Drug-eluting Stents: The Next Generation

Bioabsorbable Polymers

It is accepted that polymer breakdown occurs through various mechanisms,^[16] but for the purpose of this article the exact terminology has been simplified and bioabsorbable will be used to describe all mechanisms of polymer breakdown. Early investigations noted a wide range of vascular inflammatory response to different bioabsorbable polymers.^[17] However, in a separate investigation it was noted that high molecular weight poly-L-lactic acid caused no acute or chronic inflammation in porcine coronary arteries.^[18] It should also be noted that despite a possible proinflammatory stimulus the polymer will completely degrade within 6–9 months, usually through hydrolysis to leave only a BMS in situ. This has subsequently led to large multicenter investigations of next-generation DES utilizing bioabsorbable polymers.

The first large-scale trial to investigate the potential clinical benefit of bioabsorbable polymers was the Cobalt–chromium Stent With Antiproliferative for Restenosis (COSTAR II)study.^[19] The CoStar™ (Conor Medsystems, CA, USA) stent consisted of a cobalt–chromium alloy platform with laser-cut reservoirs containing polylactic-co-glycolic acid polymer with the antiproliferative drug paclitaxel. This study randomized 1700 patients to either the CoStar or TAXUS® Express (Boston Scientific Corp. ma, usa) DES. Results were unfortunately disappointing; CoStar failed to meet noninferiority criteria versus TAXUS Express, with significantly higher rates of the 8-month primary end point of major adverse cardiac events (MACE). This was largely driven by a higher rate of target vessel revascularization (TVR) in the CoStar arm (8.1 vs 4.3%; p = 0.002) and higher rates of binary in-stent restenosis, in keeping with a higher 9-month in-segment late loss for CoStar compared with TAXUS Express (0.49 vs 0.18 mm; p < 0.0001) in the angiographic substudy population. However, despite this early setback, research interest has continued to pursue a bioabsorbable polymer DES concept (Table 2).

Thus far, the most comprehensive clinical trial data from commercially available bioabsorbable polymer DES, relate to the stents of the BioMatrix™ family (Biosensors, CA, USA) and the Nobori™ stent (Terumo, Tokyo, Japan). The stent platform is of stainless steel design with quadrature-linkage, with a 50:50 matrix of polylactic acid (PLA) and Biolimus A9™ (a semi-synthetic sirolimus analogue with tenfold greater lipophilicity) applied only to the abluminal stent surface. It is reported that the PLA polymer is completely converted to lactic acid by 6 months and via the Krebs cycle to carbon dioxide and water between 6 and 9 months.

The Limus Eluted from A Durable versus ERodable Stent coating (LEADERS) multicenter noninferiority trial randomized 1707 patients to either the BioMatrix Flex or Cypher Select® stent (Cordis Corp., FL, USA).^[20] The BioMatrix Flex stent was found to be noninferior to the Cypher Select for the composite primary end point of cardiac death, myocardial infarction (MI), or clinically indicated TVR at 9 months (9.5 vs 10.5%; p-noninferiority = 0.003) (Figure 2). In a modest number of patients, the LEADERS OCT substudy reported greater endothelial coverage at 9 months in those receiving BioMatrix Flex compared with Cypher Select.^[21] Recently reported 2-year follow-up results confirmed the continued noninferiority of the BioMatrix Flex stent for the composite end point, a significant reduction of the MACE in those with ST elevation MI (8.1 vs 19.3%; p < 0.01) and the absence of VLST following discontinuation of dual antiplatelet activity in the BioMatrix Flex arm^[22] independent from the timepoint of discontinuation.

Promising results have also been seen with the Nobori Biolimus A9/PLA stent when compared with the TAXUS Liberté®.^[23] The Nobori 1 Phase II trial, which randomized 243 patients to either Nobori or TAXUS Liberté in a 2:1 ratio, found the Nobori to be noninferior for the primary outcome of in-stent late loss at 9 months (0.32 ± 0.50 mm vs 0.11 ± 0.30 mm; p-noninferiority < 0.001). Interestingly stent thrombosis was not demonstrated with the Nobori platform but did occur in 4.4% of TAXUS Liberté patients.

The ongoing Nobori 2, single arm, allcomers' trial, which includes diabetes, acute coronary syndrome, bifurcation and off-label usage, has reported interim analysis from the first 1000 patients, with a major device-related cardiac event (death, MI and target lesion revascularization [TLR]) of under 5%.^[24] A total of 3386 patients have now completed 6-month follow-up. The combined stent thrombosis rate is impressively low at 0.14%.

These BioMatrix Flex and Nobori programs represent the largest current pool of randomized patients investigating a novel but commercially available DES with bioabsorbable polymer. Further data will soon be available from the ongoing allcomer e-Biomatrix registry, as well as randomized clinical end point trials comparing Nobori with Cypher and Xience™. Such data, in addition to defining efficacy, should help give further signal as to whether bioabsorbable polymer strategies do in fact fulfil their promise of reduction in VLST.

The recently published Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST 4) study has added further to the accumulating body of evidence with regard to bioabsorbable polymer technology.^[25] This study utilized a 316L sandblasted microporous stainless steel stent (Yukon®), which was coated on-site with a mixture containing rapamycin, biodegradable polymer and shellac resin.^[26] In total, 2603 patients were randomized to either the novel DES, a Cypher (sirolimus) or a Xience (everolimus; Abbot, IL, USA) DES. The novel DES was found to be noninferior to the Cypher/Xience arm for the primary composite end point of cardiac death, MI related to the target vessel and TLR at 12 months. The incidence of definite and probable stent thrombosis was not significantly different although much longer follow-up is required to assess whether or not a signal towards reduced VLST is emerging (Figure 3).

The Indian manufacturer Sahajanand (Gujarat, India) presented initial results of their bioabsorbable polymer platform – the Supralimus DES – at TCT09.^[27] Based on the stainless steel Matrix® stent, Sahajanand have applied a copolymer consisting of poly-L-lactide, polyvinyl pyrollidone, poly-lactide-co-caprolactone and polylactide-co-glycolide. This results in biphasic release of sirolimus with 50% elution by day 9 and 100% elution by day 48. The polymer has completely degraded by 7 months. The Seris 1 nonrandomized study reported, in 100 patients, an in-stent late-loss of only 0.09 ± 0.28 mm at 6 months and no definite stent thrombosis at the 30-month follow-up.^[28] This encouraging result led to the subsequent Percutaneous Intervention with Biodegradable-Polymer Based Paclitaxel-Eluting or Sirolimus-Eluting versus Bare Stents (PAINT) study, which randomized 274 patients to either a Supralimus stent, an Innfinium™ paclitaxel-eluting DES or a BMS.^[29] PAINT demonstrated superiority (p < 0.01) for the two DES platforms investigated with respect to the primary end point of in-stent late loss at 9 months when compared with BMS (although there was no statistical difference between the Supralimus and Innfinium DES: Supralimus 0.32 ± 0.43 mm; Innfinium 0.54 ± 0.44 mm; BMS 0.90 ± 0.45 mm). The subsequent eSeris registry confirmed the initial clinical data in a real world population of 1181 patients in which the rate of definite/probable stent thrombosis was 0.5% with only 2.0% TLR/TVR. The proposed Seris 3 noninferiority study plans to randomize patients to Supralimus or the Xience V stent as a contemporary comparator.

Boston Scientific has recently reported the results of the Optical Coherence Tomography Drug Eluting Stent Investigation (OCTDESI)trial; part of the JACTAX stent program.^[30] The JACTAX stent consists of a Liberté™ stent platform with an abluminal coating of bioabsorbable polylactide polymer and paclitaxel. The microdot coating of polymer–drug matrix, in addition to its abluminal-only application, results in much lower concentrations of both the polymer and the drug being required on the stent, as well as the theorectical safety advantage of a nonpolymer-coated luminal surface. The focus of OCTDESI was to test this hypothesis by assessing intimal healing and the surrogate marker of percentage stent strut coverage by OCT. Patients were randomized to both low dose and high dose JACTAX DES versus TAXUS Liberté, with the primary end point being the percentage of uncovered stent struts at 6 months. Enrolling only 60 patients in total, this small study was not able to find a difference in the primary end point between the three stent platforms; however, there were no stent thromboses observed with the JACTAX arms, and late lumen loss was comparable to TAXUS Liberté, thus supporting further evaluation of this stent platform in larger groups of patients.

The innovative Nevo™ stent system (Cordis Corp., FL, USA) comprises a cobalt–chromium stent platform incorporating multiple microwells that contain a matrix of poly(lactide-co-glycolide; PLGA) bioabsorbable polymer and sirolimus. It must be noted that the stent platform has been completely redesigned from the CoStar bare metal platform on which the microwell technology is based.^[31] This system potentially improves safety through reduction of the contact area between vessel wall and polymer by 75%, and enables 80% sirolimus release by 30 days. The Nevo RES one trial randomized 394 patients to either the Nevo or TAXUS Liberté stent.^[32] The trial was designed on a noninferiority basis, with a secondary superiority analysis if noninferiority was confirmed for the primary end point of late lumen loss. At 6-month follow-up, the mean late lumen loss in the Nevo arm was significantly lower than with TAXUS Liberté (0.13 vs 0.36 mm; p < 0.001). In addition, one probable and one possible stent thrombosis were observed with the TAXUS Liberté arm whereas no stent thromboses were observed in the Nevo arm. Large-scale randomized trials and registries are now ongoing.

Elixir Medical (CA, USA) reported several first-in-man studies at TCT09 using a cobalt alloy stent platform with bioabsorbable polylactide polymer and either novolimus (5 µg/mm) or myolimus (3 µg/mm) as the antiproliferative agent.

A first-in-man single-arm multicenter registry of the Elixir/Novolimus stent in nine patients demonstrated in-stent late loss of 0.16 ± 0.23 mm with no MACE.^[33] Further investigation is planned. A multicenter registry of the Elixir/Myolimus stent,^[34] reported in-stent late-loss of only 0.08 ± 0.16 mm at 6 months in 15 patients. The 12-month quantitative angiographic (QCA) results of a parallel group of patients are awaited.

The Biomime™ stent (Meril, Gujarat, India) is based on the CE marked NexGen™ cobalt–chromium stent, which has a unique electropolished surface and very low stent strut thickness (65 µm) with the aim of improving laminar blood flow, flexibility, conformability and trackability. To this platform, a matrix consisting of a custom biodegradable polymer (a combination of PLA and PLGA) and sirolimus at a concentration slightly lower than that on Cypher (1.25 vs 1.4 µg/mm²) resulting in slightly lower tissue concentration. Similar to Cypher, the release profile enables over 80% drug elution by day 30. A clinical registry of the Biomime DES including mandatory 8-month angiographic follow-up in 250 patients from multiple Indian centers is planned, the results of which will guide design of further head-to-head studies.^[35]

The innovative solution to small vessel stenting – the Sparrow™ 'stent in a wire' system (CardioMind, CA, USA) with its battery-released, self-expanding, ultra-thin strut nitinol stent, also includes a bioabsorbable PLA/PLGA copolymer coating and sirolimus (6 µg/mm). The ongoing CardioMind Sparrow™ DES system (CARE II) trial aims to randomize up to 220 patients to the Sparrow DES, Sparrow bare metal and a propriety cobalt–chromium stent (Microdriver®/Driver®).^[36] Encouraging feasibility data were recently presented from the initial 100 patients with 8-month data expected mid-2010.

Interv Cardiol. 2010;2(3):341-350. © 2010  Future Medicine Ltd.

Cite this: Drug-eluting Stents: The Next Generation - Medscape - Jun 01, 2010.