Summary
Background
The zotarolimus-eluting stent (ZES) is a new drug-eluting stent that delivers zotarolimus, a synthetic analogue of sirolimus, through a biocompatible phosphorylcholine polymer coating. ZES has shown promising results compared with bare-metal stents, but its safety and efficacy against sirolimus-eluting (SES) and paclitaxel-eluting (PES) stents is yet to be established.
Aims
We aimed to summarize current evidence from randomized trials comparing ZES with SES and PES.
Methods
We searched the Medline, Embase and CENTRAL databases for randomized studies comparing ZES with SES and PES for percutaneous coronary intervention. Relevant clinical and angiographic outcomes were extracted and combined using random and fixed-effect models for heterogeneous and homogenous outcomes, respectively.
Results
Seven randomized trials met the inclusion criteria: ZES group, n = 3787; SES group, n = 2606; PES group, n = 1966. Compared with SES, ZES was associated with significantly higher odds of clinically driven target vessel revascularization (odds ratio [OR] 2.36, 95% confidence interval [CI] 1.78–3.14) and target lesion revascularization (OR 2.46, 95% CI 1.36–4.46). Compared with SES, ZES had higher in-stent restenosis (OR 6.13, 95% CI 3.96–9.50), late lumen loss ‘in-stent’ (mean difference [MD] 0.39 mm, 95% CI 0.34–0.44) and late lumen loss ‘in-segment’ (MD 0.18 mm, 95% CI 0.15–0.21). ZES was associated with higher in-stent late lumen loss than PES (MD 0.18 mm, 95% CI 0.07–0.28). There were no differences in mortality, reinfarction or stent thrombosis with ZES compared with SES and PES.
Conclusion
ZES is not superior to PES and is inferior to SES in terms of angiographic outcomes and clinically driven revascularization.
Résumé
Justification
Le stent actif au zotarolimus est un nouveau stent libérant du zotarolimus, analogue synthétique du sirolimus, au travers d’un polymère biocompatible (phosphorylcholine). Les résultats initiaux sont prometteurs en comparaison des stents métalliques mais l’efficacité et la sécurité, comparativement aux stents au sirolimus ou au paclitaxel, n’ont pas été établies. L’objectif était donc de faire la synthèse des données actuelles des études randomisées comparant ces trois types de stents (zotarolimus, sirolimus et paclitaxel).
Méthode
Nous avons interrogé les bases Medline, Embase et CENTRAL, en nous intéressant aux études randomisées comparant ces différents types de stents pour les interventions coronaires percutanées. Les données cliniques et angiographiques, ainsi que les données évolutives ont été extraites et associées en utilisant des modèles préétablis (randomisés et fixes) pour évaluer les données évolutives en incluant leur caractère homogène ou hétérogène.
Résultats
Sept études randomisées répondaient aux critères d’inclusion incluant 3787 patients dans le groupe zotarolimus, 2606 patients dans le groupe sirolimus et 1966 patients dans le groupe paclitaxel. Le groupe zotarolimus est associé à un taux accru d’efficacité sur la revascularisation du vaisseau site (OR 2,36, IC 95 % 1,78–3,14) et de traitement de la lésion cible (OR 2,46, IC 95 % 1,36–4,46), comparativement aux stents au sirolimus. Le stent au sirolimus était associé à un taux de resténose intra-stent plus élevé (OR 6,13, IC 95 % 3,87–9,50), une réduction de calibre intra-stent (différence moyenne 0,39 mm, IC 95 % 0,34–0,44) ainsi qu’à la réduction de calibre du segment considéré (différence moyenne 0,18 mm, IC 95 % 0,15–0,21) comparativement aux stents au sirolimus. Enfin, le stent au zotarolimus est associé avec une réduction de calibre intra-stent plus élevé (différence 0,18 mm, IC 95 % 0,07–0,28) comparativement au paclitaxel. Il n’y avait pas de différence du taux de réinfarctus ou de thrombose de stent avec le stent au zotarolimus, comparativement aux stents au sirolimus ou au paclitaxel.
Conclusion
Le stent au zotarolimus n’est pas supérieur au stent au paclitaxel et est inférieur en termes d’efficacité sur les critères angiographiques et l’indication à une revascularisation sur les critères cliniques, comparativement au stent au sirolimus.
Introduction
The first commercially available drug-eluting stents (DES) – the sirolimus-eluting stent (SES) and the paclitaxel-eluting stent (PES) – significantly reduced rates of restenosis and repeat revascularization after percutaneous coronary intervention (PCI) compared with bare-metal stents, in a wide variety of patients . However, the long-term safety of these stents has been questioned by the reports of increased incidence of stent thrombosis, especially with PES . Arterial wall inflammation, delayed healing and poor endothelialization are some of the factors thought to be responsible for late stent thrombosis events after DES implantation .
Zotarolimus is a novel agent with structural homology to sirolimus, developed exclusively for its use in DES. The zotarolimus-eluting stent (ZES) has a low profile, a thin strut design and a biocompatible phosphorylcholine polymer coating (which mimics the red blood cell outer membrane), and it elutes more than 90% of the drug in the first few weeks after implantation . These advances in stent design, polymer and drug elution kinetics are thought to reduce platelet adhesion and improve arterial healing, and may therefore decrease the incidence of stent thrombosis compared with SES and PES. ZES has been found to have better neointimal strut coverage compared with SES, as measured by optical coherence tomography at 9 months . Also, a randomized controlled trial (RCT) comparing ZES with a bare-metal stent showed a reduction in the rates of angiographic and clinical restenosis, with no difference in stent thrombosis . Despite early success, the role of ZES compared with SES and PES is unclear. RCTs comparing ZES with SES and PES have shown mixed results. Therefore, we decided to perform a meta-analysis of RCTs comparing ZES with SES and PES for PCI.
Methods
Objective
Our goal was to compare ZES with two established stents used for PCI – SES and PES – in terms of angiographic and clinical endpoints.
Search strategy
We performed a systematic search of the Medline, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase databases for RCTs comparing ZES with SES and/or PES, published before 30 September 2010. The keywords ‘zotarolimus’ and ‘zotarolimus eluting stent’ were used. All retrieved abstracts and/or articles were reviewed for possible inclusion. The references of review articles and included studies were hand-searched for any relevant studies. In addition; the manufacturer’s website ( http://www.medtronic.com/for-healthcare-professionals/products-therapies/cardiovascular/coronary-stents/index.htm ) was screened for any potentially relevant studies on 30 September 2010. No language restriction was imposed. RCTs comparing ZES with SES and/or PES and reporting angiographic and clinical endpoints were eligible for inclusion. Non-randomized studies or registries; comparisons with stents other than SES or PES and studies reporting no clinical or angiographic endpoints were excluded.
Data extraction and validity assessment
Two investigators (A.S. and A.B.) independently searched the databases for eligible studies. The original manuscripts of potentially relevant studies were reviewed. The study characteristics and endpoints were entered on a prespecified data form. The following study characteristics were extracted: sample size; method of randomization; inclusion and exclusion criteria; mean age; use of angiographic follow-up; primary endpoint; duration of dual antiplatelet therapy; follow-up duration; method of evaluation of angiographic outcomes; and criteria for target vessel or lesion revascularization. Any inconsistencies were reviewed with the help of a third author.
Endpoints
The following clinical endpoints were evaluated: major adverse cardiac events (MACE); mortality; myocardial infarction; target vessel revascularization (TVR); target lesion revascularization (TLR); and stent thromboses. The following angiographic outcomes were evaluated: in-stent and in-segment restenosis; and in-stent and in-segment late lumen loss.
Statistical analysis
A study-level analysis was done. Data were analysed using Review Manager 5 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). Odds ratios (ORs) and 95% confidence intervals (CIs) were used as summary statistics for all outcomes except the continuous variables in-stent and in-segment late lumen loss, for which mean differences were calculated. Studies were evaluated for heterogeneity by visual inspection of the CIs and by means of I 2 [I 2 = (Q–df)/Q], where Q is the χ 2 statistic and df is degree of freedom. A value of I 2 > 30% was considered as an indicator of significant heterogeneity. A Mantel–Haenszel fixed-effect model was used to calculate the pooled ORs for non-heterogeneous endpoints. Random effect (DerSimonian) analysis was performed in the presence of significant heterogeneity across the studies. A P value < 0.05 was considered significant.
Results
Seven RCTs were included in the meta-analysis ( Fig. 1 ) , resulting in a total of 8359 patients: 3787 patients in the ZES group; 2606 in the SES group; and 1966 in the PES group. The characteristics of included studies are shown in Table 1 . Three studies compared ZES with SES, two compared ZES with PES and two compared all three stents. Three studies included patients with elective PCI only, one study included stable angina or acute coronary syndrome but excluded ST-segment elevation myocardial infarction (STEMI), one study included patients with STEMI only and two included all-comers ( Table 1 ). In addition, three studies had specific angiographic criteria for inclusion, as shown in Table 1 . The mean age of the study population varied from 57 to 67 years. Patients groups were well balanced with regard to the most relevant characteristics within individual studies. All studies except SORT OUT III had routine angiographic follow-up. All studies used the Endeavor stent (Medtronic, Santa Rosa, CA, USA) in the ZES group, except for one study , which used the ZoMaxx stent (Abbott Laboratories, Chicago, IL, USA). The definitions of the relevant clinical endpoints used in the included studies are shown in Table 2 . Clinical endpoints were adjudicated by an independent committee blinded to stent assignment in all seven studies. Angiographic analysis was done at independent core laboratories blinded to stent assignment in all studies. A 3-year follow-up for the ENDEAVOR III study and 2-year follow-up for the ENDEAVOR IV and ISART-TEST-2 studies were reported subsequently, in addition to the respective 9-month, 12-month and 12-month follow-ups published initially. Also, the SORT OUT III trial reported clinical endpoints at 9 months and 18 months. The other three studies had a follow-up duration of 1 year or less ( Table 1 ). To accommodate the variable follow-up periods, we decided to combine the clinical endpoints at follow-up of up to 1 year and at longest available follow-up. No significant disagreement was found between the data retrieved by two investigators.
| Study | Number of patients | Inclusion criteria | Major exclusion criteria a | Mean age (years) | ||||
|---|---|---|---|---|---|---|---|---|
| ZES | SES | PES | ZES | SES | PES | |||
| ENDEAVOR III | 323 | 113 | NA | Elective PCI for symptomatic CAD due to native vessel lesion diameter 2.5–3.5 mm & length 14–27 mm | Recent MI or PCI; LVEF < 30%; > 40% lesion other than target lesion; unprotected left main; chronic total occlusion; TIMI flow grade < 2 | 61.4 | 61.7 | NA |
| ENDEAVOR IV | 773 | NA | 775 | Clinical CAD or positive functional study with single de novo lesion diameter 2.5–3.5 mm & length < 27 mm | Recent AMI; LVEF < 30%; left main or ostial lesion | 63.5 | NA | 63.6 |
| ISAR-TEST-2 | 339 | 335 | NA | Ischaemic symptoms or evidence of myocardial ischaemia with > 50% de novo stenosis in native vessels | Left main disease; in-stent stenosis; cardiogenic shock | 67.2 | 66.6 | NA |
| SORT OUT III | 1162 | 1170 | NA | Chronic stable angina or ACS | None | 64.3 | 64.3 | NA |
| ZEST | 883 | 878 | 884 | Stable angina or ACS with ≥ 1 lesion | STEMI; LVEF < 25%; shock; left main disease | 61.7 | 61.9 | 62 |
| ZEST-AMI | 108 | 110 | 110 | STEMI | LVEF < 30%; left main disease; previous MI; shock | 61.9 | 57.8 | 59.3 |
| ZoMaxx I | 199 | NA | 197 | Stable or unstable angina or objective evidence of ischaemia with lesion diameter 2.5–3.5 mm & length 10–30 mm | Recent MI; LVEF < 30%; left main disease or ostial lesion within 2 mm | 63 | NA | 63 |
| Study | Routine angiographic follow -up | Primary endpoint | Longest available follow -up (months) | Stent type | Duration of dual antiplatelet therapy (months) | ||
|---|---|---|---|---|---|---|---|
| ZES | SES | PES | |||||
| ENDEAVOR III | 8 months | In-segment late lumen loss at 8 months | 36 | Endeavor (Medtronic) | Cypher (Cordis) | NA | 3 |
| ENDEAVOR IV | 8 months | TVF b at 9 months | 24 | Endeavor (Medtronic) | NA | Taxus Express (Boston Scientific) | 6 |
| ISAR-TEST-2 | 6–8 months and 2 years | Binary restenosis | 24 | Endeavor (Medtronic) | Cypher (Cordis) | NA | 12 |
| SORT OUT III | Not done | MACE at 9 months | 18 | Endeavor (Medtronic) | Cypher Select/Plus (Cordis) | NA | 12 |
| ZEST | 9 months | MACE c at 12 months | 12 | Endeavor (Medtronic) | Cypher Select (Cordis) | Taxus Liberte (Boston Scientific) | 12 |
| ZEST-AMI | 8 months | MACE at 12 months | 12 | Endeavor (Medtronic) | Cypher (Cordis) | Taxus Liberte (Boston Scientific) | 12 |
| ZoMaxx I | 9 months | In-segment late lumen loss at 9 months | 9 | ZoMaxx (Abbott) | NA | Taxus Express 2 (Boston scientific) | 6 |
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