Coronary Heart Disease Clinical Trial
Official title:
Comparison of Efficiency of High Dose Atorvastatin and Endothelial Progenitor-Capture Stents and Bare Metal Stents in Reduction of Neointimal Formation in Patients With Non ST-Segment Elevation Acute Coronary Syndromes
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment
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