TAXUS I - TAXUS I

Description:

The goal of this trial was to assess the efficacy of the paclitaxel coated slow-release versus bare stent for treatment of de novo or restenotic lesions (<=12 mm).

Hypothesis:

To evaluate the safety and feasibility of the TAXUS paclitaxel coated slow-release NIRx stent system compared with bare NIR stents for treatment of coronary lesions.

Study Design

Study Design:

Patients Enrolled: 61
Mean Follow Up: 30 days

Patient Populations:

Lesion length <=12 mm, 50-99% diameter stenosis, and vessel diameter 3.0-3.5 mm.

Exclusions:

History of acute MI; LVEF <30%; stroke within 6 months; renal dysfunction (serum creatinine >1.7 mg/100 mL); contraindication to aspirin, clopidogrel, or ticlopidine; or target lesions requiring >1 study stent for full coverage.

Primary Endpoints:

MACE at 30 days (all-cause death, Q-wave MI, target vessel revascularization, and stent thrombosis)

Secondary Endpoints:

MACE at 6 and 12 months, IVUS at 6 months. Angiographic endpoints at 6 months: binary restenosis (i.e., >50% diameter stenosis); reference vessel diameter (RVD); MLD; percent diameter stenosis (%DS); late lumen loss; and late loss index.

Drug/Procedures Used:

Paclitaxel-eluting slow-release NIRx stent (n=31) versus bare NIR stent (n=30) for treatment of de novo or restenotic lesions (<=12 mm). Stents were deployed according to conventional techniques with intravascular ultrasound (IVUS) guidance.

Concomitant Medications:

Prestenting, patients were treated with aspirin (>80 mg), clopidogrel (300 mg), and heparin (to maintain ACT >=250 sec). After stenting, patients were treated with aspirin (>80 mg/d) for >=12 months and clopidogrel (75 mg/d) for 6 months.

Principal Findings:

The majority of patients had de novo lesions (n=59), and only 2 had restenotic lesions. Coated stents tended to more frequently be implanted in left anterior descending (LAD) lesions (54.8% LADs in coated stent arm versus 26.7% in bare stent arm, p=0.090). The primary endpoint of 30-day major adverse cardiac events (MACE) did not occur in either treatment arm (0%). By 6 months, the MACE rate was 0% in the coated stent arm versus 7% (n=2) in the bare stent arm (p=NS) and at 12 months 10% versus 3% (p=NS). At 6-month angiography, the coated stent arm had larger minimal lumen diameters (MLDs) (2.60 versus 2.19 mm, p=0.007), smaller percent stenosis (13.6% versus 27.2%, p<0.001), and smaller late lumen loss (0.36 mm vs 0.71 mm, p=0.008). On 6-month IVUS, mean minimal lumen area was larger in the coated stent arm (5.6 vs 4.8 mm2, p=0.027), and neointimal hyperplasia was reduced (14.8 vs 21.6 mm3 p=0.028).

Interpretation:

Among patients with de novo or restenotic lesions <=12 mm, treatment with TAXUS I paclitaxel coated slow-release stent showed no difference in the primary endpoint of 30 day MACE compared with treatment with a bare stent. Albeit small, TAXUS I was the first randomized, multicenter trial of paclitaxel-eluting stents in humans. No benefit in MACE was observed through 12 months; however, both angiographic and IVUS endpoints were improved with the paclitaxel-eluting stent. Based on the safety and feasibility of the results in TAXUS I, additional larger randomized TAXUS studies are underway to evaluate the efficacy of paclitaxel-eluting stents.

Expert Opinion by Joseph P. Carrozza, Section Chief of Interventional Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, Harvard Medical School
Not since the advent of endovascular stenting has there been more enthusiasm for a breakthrough technology, as we are experiencing with the drug-eluting stents. Despite superior safety and efficacy compared with balloon angioplasty alone, restenosis remains the “Achilles heel” of stenting as well as all other endoluminal therapies.

Recently the large SIRIUS trial demonstrated an 83% reduction in late loss with the sirolimus-eluting stent compared to the bare velocity stent. Sirolimus blocks the progression of the smooth muscle cell from G phase to S phase by raising levels of a cyclin-dependent kinase inhibitor p27. This led to a 90% reduction in in-stent restenosis and a 75% reduction in in-lesion restenosis. More importantly target lesion revascularization was reduced from 19.2% to 6.4%. This affirmed that in-situ delivery of sirolimus safely and profoundly profoundly inhibits neointimal hyperplasia and improves clinical outcome.

In the current issue of Circulation, Grube and colleagues report the 6 and 12 month clinical and angiographic results from the TAXUS I trial, a randomized double-blind study of a polymeric, slow-release paclitaxel-eluting stent for the treatment of de novo coronary lesions. Paclitaxel is a lipophilic taxane derivative that targets the mitosis phase of the cell cycle, by interfering with microtubule assembly and disassembly. This 61-patient TAXUS I trial served as the “first in human” clinical evaluation of a polymer-based paclitaxel-eluting stent. Angiographic restenosis was reduced from 10% to 0% in lesions treated with the drug-eluting stent. Late lumen loss was reduced from 0.71 mm to 0.036 mm, and no subacute thromboses were observed.

It is important to remember that the relatively low incidence of diabetes mellitus, exclusion of stents smaller than 3 mm, and a mean lesion length of approximately 11 mm predict a relatively low rate of restenosis in both groups. This is supported by a restenosis rate of only 10% for patients treated with the NIR stent.

Recently, preliminary data from the larger TAXUS II trial were reported and demonstrated a similar reduction in late loss and binary restenosis from 22% to 5.5%. Thus, any comparisons to the much larger SIRIUS trial, in which longer lesions in smaller vessels were treated in a cohort with a higher incidence of diabetes mellitus, would be inappropriate. Nevertheless, the results of this feasibility trial are encouraging and suggest that when paclitaxel is delivered locally via a polymer coated stent, a profound reduction in new intimal hyperplasia can be achieved. More importantly, the absence of adverse events such as subacute stent thrombosis suggests that one does not have to sacrifice safety for long-term biologic efficacy.

The interventional community eagerly awaits the results from the TAXUS IV study, in which a larger number of patients with more complex lesions were randomized to either the bare or the paclitaxel-eluting Express stent. If the results of TAXUS IV are consistent with those of the TAXUS I and II, then a second class of drugs may be added to the interventionalist’s armamentarium.

References:

Circulation. 2003;107:38-42.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Interventions and Coronary Artery Disease

Keywords: Mitosis, Coronary Artery Disease, S Phase, Drug-Eluting Stents, Sirolimus, Constriction, Pathologic, Hyperplasia, Angioplasty, Balloon, Coronary, Paclitaxel, Microtubules, Expert Testimony, Polymers, Myocytes, Smooth Muscle, Thrombosis, Biological Products, Diabetes Mellitus, Cyclin-Dependent Kinase Inhibitor p27


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