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.
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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