Conversations with Experts: Is the Future of Coronary Stenting Dissolving?
The future of stent technology is informed by its history: coronary stents were developed to solve the problems of balloon angioplasty and, more recently, bioresorbable scaffolds have been developed to help solve the problems of restenosis associated with earlier-generation stents. In this edition of Conversation with Experts, Spencer B. King III, MD, is joined by Professor Ian Meredith, AM BSc, MBBS, PhD, director of MonashHeart, Monash Health in Melbourne, Australia, to discuss the future of coronary stenting and the role that bioresorbable technology will play.
Dr. King: Essentially, the history of stenting is a history of trying to solve problems that we keep creating. Stents were developed to overcome the shortcomings of balloon angioplasty, but stents also stimulated a lot of cell growth and neointima development, and also resulted in restenosis. Various mechanisms for opposing that proliferation were developed; the most widely applied worldwide now is the drug-eluting stent. Of course, it presents its own set of issues.
So, Ian, help us think about the current advances in stenting, and what direction we're taking in terms of dealing with the late problems that have occasionally occurred with drug-eluting stents.
Dr. Meredith: Well, Spencer, I think you summed up the situation very well. It seems that every corner we've turned to solve a problem we are confronted by a new one. We can probably all agree that we want drug-eluting stents to be easily delivered, be very flexible, and have great acute performance characteristics—as well as have great safety and efficacy. While we've improved efficacy and performance, we've done so at the loss of safety from time to time.
As you well know, there are three components of drug-eluting stents: the metal scaffold, the drug, and the polymer that carries the drug. Most research groups focused on the polymer as the culprit for ongoing safety issues, and have therefore aimed to remove or minimize the polymer.
Dr. King: In that vein, I know that you're the principal investigator for the EVOLVE trial testing the widely-used stents against those with a modifiable polymer coating. Can you share with us some of the findings and aims of that trial, and what's being done with the polymers?
Dr. Meredith: The EVOLVE trial compares the PROMUS Element™ stent with the SYNERGY™ stent platform. SYNERGY, as you know, is a slightly thinner version of the PROMUS Element stent (0.0029" stent strut thickness compared to 0.0032"), but it has an ultra-thin, bioresorbable poly(lactic-co-glycolic acid) [PLGA] polymer coating. The dose of everolimus is the same as with the PROMUS Element, but it is released from this ultra-thin veneer of abluminal PLGA.
The design goal of the SYNERGY stent is, in essence, to provide early healing and freedom from long-term polymer exposure. This platform has afforded similar clinical and angiographic outcomes observed with durable and conformable polymer DES. Overall, the EVOLVE program is going very well—initially with the original first-in-human study EVOLVE I, then a QCA study, and then a larger, multicentered study EVOLVE II. (Editor's note: The SYNERGY stent was granted the CE Mark in October 2012. Enrollment for EVOLVE II was completed in October 2013, and data from that trial will support eventual approval submissions in the United States.)
Dr. King: So, after these drug-eluting stents have performed their major function of inhibiting that neointimal proliferation, only metal is left. Has that solved the problem of late stent thrombosis?
Dr. Meredith: Well, not entirely, but it certainly has shown that you can have very, very minimal polymer load on the stent, yet still achieve excellent clinical results. The SYNERGY stent features the smallest stent strut thickness (0.0029") and a very minute amount of PLGA polymer applied only to the abluminal side. The polymer is absorbed shortly after the drug elutes at approximately 3 to 4 months. (Editor's note: The absorption timeframe for drug and polymer with SYNERGY stent technology is approximately 3-4 months, versus upwards of 18 months in the ABSORB study.) In the EVOLVE trial, the rate of stent thrombosis, even late stent thrombosis, was 0% at 2 years, but in order to really know the benefit of these platforms you need many thousands of patients followed for a very long period of time. Data from the EVOLVE and EVOLVE II clinical trials are very promising, but to answer your question directly, we don't know whether the platform has truly led to a lower rate of late stent thrombosis yet. Future studies will enlighten us.
Dr. King: That's the good news: stent thrombosis is becoming rarer. Certainly, if the polymers were an issue, and the polymer goes away, that seems like an advance. Now, there is a lot of interest, yet unsolved, about antiplatelet therapy in patients with stents—particularly in terms of moving towards a shorter duration of dual antiplatelet therapy. What do you think will be the role of antiplatelet therapy in bioresorbable stent use? Will it be unnecessary in the long-term care of those patients?
Dr. Meredith: I doubt it. The honest answer is we don't know, but my instincts tell me that we will continue to use antiplatelet therapy. We have a large body of evidence that dual antiplatelet therapy is beneficial for patients with ischemic heart disease and atherosclerotic vascular disease, whether or not they need stents.
The real issue we're dealing with is changing the perception that dual antiplatelet therapy cannot be withdrawn for another procedure, surgical or otherwise, without risk or compromise. If we can have confidence that a drug-eluting stent will remain patent when dual antiplatelet therapy is withdrawn (particularly early after deployment) and we were not reliant on it for day-to-day stent patency, we could focus on using it as a therapy rather than a safety harness. We could tell patients, "You're not absolutely bound to using dual antiplatelet therapy to prevent stent thrombosis." That's the subtle difference. Physicians will feel much more comfortable about the use of drug-eluting stents in the future and not be so concerned about the use of dual antiplatelet therapy.
Dr. King: The other question to consider is whether the metal scaffold should go away. Is there actually a problem with the metal? What do you perceive as the reason for considering getting rid of the scaffold and moving towards totally bioresorbable stents?
Dr. Meredith: That's a great question, especially considering we have 40 million patient-years of experience with metal stents, which are, by and large, very effective and very safe when the problem of restenosis is set aside. Some might think, "If it ain't broke, don't fix it." However, the rationale for moving away from these stents is that the metal scaffold constrains the vessel from its normal function. Once the vessel is stented, the characteristics of the smooth muscle and the endothelial cells are changed; in a way, that removes the initial obstruction, of course, but the constraint may increase the risk of later neoatherosclerosis due to the altered shear stresses and the altered pulsatile responsiveness of the vessel.
There is certainly evidence to suggest that the stent platform does create change that might propagate the atherosclerosis—the very thing you're trying to avoid. Today's drug-eluting stents are extremely safe and effective. The question is if bioresorbable vascular scaffolds will match their performance—from both an acute performance and clinical efficacy perspective.
Dr. King: In your personal clinical experience, how have totally bioresorbable stents performed?
Dr. Meredith: The totally bioresorbable stents we have available at the moment are effective, but there is a limited range of sizes, and, compared to metal stents, they are more limited in terms of flexibility and plasticity (Absorb BVS and DESolve® BVS [Elixir Medical Corporation; Sunnyvale, CA]). Even though the current generation of bioresorbable stents is very effective in opening up the artery, they do not adapt to the vessel-appropriate size that well. We only have exposure to early-generation devices; these will become more sophisticated in time.
Deliverability is good, but you have to realize that the stent struts are thicker because of their need to be bioresorbable. There needs to be significant scaffolding or stent-like effects for a period of time before complete resorption—particularly during the acute inflammation and period of smooth muscle proliferation. So, their deliverability and flexibility are perhaps a little less than we have experienced with the modern iterations of the fourth-generation metal stents. It is also important to remember that these are thick-strut platforms, and thick struts may delay vessel healing.
Certainly, the body of knowledge is building, Spencer, and we are now getting real-world data. We are still desperately in need of large, properly structured, randomized control trial evidence with a head-to-head comparison of these bioresorbable stents and the best-performing metal stents—whether they are made with a conformable polymer or abluminal bioresorbable polymer.
The one theoretical advantage, as we said before, is the potential physiological restoration of the vessel that one could get with a bioresorbable scaffold, and that may prove to be a great long-term advantage in preventing very late events and neoatherosclerosis. However, thicker struts—and possibly longer duration of dual antiplatelet therapy—may limit long-term possible benefits.
Dr. King: Well, we can guarantee that there will be no in-stent neoatherosclerosis if the stent is totally absorbed. It will be interesting to see if this turns out to be a cure for what is ultimately a rare complication. When it happens, though, neoatherosclerosis is just the latest in the saga of problems that interventional techniques keep creating for vascular biology.
We're in the early stages yet, but if we're looking down the road, what do you anticipate in terms of various improvements in bioresorbable stents?
Dr. Meredith: I think the whole idea of having a bioresorbable stent is very elegant and appealing, and that's a great place to start any scientific endeavor. I suspect that we will simply see further and further improvement in the structure and the design—such as significantly smaller strut thicknesses, more compliance, and more malleability—that will all lead to better performance. In the future, I also predict that we will have the ability to fine-tune the drug delivery and the stent life. We may be able to specify that we only want the stent for 9 to 12 months before it is completely absorbed. At that point, we can allow the natural healing process to take place and the vessel will return to its normal physiological function.
I believe that these stent platforms are here to stay. Our focus now will be on increasing their deliverability and plasticity so that we can use them readily and easily in every frontier of interventional coronary artery disease management.
Dr. King: Well, it's certainly an exciting brave, new world of stenting, and I often wonder if it will alter our approach to interventional cardiology. Until now, research and practice has been aimed at reducing the obstruction and alleviating ischemia; but we're left with one other problem: the progression of disease and the underlying vulnerable plaque. Do you see preemptive stenting of arteries to prevent further plaque development in our future?
Dr. Meredith: That's a wise observation, Spencer. I think if we can solve the long-term safety issues of a totally bioresorbable stent, I think there will be a place for preemptive stenting. As we move forward, it will also be important to determine what is a truly "vulnerable plaque" or a "vulnerable patient" who is at high risk for a fatal event—whether that's through genotyping or simply characterization of physical, cellular, and chemical elements of suspicious plaques remains to be seen.
Dr. King: Right, we've developed a treatment and now we need to figure out who really needs it. Thank you for joining us, Ian. We really enjoyed speaking with you.
Dr. Meredith: Thanks very much, Spencer. Absolute pleasure as well.
Spencer B. King, III, MD, is president of the Saint Joseph's Heart and Vascular Institute and Professor of Medicine Emeritus at Emory University School of Medicine in Atlanta. He is also editor-in-chief of JACC Cardiovascular Interventions. He has been a pioneer in interventional cardiology, directing the first trial of angioplasty versus surgery.
DISCLOSURES: This material was sponsored by Boston Scientific Corporation.
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