Zotarolimus(ABT-578)

Zotarolimus(ABT-578) is an anti-proliferative drug used exclusively in coronary drug eluting stent [1].

Zotarolimus(ABT-578) is an analogue of rapamycin and an anti-proliferative drug. Zotarolimus exhibited high affinity to the immunophilin FKBP12 and inhibited T cells proliferation [1]. Zotarolimus inhibited FKBP-12 binding with IC50 value of 2.8 nM. In human coronary artery cells, zotarolimus inhibited smooth muscle cell (SMC) and endothelial cell (EC) proliferation with IC50 values of 2.9 and 2.6 nM, respectively [2]. In human blood-derived peripheral blood mononuclear cells (PBMC) and rat splenocytes, zotarolimus inhibited Con A-induced human and rat T cell proliferation with IC50 values of 7.0 and 1337 nM respectively in a concentration-dependent way. In lymphocytes derived from humans or rats, zotarolimus inhibited the human and rat mixed lymphocyte reaction (MLR) with IC50 values of 1.2 and 1465 nM respectively in a concentration-dependent way. Also, zotarolimus inhibited human coronary artery smooth muscle cell proliferation induced by growth factor with IC50 value of 0.8 nM [3].

In crossbred juvenile swine, zotarolimus-eluting PC-coated stents induced a lower percent lumen stenosis, less neointimal area, less neointimal thickness and greater lumen area [2]. In a rat adjuvant DTH model mediated by T cell, zotarolimus inhibited the rat adjuvant DTH response with ED50 value of 1.72 mg/kg/day [3].

References:
[1].  Brugaletta S, Burzotta F, Sabaté M. Zotarolimus for the treatment of coronary artery disease: pathophysiology, DES design, clinical evaluation and future perspective. Expert Opin Pharmacother, 2009, 10(6): 1047-1058.
[2].  Garcia-Touchard A, Burke SE, Toner JL, et al. Zotarolimus-eluting stents reduce experimental coronary artery neointimal hyperplasia after 4 weeks. Eur Heart J, 2006, 27(8): 988-993.
[3].  Chen YW, Smith ML, Sheets M, et al. Zotarolimus, a novel sirolimus analogue with potent anti-proliferative activity on coronary smooth muscle cells and reduced potential for systemic immunosuppression. J Cardiovasc Pharmacol, 2007, 49(4): 228-235.

Late-term clinical outcomes with zotarolimus- and sirolimus-eluting stents. 5-year follow-up of the ENDEAVOR III (A Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions).[Pubmed:21596327]

JACC Cardiovasc Interv. 2011 May;4(5):543-50.

OBJECTIVES: This study sought to compare late safety and efficacy outcomes following percutaneous coronary revascularization with zotarolimus-eluting stents (ZES) and sirolimus-eluting stents (SES). BACKGROUND: Despite higher late lumen loss and binary restenosis with ZES compared with SES, it is uncertain whether differences in early angiographic measures translate into more disparate late clinical events. METHODS: Clinical outcomes were prospectively evaluated through 5 years in the ENDEAVOR III (A Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) that randomized 436 patients of relatively low anatomic and clinical risk to treatment with ZES (n = 323) or SES (n = 113) and evaluated a primary endpoint of 8-month angiographic late lumen loss. RESULTS: At 5 years (completeness of follow-up: 95.2%), pre-specified endpoints of all-cause mortality (5.2% vs. 13.0%, p = 0.02), myocardial infarction (1.0% vs. 4.6%, p = 0.03), and the composite event rates of cardiac death/myocardial infarction (1.3% vs. 6.5%, p = 0.009) and major adverse cardiac events (14.0% vs. 22.2%, p = 0.05) were significantly lower among patients treated with ZES. Rates of target lesion (8.1% ZES vs. 6.5% SES, p = 0.68) and target vessel revascularization were similar between treatment groups. Stent thrombosis was infrequent and similar in both groups (0.7% ZES vs. 0.9% SES, p = 1.0). Between 9 months and 5 years, progression of major adverse cardiac events was significantly more common with SES than with ZES (16.7% vs. 7.8%, p = 0.015). CONCLUSIONS: Despite initially higher angiographic late lumen loss, rates of clinical restenosis beyond the protocol-specified angiographic follow-up period remain stable with ZES compared with the rates for SES, resulting in similar late-term efficacy. Over 5 years, significant differences in death, myocardial infarction, and composite endpoints favored treatment with ZES. (The Medtronic Endeavor III Drug Eluting Coronary Stent System Clinical Trial [ENDEAVOR III]; NCT00217256).

Long-term clinical and economic analysis of the Endeavor zotarolimus-eluting stent versus the cypher sirolimus-eluting stent: 3-year results from the ENDEAVOR III trial (Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions).[Pubmed:20129546]

JACC Cardiovasc Interv. 2009 Dec;2(12):1199-207.

OBJECTIVES: The aim of this study was to evaluate clinical and economic outcomes for subjects receiving zotarolimus-eluting (ZES) (n = 323) versus sirolimus-eluting stents (SES) (n = 113) in the ENDEAVOR III (Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) clinical trial. BACKGROUND: Although previous clinical trials have evaluated long-term clinical outcome for drug-eluting stents, none considered their economic implications. METHODS: We analyzed case report form information with quality-of-life adjustment and Medicare cost weights applied from secondary sources; compared differences in clinical outcomes, quality-adjusted survival, medical resource use, and medical costs; and evaluated cost-effectiveness through 3-year follow-up. RESULTS: The use of ZES versus SES reduced the 3-year rates/100 subjects of death or myocardial infarction (3.9 vs. 10.8; difference, -6.9; 95% confidence interval [CI]: -13.0 to 0.8; p = 0.028), with no difference in target vessel revascularization rates (17.9 vs. 12.2; difference, 5.7; 95% CI: -3.7 to 15.1; p = 0.23) but greater use of coronary artery bypass graft (CABG) surgery (3.5 vs. 0.0; difference 3.5; 95% CI: 1.3 to 5.7; p = 0.002). After discounting at 3% per annum, total medical costs for ZES versus SES were similar ($23,353 vs. $21,657; difference, $1,696; 95% CI: -$1,089 to $4,482, p = 0.23), and the 3-year cost-effectiveness ratio was $57,002/quality-adjusted life year. CONCLUSIONS: Despite a reduction in death or myocardial infarction and no difference in total revascularizations, medical costs were not decreased due to increased CABG repeat revascularization procedures for subjects receiving ZES versus SES. If future trials observe similar differences, improved safety with no difference in medical costs, the use of ZES versus SES will be a clinically and economically attractive treatment strategy. (The Medtronic Endeavor III Drug Eluting Coronary Stent System Clinical Trial [ENDEAVOR III]; NCT00217256).

Zotarolimus (ABT-578) eluting stents.[Pubmed:16581153]

Adv Drug Deliv Rev. 2006 Jun 3;58(3):437-46.

Drug-eluting stents have revolutionized the field of interventional cardiology and have provided a significant innovation for preventing coronary artery restenosis. Polymer coatings that deliver anti-proliferative drugs to the vessel wall are key components of these revolutionary medical devices. This article focuses on the development of stents which elute the potent anti-proliferative agent, zotarolimus, from a synthetic phosphorylcholine-based polymer known for its biocompatible profile. Zotarolimus is the first drug developed specifically for local delivery from stents for the prevention of restenosis and has been tested extensively to support this indication. Clinical experience with the PC polymer is also extensive, since more than 120,000 patients have been implanted to date with stents containing this non-thrombogenic coating. This review provides background on pre-clinical studies with zotarolimus, on the development of the biocompatible PC polymer and on the clinical trials conducted using two stent platforms which deliver this drug to patients with coronary artery disease.

Late safety, efficacy, and cost-effectiveness of a zotarolimus-eluting stent compared with a paclitaxel-eluting stent in patients with de novo coronary lesions: 2-year follow-up from the ENDEAVOR IV trial (Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions).[Pubmed:20129547]

JACC Cardiovasc Interv. 2009 Dec;2(12):1208-18.

OBJECTIVES: The aim of this study was to assess, after 2 years of follow-up, the safety, efficacy, and cost-effectiveness of a zotarolimus-eluting stent (ZES) compared with a paclitaxel-eluting stent (PES) in patients with native coronary lesions. BACKGROUND: Early drug-eluting stents were associated with a small but significant incidence of very late stent thrombosis (VLST), occurring >1 year after the index procedure. The ZES has shown encouraging results in clinical trials. METHODS: The ENDEAVOR IV trial (Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions), a randomized (1:1), single-blind, controlled trial (n = 1,548) compared ZES versus PES in patients with single de novo coronary lesions. Two-year follow-up was obtained in 96.0% of ZES and 95.4% of PES patients. The primary end point was target vessel failure (TVF), and safety end points included Academic Research Consortium-defined stent thrombosis. Economic end points analyzed included quality-adjusted survival, medical costs, and relative cost-effectiveness of ZES and PES. RESULTS: The TVF at 2 years was similar in ZES and PES patients (11.1% vs. 13.1%, p = 0.232). There were fewer myocardial infarctions (MIs) in ZES patients (p = 0.022), due to fewer periprocedural non-Q-wave MIs and fewer late MIs between 1 and 2 years. Late MIs were associated with increased VLST (PES: 6 vs. ZES: 1; p = 0.069). Target lesion revascularization was similar comparing ZES with PES (5.9% vs. 4.6%; p = 0.295), especially in patients without planned angiographic follow-up (5.2% vs. 4.9%; p = 0.896). The cost-effectiveness of ZES and PES was similar. CONCLUSIONS: After 2 years of follow-up, ZES demonstrated efficacy and cost-effectiveness comparable to PES, with fewer MIs and a trend toward less VLST. (The ENDEAVOR IV Clinical Trial: A Trial of a Coronary Stent System in Coronary Artery Lesions; NCT00217269).

Zotarolimus is a tetrazole-containing Rapamycin analog which is used as animmunomodulator, and is useful in the treatment of restenosis, immune, and autoimmune diseases.

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