ISAR-TEST 5 Published: Polymer-Free Dual DES Noninferior to Resolute
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A polymer-free drug-eluting stent (DES) that releases both sirolimus and probucol is equivalent to a new-generation, permanent-polymer zotarolimus-eluting stent with regard to hard clinical endpoints out to 12 months and angiographic endpoints at 6 to 8 months, according to results from the ISAR-TEST 5 trial published online July 18, 2011, ahead of print in Circulation.
Data from the ISAR-TEST 5 (Intracoronary Stenting and Angiographic Results: Test Efficacy of Sirolimus- and Probucol-Eluting Versus Zotarolimus-Eluting Stents 5) trial were first presented in September 2010 at the annual Transcatheter Cardiovascular Therapeutics symposium in Washington, DC.
In the trial, the zotarolimus-eluting Resolute stent (Medtronic Cardiovascular, Santa Clara, CA), featuring a permanent polymer on a cobalt-chromium alloy platform, was compared with the “Dual DES.” This stent consists of a microporous, thin-strut stainless steel platform coated with a resin-based mix of sirolimus and probucol, and no polymer.
For ISAR-TEST 5, researchers led by Steffen Massberg, MD, of Deutsches Herzzentrum (Munich, Germany), randomized 3,002 patients at 2 German centers to treatment with either the Dual DES (n = 2,002) or Resolute (n = 1,000) stents. The only major exclusion criteria were left main lesions and cardiogenic shock. Dual antiplatelet therapy was recommended for at least 6 months. More than 1 lesion was treated in over a third of patients in each group (P = 0.26). Other baseline and procedural characteristics were similar, with the exception of MLD post procedure and total stent length, which were both higher in the Resolute group (P = 0.04 and 0.01, respectively).
At 1 year, the composite of cardiac death, target vessel MI, or TLR (primary endpoint) was equivalent in both groups (P for noninferiority = 0.006). Other clinical outcomes such as all-cause death, MI, TLR, and definite or probable stent thrombosis were also similar (table 1).
Table 1. Outcomes at 1 Year
|
Dual DES |
Resolute |
P Value |
Primary Endpoint |
13.1% |
13.5% |
0.74 |
All-Cause Death |
3.6% |
4.7% |
0.13 |
MI |
3.9% |
3.8% |
0.91 |
TLR |
10.3% |
10.4% |
0.94 |
Definite/Probable Stent Thrombosis |
1.1% |
1.2% |
0.80 |
On angiography at 6 to 8 months (76.3% participation), the Dual DES continued to show similar results to Resolute with regard to endpoints including in-segment binary restenosis, in-stent MLD, and in-stent late lumen loss (table 2).
Table 2. Angiographic Outcomes at 6 to 8 Months
|
Dual DES |
Resolute |
P Value |
In-Segment Restenosis |
13.3% |
13.4% |
0.95 |
In-Stent MLD, mm |
2.23 ± 0.70 |
2.28 ± 0.68 |
0.07 |
In-Stent Late Lumen Loss, mm |
0.31 ± 0.58 |
0.30 ± 0.56 |
0.50 |
There was no interaction between treatment effect with either stent and any subgroup defined by age, sex, diabetes, or vessel size. Neither was there any interaction between outcome and enrolling center or periprocedural antithrombotic therapy.
“This is the first demonstration of clinical efficacy of a novel DES which uses a dual-drug combination and no polymer,” the researchers write. “The demonstration of excellent clinical outcomes in a broadly inclusive patient population without recourse to durable polymer coatings may represent an important development in DES technology.”
In an e-mail communication with TCTMD, Dr. Massberg indicated that he was not surprised by the results. “ISAR-TEST 5 was a clinical confirmation of the good angiographic results seen with the polymer-free dual drug eluting stent in the smaller sized ISAR-TEST 2 trial,” which compared the Dual DES with the sirolimus-eluting Cypher (Cordis, Miami Lakes, FL) and zotarolimus-eluting Endeavor (Medtronic) stents.
Probucol Lends Sirolimus a Hand
Dr. Massberg said it is not entirely clear how the antioxidant probucol contributes to the Dual DES’s efficacy. “Probucol is one of very few drugs shown to reduce restenosis after plain PTCA,” he said. “However, we do not know whether its antioxidant action is strong enough to contribute additional benefits on top of those achieved by sirolimus in the setting of this particular DES. It is more than likely that the main effect of probucol is the induction of a slower, more effective sirolimus release kinetic.”
David E. Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA), agreed. “They used probucol because it’s very lipophilic,” he told TCTMD in a telephone interview. “It’s basically the carrier for the drug. It helps facilitate absorption of the drug into the vessel wall and drug retention in the vessel itself. That’s the purpose of the probucol.”
In terms of the overall results, “the big picture is you’ve got a nonpolymeric stent that seems to perform clinically as efficaciously as a biopermanent polymer DES with similar safety,” he said.
However, “is ‘as good as’ good enough?” Dr. Kandzari asked, especially when “with Xience and Resolute, for instance, which are biopermanent polymer stents, we’re now seeing some of the best outcomes we’ve ever observed in DES trials.”
True Value of Dual DES Based on Intuition
Moreover, the main proposed advantage of a nonpolymer or bioabsorbable polymer DES is thought to stem from its ability to reduce stent thrombosis risk and thereby shorten the duration of dual antiplatelet therapy.
“This is the most attractive hypothesis underlying the development of this novel DES,” Dr. Massberg said. “However, studies with longer follow-up and differential duration of dual antiplatelet therapy are required to provide supportive evidence for the enthusiasm that currently surrounds polymer-free DES technology.”
“The intuition is if you don’t have the polymer, there may be less hypersensitivity, positive remodeling, and potentially less stent thrombosis or the opportunity for abbreviated dual antiplatelet therapy,” Dr. Kandzari said. “It all sounds great, and it seems intuitive, but should these devices be adopted [based on] intuition alone?”
Companies ‘Riding in the Peloton’
He noted that of the various companies developing nonpolymer or bioresorbable polymer DES, none are currently initiating studies to prove this hypothesis. “Everybody’s riding together in the peloton, to use a Tour de France reference. Everybody’s looking at each other waiting for somebody to make a break,” Dr. Kandzari said. “Once somebody with a new technology actually proves its value, then others will quickly race to catch up.”
Regardless of when this happens, the technology does show promise, he added. “I do think the next generation of drug-eluting stents will be either polymer free or have bioresorbable polymer,” Dr. Kandzari said. “This is clearly the direction we’re moving in. The interventional community is showing that there’s still going to be a persistent need for metallic stent-based platforms, but stents without polymers or bioresorbable ones will become more the standard, even if the standard might not be scientifically proven yet.”
Source:
Massberg S, Byrne RA, Kastrati A, et al. Polymer-free sirolimus- and probucol-eluting versus new generation zotarolimus-eluting stents in coronary artery disease. The Intracoronary Stenting and Angiographic Results: Test Efficacy of Sirolimus- and Probucol-Eluting Versus Zotarolimus-Eluting Stents 5 (ISAR-TEST 5) trial. Circulation. 2011;Epub ahead of print.
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Jason R. Kahn, the former News Editor of TCTMD, worked at CRF for 11 years until his death in 2014…
Read Full BioDisclosures
- Funding was provided in part by the Bavarian Research Foundation and by the European Union.
- Dr. Massberg reports no relevant conflicts of interest.
- Dr. Kandzari reports receiving research and grant support from and serving as a consultant for Abbott Vascular, Medtronic, and Micell Technologies.
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