7-hexanoyltaxol and Coronary-Restenosis

Restenosis rates are lower with stent implantation than with balloon angioplasty. Nevertheless, even with the use of stenting, restenosis still occurs in approximately a third of patients with diabetes, small coronary vessels and long lesions. Animal studies with paclitaxel (Taxol, Bristol-Myers Squibb)-eluting stents, mainly in endothelium-denuded normal vessels, have shown that although paclitaxel reduces restenosis in the short-term, this may only delay rather than prevent restenosis. In clinical trials, stents eluting the paclitaxel derivative, 7-hexanoyltaxol, or paclitaxel without a polymer, also delay rather than prevent restenosis. Slowing the release of paclitaxel with a polymer base in the TAXUS trade mark series of clinical trials reduced the revascularization rate at 12 months, indicating that polymer-based paclitaxel is effective for longer periods of time. Further follow-up is necessary to determine whether polymer-based release of paclitaxel represents a longer delay or prevention of restenosis. To date, paclitaxel is showing promise as an eluting agent to prevent restenosis associated with stenting.

Topics: Animals; Bridged-Ring Compounds; Clinical Trials as Topic; Coronary Restenosis; Humans; Paclitaxel; Polymers; Stents

The restenosis rate is lower with stent implantation than with balloon angioplasty. Nevertheless, even with the use of stenting, restenosis still occurs in approximately one-third of patients with diabetes, small coronary vessels, and long lesions. The two drugs commonly used in eluting stents are sirolimus and paclitaxel. Systemically administered sirolimus decreased vascular proliferation in animal models. After preliminary trials showing benefit with sirolimus-eluting stents in de novo coronary lesions, the large-scale SIRIUS (Sirolomus-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions) trial was undertaken. SIRIUS showed that sirolimus reduced restenosis and target vessel revascularisation, compared to bare stents. These benefits were also apparent in the diabetic, and small- and long vessel subgroups. The RESEARCH (Rapamycin-eluting Stent Evaluated At Rotterdam Cardiology Hospital) registry have established that sirolimus-eluting stents are superior to bare stents in practice. Thus, the benefits of sirolimus-eluting stents over bare stents have been clearly established, and sirolimus can be considered the benchmark eluting agent for the prevention of coronary artery restenosis. Animal studies with paclitaxel-eluting stents, mainly in endothelium denuded normal vessels, have shown that paclitaxel reduces restenosis in the short-term, and that this may be a delay, rather than a prevention of restenosis. In clinical trials, stents eluting the paclitaxel derivative 7-hexanolytaxol, or paclitaxel without a polymer, delay rather than prevent restenosis. Slowing the release of paclitaxel with a polymer base in the TAXUS (Taxol(trade mark) [paclitaxel]-eluting stent) series of clinical trials reduced the revascularisation rate at 12 and 18 months, indicating that polymer-based paclitaxel is effective for longer. The results of the REALITY trial comparing the sirolimus- and paclitaxel-eluting stents in diabetics and other high-risk patients are eagerly awaited.

Topics: Animals; Bridged-Ring Compounds; Clinical Trials as Topic; Coronary Restenosis; Humans; Myocardial Revascularization; Paclitaxel; Sirolimus; Stents

The Study to COmpare REstenosis Rate between QueST and QuaDDS-QP2 (SCORE) trial was a multicenter, randomized, open-label trial comparing the safety and performance of 13- and 17-mm QuaDDS stents (n = 126) (Quanam Medical Corp., Santa Clara, California/Boston Scientific Corp., Natick, Massachusetts) versus uncoated control stents (n = 140) in focal, de novo coronary lesions.. The pioneering drug-delivery QuaDDS stent used four to six acrylate polymer sleeves, each loaded with 800 microg of the paclitaxel derivative 7-hexanoyltaxol.. Clinical end points were assessed at 1, 6, and 12 months post procedure. Quantitative coronary angiography and intravascular ultrasound were performed post procedure and at six-month follow-up.. In the QuaDDS group, early stent thrombosis and myocardial infarction (MI) rates were significantly higher, leading to premature cessation of enrollment. For the QuaDDS group, the stent thrombosis rate increased from 3.2% to 10.3% between 1 and 12 months, associated with increased non-Q-wave MI and death rates. The angiographic restenosis rate at six months was reduced from 32.7% (control) to 7.4% (p < 0.0001). However, the primary end point was not met with six-month target vessel revascularization (TVR) rate as well as the composite major adverse cardiac event rates (cardiac death, MI, and TVR) comparable between groups.. Despite angiographic indications of potential anti-restenotic benefit, increased rates of stent thrombosis, MI, and cardiac death associated with the QuaDDS stent show an unacceptable safety profile.

Topics: Aged; Bridged-Ring Compounds; Coated Materials, Biocompatible; Coronary Angiography; Coronary Disease; Coronary Restenosis; Coronary Thrombosis; Death, Sudden, Cardiac; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Myocardial Infarction; Polymers; Stents; Time Factors; Treatment Outcome

Inhibition of neointimal tissue growth has been demonstrated in preliminary human feasibility studies with a stent-based polymer sleeve delivering 7-hexanoyltaxol. The Study to COmpare REstenosis rate between QueST and QuaDS-QP2 (SCORE) trial is a human, randomized, multicenter trial comparing 7-hexanoyltaxol (QP2)-eluting stents (qDES) with bare metal stents (BMS) in the treatment of de novo coronary lesions. The purpose of this substudy was to evaluate the acute expansion property and long-term neointimal responses of qDES compared with BMS as assessed by intravascular ultrasound (IVUS).. A total of 122 (qDES 66, BMS 56) patients were enrolled into the IVUS substudy. All IVUS images (immediately after the procedure and at 6-month follow-up) were analyzed at an independent core laboratory in a blind manner. At baseline, qDES achieved stent expansion similar to BMS. At follow-up, qDES showed reduced neointimal growth by 70% at the tightest cross section and by 68% over the stented segment (P<0.0001 for both), resulting in a significantly larger lumen in qDES than in BMS. Unlike intracoronary brachytherapy, there was no evidence of negative edge effects, unhealed dissections, or late stent-vessel wall malapposition over the stented and adjacent references segments in either group.. Detailed IVUS analysis revealed that qDES had comparable acute mechanical and superior long-term biological effects to BMS. Although the long-term benefits and limitations of this technology require further investigation, the reduction in neointimal thickenings demonstrated that local delivery of 7-hexanoyltaxol through polymer sleeves augments conventional mechanical treatment of atherosclerotic disease.

Topics: Blood Vessel Prosthesis Implantation; Bridged-Ring Compounds; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug Implants; Female; Humans; Male; Middle Aged; Prospective Studies; Stents; Time; Treatment Outcome; Tunica Intima; Ultrasonography, Interventional

We recently reported delayed angiographic restenosis in 15 patients who received 7-hexanoyltaxol (QP2)-eluting polymer stents (QuaDS) for the treatment of in-stent restenosis. This study presents the histological findings of atherectomy specimens from a subset of these patients receiving implants.. Between October and December 2001, 5 patients treated with QuaDS-QP2 stents underwent directional coronary atherectomy at 11.2+/-1.0 months for recurrent in-stent restenosis. Restenotic lesion composition was assessed with special stains, immunohistochemistry with quantitative image analysis, and, in one specimen, transmission electron microscopy. Atherectomy specimens contained fibrin interspersed in a smooth muscle cell-rich neointima with proteoglycan matrix. In 2 of 5 specimens, large aggregates of macrophages and T-lymphocytes were noted. These areas of active inflammation demonstrated a relatively high proliferation index by Ki-67 antibody staining, whereas the proliferation index in smooth muscle cell-rich restenotic areas was low.. Restenotic lesions from QuaDS-QP2-eluting stents at 12 months show persistent fibrin deposition with varying degrees of inflammation. These pathological changes, representing delayed healing, are usually observed up to only 3 months in human coronary arteries with stainless steel balloon-expandable stents. The nonreabsorbable polymer alone may have induced chronic inflammation.

Topics: Aged; Atherectomy, Coronary; Blood Vessel Prosthesis Implantation; Bridged-Ring Compounds; Chronic Disease; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Delayed-Action Preparations; Drug Implants; Female; Humans; Inflammation; Male; Middle Aged; Mitotic Index; Polymers; Recurrence; Reoperation; Stents

To examine the influence of vessel wall calcium on neointimal hyperplasia (NIH) following bare metal stent (BMS) and drug-eluting stent (DES) implantation.. While procedural complications with coronary stenting in calcified lesions are well reported, little is known about subsequent NIH on plaque calcium following either BMS or DES implantation.. In the Study to COmpare REstenosis Rate between QueST and QuaDDS-QP2 (SCORE) trial, 6 months follow-up volumetric intravascular ultrasound data were available for 41 lesions (BMS, 19; DES, 22). NIH thicknesses on superficial, deep, and noncalcified plaque were calculated at every 0.5 mm intervals over the stented segment. Calcified and less-calcified cross-sections were defined as those containing arcs of plaque calcium > or = 90 degrees and < 90 degrees , respectively.. In BMS, mean NIH thickness on both superficial (0.24 +/- 0.23 mm) and deep calcium (0.25 +/- 0.21 mm) was significantly smaller than that of noncalcified plaque (0.31 +/- 0.22 mm) (P < 0.0005). NIH area was significantly smaller in calcified cross-sections compared to less-calcified cross-sections (2.1 +/- 1.2 mm2 vs. 3.1 +/- 1.9 mm2, P < 0.0001). While in contrast, in DES, mean NIH thickness was similar, irrespective of the presence or location of calcium (0.03 +/- 0.05 mm vs. 0.03 +/- 0.06 mm vs. 0.03 +/- 0.05 mm, superficial vs. deep vs. noncalcified plaque, P = NS). NIH area was also similar between calcified and less-calcified cross-sections (0.3 +/- 0.6 mm2 vs. 0.3 +/- 0.6 mm2, P = NS).. These results suggest that while plaque calcium may influence NIH following BMS implantation, NIH suppression using DES does not appear to be affected by the presence or location of calcium.

Topics: Bridged-Ring Compounds; Calcinosis; Clinical Trials as Topic; Coronary Artery Disease; Coronary Restenosis; Drug Delivery Systems; Humans; Hyperplasia; Metals; Retrospective Studies; Stents; Treatment Outcome; Tunica Intima; Ultrasonography, Interventional