ST-elevation Myocardial Infarction Clinical Trial
Official title:
Comparison of Biolimus Eluted From an Erodable Stent Coating With Bare-Metal Stents in Acute ST-Elevation Myocardial Infarction and In Vivo 3-Vessel Assessment of Time-Related Changes of Culprit and Non-Culprit Lesions by IVUS/OCT in AMI
Stent study:
Treatment of patients with acute myocardial infarction with drug eluting stents (DES) is
effective but there remain concerns regarding the long-term safety and adverse effects on
the adjacent arterial wall. The biolimus-eluting Biomatrix stent addresses the issues by
incorporating modifications as a biodegradable polymer and a drug application solely to the
abluminal stent surface. While clinical data about the biolimus-eluting stent show a
favorable safety and efficacy profile, they require confirmation in a dedicated randomised
trial in the subset of patients with STEMI. Therefore, the study is designed to compare the
safety and efficacy of biolimus-eluting Biomatrix stent as compared to a bare metal stent of
otherwise identical design in a prospective, multicenter, randomized, controlled superiority
trial in patients with acute ST-elevation myocardial infarction.
Stent and Plaque Imaging Substudy:
In a substudy of the above mentioned stent trial, the investigators will perform a
prospective, multicenter, longitudinal cohort study of 100 consecutive STEMI patients
undergoing urgent coronary angiography and will employ high-resolution Optical Coherence
Tomography (OCT) imaging technology and intra-vascular ultrasound and virtual histology
(IVUS-VH) of the culprit STEMI lesions pre- and postprocedural as well as at a 13 months
follow up. Assessment of vascular wall responses, including volumetric measurements of
vessel, stent, lumen, peri-stent plaque, and intimal hyperplasia, indices of remodeling,
stent expansion, and stent-vessel wall apposition in response to biolimus-eluting and
bare-metal stent implantation will be performed. Moreover, IVUS, IVUS-VH and OCT will be
performed in all three epicardial vessels in order to quantify and map the number, frequency
and distribution of ruptured plaques at baseline and follow-up and quantify the
morphological changes of ruptured and vulnerable plaques at baseline and follow-up and
quantify the morphological changes over time in response to standard medical treatment.
Therefore, new insight regarding the frequency, distribution, composition and evolution of
coronary artery plaques and their prognostic impact on patients clinical outcome can be
expected from the present study. Since patients suffer from a recurrent ischemic event rate
of 5-10% during the first year, these findings may have important therapeutic implications
for the medical treatment of affected patients to further reduce the risk of recurrence and
improve prognosis.
Background
Stent Study:
A routine invasive strategy using percutaneous coronary intervention (PCI) has been shown to
improve survival and freedom from recurrent myocardial infarction compared to a thrombolysis
in patients with acute ST-elevation myocardial infarction (STEMI). In addition to standard
medical treatment, PCI with the use of coronary artery stents not only eliminate the
underlying stenotic lesion, but afford a mechanical mean of plaque stabilization, normalize
coronary blood flow, reduce shear stress, and local intracoronary thrombosis.
Notwithstanding, the implantation of coronary artery stents is associated with arterial
injury initiating a vasculo-proliferative cascade and as a result provoke structural changes
of the vessel wall. The implantation of bare-metal stents (BMS) during primary percutaneous
coronary interventions (P-PCI) in STEMI patients resulted in restenosis in up to 20% of
patients and has not been shown to reduce the rate of mortality and reinfarction. Randomised
trials and meta-analyses showed that the use of drug-eluting stents (DES) compared with BMS
in patients with STEMI significantly reduces the rate of target lesion revascularization
(TLR) without negative impact on the rate of death and myocardial infarction up to one year.
However, there remain important caveats surrounding the safety of DES in patients with STEMI
and evidence of harm may only arise during longer term follow up. DES implantation into
culprit lesions of patients with acute coronary syndromes has been identified as independent
predictor of late stent thrombosis. DES as opposed to BMS implanted into a pro-thrombotic,
inflammatory milieu of ruptured plaques in STEMI patients may lead to aneurysmal changes of
the adjacent vessel wall. First generation DES implanted into STEMI lesions were found to be
associated with substantial delay in healing compared to BMS. Moreover, DES implanted into
STEMI lesions have been associated with a higher frequency of incompletely apposed struts
and uncovered struts as assessed by OCT compared with DES implanted into stable lesions.
These data suggest a significantly increased risk of late thrombotic complications related
to DES. The phenomenon of aneurysmal change of the vessel wall may lead to incomplete stent
apposition, which in turn may predispose to late complications such as stent thrombosis,
recurrent myocardial infarction, and death. In conclusion, although coronary artery stents
constitute a routine medical intervention to improve the acute and long-term result in STEMI
patients, only very limited information exists as to the long-term clinical outcome and
structural changes of the adjacent vessel wall.
First generation DES with controlled release of sirolimus or paclitaxel from durable
polymers have reduced angiographic and clinical measures of restenosis in patients with
STEMI. Limus analogues are more effective as site-specific agents than paclitaxel to reduce
neointimal growth and repeat revascularisation procedures. However, late stent thrombosis is
more germane to first-generation drug-eluting stents than to bare-metal stents owing to
delayed healing and re-endothelialization. Furthermore, hypersensitivity reactions from the
polymers may further increase the risk of stent thrombosis. These effects may be
particularly pronounced in ruptured plaques of STEMI patients due to the direct contact with
the necrotic core.
The biolimus-eluting stent to be studied in the present proposal has several features, which
attenuate the above mentioned adverse effects. First, the polymer-drug combination is
applied solely to the abluminal stent strut surface (rather than circumferential), thus
maximizing the exposure to the vessel wall while minimizing release into the circulation.
Second, the drug (biolimus A9) is released from a biodegradable polymer, which completely
degrades into carbondioxide and water during a 6-9 months period, rendering the stent more
closely to a BMS. Recently, the safety and efficacy of the biolimus-eluting stent using a
biodegradable polymer was demonstrated in a large trial of 1,707 patients undergoing PCI.
While the overall results showed non-inferiority for all safety and efficacy endpoints as
compared with the sirolimus-eluting stent, the biolimus-eluting stent showed improved
outcome in terms of MACE, stent thrombosis and TLR in the pre-specified subgroup of STEMI
patients.
While clinical data as described above show a favorable safety and efficacy profile, the
promising results ot the subgroup analysis require confirmation in a dedicated randomized
trial in the subset of patients with STEMI. The present study is therefore designed to
compare the safety and efficacy of the biolimus-eluting Biomatrix stent with a bare-metal
stent of otherwise identical design in a prospective, multi-center, randomized, controlled
trial in patients with acute ST-elevation myocardial infarction. To address the issue of
late acquired stent apposition and stent strut coverage, an imaging substudy using grayscale
IVUS and OCT will be performed.
Imaging Substudy:
A) Stent Imaging Substudy The implantation of drug eluting stents into a pro-thrombotic,
inflammatory milieu of ruptured plaque in STEMI patients may lead to aneurysmal changes of
the adjacent vessel wall possibly leading to incomplete stent apposition, which in turn may
constitute a risk factor for late complications with adverse outcome. Delayed and incomplete
stent strut coverage and endothelialization is another vessel wall reaction and possibly
related to adverse late outcome by increasing the risk of late stent thrombosis. OCT
provides a valuable modality for the assessment of stent strut coverage with 10x higher
resolution than IVUS. Recently, biolimus-eluting stents have been shown to result in more
complete stent strut coverage after 9 months as compared to sirolimus-eluting stents in the
OCT substudy of the LEADERS trial. To compare the biological behaviour of a newer generation
DES with biodegradable polymer as compared to a bare-metal stent, an imaging substudy using
IVUS and OCT for detailed analyses of the post-procedural and follow-up vessel wall
behaviour will be performed.
B)Plaque Imaging Substudy Although the short-term outcome of patients with ACS and STEMI has
improved in recent years, clinical outcome at one year remains complicated by recurrent
myocardial infarction and death in 10-15% of patients. Previous studies using angioscopy
suggest delayed plaque healing, persistent thrombus, and recurrent plaque rupture as
principal mechanisms for lesion progression and its clinical complications. However, these
studies are limited by a small sample size, omission of follow-up imaging, lack of
correlation with easily accessible serum markers, and unavailability of high resolution
imaging technology such as OCT. Moreover, it is estimated that patients with ACS have more
than one ruptured plaque in >40-80% of cases, which frequently are left untreated and
therefore may contribute to long-term adverse clinical outcome.
Frequency, distribution, composition (TCFA versus non TCFA), and time-related changes of
plaques of the entire coronary tree in patients with STEMI have not been documented so far,
mainly due to technical limitations of the OCT imaging method. New-generation OCT systems
available for the present study will allow the systematic assessment of long coronary
segments. The combination of IVUS-VH and OCT will substantially improve the accuracy for
detection of plaques and especially of TCFA.
Therefore, new insights regarding the frequency, distribution, composition and evolution of
coronary artery plaques and their prognostic impact on patients clinical outcome can be
expected from the present study. Since patients with ST-segment elevation myocardial
infarction suffer from a recurrent ischemic event rate of 5-10% during the first year, these
findings may have important therapeutic implications for the medical treatment of affected
patients to further reduce the risk of recurrence and improve prognosis.
Objective
To establish superiority of the biolimus-eluting (Biomatrix) stent compared with an
otherwise identical bare-metal stent (Gazelle) in terms of the composite endpoint of death,
target-vessel related myocardial infarction at 1 year.
Imaging Substudy To compare neointimal thickness and strut coverage between both stent types
in lesions of STEMI patients at 13 months and assessment of frequency, distribution and time
related changes of culprit versus non culprit lesions of patients with acute ST-segment
elevation myocardial infarction.
Methods
Stent study
This is a prospective, multi-center, randomized, assessor-blind, trial to be conducted at
several swiss and european interventional cardiology sites. A total of 1100 patients will be
randomized on a 1:1 basis to either the biolimus-eluting stent with biodegradable polymer or
a bare-metal stent. The number of stents is not limited per patient, but it must be
consistently implanted according to the assigned treatment allocation. All patients will be
followed clinically for up to 5 years after stent implantation.
Imaging substudy
100 of 1100 randomized patients fulfilling the specific inclusion criteria (see above) will
undergo IVUS-VH and OCT of the culprit lesions prior to and after stent implantation as well
as during follow up. Moreover, IVUS-VH/OCT will be performed in all three major epicardial
vessels at baseline and follow up. The imaging study will be performed at the University
Hospital Bern, Geneva, Lausanne and Cardiocentro Lugano, all Switzerland.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment
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