Polymer-Free DES Hold No Long-term Advantage: ISAR-TEST-5

A little more than a decade after implantation, patients with mostly stable and unstable angina do similarly well no matter whether their drug-eluting stent did or did not have a polymer, according to results from ISAR-TEST-5.

The device-oriented composite endpoint (DOCE) occurred in 43.8% of patients treated with a polymer-free sirolimus- and probucol-eluting stent (ISAR VIVO; Translumina Therapeutics, and Coroflex ISAR; B. Braun) and 43.0% of those treated with the durable-polymer zotarolimus-eluting stent (Resolute; Medtronic), a nonsignificant difference.

Sebastian Kufner, MD (Deutsches Herzzentrum, Munich, Germany), who led the study published online ahead of the July 14, 2020, issue of the Journal of the American College of Cardiology, said they had expected results to favor the polymer-free DES over the longer-term follow-up.

“In the end, we didn’t see any difference between this polymer-free technology and the permanent-polymer device at all,” he said. “On the one hand, that’s quite disappointing because there was no additional benefit, but on the other hand it also means that with these new-generation drug-eluting stents, the polymer-free drug-eluting stent does have the same safety and efficacy as a current benchmark stent, which is good news.” 

The polymer-free stent technology was developed given concerns about the long-term consequences of the durable-polymer coating that remains after the drug is released. Delayed arterial healing and de novo atherosclerosis within the stented segment were thought to be mediated partly by an inflammatory reaction to this coating. In ISAR-TEST-5, the rate of definite or probable stent thrombosis was very low and did not differ between the devices, including in a landmark analysis that focused on events from 1 to 10 years. From 12 months onward, the rate of stent thrombosis was 0.5% with the polymer-free DES and 0.7% with durable-polymer DES (P = 0.52).  

That the very late stent thrombosis rates fall below 1%, said Kufner, is “a very strong signal that the new drug-eluting stents we have currently on the market might have overcome the problem of late stent thrombosis which was a major problem for the earlier-generation drug-eluting stents.”

This cohort does represent daily clinical practice. It’s not a cherry-picked population with very good lesions. Sebastian Kufner

Eric Secemsky, MD (Beth Israel Deaconess Medical Center, Boston, MA), who wasn’t involved in the study, said technology has matured so much since the first introduction of DES that stent-related adverse events are extremely rare.

“There are a lot of histopathological reasons why polymers may be the cause of late events, such as stent thrombosis and neoatherosclerosis,” Secemsky told TCTMD. “The idea is that it might be some sort of inflammation and hypersensitivity to the polymer, as well as endothelial dysfunction. In theory, it makes a lot of sense, but then you try to translate that into clinical practice and it looks like, from this study, if there is a difference [between the stent technologies] it’s very small.”

While the polymer may portend risk for some patients, eliminating it does not appear to be clinically advantageous on a larger scale when compared with the durable-polymer Resolute DES, he added. “We’ve done so much to adjust the properties of the stent, and we really have fantastic stents on the market now,” said Secemsky.  

High Rate of Patient-Oriented Events

The ISAR-TEST-5 study included 2,002 patients treated with the polymer-free DES and 1,000 patients treated with Resolute. Patients in the trial were approximately 68 years old, more than three-quarters were men, and two-thirds had hypertension or hyperlipidemia. Roughly 30% had a prior MI and 10% had previous bypass surgery. In terms of clinical presentation, approximately 60% presented with stable angina, 30% with unstable angina, and 10% with acute MI.

Clinical outcomes at 12 months showed the novel polymer-free DES were noninferior to the Resolute device with respect to the primary endpoint of cardiac death, target-vessel MI, and target lesion revascularization. Rates of definite or probable stent thrombosis were also similar at 12 months. At 5 years, there still were no differences in the primary endpoint or risk of definite/probable stent thrombosis between the two devices.

At 10 years, complete follow-up was available for 1,696 patients treated with polymer-free DES and 857 treated with the durable-polymer Resolute stent. There was no difference in DOCE between the two stents, nor was there any difference in any of the individual components of the primary endpoint. Regarding the patient-oriented composite endpoint (POCE), which included all-cause mortality, any MI, or any revascularization, there was no difference in events between the polymer-free and durable-polymer DES (66.2% vs 67.7%, respectively; P = 0.22). At 10 years, 35.0% of patients given the polymer-free DES and 37.3% of patients given the Resolute stent had died (P = 0.16).

Overall, definite or probable stent thrombosis occurred in 1.6% of patients who received the sirolimus/probucol-eluting stent and 1.9% of those treated with the zotarolimus-eluting stent, a nonsignificant difference.

To TCTMD, Kufner pointed out that approximately 20% of patients treated with the polymer-free and durable-polymer DES required revascularization of the target lesion by 10 years, which he said is rather high. However, the vast majority of events were “any revascularization,” affecting 45.9% of patients treated with the polymer-free DES and 47.0% of those who received the durable-polymer device (P = 0.56). “Almost 50% of patients had another revascularization within the 10-year follow-up, and this underlines the importance for other strategies [for] secondary prevention as well as research into secondary prevention to address this issue,” he said.

Secemsky agreed, noting that while differences between the study arms were small, the total event rates were high. “We don’t really have a full handle on how to minimize the risk of cardiovascular disease and that’s apparent here,” he said. “We haven’t really figured out how to reduce risk outside of the stented area.”

He pointed to the DAPT Study testing different durations of dual antiplatelet therapy for reducing the risk of stent-related adverse events. That trial, however, also showed that dual antiplatelet therapy reduced spontaneous MI in nonstented vessels. “We might have really gotten to the plateau point where we’ve reduced stent-related adverse events to where we should now be focusing elsewhere,” Secemsky noted.

We haven’t really figured out how to reduce risk outside of the stented area. Eric Secemsky

In an editorial, Ori Ben-Yehuda, MD (Cardiovascular Research Foundation, New York, NY), makes a similar argument about the importance of secondary prevention.

“Stent technology has undoubtedly improved and will continue to evolve, but coronary atherosclerosis, the underlying process which drives coronary events, is a diffuse disease,” writes Ben-Yehuda. “Short of a full metal jacket (with its own set of issues!), stenting, as currently practiced, only addresses ischemia-producing lesions, leaving behind potentially vulnerable plaques as well as lesions that may progress over time. Both in future research and in our clinical care, a holistic approach is therefore necessary to improve long-term outcomes, with specific choice of stent among modern-generation stents being of lesser importance.”

Regarding follow-up, Kufner noted that interventional trials testing different stent technologies are typically 1 to 3 years in duration, with some extended to 5 years, but very few go beyond that. “This is quite astonishing because we implant these devices in our patients and they go away with these stents and live with them for decades,” he said. “I think it’s important to have some studies with long-term follow-up to know where we are heading.” 

ISAR-TEST-5, its investigators say, included a rather broad selection of patients. They were typically older than in other trials and represented a higher-risk population. This likely explains the higher mortality rate when compared with other DES studies with 10-year follow-up, they suggest. “These patients were quite sick,” said Kufner. “There was a high percentage of patients with diabetes mellitus, with multivessel disease, and 40% presented with acute coronary syndrome. In some way, this cohort does represent daily clinical practice. It’s not a cherry-picked population with very good lesions.”