ISAR-TEST 4: Long-term data support benefits of new-generation DES

Sripal Bangalore

CHICAGO — New data from the ISAR-TEST 4 study show that new-generation drug-eluting stents, with either a permanent or biodegradable polymer, are associated with better outcomes at 10 years, as compared with an early-generation DES with a permanent polymer.

“New-generation DES offer the potential for enhanced late outcomes in comparison with early-generation DES,” researcher Sebastian Kufner, MD, from Deutsches Herzzentrum, Munich, said during the American Heart Association Scientific Sessions. “However, assessment of extended long-term outcomes for these devices is lacking, which is specifically true regarding the comparison between new-generation DES with biodegradable or permanent polymers. Extended long-term follow-up data, up to 10 years, of new-generation DES with different polymer-coating strategies remains a notable scientific gap.”

Long-term MACE, all-cause mortality

In the ISAR-TEST 4 trial, Kufner and colleagues randomly assigned patients in a 2:1:1 fashion to PCI with a new-generation sirolimus-eluting stent with a biodegradable polymer (Yukon Choice PC, Translumina; n = 1,299), a new-generation everolimus-eluting stent with a permanent polymer (Xience, Abbott Vascular; n = 652) or an early-generation SES with a permanent polymer (Cypher, Cordis; n = 652).

The primary endpoint was MACE, defined as a composite of all-cause death, MI and target lesion revascularization, at 10 years. Secondary endpoints included the individual components of the primary endpoint and definite or probable stent thrombosis at 10 years. Ten-year follow-up was available for 83% of the patients.

At 10 years, the incidence of MACE was different across treatment groups (P = .003), which was mainly driven by an 18% to 21% RR reduction with both new-generation DES vs. the early-generation DES. Specifically, when compared with the early-generation permanent-polymer SES (54.9%), the incidence of MACE was lower with both the new-generation biodegradable-polymer SES (47.7%; HR= 0.82; 98.3% CI, 0.69-0.96) and the new-generation permanent-polymer EES (46%; HR = 0.79; 98.3% CI, 0.65-0.96).

The incidence of MACE, however, was not significantly different with the new-generation biodegradable-polymer SES vs. the new-generation permanent-polymer EES (HR = 1.04; 98.3%, 0.87-1.24).

There was a difference in mortality across treatment groups (P = .02), which was also driven by lower mortality rates with both the new-generation biodegradable-polymer SES (31.8%; HR = 0.82; 95% CI, 0.7-0.97) and the new-generation permanent-polymer EES (30.3%; HR = 0.78; 95% CI, 0.64-0.95) vs. the early-generation permanent-polymer SES (37.2%).

Again, the difference in mortality rates between the new-generation biodegradable-polymer SES and the new-generation permanent-polymer EES was not statistically significant (HR = 1.05; 95% CI, 0.88-1.26).

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Kufner also said the increasing event rates during long-term follow-up between years 4 and 10 are worth highlighting.

Comparable clinical outcomes

Although rates of TLR were numerically lower with both new-generation DES in comparison with the early-generation DES, there were no statistically significant differences between groups.

The rates of definite or probable stent thrombosis at 10 years were also numerically lower with both new-generation DES vs. the early-generation DES, but the difference was not statistically significant, according to the data.

“Noteworthy are the comparably low event rates out to 10 years for definite or probable stent thrombosis, ranging from 1.8% with the new-generation biodegradable-polymer SES to 2.5% with the new-generation permanent-polymer EES to 3.7% with the early-generation permanent-polymer SES,” Kufner said.

In an overview of clinical outcomes at 10 years, Kufner said not only were there differences concerning MACE and all-cause mortality, there was also a difference in definite stent thrombosis, which derived from a more than twofold higher incidence with the early-generation DES, compared with both new-generation DES (P = .03).

Results for the primary endpoint were similar across prespecified subgroups based on age, sex and diabetes status. In intergroup comparisons, data generally favored both new-generation DES over the early-generation DES, but they were not significantly different when comparing the new-generation biodegradable-polymer SES with the new-generation permanent-polymer EES.

The ISAR-TEST 4 trial was an investigator-initiated trial conducted at two centers in Munich from 2007 to 2008. The study had broad inclusion criteria, Kufner said, and included patients with ischemic symptoms or evidence of myocardial ischemia in the presence of more than 50% stenosis in a native coronary artery. The main exclusion criteria were target lesion in the left main stem and in-stent restenosis.

Patients with complete follow-up were followed for a median of 10.6 years, whereas those with incomplete follow-up were followed for a median of 5.9 years.

Baseline characteristics were well-balanced among treatment groups, with a mean patient age of 66 years. About 30% of the population had diabetes and more than one-third presented with ACS.

In terms of lesion characteristics at baseline, the majority of those treated were in the left anterior descending artery. Lesion complexity was also high, according to Kufner, with more than 70% of patients having a lesion with a morphology of B2/C.

“In this unique analysis, new-generation DES are superior to early-generation DES in terms of clinical outcomes. The favorable outcome after new-generation DES is driven by increasing event rates over time in patients treated with early-generation DES,” Kufner said. “Both new-generation DES, with either biodegradable or permanent polymer, showed comparable clinical outcomes out to 10 years.”

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A need for continued improvement

To place the findings in context, Sripal Bangalore, MD, MHA, FACC, FAHA, FSCAI, professor of medicine, director of research of the cardiac catheterization laboratory and director of the Cardiovascular Outcomes Group in the Cardiovascular Clinical Research Center at NYU Langone Health, highlighted the number of problems seen with first-generation DES, including very late stent thrombosis, late acquired stent malapposition and late catch-up phenomenon.

“In other words, although these stents prevented restenosis early on, the risk of restenosis accrued after 1 year of follow-up,” Bangalore, who is also a Cardiology Today Next Gen Innovator, said during a discussion of the ISAR-TEST 4 results.

To solve these problems, physicians and researchers sought to make polymers more biocompatible and improve cording technology, leading to second-generation durable-polymer DES. The next steps, according to Bangalore, included development of biodegradable-polymer DES and polymer-free DES. All of these improvements in stent technology, he said, have led to improved outcomes.

The 1-year results of ISAR-TEST 4, published nearly a decade ago, provided a framework for testing the potential clinical advantage of biodegradable-polymer DES over the medium or long term, Bangalore said. Consequently, the researchers followed these 2,600 high-risk patients over 10 years for not just all-cause mortality, but many other important endpoints as well, he added.

“The results are very clear,” Bangalore said. “If you compare second-generation durable-polymer DES or biodegradable-polymer DES vs. first-generation durable-polymer DES, there is not only a significant reduction in MACE, but there is also a significant reduction in death and stent thrombosis. And, if we look at the other endpoints, they are numerically lower when compared with the first-generation durable-polymer DES.”

These data are actually consistent with meta-analyses of randomized trials and registries of medium-term follow-up, according to Bangalore. This trial, he noted, extends those results to 10-year follow-up.

“One take-home message is that improvement in stent design can have meaningful impact on hard outcomes, including death and/or MI,” he said.

The second important finding is that the biodegradable-polymer DES showed no late superiority over the second-generation durable-polymer DES, which is also consistent with meta-analyses of randomized trials of comparable strut thickness, according to Bangalore.

“This leads us to question, at least in certain health systems, whether the higher price tag of these stents is justified,” he said. “Finally, I want to emphasize that if we look at current-generation DES, after 1 year, the MACE rate accrues at a staggering rate of 3.3% per year, so we need to make continued progress in stent or scaffold technology and perhaps a focus beyond biodegradable polymer technology is warranted.” – by Melissa Foster

References:

Kufner S. LBS.06 – Late-Breaking Science in Coronary Revascularization. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Bangalore S. Circulation. 2018;doi:10.1161/CIRCULATIONAHA.118.038378.

Kufner S, et al. Circulation. 2018;doi:10.1161/CIRCULATIONAHA.118.038065.

Disclosures: Kufner reports no relevant financial disclosures. Bangalore reports he is a consultant for or serves on the advisory board of Abbott Vascular, Biotronik, Amgen and Pfizer, and he has received research grants from Abbott Vascular and the NHLBI.