. Serruys, M.D., F.A.C.C.: Dr. Molewaterplein, 40 Rotterdam, Netherlands, p.w.j.c.serruys@erasmusmc.nl ; C. Richard Conti, M.D., M.A.C.C., 1600 Archer Rd M438, PO Box 100277, Gainesville, FL 32610-0277 conticr@medicine.ufl.edu