You are principal investigator for EVOLVE II, looking at the Synergy biodegradable polymer stent, and co-primary investigator for ABSORB III, for the Absorb bioresorbable stent.
The first Absorb BVS (bioresorbable vascular scaffold) was placed at our facility in early January for the ABSORB III trial, and the first Synergy in late November 2012 for EVOLVE II. The Christ Hospital Heart and Vascular Center is leading the country in both trials, which are the pivotal trials for U.S. FDA approval.
I look at these devices as being somewhat complementary. I think they are both exciting.
Can you tell us about the Absorb BVS?
The Absorb BVS (Abbott) has a relatively thick strut, about .059”, with the equivalent radial strength of the Vision stent. Even though it is non-metallic (it is a polymer), the BVS is still limited to relatively simple lesions: straightforward, non-tortuous, non-calcified vessels. Complete anatomic recovery with the BVS occurs in about 18-24 months, meaning the platform is gone. Physiologic recovery, meaning the artery can respond to normal stimuli by constricting or opening up wider, occurs within 1 year. The artery can auto-regulate and behave like a normal artery. Even though the struts are still visible at one year, they are like overcooked spaghetti: flimsy, with no structural integrity, and they are very flexible and conformable. The BVS offers normal physiology and anatomic recovery — without a metal backbone or scaffold.
The Synergy stent has a metal platform, but a biodegradable polymer.
I am very enthusiastic about the EVOLVE trial and the Synergy stent (Boston Scientific), specifically. The Synergy stent is the most flexible, conformable, metal platform drug-eluting stent (DES) yet. The platform itself has a thinner strut than the BVS: .029”. It is made from platinum chrome. Synergy is even a little more flexible and conformable than the current Promus Element Plus. This is an important attribute because of geometric distortion of the artery, meaning how the vessel changes when the stent is placed. If the vessel has bends or is tortuous, the stent tends to straighten out the artery, because the stent is metal and less flexible than the artery. That degree of change in the angulation of the vessel has actually been directly correlated with risk for recurrent restenosis. We submitted an abstract for the American College of Cardiology Scientific Sessions that is an angiographic analysis of the PLATINUM trial where the Xience/Promus stent is compared to Promus Element. We observed that the degree of arterial distortion with tortuous vessels was significantly greater with Xience/Promus than with Promus Element. Synergy, to make a long story short, takes it a step further and is even more flexible and conformable than the Promus Element stent. It has a reduced metal volume and thinner struts with the same stent design as Promus Element.
[Editor's note: Readers may also find the PLATINUM trial results on vessel straightening at the link following]: http://tinyurl.com/stentstraighten
Stent flexibility is also one of the key determinants of stent fracture, which we are now recognizing as being a significant and common cause of late stent failure, which presents as restenosis and clinically-driven target lesion revascularization (TLR). If we look at the best-in-class Xience/Promus stent and the results of either SPIRIT IV, late results out to three years, or XIENCE V USA, a registry which has a more complex group of patients, TLR after the first year is between 2-3% per year. Adding 4-5 more years means a 10-12% failure rate, in part due to stent fracture. It appears that the more flexible and conformable the stent, the less prone it is to fracture. There are constant forces placed on a stent by the vessel as it moves. The heart is squeezing and rotating with every beat. Stents are not static like a drainage tube in your yard. Stents are subject to stresses placed on them in a dynamic fashion.
Kuramitsu et al recently published a study in Circulation: Cardiovascular Interventions looking at multivariate predictors of stent fracture.1 Only 6-9 months after placement, stent fracture was identified in 2.9% of 1339 lesions (3.9% of total patients) treated with the Xience stent. The three major determinants of stent fracture were hinge motion, ostial location and tortuosity. In order of importance, number one was hinge motion, i.e. rocking back and forth on a bend. Ostial location was number two. Think of what happens: the coronary is attached to the aorta. The distal artery is attached to the heart. The heart is squeezing and rotating in the chest. So what area of the vessel experiences torque? Where it is attached, to the aorta. Number three was tortuosity.
The platform of Synergy is a crucial design element that may be overlooked.
While Synergy is likely going to be the first FDA-approved stent with a bioresorbable polymer, that is not the whole story. You have to look at the whole device. We don’t just put in the polymer.
It is true, however, that Synergy has the lowest polymer load of any bioresorbable polymer stent either approved anywhere in the world or under clinical testing at this time. It is only 4 microns thick, half the thickness of a human red blood cell. The polymer is only on the outer surface of the stent, the abluminal surface. That is important because polymer load can contribute to inflammation and is also a determinant of the rate of resorption. The Synergy polymer is 90% gone within 90 days. Synergy has, by a factor of at least two-fold, the shortest time course for polymer bioabsorption compared to other similar stents under study. It takes 60-90 days for the drug to leach off, and then the polymer goes away and leaves behind the platinum chrome thin-strut metal platform. The remarkable thing about PLGA, the polymer used on Synergy, is that it is has been engineered to resorb within 90 days and to give off everolimus in the same concentration (100 µg/cm2 of stent surface area) present in the Promus Element or in the Xience/Promus stent. Everolimus-eluting stents are the best in class among all drug-eluting stents: Xience/Promus, Promus Element and now, Synergy. Synergy’s benefits include greater flexibility, conformability, thinner struts, the lowest polymer load, most rapid polymer resorption, and the best-in-class drug, everolimus.
The abluminal coating is an interesting aspect.
Yes, most DES have what we call conformable polymers, meaning the polymer circles the entire strut. For example, Xience/Promus and Promus Element have a 7.8 micron conformable polymer. Other devices include the BioMatrix Flex, studied in the LEADERS trial, which actually has a thicker strut than Synergy, .047” versus .029”, and the polymer is PLA, 10 microns thick on the abluminal surface. The BioMatrix Flex is a biolimus-eluting stent, and has received attention in Europe and outside the U.S. Resorption still takes about 9 months, more than twice what the PLGA on Synergy takes to resorb. There is also the Biotronik Orsiro hybrid DES, for which U.S. clinical trials are being planned. It has conformable PLA, meaning the polymer is on the outside abluminal in addition to the inside adluminal strut, and it is 7.4 microns thick on the outside and about 3.5 microns on the inside. The polymer load, as you would expect, is greater than Synergy. Time course for resorption is about 15 months.
Can you talk about how Synergy is being studied in EVOLVE II?
We have done more than 20 patients already for EVOLVE II. The trial will include 1700 patients randomly assigned in a single-blind fashion 1:1 to either Promus Element Plus or Synergy. Patients can have up to three lesions ≤34 mm in length in two epicardial vessels. Synergy comes in sizes up to 38 mm long, with diameters of 2.25 mm up to 4.0 mm. EVOLVE II is a non-inferiority trial, based on the idea that we think Synergy will be at least as good as Promus Element Plus at one year, based on the endpoint of target lesion failure, a composite of cardiac death, target vessel-related myocardial infarction or target lesion revascularization. About 30 patients will also be enrolled into a pharmaco-kinetic (PK) substudy. These patients will all be treated with Synergy, and frequent blood draws will be obtained over the first 48 hours to evaluate the concentration of everolimus in the blood. Once the randomized trial is done, we will enroll another 250-300 medically treated diabetics. These patients will undergo the same criteria, but will not be randomized to Promus Element Plus, just treated with Synergy, so we can enrich the diabetic subpopulation.
What do you envision as Synergy’s eventual role in clinical practice?
I think Synergy will have all the criteria for a workhorse stent. When you make it easier for the operator to use a stent, and if measurable clinical outcomes are at least as good or better, then I think interventional operators follow the path of least resistance. You try to make the tough cases easier on yourself. We often see multi-lesion, multi-vessel, turned-down-for-surgery cases. Complex disease still exists in patients with SYNTAX scores <32.
Synergy’s flexibility and conformability should make it less prone to fracture. We observed this in 2-year follow-up of the PLATINUM trial, which compared Xience Promus to Promus Element. Between 1-2 years, there was almost a 70% relative reduction in ischemia-driven, meaning clinically-driven, target lesion revascularization in favor of Promus Element compared to Xience/Promus. In this case, we believe that the flexibility and fracture resistance of the Promus Element may well contribute to that reduction. Even though the same polymer and drug are on two different stent platforms, if one platform is more flexible and less prone to fracture, late failure rates will be less. While the resorbable polymer is indeed very important, Synergy’s flexibility and conformability may prevent late stent fracture, which means it prevents late target lesion revascularization.
What do you envision for the Absorb BVS?
Absorb is not going to be a high performance stent, to the same extent, because it is bulkier and has a higher profile. Synergy’s stent strut thickness is .029” versus Absorb’s .059”. Yet what makes a completely absorbable platform so intriguing is its flexibility and conformability — nothing is more flexible and conformable than a stent that goes away. Absorb also allows adaptive remodeling. Our arteries have the capacity to accommodate about a 40% increase in volume, meaning most people don’t even get evidence of a blockage until they have a 40% expansion of their vessel. The arteries enlarge as they fill with cholesterol. Adaptive remodeling is restored when the metal scaffold or girdle goes away. Neo-atherosclerosis, the development of new atherosclerosis on the stent itself, affects both bare metal and to an even greater degree, drug-eluting stents. There is nothing to form neo-atherosclerosis on if the stent goes away. Lastly, Absorb restores auto-regulation. If you are going to run 15 minutes on a treadmill, as a young person, your arteries are going to dilate because your heart needs more blood flow. Think about this: if you had a long metal girdle in your left anterior descending, it is not going to allow the artery to expand. Even though the artery has been “held open” and it heals open, the ability to auto-regulate is lost with metallic platforms, while the ability to auto-regulate is restored within a year of getting the BVS Absorb stent.
In short, with BVS, flexibility and conformability are ultimate, adaptive remodeling capacity is returned, neo-atherosclerosis is unlikely when the device is no longer present, and auto-regulation is maintained within a year — all very different from metal stents. There are other benefits, including imaging, CT scanning, MR, and no metal stent if you want to operate and put in a graft. Within 24 months, the patient is left with a normal appearing and normal functioning artery.
Disclosure: Dr. Kereiakes has served as a consultant and on the scientific advisory board of Boston Scientific, Abbott Vascular, and REVA Medical Inc.
Dr. Dean Kereiakes can be contacted at firstname.lastname@example.org.
1. Kuramitsu S, Iwabuchi M, Haraguchi T, Domei T, Nagae A, Hyodo M, et al. Incidence and clinical impact of stent fracture after everolimus-eluting stent implantation. Circ Cardiovasc Interv. 2012 Oct;5(5):663-671. doi: 10.1161/CIRCINTERVENTIONS.112.969238.