The Science Behind the SYNERGY™ Stent with Dr. Dean J. Kereiakes
Principal investigator of EVOLVE II details the SYNERGY Stent design, the need for bioabsorbable polymer technology, and the current clinical data.
Well, the SYNERGY Stent advantages that I'd like to point out include its thin strut, 74-micron, 29-thousandths of an inch, the platinum chrome metal alloy. We know that platinum chrome has roughly twice the radial strength and half the recoil of cobalt chrome, and greater visibility. In addition, the offset peak to peak with two connectors between rings throughout the body of the stent design give this platform greater flexibility and conformability. And the polymer is four microns thin. It's limited to the abluminal surface only, which you will learn is strategic. The drug is Everolimus in a dose density of 100 microgram per centimeter squared, similar to XIENCE/PROMUS. Well, strut thickness directly impacts stent healing. I learned this from Julio Palmaz ten years ago, with more recent publication on the bottom left, showing a stepwise reduction in stent strut thickness, associated with a stepwise increase in endothelial strut coverage at 14 days in a rabbit. Thicker struts take longer to cover, and it's less complete. They're also more thrombogenic. On the bottom left, you see a comparison between a thin VISION stent and a thick VISION stent. They're identical stents except for strut thickness. Nevertheless, at three days, there's more clot thrombus adherent to the thicker strut device. Why? On the bottom right, it's because there's zones of low sheer stress that are set up downstream behind these thicker struts. And that's where thrombus forms.
Polymer is a key component of a DES platform. The purpose of polymer is to be a reservoir for drug and to provide programmed drug delivery. Even though polymer has no function after drug release is complete, it can still impact the late safety and efficacy of the device. And even the very best permanent polymers, whether it's XIENCE/PROMUS/PVDF, Integrity Resolute, BioLinx, have still been incriminated in inflammation, neoatherosclerosis, and thrombosis risk. With SYNERGY, polymer absorption equals drug release. These two processes are in parallel as shown, and they're 90 percent complete within 90 days, leaving behind an endoluminal mural depo of Everolimus that extends beyond the time course of polymer resorption. Polymer distribution can affect the time course and extent of endothelial coverage. On the right side of the slide is abluminal only distribution, on the outside of the strut, as we have with SYNERGY. On the left side of the slide is a conformal surrounding the strut distribution as we see with PROMUS and XIENCE. At 21 days in cell assay, the extent of endothelial coverage is better with abluminal only distribution. And the function, the maturation of these endothelial cells as reflected by VE Cadherin staining is better as well. With SYNERGY, once polymers resorb, you're left with bare metal platinum chrome. This experiment compares bare metal platinum chrome on the left with platinum chrome covered by the best in class permanent PVDF polymer on the right. And what you see is that the time course and extent of endothelial coverage to the function and maturation of endothelial cells, both at 7 and 14 days, is significantly better with bare metal platinum chrome. Although we think of this best in class, permanent PVDF polymer as being thromboresistant, both platelet adhesion and activation were significantly less with bare metal platinum chrome. All of these factors, whether it's thin metal strut, thin polymer, low polymer load, rapid polymer resorption or the drug Everolimus combine to facilitate and expedite healing so that in this cumulative SYNERGY OCT experience summarized on this slide, within 2 to 3 months of stent deployment, you've got over 90 percent strut and stent coverage.
In the EVOLVE II Pivotal Trial for US FDA approval of the SYNERGY Stent, we included subjects with up to three target stenoses and up to two major epicardial vessels. You could have a max of two lesions in one vessel. Lesion lengths at 34 millimeters or less and reference vessel diameters of 2.25 to 4.0. We took 1684 patients, randomly assigned one to one to either PROMUS Element Plus or SYNERGY. The primary end point was target lesion failure at one year. This is a composite cardiac death. Target vessel MI and ischemia driven target lesion revascularization. I think it's important to point out that the definition of periprocedural MI that contributed to MI as part of TLF is a threefold bump in CKMB with no clinical correlates. This is consistent with the 2007 universal definition, and is extremely sensitive. DAPT was prescribed by protocol for at least six months or longer as tolerated. And there are 203 diabetics that were treated with SYNERGY Stent as part of a diabetic sub study – this was in addition to the randomized cohort - to seek a diabetic label in this population. Primary end point, 12-month TLF, intention to treat, with 6.7 percent SYNERGY, 6.5 percent PROMUS Element Plus. So as you can see, the upper confidence bound is well within the non-inferiority margin of 4.4 percent. As pre-specified, the protocol analysis was 6.4 percent for both devices. Again, the upper confidence bound is well within the non-inferiority margin. We needed a P value of less than 0.025 in both of these analyses. Each P value has three zeros in it. This is I think definitive. SYNERGY is not inferior to PROMUS Element Plus for TLF at one year. The individual components to TLF, although under powered, were not different between the devices. And importantly, ARC definite/probable stent thrombosis, despite the fact that this was the most complex clinical and angiographic cohort of patients ever enrolled in a regulatory trial for stent approval in the United States, there are only three SYNERGY-treated patients that had stent thrombosis to one year -- 0.4 percent. No definite stent thrombosis in a SYNERGY-treated patient beyond 24 hours. And one of those two definite stent thromboses never received aspirin. In the diabetic cohort - and this was presented by Stephan Windecker, EuroPCR this year - there were 466 diabetics. The primary end point was target lesion failure at one year, compared to an objective performance goal. This goal was established in analysis as SPIRIT II-IV compare in the EVOLVE First Human Use experience with SYNERGY. The performance goal was set at 14.5 percent in the observed TLF in the diabetic population; it was only 7.5 percent. I think it's remarkable, when you consider the definition of periprocedural MI. In fact, it wasn't different from the global SYNERGY treatment population in the trial as a whole. So in conclusion, I think the current DES permanent polymer served no useful function after drug release is complete, and evolution to bioabsorbable polymer DES is certainly an attractive concept.