Bioresorbable Stents and Polymers: Do We Need Better DES?

Tricia Ward

Disclosures

August 18, 2016

Editor's Note: In the fall of 2015, the first drug-eluting stent with a bioresorbable polymer was approved by the US Food and Drug Administration (FDA) for use in the United States, and in July 2016, the US got its first totally bioresorbable stent. European interventional cardiologists have experience with many more stent types than their American counterparts, so theheart.org | Medscape interviewed Dr Robert Byrne from Deutsches Herzzentrum, Munich, about the rationale behind the various technologies and whether there is a need for a better drug-eluting stent (DES).

Robert A. Byrne, MB BCh, PhD

theheart.org | Medscape: Let's first discuss the bioresorbable polymer stent. This is a permanent metal DES with a polymer that breaks down over time. What is the reason for developing such a stent?

Robert A. Byrne, MB BCh, PhD: The background, of course, is the issue of delayed arterial healing with DES, which is behind many problems, including late stent thrombosis, late restenosis, and neoatherosclerosis. Although the causes are multifactorial, it seems that a central component is a latent inflammatory reaction to the permanent polymer coatings on the original FDA-approved DES, which were mostly methacrylate based. That makes the concept of a stent coated with a bioabsorbable or a biodegradable polymer attractive. It's there when you need it to control the drug release in the first 30 days, and then it's broken down usually from poly-L lactide (PLLA) or poly-lactic-co-glycolic acid (PLGA) into carbon dioxide and water after sometime between 3 and 24 months, depending on the technology [approximately 3 months for the Synergy™ stent]. What's left behind is essentially a bare metal stent.

theheart.org | Medscape: The US has one DES with a bioresorbable polymer (Synergy), but there are others available in Europe.

Dr Byrne: In Europe, we have a large number of bioabsorbable or biodegradable polymer-based stents. At my center, we've had good experience with the BioMatrix biolimus stent (Biosensors International) one of the first biodegradable polymer stents to receive CE mark approval. It was the stent used in the LEADERS trial[1] published in 2008 and it has a somewhat thicker structure than other DES.

The other notable ones are the Orsiro stent (Biotronik) and the Ultimaster® (Terumo), which was the follow-on stent to the N0bori® stent. Both of these have very similar drug-release kinetics to the BioMatrix stent. Deutsches Herzzentrum was involved in the development of the Yukon® Choice PC (Translumina therapeutics), which is a thin-strut polylactic acid–based sirolimus-eluting stent.

theheart.org | Medscape: Given the potential disadvantages of polymers, what experience do you have with polymer-free stents?

Dr Byrne: It would be nice to work completely polymer-free because it seems that the polymer is the nidus for persistent inflammation which drives these late adverse events. We and other investigators have had quite a lot of experience with completely polymer-free DES, where you use other mechanisms to control the drug release—for example, surface modification with micropores or wells on the surface of the stent and a higher drug dosage. The goal is to compensate for inferior drug-release kinetics and achieve good antirestenotic efficacy. But by and large, it hasn't worked out so far.

 
The goal [for polymer-free stents] is to compensate for inferior drug-release kinetics and achieve good antirestenotic efficacy. But by and large, it hasn't worked out so far.
 

We published a number of studies from the ISAR-TEST stent program[2] showing a late luminal loss of between 0.45 mm and 0.50 mm, which is clearly inferior to the best-in-class DES in broadly inclusive patient populations, where you normally get 0.20-0.30 mm. It's still better than the old bare metal stents (BMS) that had late lumen loss of 0.8 mm to 1.0 cm. Interestingly, the original Endeavor® zotarolimus-eluting stent (Medtronic) had a polymer that made the drug release even quicker than if you had no polymer at all, and that stent was associated with quite high late luminal loss (approximately 0.6 mm).[3] This underlines the importance of drug release kinetics in determining late loss.

theheart.org | Medscape: I should note that polymer-free stents are not approved for use in the United States, but there are a few with CE mark available in Europe.

Dr Byrne: We have a number of CE mark–approved stents that are completely polymer-free, but as I said, these are associated with a somewhat suboptimal anti-restenotic efficacy. Interestingly, the BioFreedom stent studied in the LEADERS FREE trial[4] uses a surface-modified backbone. They then apply the drug without polymer directly to the stent. They chose biolimus A9™ as the drug (also called umirolimus); it seems to be able to overcome the shortcomings of not having a polymer, to some extent. They have showed a late luminal loss that is more encouraging than our experience.[5]

The other approach is to use a second drug on the stent backbone. Basically, you accept the suboptimal antirestenotic efficacy compared with a regular sirolimus application and you add a second drug to attack a different element of the restenotic response cascade. Preclinical work suggested that estrogen may promote endothelial healing and reduce restenosis,[6] but when we tested this on a stent in clinical studies, it didn't pan out.[7] We had some success with probucol, which is a powerful antioxidant that was shown to reduce restenosis in the patients undergoing angioplasty if they took it in pill form before the angioplasty and then for a period of weeks after the angioplasty.[8]

We tested a probucol stent in a large-scale randomized controlled trial against a best-in-class Resolute stent (Medtronic) in the ISAR TEST 5 study,[9] which, at the time it was published, was the largest DES trial in the literature, with 3002 patients. The probucol stent proved to be noninferior to the durable-polymer DES at 12 months. We recently published a 5-year follow-up of this technology[10] hoping to detect an improvement in late outcomes, but we didn't see that. Instead, the results with both stents were excellent, with very low rates of adverse events with both the durable polymer zotarolimus-eluting Resolute stent and this dual-drug, polymer-free stent. One of the problems for any new stent technology is that the new-generation durable-polymer DES have set the bar very high.

theheart.org | Medscape: Given that the bar is so high and the results are very good for contemporary DES, is it still worth trying to develop something better?

Dr Byrne: That question comes up a lot. The outcomes with the new-generation DES are excellent out to 1 year, but their Achilles heel is this small rate of late catchup restenosis and late stent thrombosis, which probably works out as around about 0.2%-0.3% per year. In terms of absolute risk, that's very small, but we know that stent thrombosis is often a catastrophic event, invariably associated with myocardial infarction (often quite large) and a not inconsiderable rate of mortality.

We also know from autopsy studies[11] and from optical coherence tomography[12] follow-up of patients that a dominant cause of late stent failure is neoatherosclerosis, which is new atherosclerosis forming inside the stent. This is definitely accelerated in comparison with a BMS. It could be that the inflammatory reaction to polymer is driving this process. This is the rationale for pursuing advances in these technologies even though the bar is high.

theheart.org | Medscape: Back in 2006, it was suggested that DES have a higher risk for late-stent thrombosis than BMS and that that is why BMS continued to be used. Later analyses seem to suggest that on balance, DES are safer than BMS[13] and that any risk for late stent thrombosis may be tied to first-generation DES.[14] Is that a fair assessment?

Dr Byrne: I think so. DES were a game changer in interventional cardiology and enabled us to attack a really complex disease pattern that was formerly treated very conservatively or was the preserve of the cardiac surgeon. The two issues which impeded their universal uptake were delayed arterial healing and its consequences (as I mentioned earlier), and cost. The iteration of this technology has leveraged three important advances: thinner stent struts; a lower drug dose and a switch to exclusively sirolimus-based analogs which lead to better healing profiles; and a move toward more biocompatible polymers.

A biodegradable polymer is a good example of a development to address the first problem. In terms of cost, both in Europe and in the United States, the cost came down dramatically. For this reason, the use of DES at our institution has been 100% for the past 6-8 years or more.

theheart.org | Medscape: You don't use any BMS?

Dr Byrne: We don't use BMS. Maybe for a niche indication—for example, very, very large vessels where you have to use a stent that is developed for the peripheral arterial system. That would be our only indication nowadays for a BMS implantation. The reason for our adoption of DES is the dramatic reduction in restenosis. Restenosis rates are 50%-70% lower[15] compared with BMS. That's a paradigm shift.

theheart.org | Medscape: The first-generation paclitaxel-eluting TAXUS™ (Boston Scientific) stent is generally accepted as a lower-performing DES; however, there are data that the first-generation sirolimus-eluting Cypher (Cordis) stent (now discontinued) has performed better in contemporary studies[16,17] versus earlier studies indicating that issues beyond the stent, such as improved technique and longer duration of dual antiplatelet therapy, affect outcomes. Do you think that next-generation DES are a real advance over first-generation DES if you exclude the TAXUS stent?

Dr Byrne: It's an interesting question, but the short answer is that I believe definite progress has been made in outcomes for next-generation DES over first-generation stent technology, and not just progress over and above the TAXUS stent. It's correct to point out that there was a differential efficacy (seen in many studies and registries) in that the Cypher stent was better than TAXUS probably in the acute phase and definitely in the late–follow-up setting. But we now have good evidence from meta-analyses,[18] large-scale randomized controlled trials,[19] and registry data[20] (although there are outliers) which show that current-generation gold-standard DES have surpassed the performance of the Cypher stent.

Now, in parallel to that, there have been developments in the stent backbones—mainly a switch toward thinner stent struts. We know that thinner stent struts cause less injury at the time of implantation,[21] are associated with lower rates of neointimal hyperplasia,[22] and cause less flow disturbance[23] after implantation. They're probably associated with lower rates of thrombosis in the acute phase. Thinner struts also enable a much lower crossing profile when the stent is crimped on the balloon, which has made a dramatic improvement in the deliverability of stents over the past 10 years. So it's not just progress in terms of better drug elution but also in relation to stent backbone development.

theheart.org | Medscape: That brings us to fully bioresorbable stents. The backbone of the bioresorbable stents/scaffold has thicker struts than contemporary DES and most are made with plastic, correct?

Dr Byrne: Yes. The challenge with this technology to-date has been to deliver a device with a radial strength that approaches that of conventional metallic backbone DES. Plastic just doesn't have as high a radial strength as metal alloys. The technologies that leverage lactic acid tend to have considerably thicker stent struts, of the order of 150 µm, which doesn't compare favorably with the 50-90 µm of traditional metallic stents.

These thicker struts cause more injury at the time of implantation. They are more difficult to deploy into the vessel wall. The analogy used is that of a snowshoe: If you've got a broad surface area, of course it's more difficult to sink into the snow, and a broad surface area in a stent makes it more difficult to implant into the vessel wall. That may be the cause of flow disturbances after implantation, and that might be a trigger for the slightly increased thrombotic risk with these stents.[24,25]

The second factor is that despite these modifications [thicker struts], the radial strength is not as good as with metallic DES. When you look at the six randomized controlled trials[24,26,27,28,29,30] that are available now and you look at the mean minimal luminal diameter after implantation, it favors the metallic DES. And we know that mean minimal luminal diameter is an important determinant of stent thrombosis.[31] I think these two factors contribute to the slightly higher rate of stent thrombosis we see with these devices compared with metallic DES.

theheart.org | Medscape: In the United States, the Absorb™ bioresorbable vascular scaffold (Abbott Vascular) is the only one available, but there are a few others with CE mark. Can you tell us about those?

Dr Byrne: In addition to Absorb, the DESolve™ Myolimus-Eluting Bioresorbable Coronary Scaffold System (Elixir Medical Corporation) is CE mark approved. It hasn't had widespread commercial rollout but is available in some jurisdictions. Just recently, the Magmaris magnesium absorbable stent (previously called Dreams [Biotronik]) was released. Cardiologists in Europe are just getting their hands on this stent. We haven't implanted any at Deutsches Herzzentrum. It will be interesting to see how this stent performs outside the setting of highly selected patients in a single-arm trial.[32,33]

theheart.org | Medscape: The argument in favor of bioresorbable stents is that any benefits will be accrued over the long haul.

Dr Byrne: In many respects, it's a no-brainer: All things being equal, it would be preferable to have a stent with sufficient mechanical strength to deliver maximal performance in the first 30 days to 1 year after implantation and then have it dissolve or break down, leaving no backbone in the vessel wall. There are many potential benefits, including restoration of vasomotion, removing the nidus for late stent-related adverse events, and allowing future bypass grafting of the vessel segment (if needed). I don't think many of us need much convincing that that would be preferable. The problem is that all things are not equal, so how much of an inferiority are we going to accept compared with current-generation DES? As I said earlier, the bar is high.

 
It would be nice to have data showing definitive late benefit with these [bioresorbable] stents, but we are probably not going to have long-term data from large-scale trials until 2020 or 2021.
 

theheart.org | Medscape: When I interviewed you last year about bioresorbable stents, you said that about 10%-20% of the patients might be appropriate candidates. Has that changed?

Dr Byrne: We're probably treating about 5%-10% of patients with bioresorbable stents. The patients who are potentially going to derive maximum benefit over time are younger patients who would otherwise have to deal with the adverse effects of a permanent metallic stent in the vessel wall over the decades remaining in their lifespan. And the types of patients would be those with straightforward lesions. We certainly avoid deploying bioresorbable stents in lesions with heavy calcification because of the issues of radial strength. Even if you perform a very aggressive lesion preparation, you can have a suboptimal result. We also tend to avoid bifurcations, where a two-stent technique is possible or maybe needed. We don't have a good solution yet with the bioabsorbable stents in the bifurcation area.

theheart.org | Medscape: And are you still recommending that patients with bioresorbable vascular stents/scaffolds be enrolled in clinical trials or postimplantation surveillance studies?

Dr Byrne: I think that's important. We need more data with these stents, and if we are implanting these, ideally we should try to enroll the patients in a randomized trial, or at least have a systematic follow-up protocol so that we can gather more information, especially on late outcomes.

theheart.org | Medscape: How do you discuss the different stent options with patients?

Dr Byrne: You have to take some time to discuss the issue. The bioresorbable stents are certainly intuitively attractive for patients. As more experience has been gathered in Europe over the past few years, some patients are already aware from the lay media of potential issues in regard to stent thrombosis with these devices. Many of the patients are quite well informed, and you have to give a fair appraisal of the data and say that these stents require further study. It would be nice to have data showing definitive late benefit with these stents, but we are probably not going to have long-term data from large-scale trials until 2020 or 2021, when the ABSORB 4 dataset should be available.

theheart.org | Medscape: Are there any other upcoming stent data that we should look out for?

Dr Byrne: I am very much looking forward to the ABSORB-II 3-year results. These will serve as a proof of concept if you want to see whether vasomotion is improved within 3 years with the bioresorbable stent as compared with the regular metallic DES. We should have some results in 2016. The AIDA study is the first large-scale study comparing bioresorbable stents with conventional DES in more broadly based patient populations.[34] That could be very interesting; we might have some data this year.

Getting back to your earlier question about DES vs BMS, the largest study examining this, the NORSTENT trial, will present results in more than 9000 patients at the upcoming European Society of Cardiology meeting in Rome.

theheart.org | Medscape: A conversation about stents would not be complete without mentioning duration of dual antiplatelet therapy (DAPT). How much does the stent type factor into the decision about duration of DAPT, or is it more patient/lesion-related? Would you ever say, "This is a polymer-free stent, so 3 months of DAPT is enough, but if this were a regular DES it should be 12 months"?

Dr Byrne: The patient—and the lesion, in particular—have to be taken into account. You have to consider cases that are more likely to have stent thrombosis; this could be bifurcation stenting, long-segment stenting, or small-vessel stenting. And there are lesions where the consequences of late stent thrombosis are likely to be dire, such as the left main stem or proximal left anterior descending artery. We consider prolonged DAPT out to 24 months in patients who we perceive to be at either high risk or high jeopardy from their stent implantation. The time scale in the DAPT study[35] was 30 months, so it's somewhere in the time window of 24-30 months for these patients.

Of course, you also have to factor in the risk of bleeding. In high–bleeding-risk patients, we would probably aim for 6- to 12-month duration, even if they have high-risk ischemic risk.

Does the stent type itself play a role in that judgment? I think it does, but I would also say that between the currently available generation durable or biodegradable polymer metallic DES, I don't think that there is much difference in terms of late performance. Now, if you are talking about fully bioresorbable stents, then I think there might be a difference. Certainly our practice is to continue DAPT for 12 months in these patients.

There have been reports of late events with the bioresorbable stents after discontinuation of the ADP receptor antagonist.[36] This might be related to the mechanical disintegration or breakdown of the stent. Some people are advocating a longer duration of DAPT with fully bioresorbable stents maybe out to 24 months. The European guidelines recommend 6 months[37] for conventional DES. There is now harmonization with the update of the American guidelines,[38] and they are also moving towards 6 months for standard DES, but with bioabsorbable stents I think it's 12 months minimum at the current time point.

 
I don't think that we Europeans have been poorly served by the CE mark approval process.
 

theheart.org | Medscape: Finally, a recent study[39] found that devices (cardiovascular, neurologic, orthopedic) that received approval in Europe before FDA approval were more likely to be subsequently removed from the market than devices that got FDA approval first. Do you think the bar is too low for CE mark approval?

Dr Byrne: Each regulatory agency has to decide whether it wants a more permissive regulation for devices with perhaps earlier access for unmet clinical need, and then rigorous postmarketing surveillance which might lead to the withdrawal of the device, or whether it wants to set a higher bar for approval in the first place. With the latter, a smaller number of devices make it through and take a longer time to do so, but, of course, are less likely to run into issues that might lead to their withdrawal.

There are pros and cons to both approaches. I don't think that we Europeans have been poorly served by the CE mark approval process. It has had benefits in areas like structural heart disease, where patients have had relatively early access to important improvements in technology like transcatheter aortic valve implanting (TAVI), or TAVR, as you say.

Editor’s Note: An earlier version of this interview misspelled Nobori and incorrectly stated that the Ultimaster stent is a biolimus-eluting stent; it is a sirolimus-eluting stent. The upcoming 3-year results are from the ABSORB-II (not ABSORB) trial.

Disclosures: Robert A. Byrne, MB BCh, PhD, has disclosed the following relevant financial relationships:
Received lecture fees from: B. Braun Melsungen, AG; Biotronik; Boston Scientific.
Institutional research grants from: Heart Flow; Boston Scientific

Follow Tricia Ward on Twitter: @_triciaward

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