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ISAR TEST 4: Two-year Clinical Outcomes from a Randomized Trial of Biodegradable Polymer Drug-Eluting Stents Versus Permanent Polymer Cypher and Xience Drug-Eluting Stents

Cardiovascular Surgery
Interventional Cardiology and Cardiovascular Surgery

Robert Byrne
Presenter | see Discussant report Webcasts become available 24h after the presentation
Byrne, Robert
Open presentation slides

List of Authors:
Robert A. Byrne, MB BCh; Adnan Kastrati, MD; Klaus Tiroch, MD; Steffen Massberg, MD; Anna Wieczorek; Karl-Ludwig Laugwitz, MD; Stefanie Schulz, MD; Jürgen Pache, MD; Massimiliano Fusaro, MD; Melchior Seyfarth, MD; Albert Schömig, MD; Julinda Mehilli, MD for the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Investigators



Biodegradable polymer drug-eluting stent (DES) platforms have potential to enhance long-term outcomes following percutaneous intervention. In the setting of the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) trial we previously reported that a biodegradable polymer rapamycin-eluting stent demonstrated similar clinical efficacy to permanent polymer rapamycin-eluting and everolimus-eluting stents at 12 months.


As the hypothesized benefit of biodegradable polymer DES is first expected to accrue late after intervention, the objective of the current analysis is to examine clinical and angiographic outcomes out to 2 years.


Patients presenting with stable coronary disease or acute coronary syndromes undergoing DES implantation in de novo native-vessel coronary lesions were randomly assigned to treatment with biodegradable polymer (rapamycin-eluting; n=1299) or permanent polymer (n=1304; rapamycin-eluting [Cypher] or everolimus-eluting [Xience]) stents. The primary endpoint was target lesion failure: a device-orientated composite of cardiac death, myocardial infarction (MI) related to the target vessel, or revascularisation related to the target lesion (TLR).


The incidence of adverse events between 1 and 2 years was low in both treatment groups. At 2 years the composite of cardiac death/MI related to the target vessel was 7.1% with biodegradable polymer DES versus 7.2% with permanent polymer DES (relative risk = 0.98, 95% CI, 0.76-1.31; P=0.89). The rate of definite/probable stent thrombosis was 1.1% with biodegradable polymer DES versus 1.7% with permanent polymer DES (relative risk = 0.67, 95% CI, 0.34-1.31; P=0.24). In terms of antirestenotic efficacy, biodegradable polymer and permanent polymer DES demonstrated comparable rates of incident TLR (Δ2.2% versus Δ2.3%; P=0.79) and binary angiographic restenosis (Δ3.9% versus Δ3.0%; P=0.19) between years 1 and 2. Overall there was no significant differences between biodegradable polymer DES and permanent polymer DES concerning the incidence of the primary endpoint at 2 years (16.4% versus 17.4%, relative risk = 0.94, 95% CI, 0.78-1.13; P=0.51)


Biodegradable polymer and permanent polymer DES are associated with similar clinical outcomes at 2 years. The hypothesised late performance advantage of biodegradable polymer DES platforms remains unproven at least up to 2 years.

Jean Marco, FESC
Discussant | see Presenter abstract Webcasts become available 24h after the presentation
Marco, Jean
Open presentation slides


Biodegradable polymer coatings offer the attractive prospect of control of drug delivery without the long-term sequelae of polymer residue.
ISAR-TEST-4 is randomised trial that aims to answer one important question:
“can the late adverse clinical events related to delayed arterial healing and/or inflammatory response observed after implantation of first-generation DES with permanent polymer coatings (namely Cypher and Taxus stents) be resolved by biodegradable polymer sirolimus- eluting technology whilst maintaining the same anti-restenosis efficacy?”

ISAR-TEST-4 compares the clinical outcome of a group of patients treated with one biodegradable polymer DES (rapamycin-eluting; n = 1299) and a group of patients treated with two FDA-approved permanent polymer DES (rapamycin-eluting: sirolimus-eluting Cypher, n= 652 patients and everolimus-eluting Xience, n= 652 patients).
It is a non-inferiority trial with a predefined ∆= 3% for a composite of clinical outcome as primary endpoint and a sample size calculation of 2600 patients. Because of the nature of the events related to the permanent polymer and some uncertainties concerning the duration and long-term clinical efficacy/safety of biodegadable polymer technologies, very long-term clinical follow-up is mandatory.

The conclusions of the ISAR-TEST-4 at two-year clinical follow-up are clear:
  • The overall rate of composite clinical events did not differ between the group of patients treated with biodegradable polymer rapamycin-eluting stent (Yucon stent) and patients treated with permanent polymer DES (Cypher or Xience).
  • The long term efficacy expressed by the need for late (after 1 year) target lesion revascularisation (2.2% and 2.3% respectively) did not differ.
  • The rates of cardiac death/MI (7.1% and 7.2% respectively) and stent thrombosis (1.1% and 1.7% respectively at two years compared to 1.0% and 1.5% respectively at one year) in both groups were low, and therefore, this trial is not powered to express any comments on these hard endpoints.

Long term difference in safety of DES is difficult to demonstrate by conducting randomised clinical trials. It is important to underline that some comparative data on the rate of stent thrombosis, derived from randomised trials presented (most often by industry) as evidence of greater safety are only hypothesis with a high hazard ratio risk.
A randomised trial powered to demonstrate non inferiority or superiority of safety of one DES versus another, based on hard endpoints (death/MI or stent thrombosis), would be unfeasibly large.


The permanent polymer of the Cypher and Xience stents are different.
The late inflammatory response related to polymer has been demonstrated after autopsy by Renu Virmani in patients treated with Cypher stents but not with Xience stents (some eosinophilic infiltration, not comparable, nothing like Cypher, comment from Renu Virmani). Therefore, the low rate of late definitive/probable stent thrombosis in the group of patients treated with Cypher/Xcience may be influenced by the 50% of patients who received Xience stents.

However, at one year, comparison of the biodegradable polymer DES group versus the individual component subgroups of the permanent polymer DES group revealed no signal of performance difference: rate of cardiac death/MI related to target vessel/TLR with biodegradable polymer DES 13.8% vs. Cypher 15.2% and vs. Xience 13.6% (NS). This information is not available at 2 years but the global results are similar.
The mean lesion length was 15 mm, and the subgroup of patients with complex overlapped stent implantation was not predefined.

At autopsy, the late inflammatory events or delayed arterial healing was reported in patients receiving Cypher with long stent implantation or overlapped stents. It was not reported with other new generations of permanent polymers. As demonstrated in experimental animal studies with long-term follow-up the possible negative impact of permanent polymers is not related to all permanent polymers but seems to be more specific to some permanent polymers.


Therefore, the biodegradable polymer rapamycin-eluting stent Yucon is non-inferior to the two permanent polymer-based sirolimus-eluting (Cypher), or everolimus-eluting (Xience) in terms of clinical efficacy and safety over 2 years.
It is not possible to extend the conclusion of the ISAR-test 4 trial to all permanent or biodegradable polymers or to other DES with other biodegradable polymers.


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Clinical Trial Update I
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.