Stent Polymer Face-off Calls Bioresorbable Coatings Into Question

The latest and largest trial to compare durable-polymer versus biodegradable-polymer stents—this time in the setting of acute coronary syndromes—should convince the field once and for all that a polymer that does its job and disappears may not be important for drug-eluting stent performance, investigators say.

Presenting the HOST-Reduce-Polytech-ACS trial during a late-breaking clinical trial session at TCT Connect 2020, Hyo-Soo Kim, MD, PhD (Seoul National University Hospital, Korea), noted that the durable-polymer stent was not only noninferior to the biodegradable-polymer device, but also may have had some technical advantages.

“Most clinicians and industrial companies believe that a biodegradable-polymer DES would be better than durable-polymer DES, but such a belief is not confirmed by this study,” Kim said. “On the other hand, the beneficial role of durable polymers, such as thrombo-resistance, may be real.”

The development of stents with degradable polymers grew out of concerns that polymers, used to elute the drugs, were serving as a nidus for delayed healing and thrombosis; having a polymer do its job then disappear, leaving behind a bare stent, would get around this problem. But the evolution of these polymers has been accompanied by other improvements in stent design: struts have gotten thinner and deliverability has improved, while the drugs being eluted have changed.

“Among the three components of DES, strut thickness or stent design may be more important than the other two, drug and polymer,” Kim told TCTMD in an email.

In a sign that device innovation in this space may be approaching its peak (for the time being), Kim’s presentation joined two other late breakers this morning looking at stent innovation and all three came up short. COBRA-REDUCE, using the Cobra PzF nanocoated stent and shorter DAPT duration, failed to demonstrate a reduction in bleeding, while OPTIMIZE, testing a novel low-profile, direct-stenting system using the Svelte DES, failed to match the performance of market-leading devices.

Big Numbers, Different Stents

The trial enrolled over 3,400 patients with ACS, known to carry a heightened risk of thrombosis and delayed healing after PCI, Kim noted. In all, 1,713 patients were randomized to one of four stents with a durable-polymer DES (mostly Promus Premier [Boston Scientific], Resolute Onyx [Medtronic], or Xience Alpine [Abbott]) and 1,700 to a biodegradable-polymer stent (mostly Ultimaster [Terumo], Orsiro [Biotronik], or Biomatrix Flex [Biosensors]). After trial withdrawals, loss to follow-up, or randomization failure, 1,638 and 1,646 patients in the durable and biodegradable groups, respectively, were followed-up at 12 months.

For the trial’s primary outcome of patient-oriented clinical outcomes (POCO: all cause death, nonfatal MI, stent thrombosis, and any repeat revascularization at 1 year), there was no significant difference between the groups, meeting the P value for noninferiority for the durable-polymer device.

For a secondary endpoint of device-oriented clinical outcomes (DOCO: cardiac death, target-vessel MI, or TLR), 1-year rates were significantly lower for the durable-polymer device. TLR rates also were lower with these devices, a difference that narrowly reached statistical significance.

One-Year Outcomes: DES Type

“Clinicians’ choice of stent for a given patient can be broader and more appropriate, considering not only polymer, but [also] stent design or mechanical properties such as strut thickness, deliverability, trackability, or visibility under fluoroscopy,” Kim concluded. “Developmental direction of next-generation stents by companies may change from polymer issues to stent design or physical properties.”

Further follow-up will be needed to see whether the now disappeared polymer has any effects on late clinical outcomes, he added.

To TCTMD, Kim said he and his co-investigators plan to follow their patients out to 3 years, noting: “The potential advantage of a degradable-polymer DES would appear in the chronic phase when this becomes a bare-metal stent, after complete dissolution of the polymer. But this is not confirmed yet.”

In the meantime, signals have emerged that certain permanent polymers may actually do better than a bare-metal surface, he explained. “There have been several data supporting that the fluoro-copolymer on Xience/Promus has a thromboresistant effect and that the BioLinx polymer on Onyx has an excellent biocompatibility. Thus, such durable-polymer DES showed less thrombosis and were cleaner than BMS in the in vitro study, as well as in vivo animal study.”

Also of note, trial investigators said that the event curve for the degradable-polymer stents in their study actually rose slightly after 9 months, despite the fact that the polymers would have dissolved at different time points (around 3 months for the Synergy or Ultimaster, 9-12 months for the Biomatrix Flex and Nobori, and 15 months for Orsiro). There are a number of other possible explanations for the uptick in event rates, Kim told TCTMD.

“Dissolution of polymer may induce acidic micro milieu at the stented vessel, leading to transient inflammation and vascular events. Or, bare metal after dissolution of the polymer may be more thrombogenic than the coated metal. There is a metal-toxicity theory that nickel in the stent metal is directly in contact with tissue and may dissolve and enter the tissue, leading to allergic inflammation. These three possibilities may explain the divergence of event curves between durable- versus degradable-polymer DES or increasing events in the degradable-polymer DES.”

Take a Step Back?

Discussing the results in a press conference, Dee Dee Wang, MD (Henry Ford Health System, Detroit, MI), pointed to the difficulty of understanding the relative role of the polymer versus the design given not only the range of different stents included in the trial but also the uncertainty around stent implantation success—a point driven home in some of the intravascular imaging studies presented earlier at TCT this week.

“We might need to take a step back,” she said. “Is there really a standardization for checking all these new polymers, all these new stents for intraprocedural outcomes? Should IVUS be the intraprocedural standardization for each, pre and post?”

Kim et al’s trial compared “buckets” of different stent types but isn’t large enough to look at results broken down according to individual stent designs. “Having buckets of so many stent frame designs might make it impossible to do a RCT big enough,” she pointed out. “In all honestly, then, are we doing enough optimization and standardization . . . before we test the next new coating?”

Taking the whole category of degradable coatings out of the mix might be one way to simplify this question. Asked by TCTMD whether it might be time to stop the development of bioresorbable-polymer stents, Kim said, “Personally, I think so, [although] this study did not confirm the superiority of durable-polymer DES to degradable one. The bottom line is that when you choose a DES for a given patient, you have to consider strut thickness and deliverability, guaranteeing no scratch on the surface drug or no deformation of the stent during deployment, rather than the polymer issue.” 

Following Kim’s “Main Arena” presentation, session moderator Marie-Claude Morice, MD (Ramsay Générale de Santé, Massy, France), congratulated Kim and his co-investigators. “You have remarkable results in both arms: stent thrombosis is extremely low and TLR is extremely low. That’s my [take-home] note—that patients are doing better and better, and the ones that were in your trial had a wonderful outcome whatever stent they received.”

Panelists hashed over other explanations for the neutral results including the range of devices and strut thicknesses included in the analysis, the relatively high proportion of diabetic patients in the study (~45%), the ethnic make-up of the trial, which was conducted at 35 Asian centers, or potentially issues of MI ascertainment.

Kim pushed back politely on this last point, noting that while ascertainment shortfalls are a possibility, trialists performed regular mandatory follow-up over the course of the study as well as rigorous site audits. Moreover, the nonfatal MI rates of 0.6% and 0.8% for the durable- and degradable-polymer groups, respectively, mirror those of another Asian trial, STOP-DAPT2. “I think the low instance of stent thrombosis and myocardial infarction [in our trial] may be derived by the high prevalence of IVUS usage, not underreporting,” he said.