Bioresorbable stents (BRS) in development, presented by Gregg Stone, M.D., during TCT 2017. Several of the players listed on the slider put their BRS development programs on hold after the negative data from the ABSORB III Trial, but a handful of smaller companies are still pushing the technology forward. (Pghoto by Dave Fornell)
Bioresorbable stent (BRS) technology is not dead, but the unbridled enthusiasm seen two years ago for the technology has been replaced with a much more somber, cautiously optimistic tone at the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting in September.
TCT was at the center of BRS euphoria for a couple years until September 2017, when Abbott pulled the only BRS approved for the U.S. Market, the Absorb, off the market. The late-breaking ABSORB III trial presented at TCT 2017 a few weeks later shed more light as to why, when data showed poorer outcomes compared to the market-leading Xience metallic drug-eluting stent (DES). The 2,008-patient trial showed Absorb had results comparable to Xience, but had a slightly higher percentage of target lesion failure, poor outcomes in 2.5 mm or smaller vessels and a few cases of late-stent thrombosis. The stent was also pricey and more difficult to use than metallic DES, which contributed to its low uptake in both the U.S. and European markets.
After the Absorb stent was pulled off the market, many companies developing BRS devices put them on the back burner or went silent. However, a handful of companies are still pushing full speed ahead with BRS technologies, believing their BRS offer a solution to the issues encountered with Absorb. Two companies that show a lot of promise are Reva Medical and Amaranth, which are explained in more detailed below.
Bioresorbable Stents are a Lesson in the Death of Innovation
"We should not kill an innovation just because it does not show the results you are hoping for in a trial," said Juan F. Granada, M.D., president and CEO of the Cardiovascular Research Foundation (CRF). He was very disappointed that leading interventional vendors all put their BRS programs on the back burner because of the Absorb results. He said breakthrough technologies often require a lot of trial and error to find a solution that works, similar to Thomas Edison who failed in hundreds of experiments before finally creating the first commercialized light bulb. He feels it is a mistake to say the current generation of technology is good enough and ignore potential advances in favor of research on what looks like lower-hanging fruit.
Granada is one of the top experts in bleeding-edge cardiovascular device innovation and was formerly executive director and chief innovation officer at the CRF Skirball Center for Innovation. He said it pains him to see major innovations that hold a lot of promise to solve current clinical issues make it into human trials and then get abandoned when trial results are not positive. He said new technologies need to be improved through multiple iterations through a rigorous testing process. But, some advances he has seen over the past few years seem to have completely stalled after one negative trial, bioresorbable stents being the biggest and best known of these.
Granada said he was disappointed Abbott, Boston Scientific and others basically ended their research programs for bioresorbable stent technology after presentation of the ABSORB III results last year. He admits the costs might be high to bring a new technology like this to market, but the potential benefits to patients would be enormous if a BRS could be created that has similar performance characteristics as current-generation metallic DES. Such a device could be a paradigm shift in PCI and potentially eliminate all the issues associated with a permament metallic implant, long-term dual anti platelet therapy, late-stent thrombosis, restenosis and complications if a patient needs a coronary bypass grafting.
That might be easier said than done, when the costs to prove superiority of a BRS over current metallic stents might be astronomical.
"The community is quite hesitant to make major investments," said Patrick Serruys, M.D., Ph.D., Imperial College London, who lead the European ABSORB trials. "If Abbott has been burned out after its $1 billion investment, most companies don't have that type of money, so it is going to take more time. But, it is going to come back."
Watch the VIDEO: The Current State of Bioresorbable Stents in 2018 — Interview with Patrick Serruys, M.D.
The Absorb trials showed good noninferiority of the technology, but not superiority, explained Ian Meredith, MBBS, Ph.D., global chief medical officer and executive vice president, Boston Scientific. "We started to see that good results were not maintained over time. The question now is do you put a lot of money and time into an interactive program that might only have small, incremental gains, or do we focus on areas of gross unmet needs?"
Meredith said Boston Scientific has put the development of its Renuvia bioresorbable stent "on the back burner" in favor of putting research and development money into technology areas that hold greater promise to significantly impact medicine, including heart failure and cancer therapies. "There has been huge refinements in coronary stent technology, so now the incremental differences with new improvements are relatively small. To show those improvements in a meaningful and randomized trial and aim for superiority would be a massive undertaking. Is it really worthwhile?"
Watch the VIDEO: Future Research and Development Efforts in Cardiovascular Medicine — Interview with Professor Ian Meredith, MBBS
BRS Need to Improve Safety to Move Forward
"The question is why would anyone want a permanent implant in their body?" Granada asked. "But, we need to prove bioresorbable stents are as safe as metallic stents."
Granada noted there was an early safety signal in the European Absorb trials and hinted that a larger powered trial would likely show worse outcomes over current metallic stents. The larger Absorb III Trial showed this to be the case. "In Europe, everyone stopped using Absorb, while in the U.S. we were still pushing ahead with the Absorb Trial," he explained.
"We saw a problem with late-scaffold thrombosis — not dramatic, a 1-2 percent difference," Serruys explained. "But at this stage we cannot accept that because we have such good instruments [with metallic stents] today and the bar is so high. The interventional cardiologist — the human being — will not be bothered by a difference of 1-2 percent if it is something that can be fixed, like restenosis. But what we cannot tolerate is the late-scaffold thrombosis. We had patients in ABSORB II that were doing fine, and then at three years, boom-bang, they had late-stent thrombosis, and that is not acceptable. That was the signal to say this is not yet under control and we have to find something superior."
Read the article "Current State of Bioresorbable Stent Technology," which details the issues raised in the ABSORB III Trial presented at TCT 2017.
In addition to safety issues, there were problems with Absorb that Granada said need to be addressed in any next generation BRS to be successful. "The Absorb was a device that brought its own complexities, including the need to pre-dilate and post-dilate and to be careful not to over-dilate because it fractured the struts," he said. "It also was not easy to navigate because it was too rigid."
Serruys said several new start-up technologies were presented at the innovation sessions at EuroPCR 2018, which might become game changers to improve BRS technology. This includes new ways to cut BRS from a sheet of film to create very think struts, rather than extruding the stents, which cause bulkier devices. A consortium of Japanese partners developed a magnesium BRS with a thin nano-coating that delays breakdown of the stent for several months.
Reva is Pursuing a New BRS FDA Trial
On the TCT 2018 expo floor, Reva was the only vendor showing a commercially available BRS. Its Fantom bioresorbable stent is one of only two BRS on the European market, and the only one that is made of a polymer (the other is a magnesium stent offered by Biotronik). Reva Medical CEO Reggie Groves said the company is in discussion with the U.S. Food and Drug Administration (FDA) to start an investigational device exemption (IDE) trial to bring the stent to the U.S market.
The Reva platform uses a new type of polymer that is different from the polylactic acid (PLA) used in the Absorb and several other stents that are in development. The Tyrocore polymer used in the Fantom includes iodine, so it is the first all-polymer stent that can be seen on angiography without the need for radiopaque markers. It also offers a stent strut thickness smaller than the Absorb at 125 microns (Absorb was about 150). The newest generation Fantom Encore approved in Europe this summer has a 95 micron strut thickness, which is closer to the 80-90 thickness of standard metallic DES, which should make it much more flexible than Absorb and easier to maneuver inside vessels. Groves said the device can be over-expanded 0.5-0.75 mm depending on the size stent used.
The Fantom received CE mark in 2017, the Fantom Encore in 2018. The same Tyrocore polymer is also used in Reva's Motiv BRS, which became the first BRS to gain a CE mark in July 2018 for use in peripheral arteries below the knee (BTK).
In sessions at TCT 2018, data was presented from four Reva studies. The FANTOM STEMI pilot study included data from nine patients and showed the X-ray visible and easy to use worked effectively during these emergency procedures. The FANTOM II two-year clinical results demonstrated safety and efficacy of Fantom with a low 5 percent rate of major adverse cardiac events (MACE) and one very late scaffold thrombosis event for a rate of 0.4 percent. Two-year optical coherence tomography (OCT) imaging results from the FANTOM II study showed an excellent healing profile for Fantom with sustained vessel lumen patency and no evidence of chronic scaffold recoil through two years.
Learn more about the Reva stent in the VIDEO: Editor’s Choice of the Most Innovative New Technology at TCT 2018
Amaranth Pending European Approval, Trial in 2019 for 85-micron BRS
Amaranth Medical has developed several BRS platforms and presented positive trial data at TCT 2018. Its 115-micron Aptitude has been submitted for European CE mark clearance, which might come in late 2018. The company also developed the 98-micron Magnitude and the 85-micron Defiance BRS, which is currently the thinnest strut BRS developed to date.
The Defiance stent is comparable in strut size to the market-leading metallic DES. Xience V has 81-micron struts and Resolute and Endeavor are 91 microns. The thinner struts are expected to make the device easier to use and improve performance in tortuous vessels and small vessels with outcomes similar to metallic DES. The company said it will begin a clinical study of Defiance in 2019.
“The prospect of a viable BRS with 85-micron struts — as thin as a metallic drug-eluting stent — is unthinkable with the limitations of most polymer production techniques," said Antonio Colombo, M.D., director of the hemodynamics division at Ospedale San Raffaele in Milan, Italy. He is co-principal investigator along with Granada for the Amaranth RENASCENT BRS studies. "If Defiance produces clinical results comparable to Amaranth’s other pipeline products, it could be a truly unique offering.”
At TCT 2018, Colombo presented nine-month follow-up results of the 70 patients implanted with the sirolimus-eluting Magnitude. “At nine months, Magnitude continues to perform clinically well and it sets a new standard for thin-strutted scaffold performance. The Magnitude BRS displays similar mechanical performance compared to metallic drug-eluting stent not requiring changes in the implantation technique. We are approaching a new phase in the investigation of this device with plans to conduct a larger head-to-head comparative study against metallic DES.”
Colombo reported patients experienced a low rate of peri-procedural major adverse cardiac events (2.9 percent MACE) and a binary restenosis rate of 4.5 percent. Optical coherence tomography (OCT) showed nearly complete strut coverage (97 percent) and low rate of strut malapposition (0.2 percent). In addition, a metallic stent-like scaffold area was observed after implantation and maintained at the nine-month follow-up visit, demonstrating sustainable mechanical stability.
“At 98 microns, the Magnitude scaffold has started to match the technical and mechanical performance of metallic drug-eluting metal stents,” added Granada. “The thin struts on Magnitude allow the easier navigation of the scaffold through more tortuous anatomies; its mechanical strength allows operators to use a more 'conventional' deployment strategy.”
At TCT 18, Granada provided an update on preclinical results of the Defiance BRS. "Results continue to demonstrate that miniaturization of strut thickness is technologically achievable without affecting mechanical performance. Reducing strut thickness to the 85-micron range has the potential to impact healing response and restenosis favorably, and overcome the issues encountered with first generation BRS. I am eager to see this device tested in clinical trials soon.”
Disappointing Absorb Results Refocused Efforts on Metallic Stent Advances
"We have an expectation that something new is always something better, and certainly intuition would suggest bioresorbable scaffolds would be one of the new groundbreaking technologies in interventional cardiology. But, to date, that has not been the case," explained David Kandzari, M.D., director of interventional cardiology and chief scientific officer, Piedmont Heart Institute, Atlanta, Ga. "We recognize from this experience that metallic stents are indeed, so far, superior to bioresorbable scaffolding properties and provide the best outcomes for patients both in regard to efficacy and safety. While enthusiasm for bioresorbable stents has certainly been tempered, it has also opened an opportunity to refocus on metallic stent designs, thinking more about thinner strut stents to improve outcomes."
Kandzari said stent designs could be improved to lower the metallic footprint in the artery to lessen adverse events. Other opportunities include lesion specific stent designs, such as tapered stents for long lesions, dedicated bifurcation stents, and devices that might have bioresorbable connectors to allow the return of pulsatility and adaptive flow dynamics in the vessel segment.
Indeed, the focus at TCT and by large vendors in 2018 been definitely returned to metallic DES platforms.
For information on recent metallic stent advances, read the article "New Directions and Trends in Coronary Metallic Stents."