Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents-4 - ISAR-TEST 4

Description:

The goal of the trial was to evaluate the efficacy and safety of percutaneous coronary intervention (PCI) using a biodegradable polymer drug-eluting stent (DES) compared with the permanent polymer-based DES (Cypher or Xience) among patients with stable coronary disease or acute coronary syndromes (ACS) with de novo native-vessel stent implantation.

Hypothesis:

PCI with biodegradable polymer DES would be noninferior to PCI with a permanent polymer-based DES with regard to the composite endpoint of cardiac death, myocardial infarction (MI) related to the target vessel, or target lesion revascularization (TLR) at 12 months among patients undergoing de novo native-vessel stent implantation.

Study Design

  • Randomized
  • Blinded
  • Parallel
  • Stratified

Patients Enrolled: 2,603
Mean Follow Up: 1 year; subanalysis 2 years
Mean Patient Age: 67 years
Female: 24%
Mean Ejection Fraction: Mean 53%

Patient Populations:

  • Ischemic symptoms or evidence of myocardial ischemia in the presence of ≥50% de novo stenosis in a native coronary artery

Exclusions:

  • Cardiogenic shock
  • Target lesion in the left main stem
  • Malignancies with life expectancy <1 year
  • Allergy to study medication

Primary Endpoints:

  • Composite of cardiac death, MI related to the target vessel, or revascularization related to the TLR at 1 year, evaluated for noninferiority

Secondary Endpoints:

  • In-segment binary restenosis at follow-up angiography
  • In-stent late lumen loss; all-cause mortality
  • Definite/probable stent thrombosis by ARC definition

Drug/Procedures Used:

Patients were randomized in an open-label manner to stenting with the biodegradable polymer DES (rapamycin-eluting; n = 1,299) or permanent polymer DES (n = 1,304; rapamycin-eluting Cypher, n = 652; or everolimus-eluting Xience, n = 652). Repeat angiography was performed at 6-8 months.

Concomitant Medications:

  • Prior to PCI: clopidogrel 600 mg and aspirin 500 mg
  • Post PCI: clopidogrel 150 mg daily until discharge and 75 mg daily thereafter for at least 6 months; aspirin 200 mg daily indefinitely

Principal Findings:

The majority of patients underwent PCI for stable angina (59%), followed by unstable angina (29%) and acute MI (12%). At study entry, multivessel disease was present in 86% of patients; multilesion intervention was performed in 28.9% of the biodegradable polymer group and 26.1% of the permanent polymer group (p = 0.11). The target vessel was the left anterior descending artery in 44.5% of patients, left circumflex artery in 27%, and right coronary artery in 29%. The majority of patients (72%) had complex morphology (B2/C lesions).

Clinical outcomes at 30 days did not differ between groups, with cardiac death, MI related to the vessel, or TLR occurring in 4.4% of the biodegradable polymer group and 4.5% of the permanent polymer group (p = 0.87). There were five cases of definite stent thrombosis in each group (0.4%). At the 6- to 8-month follow-up angiography, there was no difference between groups in in-stent late lumen loss (p = 0.49) or in-segment binary restenosis (p = 0.85).

The primary endpoint of cardiac death, MI related to the target vessel, or TLR at 12 months, which occurred in 13.8% of the biodegradable polymer group and 14.4% of the permanent polymer group, met the criteria for noninferiority between the groups (relative risk [RR] 0.96, 95% confidence interval [CI] 0.78-1.17, p-noninferiority = 0.005; p-superiority = 0.66). Among the individual components of the composite, cardiac death occurred in 2.8% and 3.2%, respectively (RR 0.85, 95% CI 0.54-1.33); MI related to the target vessel in 4.1% and 3.6%, respectively (RR 1.16, 95% CI 0.78-1.71); and TLR in 8.8% and 9.4%, respectively (RR 0.93, 95% CI 0.72-1.21). Frequency of ARC definite/probable stent thrombosis at 1 year was similar between the groups (1.0 vs. 1.5%, respectively; RR 0.68; 95% CI 0.34-1.38; p = 0.29). Results for the primary endpoint were consistent in both the group of DES patients treated with the Cypher stent (15.2%, RR 0.90, 95% CI 0.71-1.16 vs. the biodegradable polymer group) and the group treated with the Xience stent (13.6%, RR 1.01, 95% CI 0.78-1.31 vs. the biodegradable polymer group).

In a subanalysis, outcomes were compared between 652 patients treated with EES and 652 treated with SES. At 2 years, the incidences of cardiac death, target vessel MI, and TLR were similar between the EES and SES arms (16.0% vs. 18.8%, RR 0.85, 95% CI 0.65-1.11, p = 0.23). Similarly, all-cause mortality (6.4% vs. 6.7%, p = 0.75), definite or probable stent thrombosis (1.4% vs. 1.9%, p = 0.52), and target lesion revascularization (9.9% vs. 13.5%, p = 0.06) were similar between the EES and SES arms, respectively. In the subgroup of patients who did not have TLR at 6-8 months, angiographic follow-up was available for 70% of patients, and binary restenosis seemed to be higher in the SES arm at 2 years, as compared with EES (16.9% vs. 12.7%, p = 0.03). Late lumen loss was similar at 2 years (0.29 mm vs. 0.31 mm, p = 0.59).

Three-year results: The incidence of the primary endpoint was similar between the biodegradable and permanent polymer arms (20.1% vs. 20.9%, p = 0.59). Individual endpoints including all-cause mortality (9.3% vs. 9.8%, p = 0.71), target vessel MI (4.6% vs. 4.4%, p = 0.77), and TLR (13.9% vs. 14.2%, p = 0.79) were also similar between the two arms. ARC defined definite/probable stent thrombosis (1.2% vs. 1.7%, p = 0.32), and definite stent thrombosis (0.7% vs. 1.0%, p = 0.39) were both similar at 3 years.

In the EES versus SES subanalysis, the primary endpoint was similar at 3 years (19.6% vs. 22.3%, p = 0.26), as were all-cause mortality (9.3% vs. 10.3%, p = 0.57), TLR (12.8% vs. 15.5%, p = 0.15), and definite or probable stent thrombosis (1.4% vs. 1.9%, p = 0.51).

Interpretation:

Among patients undergoing de novo native-vessel stent implantation with either stable coronary disease or ACS, PCI with a biodegradable polymer DES was noninferior to PCI with a permanent polymer-based DES with regard to the composite endpoint of cardiac death, MI related to the target vessel, or TLR at 12 months.

Currently approved DES are designed with a permanent polymer-based coating for drug loading and release. While these stents have proven efficacious in significantly reducing the need for repeat revascularization compared with bare-metal stents, the coating remains exposed to the coronary artery for an extended time, possibly delaying vascular endothelization. This delay in endothelization likely plays a role in the development of stent thrombosis. Different platforms are being developed in an attempt to prevent this concern, including fully biodegradable stent and polymer platforms, with mixed results. In the LEADERS trial, a biolimus-eluting biodegradable polymer DES was found to be noninferior to the permanent polymer Cypher DES. Results of these two trials show promise with this platform. One potential of such a platform is that long-term clopidogrel therapy may not be required with this type of DES if endothelization is not delayed and the risk of stent thrombosis presumably subsides. Further 2-year follow-up data on stent thrombosis and other endpoints are being collected in ISAR-TEST 4.

A subanalysis of patients receiving DES, EES, and SES seemed to demonstrate similar clinical outcomes at 2 years, although binary restenosis seemed to be lower in the EES arm of the angiography cohort. Although this trial was not powered for these analyses, these results are interesting, and represent one of the few head-to-head comparisons between first- and second-generation DES.

This is the largest trial comparing outcomes after biodegradable versus permanent polymer DES, and shows comparable outcomes at 3 years. These results are very encouraging, and represent an important advance in the field. Future studies will need to outline the optimal duration of antiplatelet therapy with biodegradable stents. Longer follow-up is also necessary.

References:

Byrne RA, Kastrati A, Massberg S, et al., on behalf of the ISAR-TEST 4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents) Investigators. Biodegradable Polymer Versus Permanent Polymer Drug-Eluting Stents and Everolimus- Versus Sirolimus-Eluting Stents in Patients With Coronary Artery Disease: 3-Year Outcomes From a Randomized Clinical Trial. J Am Coll Cardiol 2011;58:1325-1331.

Byrne RA, Kastrati A, Kufner S, et al. Randomized, non-inferiority trial of three limus agent-eluting stents with different polymer coatings: the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Trial. Eur Heart J 2009;Aug 30:[Epub ahead of print].

Presented by Dr. Julinda Mehilli at the European Society of Cardiology Congress, Barcelona, Spain, August 2009.

Presented by Dr. Robert Byrne at the Transcatheter Cardiovascular Therapeutics Meeting (TCT 2010), Washington, DC, September 24, 2010.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Chronic Angina

Keywords: Risk, Myocardial Infarction, Follow-Up Studies, Angina, Stable, Coronary Restenosis, Drug-Eluting Stents, Ticlopidine, Sirolimus, Constriction, Pathologic, Angioplasty, Balloon, Coronary, Percutaneous Coronary Intervention, Thrombosis, Confidence Intervals


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