Endothelial Progenitor Cells-capture Stents in Acute Coronary Syndromes
Condition: Acute Coronary Syndromes; Coronary Heart Disease
MeSH terms: Heart Diseases; Acute Coronary Syndrome; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      Randomized prospective study to compare the efficiency and safety of EPC-capture stents
      (Genous, OrbusNeich) and bare metal stents with concommitant high dose atorvastatin in
      reduction of neointimal formation assessed by quantitative coronary angiography and IVUS.
      Also the association between the function (transcriptional activity, migration) and number of
      circulating EPCs and angiographic outcomes will be investigated.
    

Detailed description: 
      The short and long-term efficiency of PCI is limited to in-stent restenosis (ISR) and stent
      thrombosis. Expansion of the stent in the target artery induces local injury of the vessel
      wall, primarily from the disruption of the endothelial lining. Following the injury, the
      reparatory mechanisms are activated leading to recovery of the endothelial coverage over the
      stent struts. Disruption of the endothelium causes the activation and adherence of platelets
      (minutes-hours) and recruitment of the monocytes and leukocytes (hours to days). The time
      that elapses between the endothelial disruption caused by the expanded stent and full
      coverage of the struts with new endothelial cells carries the highest risk of in-stent
      thrombosis.

      During this same time frame, the initial events of ISR occur, - primarily migration and
      proliferation of smooth muscle cells. The key event in rebuilding the endothelial layer over
      the stent struts is the recruitment of circulating endothelial progenitor cells (EPC), their
      adherence and attachment to the surface of the stent and vascular wall between the struts.
      The full coverage of the prothrombotic metal struts with new endothelial cells reduces the
      initially high risk of thrombosis. The repair processes are completed after 1 month when bare
      metal stents are used, and over 6 months after DES implantation.

      The course of events is different after implantation of drug-eluting stents. Recruitment of
      the inflammatory cells as well as smooth muscle cells is reduced and slowed. This effect is
      associated with a reduced potential for neointima formation (ISR), but also with an
      unfavorable lag in reendothelialisation.

      As shown in studies using angioscopy, thrombus formation over the DES struts can be seen as
      long as 6 months after PCI. The effect is probably caused by the inhibitory effects of
      immunosuppressive, antimitotic and antiinflammatory drug released from the stent on the EPCs
      adhering to the place of vascular injury and the struts. The use of DES significantly reduced
      the risk of ISR, but the slowing and prolongation of the reparatory process may increase the
      risk of the late in-stent thrombosis as well as other unwanted effects, such as edge effect
      and formation of the coronary aneurysms. The risk of late thrombotic effects of DES is mainly
      associated with discontinuation of dual antiplatelet therapy, therefore the treatment should
      be continued for at least 12 months or even indefinitely. The following groups of patients
      have a particularly high risk of in-stent thrombosis: acute coronary syndromes, cardiogenic
      shock, diabetes, procedure-related parameters (coronary dissection, long lesion, small vessel
      diameter, use of multiple stents). On the other hand, prolonged dual anti-platelet therapy is
      associated with significant risk (bleeding, thrombocytopenia) especially in patients with
      peptic ulcer disease and in the elderly. Discontinuation of this therapy is also indicated in
      patients undergoing surgery, which may increase the risk of thrombotic events.

      The concept of EPC-capture stents. Numerous studies have shown that circulating EPCs
      contribute to the repair of the endothelium after injury, most likely by repopulating the
      site of stent implantation. The number of circulating EPCs is considered a marker of the
      turnover of the endothelium, as well as a promising marker of the cardiovascular risk. EPCs
      can be identified by the presence of surface markers - CD34, CD133 - or vascular endothelial
      growth factor type 2 receptor (VEGFR2) which can be identified using labeled monoclonal
      antibodies. Since EPCs represent a pool of cells which contribute to the endothelial repair
      after vascular injury, the increased homing and retention of these cells at the site of stent
      implantation may increase and speed up the process of endothelisation.

      Introduction of a bioengineered stent with the immobilised antibody against CD34 antigen
      bound to the surface of the struts represents significant progress in the prevention of
      thrombotic events. The surface of the BMS is primed to obtain biocompatible matrix and the
      murine monoclonal antibody against human epitopes of CD34 are attached by covalent binding.

      Animal Models Animal studies revealed that the number of EPCs attaching to the stent struts
      is significantly higher after 1 and 48 hours post implantation and at 48 hours, more than 70%
      of the surface of stent struts is covered with endothelial cells. The cells are spindle
      shaped and aligned with the direction of blood flow forming the confluent monolayer dispersed
      over the stent struts and between them.

      There is also a trend towards lesser intensity of the neointimal formation and stenosis areas
      in comparison to the BMS after 28 days. More than 80% of cells captured by the monoclonal
      antibody express the markers of endothelial cells, while only 30% of the cells are positive
      for EC markers on the surface of BMS. The complete endothelial coverage was observed just 48
      hours after using the EPC-capture stents and a significant degree of endothelialisation was
      present within 1 hour after implantation.

      Clinical Trials EPC-capture stents received the CE mark and are commercially available since
      2005. So far, the results of two studies carried out in patients with stable CAD were
      published. First in-man study (Healthy Endothelial Accelerated Lining Inhibits Neointimal
      Growth, HEALING-FIM) demonstrated the safety and feasibility of the use of EPC-capture stents
      (Genous, OrbusNeich) in 16 patients with stable CAD with 100% procedural success and 6.3%
      rate of MACE in 9-month follow-up. The multicenter HEALING II study included 63 patients with
      stable CAD, 67% had hyperlipidemia, 16% diabetes, 24% a history of myocardial infarction and
      52% a positive family history of CAD. Patients with either de novo or non-stented restenotic
      primarily type B2 and C lesions in target native coronary vessels with a diameter of 2.5-3.5
      and a 9.83 mm average length were enrolled. At 6 and 9-months follow-up, the clinically
      driven target lesion revascularisation (TLR) rate was 6.3% and the MACE rate was 7.9%. The
      binary restenosis was 0% and late loss 0.48 mm. There were no additional events at additional
      18-months follow-up. The dual antiplatelet therapy was maintained for 1 month and no
      thrombotic events were recorded. Importantly, in angiographic control, the late loss
      regressed by 18% between 6 and 18 months of follow-up. Further important data will be
      available when the HEALING IIB (ClinicalTrials.gov Identifier: NCT00349895) multicenter study
      with control angiography after 6 and 18 months is completed. This study will further clarify
      the role of combined therapy with statins and implantation of EPC capture stents. All 90
      patients receive 80mg of atorvastatin at least 2 weeks prior to the procedure in order to
      achieve EPC mobilisation.

      In addition, the manufacturer launched an eHEALING real-life registry which aims to analyse
      the outcomes in more than 5000 patients after EPC-capture stents implantation. So far over
      2500 patients were included in the eHEALING registry.

      Statins and EPC-capture stents Importantly, the number of circulating EPCs positively
      correlates with a favorable clinical outcome. Only patients with a low number of EPC
      sustained MACE and ISR at 6 months follow-up, which shows that the endogenous capacity to
      mobilise the EPC is very important in vascular healing after stent implantation. HEALING II
      patients on statins had an approximately twofold increase in the EPC number when compared to
      patients without statins. The safe and efficient way to mobilise cells is statin therapy
      which does not only significantly increase the number of EPC, but also improves their
      functional capacity. This is a particularly important issue in patients with diabetes and in
      the elderly, where the number of EPCs is significantly lower in comparison to younger and
      non-diabetic subjects. Also, the functional capacity of the EPCs is impaired in patients with
      diabetes and multiple CVD risk factors.

      So far no trial addressed the use of Genous stents in patients with non ST-elevation ACS.
      Present randomized study will prospectively compare the EPC-capture stents and bare metal
      stents with concommitant high dose atorvastatin in reduction of neointimal formation assessed
      by quantitative coronary angiography and IVUS. Also the association between the function and
      number of circulating EPCs and angiographic outcomes will be investigated.
    

Intervention name(s): coronary stent (Genous, OrbusNeich) with immobilised anti-CD34 antibody to capture circulating endothelial progenitor cells
Intervention type(s): Device
Intervention description(s): coronary stent covered with anti-CD34 antobody, (Genous, R-stent, produced by OrbusNeich). 30 patients will undergo PCI with implantation of Genous stent and 30 patients will receive bare metal stent (BMS)
Other intervention name(s): Genous, OrbusNeich
Intervention MeSH terms: Antibodies
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: acute coronary syndromes; endothelial progenitor cells; coronary stent