Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction (STEMI) (COMFORTABLE)

March 29, 2016 updated by: University Hospital Inselspital, Berne

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

1161

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Switzerland
      • Bern, Switzerland, 3010
        • Department of cardiology
      • Geneva, Switzerland, 1211
        • Dep. of Cardiology
      • Lugano, Switzerland, 6900
        • Dep. of Cardiology
      • University of Lausanne, Switzerland, 1011
        • Dep. of Cardiology
      • Zürich, Switzerland, 8091
        • Dep. of Cardiology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age equal or more than 18 years
  • Chest pain > 10 minutes
  • Primary pci
  • ST-segment elevation of > 1 mm in > 2 contiguous leads, or (presumably new) left bundle branch block, or true posterior MI with ST depression of > 1 mm in > 2 contiguous anterior leads
  • Presence of at least one acute infarct artery target vessel with one or more coronary artery stenoses in a native coronary artery from 2.25-4 mm in diameter that can be covered with 1-multiple stents

Exclusion Criteria:

  • Female of childbearing potential (age 50 and last menstruation within the last 12 months), who did not underwent tubal ligation, ovariectomy or hysterectomy
  • Known intolerance to aspirin, clopidogrel, heparin, stainless steel, biolimus or contrast material
  • Inability to provide informed consent
  • Currently participating in another trial before reaching first endpoint
  • Mechanical complication of acute myocardial infarction
  • Acute myocardial infarction secondary to stent thrombosis
  • Planned surgery within 6 months of PCI unless dual antiplatelet therapy is maintained throughout the perisurgical period
  • Noncardiac comorbid conditions are present with life expectancy 1 year or that may result in protocol malcompliance
  • History of bleeding diathesis or known coagulopathy
  • Use of Coumadin

  • Additional for Imaging Substudy:

    • Age > 90 years
    • Hemodynamic instability
    • Renal failure
    • OCT/IVUS technically not feasible
    • Any patient in whom angiography demonstrates the infarct lesion to be at the site of a previously implanted stent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 1
Biolimus eluting Stent (Biomatrix)
Device: Biolimus eluted from an erodable stent coating (Biomatrix)
The Biolimus-eluting stent (Biomatrix) has a corrugated ring design available in six and nine cell models and is laser cut from 316L VM stainless steel hypotube. The nominal dosage of Biolimus A9 goes from 133 to 442 microgram. The producer of the drug is Nippoon Kayaku Co., Ltd Takasaki Plant, 239, Iwahanamachi, Takasaki-shi, Gumma 370-1028 Japan. The biodegradable polymer is polylactic acid, which has become one of the most commonly used biodegradable polymers. Polylactic acid, its co-polymers, and mixtures have been evaluated in the preclinical, and clinical studies, revealing a favorable biocompatability profile. The polymer has been demonstrated to be safe when used as implant of drug release-control polymer for both animals and humans.
Active Comparator: 2
Bare metal stent (Gazelle)
Device: bare-metal stent (Gazelle)
A bare-metal stent of identical design without surface application of polymer and drug.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Major adverse cardiac events (MACEs) in the overall population, defined as the composite of cardiac death, target-vessel related myocardial infarction (Q-wave and non-Q-wave), or ischemia-driven target lesion revascularization within 12 months
Time Frame: 30 days, 6 months, 1,2 and 5 years
30 days, 6 months, 1,2 and 5 years

Secondary Outcome Measures

Outcome Measure
Time Frame
All deaths
Time Frame: 30 days, 6 months, 1,2 and 5 years
30 days, 6 months, 1,2 and 5 years
Clinically and non-clinically indicated target lesion revascularizations
Time Frame: 30 days, 6 months, 1, 2 and 5 years
30 days, 6 months, 1, 2 and 5 years
Stent thrombosis ARC defined
Time Frame: 30 days, 1,2 and 5 years
30 days, 1,2 and 5 years
Stent strut coverage as assessed by OCT
Time Frame: 13 months
13 months
Malapposition as assessed by OCT/IVUS
Time Frame: 13 months
13 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Inselspital, Berne

Collaborators

Swiss National Science Foundation

Investigators

  • Study Chair: Stephan Windecker, Professor of Cardiology, Dep. of Cardiology, University Hospital Bern
  • Study Director: Lorenz Räber, MD, Dep. of Cardiology, University Hospital Bern
  • Study Director: Peter Jüni, Professor of Biostatistics, Dep. of Social and Preventive Med., University Bern
  • Study Director: Hector Garcia Garcia, MD, Erasmus Thoraxcenter Rotterdam, The Netherlands

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2009

Primary Completion (Actual)

January 1, 2012

Study Completion (Actual)

January 1, 2016

Study Registration Dates

First Submitted

August 19, 2009

First Submitted That Met QC Criteria

August 19, 2009

First Posted (Estimate)

August 20, 2009

Study Record Updates

Last Update Posted (Estimate)

March 30, 2016

Last Update Submitted That Met QC Criteria

March 29, 2016

Last Verified

March 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 137/09
  • 1373 (Other Identifier: Inselspital)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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