Bioabsorbable Stents: “Patients want it, and it works”
Can you describe the bioabsorbable stent used in the ABSORB trial?
This bioabsorbable stent has struts made of polylactic acid and an additional polylactic acid coating contains the anti-proliferative drug everolimus. Everolimus is also used on Abbott’s Xience V stent, which is commercially available in many parts of the world. The struts and the coating on Abbott’s bioabsorbable stent are designed to be fully absorbed by the body over time. The idea behind a bioabsorbable stent is that the struts only exist for as long as needed to support the vessel as it heals, and then they disappear, so the vessel has the potential to return to a more natural, healed state.
What is the strut shape design?
The original stent design that was used in the ABSORB trial, a corrugated flower strut pattern with long ring connectors, has now been improved with corrugated sinusoid rings linked by short connectors. The newest design of Abbott's bioabsorbable stent, to be used in upcoming cohorts, is very similar. It has very good uniform support of the vessel, so the gaps between the struts are relatively small, the vessel is better supported mechanically and the drug application is more uniform. How does this particular stent compare to other bioabsorbable stents being studied? There are dramatic differences between Abbott's bioabsorbable stent and other bioabsorbable stents in development. The first bioabsorbable stent used in human beings was in Japan. It was also made of polylactic acid but didn’t have any drug coating and so its results were similar to those after placement of a bare-metal stent. In addition, the Japanese stent was very difficult to implant, so Japanese researchers stopped working on it for a coronary application.
The next trial of an absorbable stent, a magnesium bioabsorbable stent, was published recently in The Lancet. It had results that were similar to balloon angioplasty. This stent absorbed far too quickly, in only a few days, and didn’t support the vessel long enough. The researchers are now trying to make a magnesium stent that lasts longer in tissue and is coated with an antiproliferative drug, but these are major technical challenges to overcome.
Another bioabsorbable stent in development is a tyrosine-derived polycarbonate stent from REVA. The RESORB trial began enrolling patients last year and results remain to be seen.
These are the only other bioabsorbable stents I am aware of that have been in human trials.
What else can you tell us about the safety of polylactic acid as the compositional material for this stent?
Polylactic acid is not an entirely new material in the sense that it has been used in diverse applications, such as absorbable sutures, orthopedic screws and plates, for many years, and is also used for closing femoral artery puncture sites. It is a widely used material in human applications. There do not seem to be any issues with the compatibility of the material with the human body, something that has been borne out with the Japanese experience. Their stent was also made of polylactic acid, the same material we use in our stents. It did not have any apparent ill effects on the coronary arteries.
Since the polylactic acid is radiolucent, the stent is not visible on fluoroscopy, so the ABSORB stent has a radio-opaque marker at each end. This allows precise location of the stent ends in case post-dilatation or placement of a second stent is needed. In fact, I think it is easier to use this stent than most conventional metallic stents, where the end of the stent is never quite clear.
What is it about the limitations of metal stents that make a bioabsorbable stent attractive?
There are a number of reasons for developing absorbable stents. First, the concept is to support the vessel until it heals. If you have a broken arm, there is not much point in leaving the cast on after the bones have healed. There is, of course, a very small risk of late stent thrombosis with metal stents, even years after initial placement of the stent. If the stent goes away, and leaves a normal, healed vessel, then it may be that the risk of late stent thrombosis disappears. It may also be possible to safely reduce the duration of dual anti-platelet therapy. With a bioabsorbable stent, there is less concern about stopping anti-platelet therapy if the patient needs non-cardiac surgery, but we will need a great deal more clinical data to be sure. The imaging technologies of CT angiography and MRI are increasingly being used to look at coronary arteries and in the future, CT angiography will become more important for following patients long-term. Metallic stents obscure the lumen, so we cannot clearly see inside the artery if a patient has a metallic stent.
Is there any difference in how the stent is stored, handled and delivered from a conventional metallic stent?
Yes, with the ABSORB stent, we had to store it in a refrigerator with a low temperature. In the new design for the next cohort, refrigeration may not be necessary. The intent is to design a next-generation bioabsorbable stent that would be handled just as a metallic stent would be.
How does deployment of the bioabsorbable stent compare to a metallic stent?
Interestingly, it looks and feels, as far as you can tell, like an ordinary metal stent. We didn’t treat it in any special way. The original Japanese bioabsorbable stent had to be post-dilated with warm contrast, even warmer than body temperature, in order to get it fully deployed. The ABSORB trial stent felt and performed like a metal stent.
Can you discuss the one-year ABSORB trial results recently published in The Lancet?
The ABSORB trial, a prospective, open-label study with 30 patients, showed remarkably few major adverse cardiac events and zero stent thrombosis. The clinical results were excellent and the patients are doing very well. Late loss was 0.44 mm, which is similar to some drug-eluting stents, better than bare-metal stents and better than Medtronic’s Endeavor drug-eluting stent. The late loss was partly due to a loss in strength of the bioabsorbable stent that may have allowed for negative remodeling of the vessel by six months. The next-generation design, to be used in the next patient cohort, is intended to be stronger over a longer period of time, which should overcome any tendency towards this negative remodeling. As a result, we expect not to have the same degree of late loss.
Optical coherence tomography (OCT), a technique that, similar to ultrasound, uses light inside the artery but has amazing resolution compared to ultrasound, showed at the 6-month follow up that 99% of the stent struts were covered with tissue, which is very reassuring and may be a good thing in regard to late stent thrombosis. Angiographically, only 3 of the 30 patients had restenosis. Not one of these needed reintervention because of restenosis — two were at 50% and one was at 55%, fairly mild restenoses. These patients didn’t need repeat intervention because they weren’t symptomatic and didn’t have ischemia on stress testing.
Can you talk more about the remodeling of the bioabsorbable stent? Why did it occur, and how is it being combated with the next-generation design?
Normally the lumen of an artery will get smaller in the first six months after intervention because of the artery “shrinking” (negative remodeling) after balloon angioplasty and because of intimal hyperplasia (excessive healing) after stenting. A metal stent resists the negative remodeling and an anti-proliferative drug suppresses the excessive healing. Our next-generation bioabsorbable stent is designed to be stronger, to resist the artery’s negative remodeling in the first six months. Beyond the initial six months post-intervention, the lumen of an artery tends to enlarge (due to regression of intimal hyperplasia and perhaps to positive remodeling), so all a bioabsorbable stent needs to do is support the artery for the first six months to stop it getting smaller, and after that, support in the artery is no longer necessary.
Strengthwise, how will the next-generation design stent compare to a basic metal stent?
When it is first placed, the strength of the stent is very similar to some bare metal stents that had relatively low strength but very good clinical outcomes. What we don’t know is how long the strength lasts in the human coronary artery. When you place the stent, it is strong, but as it absorbs, it loses strength. In time, this is a good thing, of course.
What do we know about stent absorption timing from ABSORB?
Absorption rates will vary from patient to patient. These arteries are diseased, so presumably there will even be different absorption rates in different parts of the artery. We don’t know how long it will take for the stent to be absorbed, but we expect a time period of 18 months to 2 years. We’ll have a clearer idea when the patients have had their 2-year follow up with ultrasound and OCT, and we can see whether the stent is fully absorbed or not. Patients are having the 2-year follow up now, and we expect the results to be presented later this year.
What are the future plans for work with this stent?
It’s too early to tell. We are looking at the safety of the patients in the ABSORB trial right now, and it will depend on outcomes of these trials as to how we will design the next series of trials.
Is there thought that this stent might be useful in the future for peripheral vascular disease?
It’s too early to speculate on moving into the periphery until we know long-term how patients are doing with the current ABSORB platform.
What is the history of your involvement with the bioabsorbable stent?
Originally I was contacted to do some radial strength testing, because our group does a lot of stent testing, including strength testing. We have a unique technique for testing radial strength. Most people use a flat plate technique — they crush the stent with a flat plate and see how much force is required to crush it. Our technique involves deploying the stent in a plastic, soft tube, and putting the stent in a warm water chamber at 37 degrees Celsius. We progressively increase the pressure in the water chamber and measure change in stent cross-sectional area with an ultrasound catheter.
Stents behave very differently at room temperature compared with body temperature. At room temperature, stents fracture very easily if you apply pressure to them, whereas at body temperature, stents are much more flexible. It’s similar to chewing gum. If you put chewing gum in a freezer and take it out and hit it with a hammer, it will shatter. If you chew it, it quickly becomes soft and flexible as it warms up. We have done a great deal of radial strength testing of bioabsorbable stents over several years. In addition, we looked at the stents using scanning electron microscopy, to see what happens to the stent after post-dilatation with a balloon, for instance, and how good the stent was at resisting over-dilatation or post-dilatation. From this initial relationship, we then began discussing the first clinical trial. Our group was very fortunate and proud to be involved in Abbott’s ABSORB trial.
Patients like the idea of an absorbable stent. Sometimes cardiologists forget what patients want. I have people emailing me from all over the world wanting an absorbable stent. They want the one that does its job and goes away. Patients don’t like the idea of a permanent implant inside of their arteries.
