TAXUS II - TAXUS II

Description:

This trial compares a paclitaxel-eluting coronary stent with a bare, uncoated stent in de novo lesions. The trial was conducted with two cohorts, a slow release paclitaxel-eluting stent (cohort 1) and a moderate release paclitaxel-eluting stent (cohort 2).

Hypothesis:

In-stent volume obstruction as assessed by intravascular ultrasound (IVUS) will be reduced with use of the paclitaxel-eluting coronary stent.

Study Design

Study Design:

Patients Enrolled: 536
Mean Follow Up: Five years (data presented through 24 months to date)
Female: 24

Patient Populations:

Standard risk de novo lesions, length ≤12 mm, and reference vessel diameter ≥3.0 mm and ≤3.5 mm

Primary Endpoints:

In-stent volume obstruction as assessed by IVUS at six months

Secondary Endpoints:

Clinical procedural success; MACE (cardiac death, MI, and TVR) at 30 days, six months, and years 1-5; TLR and TVR at six months; angiographic restenosis rate at six months; quantitative coronary angiography parameters at six months; and IVUS parameters at six months

Drug/Procedures Used:

Cohort 1: Patients were randomized triple-blind to the slow release paclitaxel-eluting stent (n=131) or to an uncoated stent (n=136).

Cohort 2: Patients were randomized triple-blind to the moderate release paclitaxel-eluting stent (n=135) or to an uncoated stent (n=134).

With the slow release formulation, the drug is released over the course of approximately one month; with the moderate release formulation, the majority of the drug is released within the first two days.

Concomitant Medications:

Aspirin ≥75 mg (loading dose and maintained indefinitely) and clopidogrel (loading dose 300 mg and 75 mg/d for six months)

Principal Findings:

The primary end point of in-stent volume obstruction as assessed by IVUS at six months was >60% lower in the paclitaxel-eluting stent arm in both the slow release cohort (7.9% vs. 23.2%, p<0.0001) and the moderate release cohort (7.8% vs. 20.5%, p<0.0001) compared with a bare stent.

At the six-month follow-up, in-stent restenosis was lower in the paclitaxel-eluting stent arm compared with the bare stent arm, with both slow release (2.3% vs. 17.9%, p=0.0002) and moderate release (4.7% vs. 20.2%, p<0.0001). However, restenosis at the proximal and distal edges did not differ from the control in either cohort.

Minimal lumen diameters (MLDs) were larger in the slow release paclitaxel-eluting stent arm in the stented segment (2.23 mm vs. 1.79 mm, p<0.0001), the proximal edge (2.40 mm vs. 2.23 mm, p=0.009), and the distal edge (2.19 mm vs. 2.07 mm, p=0.039). Similar results were seen in the moderate release cohort: stented segment (2.24 mm vs. 1.76 mm, p<0.0001), the proximal edge (2.37 mm vs. 2.19 mm, p=0.005), and the distal edge (2.22 mm vs. 2.06 mm, p=0.013). Late lumen loss was lower in the paclitaxel-eluting stent arm in both the slow release cohort (0.31 mm vs. 0.79 mm, p<0.001) and in the moderate release cohort (0.30 mm vs. 0.77 mm, p<0.001).

Major adverse cardiac events (MACE; cardiac death, myocardial infarction [MI], and target vessel revascularization [TVR]) at six months was lower in the paclitaxel-eluting stent arm in the slow release cohort (8.5% vs. 19.5%, p=0.013) and the moderate release cohort (7.8% vs. 20.0%, p=0.006), driven primarily by a target lesion revascularization (TLR) reduction (slow release [SR] 4.6% vs. 12.0%, p=0.043; moderate release [MR] 3.1% vs. 14.6%, p=0.002).

Similar results were observed at 12-month follow-up: MACE (SR 10.9%, MR 9.9%, bare 21.7%, p=0.002 for SR; p=0.0048 for MR); TLR (SR 4.7%, MR 3.8%, bare 14.4%, p=0.0035 for SR; p=0.001 for MR). There were no deaths through 12 months in the slow release or moderate release groups.

Interpretation:

The TAXUS II trial showed that multiple clinical, angiographic, and IVUS findings were associated with improvements with use of the slow and moderate release paclitaxel-eluting stents, including significant reductions in six-month restenosis, MLD, late lumen loss, and MACE. The reduction in MACE was primary driven by a reduction in TVR with no difference in death or MI.

These findings are similar to those reported in the recent SIRIUS and RAVEL trials, which used a sirolimus-eluting stent. The SIRIUS trial enrolled a somewhat more technically difficult cohort, with lesions 15-30 mm in length versus ≤12 mm in the TAXUS II and smaller vessels.

While clearly beneficial in the reduction of restenosis and in the need for TVR in the short-term, it is important to note that long-term data are not yet available. The 12-month data showed few additional events or revascularizations from six to 12 months in either the bare stent or the eluting stent arms, a period when the recommended clopidogrel use had been discontinued. However, it remains to be determined if the restenotic process is being permanently reduced or just delayed. Long-term data from trials such as this should help answer these remaining questions.

Additionally, the increased cost of drug-eluting stents and the impact on the health economic system remains to be determined, although the recent SIRIUS cost analysis suggests these devices may be cost-effective with regard to one-year costs. Finally, further study is needed regarding the efficacy of this drug-eluting stent in saphenous vein grafts, stent restenosis, acute MI, and vessels outside of the diameters evaluated.

References:

1. Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, Guagliumi G, Russell ME. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based Paclitaxel-eluting stents for coronary artery lesions. Circulation. 2003 Aug 19;108(7):788-94. 2. Presented at Transcatheter Cardiovascular Therapeutics Conference, September 2002; and Late-Breaking Clinical Trials, ACC 2003 (12-month data).

3. Presented at the European Society of Cardiology, Vienna, Austria, September 2003. 4. Presented at Late-Breaking Clinical Trials during Transcatheter Cardiovascular Therapeutics Conference, September 2004(24-month data).

Clinical Topics: Invasive Cardiovascular Angiography and Intervention

Keywords: Paclitaxel, Myocardial Infarction, Follow-Up Studies, Platelet Aggregation Inhibitors, Drug-Eluting Stents, Saphenous Vein, Coronary Disease, Ticlopidine, Sirolimus, Purinergic P2Y Receptor Antagonists


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