Intracoronary Stenting and Angiographic Results–Test Efficacy of 3 Limus-Eluting STents - ISAR-TEST-2

Apr 13, 2009
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Trial Sponsor:
Funded in part by the Bavarian Research Foundation.
Date Presented:
01/01/2008
Date Published:
01/01/2009
Date Updated:
04/13/2009
Original Posted Date:
04/13/2009
References

Description:

Studies indicate that the polymer involved in drug-eluting stents (DES) may be responsible for some of the adverse effects noted with these stents. Earlier studies with polymer-free DES, however, did not demonstrate an improved antistenotic efficacy over current polymer-based DES. The current trial sought to study the safety and efficacy of incorporation of a second antistenotic agent (probucol) in addition to rapamycin (sirolimus-eluting stents [SES]) on a polymer-free platform, compared with rapamycin and zotarolimus-eluting stents (ZES) with permanent polymer platforms.

Hypothesis:

A dual DES (polymer-free stent consisting of probucol and rapamycin) would be superior to SES and ZES in patients with coronary artery disease.

Study Design

Study Design:

Patients Enrolled: 1,007
Mean Follow Up: 12 months
Mean Patient Age: 67 years
Female: 24
Mean Ejection Fraction: 53%

Patient Populations:

  • Age >18 years
  • “De novo” lesions in native coronary arteries
  • Ischemic symptoms or objective evidence of ischemia in the presence of ≥50% de novo stenosis located in native coronary vessels
  • Written informed consent

Exclusions:

  • Target lesion in the left main or bypass graft
  • Cardiogenic shock
  • Comorbidities with a life expectancy <12 months
  • Contraindication to aspirin, limus agents, probucol, stainless steel, thienopyridines
  • In-stent restenosis
  • Pregnancy

Primary Endpoints:

In-segment binary angiographic restenosis (≥50%) at 6-8 month follow-up angiogram

Secondary Endpoints:

  • In-stent late luminal loss
  • Need for target lesion revascularization due to restenosis in the presence of symptoms or signs of ischemia
  • Composite of death and MI
  • Incidence of stent thrombosis

Drug/Procedures Used:

Percutaneous coronary intervention (PCI) with dual DES, SES, or ZES in a 1:1:1 fashion

Concomitant Medications:

All patients received a loading dose of 600 mg of clopidogrel at least 2 hours prior to the intervention. All patients also received 500 mg of aspirin, and unfractionated heparin up to a total amount of 140 U/kg. After the intervention, all patients received 200 mg/day aspirin indefinitely, clopidogrel 150 mg for the first 3 days (or until discharge), followed by 75 mg/day for at least 6 months.

Principal Findings:

A total of 1,007 patients were randomized, 333 to dual DES, 335 to SES, and 339 to ZES. Baseline characteristics were fairly similar between the three groups. About 28% of the patients had diabetes. PCI was performed for stable angina in 58% of the patients, for unstable angina in about 27%, and for ST-elevation myocardial infarction (STEMI) in about 13% of the patients. The left anterior descending artery was the target vessel in about 45% of the patients, and multivessel disease was noted in most (83%) of the patients. Chronic total occlusions were present in 12% of the patients, and about 73% of the lesions were considered complex lesions. The reference vessel diameter was about 2.7 mm, with a mean lesion length of about 14.5 mm.

The primary endpoint of binary angiographic restenosis at 6-8 months was noted less frequently with the dual-DES (11.0%) compared with SES (12.0%) and ZES (19.3%) (p = 0.003 for all; p = 0.68 dual-DES vs. SES; p = 0.002 for dual-DES vs. ZES). Similarly, in-stent late lumen loss was lower with dual-DES (0.23 vs. 0.24 vs. 0.58 mm, p < 0.001 for all; p = 0.78 for dual-DES vs. SES; p < 0.001 for dual-DES vs. ZES). This corresponded to a lower incidence of target lesion revascularization at 12 months with dual-DES at 12 months (6.8%) compared with ZES (13.6%) (p = 0.001), but not SES (7.2%) (p = 0.83). The incidence of death (2.4% vs. 2.7% vs. 3.5%, p = 0.66), MI (4.2% vs. 3.6% vs. 3.2%, p = 0.8), and definite stent thrombosis (0.9% vs. 0.9% vs. 0.6%, p = 0.87) was similar between the three arms.

Interpretation:

The results of the ISAR-TEST-2 trial indicate that outcomes with a dual-DES consisting of two anti-restenotic agents, probucol and rapamycin, on a polymer-free platform, are similar to those with a rapamycin/SES, and superior to those with a ZES, both of which are permanent polymer based. These results are similar to those of the ISAR-TEST and ISAR-TEST-3 trials, which demonstrated the noninferiority of the same dual-DES in comparison with both polymer-based PES and SES.

It is unclear if this benefit is from the probucol by itself, or due to its interaction with rapamycin. These preliminary data are definitely encouraging, but further long-term safety data are necessary before these stents can be considered for routine practice. The optimal duration of dual antiplatelet therapy with these newer stents will also need to be defined.

References:

Byrne RA, Mehilli J, Iijima R, et al., on behalf of the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting STents (ISAR-TEST-2). A polymer-free dual drug-eluting stent in patients with coronary artery disease: a randomized trial vs. polymer-based drug-eluting stents. Eur Heart J 2009;Feb 24:[Epub ahead of print].

Presented by Dr. Robert A. Byrne at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2008), Washington, DC, October 2008.

Keywords: Myocardial Infarction, Angina, Stable, Coronary Restenosis, Drug-Eluting Stents, Constriction, Pathologic, Sirolimus, Percutaneous Coronary Intervention, Thrombosis, Polymers, Informed Consent, Probucol, Diabetes Mellitus


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