Conversations with The Expert: EVOLVE II: Results and Considerations | With Dean J. Kereiakes, MD
CardioSource WorldNews Interventions | Dean J. Kereiakes, MD, FACC, has been an interventional cardiologist for over twenty-five years. “My area of expertise and experience has been largely in the area of coronary stent design and development,” he said, having completed more than 25,000 catheterization laboratory procedures in the three decades he has been investigating interventional technologies. He has also participated in over 1,300 clinical research protocols including, being the national/international principal investigator on pivotal trials for U.S. FDA approval of eight different coronary stents. In this Conversation with the Expert, Dr. Kereiakes gives insight into the results of the EVOLVE II clinical trial, current trends in stent technology, and thoughts on interventional cardiology.
What was the intent and purpose of the EVOLVE II clinical trial?
The intent of EVOLVE II was to demonstrate non-inferiority for target lesion failure (TLF) at 1 year between the SYNERGY Stent™ and the PROMUS Element™ Plus stent, which is considered “best in class,” among currently available, drug-eluting stents.PROMUS Element Plus has a permanent polymer that elutes everolimus. EVOLVE II was performed to obtain U.S. Food and Drug Administration (FDA) regulatory approval for the SYNERGY Stent.
What excites you the most about the results of the EVOLVE II trial?
The trial achieved its primary endpoint—non-inferiority for TLF at 1 year and at 2 years, TLF was similar for both stent types. What excites me most is the trend for safety of SYNERGY, compared to the “best-in-class”, permanent polymer drug-eluting stent (DES), with respect to lower-stent thrombosis rates. This is intriguing because we were not comparing SYNERGY to TAXUS™ or a bare-metal stent, but to a very-high performance, very safe device, PROMUS Element Plus. Despite this fact, we still observed a 50% to 85% reduction in stent thrombosis through 2 years, depending on how the data are analyzed. However, any way you cut the data, a 50% to 85% reduction in stent thrombosis compared to a very good, very safe, “best-in-class” device is an incredible accomplishment.
Some may challenge that SYNERGY is no different than permanent polymers. How would you respond to this?
First, we made we made an important observation regarding the relative safety of SYNERGY in EVOLVE II with a 24-hour landmark, wherein there wasn’t a single definite stent thrombosis among 846 complex patients treated with SYNERGY beyond the first 24 hours following stent deployment. Using this landmark based on the premise that definite stent thrombosis is the most accurate diagnostic level of evidence for stent thrombosis—and that none were observed beyond 24 hours through 2 years, there is an 84% relative reduction in stent thrombosis by SYNERGY compared to “best-in-class” PROMUS Element Plus. The hazard ratio is 0.16 and the p value is 0.056.
EVOLVE II is not the only data in support of the relative safety of the SYNERGY Stent versus permanent polymer-coated devices. The SCAAR (Swedish Coronary Angiography and Angioplasty Register) registry recently reported on 83,000 DES-treated patients treated between 2007 and 2015, of which almost 8,000 were SYNERGY. SYNERGY treated patients had the lowest rate of definite stent thrombosis (0.25%) at 1-year follow up compared with all other stents included in analysis. Although not randomized, these are huge numbers of “real-world” patients treated in the same country, at the same hospitals, with the same doctors with the lowest rate of definite stent thrombosis. There are additional data from serial, optical coherence tomography (OCT), intravascular imaging studies that have evaluated the degree of stent apposition and stent coverage at 3 and 6 months following stent deployment. SYNERGY has rates of well over 90% to 95% at 3 months, and almost 100% by 6 months. These are the highest rates of healing that we have seen by OCT.
Additionally, EVOLVE II enrolled complex cases. The average age was 64 years, more than one-third of patients had an ACS presentation, more than 25% were biomarker (CKMB) positive prior to their index PCI, 31% had diabetes and 75% had AHA/ACC B2C complex-lesion morphology. This was a more complex clinical and angiographic profile of patients than has ever been included in a regulatory trial for FDA approval of a new stent in the U.S. At my ACC 2016 presentation of the EVOLVE II 2-year follow-up, I was impressed to hear my colleague, Bill O’Neill, stand up and say that SYNERGY was the best-performing DES he’d ever used in terms of deliverability, flexibility, profile and conformability. SYNERGY is a high-performance device—and I always want to bring my “A game” to the lab. SYNERGY makes my job easier; I don’t know what price can be put on that, but I’m glad to have technology that makes my job easier.
The results you cite range anywhere between 24 hours and 2 years. How do you see SYNERGY performing long-term?
So far, in EVOLVE II, the incidence of ARC definite/probable stent thrombosis is zero beyond 6 days (there was a single “probable” stent thrombosis at day 6). Frankly, it’s hard to beat zero. This is a very attractive profile that most interventionists would be very happy to adopt.
What are considerations you would give to your peers on choosing to adopt permanent polymers versus the bioabsorbable polymer?
We have, at this point, gone to SYNERGY as our “go-to” workhorse device. I don’t see any specific reason to pick a permanent or durable polymer device. SYNERGY has the advantages of being lower profile, more deliverable, more flexible and with zero stent thrombosis beyond the first 6 days in EVOLVE II.
The FDA has recently voted in support of the Absorb™ bioresorbable stent. Do you have any thoughts on this approval?
The ABSORB III trial demonstrated non-inferiority within a pre-specified, acceptable margin for target lesion failure (TLF) at 1 year between the Absorb bioabsorbable vascular scaffold (BVS) and the XIENCE™, cobalt-chromium, DES.
Absorb “hit the mark,” so to speak, with regard to non-inferiority for TLF at 1 year. The premise that Absorb will provide very late benefit (beyond 1 year) compared to XIENCE is tied to the concept that the metal frame causes mechanical vessel restraint, which interferes with pulsatility, and cyclic strain, which are necessary for normal vessel biology and physiology. The metal frame may also cause geometric distortion of the vessel, which alters shear stress and coronary flow velocity, particularly at the margins of the stented segment, which may promote restenosis and/or thrombosis.
The “promise” of Absorb BVS (better very-late outcomes) is yet-to-be proven. ABSORB IV, which is a randomized trial evaluating 5,000 patients followed through 5-years with a 1- and 5-year landmark analysis for TLF, will provide insight into the possible superiority of BVS compared with XIENCE. The incidence of TLF events on a per-year basis following metal platform stents appears to be related to the metal frame itself. If there is no metal frame, then outcomes could be better—that’s the premise.
Beyond emerging stent technology, what other trends in interventional cardiology do you find promising or challenging?
For the interventional cardiologist, the field has grown by leaps and bounds—from cerebrovascular intervention, peripheral vascular intervention, structural heart disease, trans-catheter valve replacement and repair.
I have stepped out of my main area of coronary stent design and development to be in the transcatheter aortic valve replacement space. We have developed a large experience, which includes first-in-man and first-in-the-U.S. experiences with specific transcatheter heart valve technologies. Conversely, I’ve chosen not to do peripheral vascular intervention, cerebrovascular intervention, or to-date, MitraClip®, although I am actively looking at other technologies in the mitral space, because I think that’s going to be a very important space. Others in my group have focused on MitraClip or other areas such as intervention for pulmonary embolus or deep vein thrombosis and endovascular aneurysm repair. My concern is that people who try to “do it all” may end up not being really good at any of it.
Finally, whatever the sub-specialty, interventionists have additional challenges, such as working within a hospital system that owns their group. Doctors need to have choices, based on hands-on experience and access to medical literature for devices that cannot be solely differentiated based on cost. Often, the individuals who buy the technology that we use to treat patients are administrators who aren’t familiar with the devices because they haven’t had them in their hands—and they certainly haven’t tried to shove them into an artery. So there has become a disconnect between the practicing physician and the product that they may or may not want to use. Hospitals, at times, make decisions based on a few dollars per device that the physicians would not make.
Overall, these are incredibly exciting times to be an interventional cardiologist. Twenty years ago, I said that an interventional cardiologist within cardiology who tried to be a “jack of all trades” would be a master of none. Practice makes perfect. Volume drives proficiency and efficiency. Now, I’d say the same thing about being an interventionist within the field of interventional cardiology—you need a focused, sub-sub-specialization within interventional cardiology more now than ever before.
Dr. Kereiakes is a fellow of the American College of Cardiology, a fellow of the Society for Cardiac Angiography, and a practicing interventionalist at the Christ Hospital Physicians Ohio Heart & Vascular practice in Cincinnati, OH.
DISCLOSURES: Dr. Kereiakes received no compensation for his participation. This material was sponsored by Boston Scientific Corporation.
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