The Synergy stent is the first FDA cleared drug-eluting stent to use a bioresorbable polymer drug carrier. When the polymer dissolves after about four months, the devices become a bare metal stent. The technology is supposed to reduce the rate of late stent thrombosis due to vessel inflammation caused by durable polymers.
The Biotronik Orsiro stent uses a bioresorbable drug-carrier polymer that dissolves to leave behind a bare metal stent. The design is meant to eliminate the effects of late stent thrombosis.
One of the big advancements in drug-eluting stent (DES) technology has been the development of bioresorbable polymers that disappear and leave behind a bare metal stent. This engineering was created to solve ongoing issues in some patients whose vessels do not tolerate the antiproliferative drug-carrying polymers well, resulting in chronic inflammation. This can lead to late-stent thrombosis and is the basis for requiring long-term dual-antiplatelet therapy (DAPT).
There were three trials (BIO-RESORT, TRANSFORM-OCT and PRISON IV) presented at Transcatheter Cardiovascular Therapeutics (TCT) 2016 that compared traditional durable polymer metallic stents with newer bioresorbable polymer metallic stents. Instead of showing improved patient outcomes as many expected, the studies suggested bioresorbable polymers are about equal in performance. Details of the trials are in a subhead section below.
The trials compared both the bioresorbable polymer Biosensor Orsiro and the Boston Scientific Synergy stents to the durable polymer Medtronic Endeavor, Resolute Integrity and Abbott Xience V stents. Synergy was expected to show better performance than the data show.
“The trials here all have really short time frames,” said Craig Thompson, M.D., senior vice president and chief medical officer, interventional cardiology, at Boston Scientific. “The real question is what does this mean for patients years down the road.”
Thompson said the purpose of using bioresorbable polymers is to reduce the late adverse event rate. The idea is to reduce the long-term vessel inflammation caused by the durable polymer, which can lead to late-stent thrombosis months or even years after stent implantation.
“The goal is to reduce inflammation in the stents,” Thompson said. “We want to eliminate late safety events, not just for months, but for years after the stent implantation.”
He said more long-term followup data is needed before a verdict can be made on bioresorbable polymers. With more than 18,000 patients enrolled in Synergy studies, he said long-term followup should show if there is any signal toward improvements in outcomes over time.
In the TRANSFORM-OCT trial, optical coherence tomography (OCT) review of stented lesions found comparable neointimal stent coverage between durable and bioresorbable polymer stents. “One thing that we have seen in intravascular imaging studies is that neointimal coverage can be good or bad,” Thompson said. He explained neointimal cell coverage of stent struts can be unhealthy if it is in a state of constant inflammation, which can lead to restenosis or stent thrombosis months or years after implantation.
“With the Synergy, you definitely have a better healing environment with these stents than with durable polymer,” Thompson explained. However, more data will be needed to show if there really are any long-term benefits on bioresorbable polymers.
TCT Trial Data
Here are data summaries for the three studies presented at TCT 2016:
BIO-RESORT — The study was the first all-comers analysis to compare the safety and efficacy of biodegradable polymer drug-eluting stents using the Boston Scientific Synergy and Biotronik Orsiro, to a durable polymer Resolute Integrity from Medtronic. At one year, patients with coronary artery disease who were treated with a biodegradable polymer stent showed no clinical benefits over patients treated with Resolute Integrity.
The primary composite endpoint of target vessel failure at one-year showed no statistically significant difference in outcomes for the Resolute Integrity treated group (N=1,173) at 5.4 percent compared to 4.7 percent with the Synergy (N=1,172) arm and 4.7 percent with the Orsiro (N=1,169). The one-year outcomes also found no statistically significant difference in stent thrombosis between Resolute Integrity and bioresorbable polymer groups (difference of 0.1 percent; p=0.77).
“In patients with coronary artery disease treated with durable polymer-coated drug-eluting stents, the life-long presence of the polymer may delay arterial healing and even cause adverse clinical events,” Clemens von Birgelen, M.D., Ph.D., co-director of the Department of Cardiology at Thoraxcentrum Twente, professor of cardiology at University of Twente in the Netherlands, principal investigator of the trial and presenter of the data at TCT. “Biodegradable polymer stents might improve long-term outcomes, but studies with early biodegradable polymer stents that had thick stainless steel struts (120 µm) showed equivocal results. However, very thin-strut (60–81µm) biodegradable polymer stents that have flexible designs and thin, refined coatings are now available.”
The BIO-RESORT study was supported by Boston Scientific, Biotronik and Medtronic.
TRANSFORM-OCT — This prospective, randomized trial using OCT to evaluate neointimal tissue strut coverage and neoatherosclerosis (NA) found that bioresorbable polymer Synergy stents are comparable to durable polymer Resolute Integrity stents. The study randomized 90 patients with multivessel disease (1:1) to Synergy or Resolute Integrity. The primary endpoints were maximum length of consecutive frames with uncovered struts at three months (powered for non-inferiority of Synergy) and the percentage of patients presenting with frames of NA at 18 months (powered for superiority of Synergy) as measured by OCT. The three-month median percentage of covered struts was 79.1 (IQR 60.4, 89.8) for Synergy and 78.4 (IQR 62.1, 87.8) for Resolute Integrity, P=0.93. The 18-month median percentage of covered struts was 99.4 (IQR 96.6-100) for Synergy and 98 (IQR 94.4-99.8) for Resolute Integrity, P=0.14. The co-primary endpoint of in-stent NA at 18 months from 98.9 percent of all eligible patients was 11.6 percent for Synergy versus 15.9 percent in Resolute Integrity (P=0.59).
“In this head-to-head in-vivo comparison of early and late healing response, the bioresorbable abluminal polymer Synergy everolimus-eluting stent was non-inferior at three-month and similar at 18-month follow-up to the durable conformal polymer Resolute zotarolimus-eluting stent,” said Giulio Guagliumi, M.D., with Ospedale Giovanni XXIII in Bergamo, Italy, who presented the data at TCT. “TRANSFORM-OCT adds a novel mechanistic dimension to the assessment of new-generation drug-eluting stents, consolidating the understanding that well designed and biocompatible polymers, regardless of whether they are durable or biodegradable, may favorably impact the long-term vascular response of these stents.”
The study had unrestricted financial support provided by Boston Scientific.
PRISON IV — Results from this randomized, multicenter trial failed to show non-inferiority of the Biotronik Orsiro stent, a hybrid, ultra-thin strut sirolimus-eluting stent with a biodegradable polymer, compared to the Abbott Xience stent with a durable polymer. The Orsiro was not able to match the Xience in terms of in-segment late lumen loss in successfully treated coronary chronic total occlusions (CTOs). In addition, although the rate of binary restenosis was low overall in this complex lesion subset, it was higher with the Orsirio arm compared with the Xience.
Between February 2012 and June 2015, a total of 330 consecutive patients with successfully recanalized native total or CTOs were randomized to the Orsiro or Xience in two Belgian and six Dutch high-volume PCI centers. Follow-up angiography was performed at nine months after the procedure. In addition, clinical follow-up was obtained during the hospital stay and at one, six, nine and 12 months.
The primary non-inferiority end point was in-segment late lumen loss assessed at nine months by angiography. Secondary angiographic end points included: in-stent late lumen loss, minimal lumen diameter, in-stent and in-segment percentage of diameter stenosis, binary restenosis and reocclusions at nine months. Secondary individual and composite clinical end points were clinically indicated target lesion revascularization/target vessel revascularization, myocardial infarction, death (cardiac and non-cardiac), stent thrombosis, target vessel failure and major adverse cardiac events.
At nine months, angiography was available in 281 of 330 (85 percent) patients. The primary non-inferiority endpoint of in-segment late lumen loss was not met for Orsiro compared with Xience (0.13±0.63 mm vs. 0.02±0.47 mm; P=0.08, two-sided; difference=0.11 mm; 95 percent confidence interval, -0.01 to 0.25; Pnon-inferiority=0.11, 1-sided). In-stent late lumen loss was comparable between Orsiro and Xience (0.12±0.59 versus 0.07±0.46 mm; P=0.52). The incidence of in-stent/in-segment binary restenosis was higher with Orsiro compared to Xience (8 vs. 2.1 percent; P=0.028) with comparable rates of reocclusions (2.2 vs. 1.4 percent; P=0.68). Clinically indicated target lesion and vessel revascularization (9.2 vs. 4 percent; P=0.08 and 9.2 percent vs. 6 percent; P=0.33), target vessel failure (9.9 vs. 6.6 percent; P=0.35) and definite or probable stent thrombosis (0.7 vs. 0.7 percent; P=1.0) were comparable in the Orsiro and Xience groups.
The risk due to possible late thrombosis events from durable polymers is a big reason for the long or permanent duration of DAPT. However, patient compliance with taking medication each day varies greatly by patient. Some patients also face increased bleeding risks from being on antiplatelet medications. For these reasons, physicians often want to take patients off DAPT. Thompson said the need for long-term DAPT is one of the trade-offs with durable polymer DES.
“You don’t want a trade-off,” Thompson said. “What a physician needs is flexibility, and with Synergy you build in a choice of whether you want to keep the patient on long-term DAPT.”
Two ongoing trials, the DAPT Study and the European SENIOR Trial, are examining DAPT duration with the Synergy stent. Thompson said Boston Scientific is gathering data through trials like these to determine if DAPT duration can be reduced to between three to six months.
The EVOLVE Short DAPT Study is a prospective, multicenter, single-arm study designed to assess the safety of three-month DAPT in subjects at high risk for bleeding undergoing PCI with a Synergy stent. It is currently enrolling patients.
The main objective of the ongoing SENIOR study is to establish the efficacy and safety of the everolimus eluting stent with a the Synergy biodegradable abluminal polymer stent associated with short DAPT in patients ≥75 years old, suffering from stable angina, silent ischemia (one month DAPT) or acute coronary syndromes (six months DAPT) related to significant coronary artery disease and requiring percutaneous coronary intervention (PCI).