Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01267838 |
| Other study ID # |
BBK2 study |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
December 28, 2010 |
| Last updated |
September 4, 2016 |
| Start date |
February 2010 |
| Est. completion date |
April 2016 |
Study information
| Verified date |
September 2016 |
| Source |
Heart Center Bad Krozingen |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Germany: Ethics Commission |
| Study type |
Interventional
|
Clinical Trial Summary
BBK- 2 - study:
STUDY-SUMMARY
Background:
The need for stenting of the main and side branch (double stenting) in the treatment of
coronary bifurcation lesion primarily depends on the complexity of the bifurcation lesion.
If the bifurcation lesion is very complex (Medina classification 111, severe stenosis of
both branches, severe calcified lesion, long lesions etc.) double stenting may be the
treatment of choice. When double stenting is required, the most frequently used stenting
techniques are T-stenting and Culotte-stenting. It is still unclear, however, which double
stent technique yields the best long-term outcome.
Aim:
This randomized study will compare the long-term safety and efficacy of T-stenting versus
Culotte-stenting in the treatment of de-novo coronary bifurcation lesions with drug-eluting
stents.
Methods:
Three-hundred patients in whom a double-stenting technique is intended for the treatment of
a de-novo coronary bifurcation lesion will be randomly assigned to T-stenting or
Culotte-stenting with an approved drug-eluting stent. Patients will undergo 9-month
angiographic follow-up with quantitative coronary angiography. Clinical follow-up is planed
at 30 days, 6 months, 1 year, 2 years, 3 years and 5 years. The primary study endpoint is
the maximal percent diameter stenosis in the bifurcation lesion at 9 months. Secondary
endpoints include binary restenosis (estimated by Quantitative Coronary Angiography (QCA)
analysis), Target Lesion Revascularisation (TLR), Freedom from Major Adverse Cardiac Events
(MACE) and the rate of stent thrombosis according to the definition of the Academic Research
Consortium (ARC definition). The study will have 90% power to detect a 25% reduction in the
primary endpoint at p < 0.05.
Description:
1. STUDY BACKGROUND:
Currently, a simple stepwise provisional T-stenting approach is most frequently used type of
treatment in coronary bifurcation lesions. When stenting of both the side branch and the
main branch (double stenting) is needed because of dissection, TIMI flow < 2, high residual
stenosis > 75% there is a variety of techniques, which have been proposed. The most common
techniques are T-stenting and Culotte-stenting.
Adriaenssens et al (1) have analysed the data of 132 patients treated with Culotte-stenting
including Quantitative Coronary Angiography (QCA) analysis and clinical follow-up 1 year
post Percutaneous Coronary Intervention (PCI). The authors demonstrated an incidence of
binary angiographic restenosis of 22% for the whole bifurcation lesion. Procedural
angiographic success was achieved in all lesions (final kissing balloon dilatation was
performed in 62 % of patients). At 12 months, 28 of 132 (21%) patients had undergone target
lesion revascularization. The incidence of stent thrombosis (at 1 year) was low (1.5%).
Ferenc et al. (2) compared systematic T-stenting with the provisional T-stenting in 202
patients of the BBK 1 study. There was no significant difference between the 2 strategies.
Overall, maximum percent diameter stenosis in the bifurcation was 31 % at 9 months,
corresponding to a binary restenosis rate of 11 %. Within 1-year follow-up, this prompted
target lesion reintervention in 9,9 % of the patients. The risk of late stent thrombosis was
low (2 %) at 2-year follow-up.
The randomised multicenter Nordic 2 study addressed the question whether Crush-stenting or
Culotte-stenting achieves better angiographic and clinical outcome after PCI in bifurcation
lesions (Erglis et al). The results demonstrated the superiority of Culotte-stenting as
compared to the Crush-stenting. Major adverse cardiac events (MACE) as primary study
endpoint occurred in 3.7 % in the Culotte study arm as compared to 4.3 in the Crush study
arm (p =0.87). Likewise, in the double stent study arm of the BBC One study the
Crush-stenting was used successfully (Hildick-Smith, TCT Late Breaking Trials 2008).
Currently, there is no data from randomized trials comparing T-stenting with
Culotte-stenting.
References:
1. Adriaenssens, T., R. A. Byrne, et al: "Culotte stenting technique in coronary
bifurcation disease: angiographic follow-up using quantitative coronary angiographic
analysis and 12-months clinical outcomes." Eur Heart J 2008 29(23): 2868-76.
2. Ferenc M, Gick M, Kienzle RP, Bestehorn HP, Werner KD, Comberg T, et al. Randomized
trial on routine vs. provisional T-stenting in the treatment of de novo coronary
bifurcation lesions. Eur Heart J 2008;29(23):2859-67.
3. Erglis A, Kumsars I, Niemela¨ M, Kervinen K, Maeng M, Lassen JF, Gunnes P, Stavnes S,
Jensen JS, Galløe A, Narbute I, Sondore D, Ma¨kikallio T, Ylitalo K, Christiansen EH,
Ravkilde J, Steigen TK, Mannsverk J, Thayssen P, Nørregaard Hansen K, Syva¨nne M,
Helqvist S, Kjell N, Wiseth R, Aarøe J, Puhakka M, Thuesen L; for the Nordic PCI Study
Group. Randomized comparison of coronary bifurcation stenting with the crush versus the
culotte technique using sirolimus eluting stents. Circ Cardiovasc Intervent. 2009;2:
27-34.
4. Hildick-Smith D, de Belder A, Cooter N et al. BBC ONE: The British Bifurcation Coronary
study, Old New and Evolving strategies; a randomised trial of simple versus complex
drug eluting stenting. TCT session -Late Breaking Trials 2008.
Trial randomisation scheme:
Time and Event Schedule
Event Screening Procedure 8-16-24 Hours 30 days 9 months 1 year 3 years 5 years Informed
consent signed X Inclusion/Exclusion criteria X Medical History X X X X X X Angina pectoris
status X X X X X X Creatine kinase (CK) and Troponin X X Medication History X X X X X X X
Adverse Event Monitoring X X X X X X X (PCI) X Re - Angiography X
2. STUDY DESIGN
This study is a prospective, randomized, single-center evaluation of the treatment in de
novo bifurcated coronary lesions comparing a technique of T-stenting with Culotte-stenting
using approved drug- eluting stents.
The primary objective of this study is a comparison of T-stenting with Culotte-stenting with
respect to the maximal percent diameter stenosis within the bifurcation at 9 months. In
addition the study will assess various safety parameters.
Three-hundred patients will be enrolled in the study at one investigational site and will be
randomly assigned to T-stenting or to Culotte-stenting of the bifurcation lesion. Any
approved drug-eluting stent can be used. The choice of stent is left to the operator's
discretion.
2.1 HYPOTHESIS
The hypothesis of this study is as follows:
In large coronary bifurcation lesions (main vessel ≥2.5mm, side branch ≥2.25mm) including
significant ostial side branch disease, Culotte-stenting compared with T-stenting reduces
maximal percent diameter stenosis at the bifurcation at 9-month follow-upby 25 %, relative.
results in a lower restenosis rate than T stenting technique with a comparable long-term
safety.
3. STUDY ENDPOINTS
3.1. Primary Study Endpoint
The primary study endpoint is:
- Maximal percent diameter stenosis at the bifurcation at 9 months.
3.2. Secondary Endpoints
The following secondary endpoints will be evaluated in this study:
- Binary restenosis (≥ 50% diameter stenosis) rate at any segment of the bifurcation at 9
month post procedure
- TLR of the main and side branch at 12 months post procedure.
- Binary restenosis (≥ 50% diameter stenosis) in the main and side branch at 9 months
post procedure.
- MACE defined as death, Myocardial infarction (Q wave and Non-Q wave), emergent cardiac
bypass surgery, or TLR at 30 days, 6 months, 1, 2, 3, 5 years.
- Device success defined as attainment of < 30% residual stenosis of the target lesion
using drug-eluting stent (DES)in the main and side branch
- Procedure time, radiation time and volume of used contrast medium
- Post-procedure thrombotic stent occlusion at 12 and 24 months according to the
Academic Research Consortium-criteria:
Stent thrombosis is classified by the ARC definition as definite, probable, or possible and
as early (0 to 30 days), late (31 to 360 days), or very late (>360 days).
The definition of definite stent thrombosis requires the presence of an acute coronary
syndrome with angiographic or autopsy evidence of thrombus or occlusion.
Probable stent thrombosis includes unexplained deaths within 30 days after the procedure or
acute myocardial infarction involving the target-vessel territory without angiographic
confirmation.
Possible stent thrombosis includes all unexplained deaths occurring at least 30 days after
the procedure. Intervening target-lesion revascularization is defined as any repeated
percutaneous revascularization of the stented segment, including the 5-mm proximal and
distal margins, that preceded stent thrombosis.
4 PATIENT SELECTION
This trial will include 300 patients with symptomatic de novo bifurcation lesion of a native
coronary artery who meet eligibility criteria and agree to participate in the study.
4.1. Inclusion Criteria
Study candidates will be included only if all the following conditions are met:
1. Clinical indication for interventional treatment of the bifurcation lesion.
2. There is indication to perform the double stenting as judged by the operator.
3. Bifurcation lesions according to the Medina classification of a native coronary artery
with a reference vessel diameter: main branch >2,5 mm; side branch >2,25 mm (the
difference between vessel diameter of the main and side branch should be ≤1 mm)
4. The target lesion (main branch and / or side branch) must be at least 50% diameter
stenosis.
5. The target lesion has not been previously treated with any interventional procedure.
6. The target vessel (main branch and side branch) must be feasible for stent implantation
(successful passage with the guide wire; successful predilatation with an appropriately
sized balloon; no heavy calcification; no diffuse distal disease that might impede run
off).
7. Patient has no other treatment planned within 30 days of the procedure.
8. Patient has been informed of the nature of the study and agrees to its provisions and
has written informed consent as approved by the Ethics Committee.
9. Patient is willing to comply all required post-procedure follow-up.
4.2. Exclusion Criteria
Candidates will be excluded from participation in this study if any of the following
conditions apply:
1. Patient had an acute myocardial infarction (> 3x normal CK ) within 72 hours preceding
the index procedure and CK has not returned to normal limits at the time of the
procedure.
2. Patient will have a known hypersensitivity or contraindication to aspirin, heparin,
clopidogrel, prasugrel, stainless steel, sirolimus, everolimus, zotarolimus, biolimus
or contrast sensitivity that cannot be adequately pre- medicated.
3. Non successful treatment of other lesion during the same procedure
4. Patient has a platelet count of <100,000 cells/mm³ or >700,000 cells/mm³, a White Blood
Cells of <3,000 cells/mm³, or documented or liver disease.
5. Patient has a history of bleeding diathesis or coagulopathy.
6. Patient has suffered a stroke within the past six months.
7. Active peptic ulcer or upper gastrointestinal bleeding within the prior 6 months.
8. Patient has a co-morbidity (i.e. cancer or congestive heart failure) that may cause the
patient to be non-compliant with the protocol, or is associated with limited life-
expectancy (less than 2 years).
9. Indication for oral anticoagulation
10. Patient must be excluded from the study if any of these angiographic criteria are met:
1. The target vessel contains intraluminal thrombus.
2. The target lesion or vessel shows angiographic evidence of severe calcification.
3. The patient has undergone previous PCI to the target vessel within 6 months.
4. Pre treatment of the lesion is done with a technique other than balloon
angioplasty.
4.3 Randomisation
Patients who fulfil inclusion and exclusion criteria and give written informed consent to
the study will be randomised according to a standard random number generation method. The
study is designed as a non-blinded, randomized, single-center trial. Patients will be
allocated to T-stenting or to Culotte-stenting using a computer-generated random sequence,
set in blocks of 20 stratified to the type of drug-eluting stent in clinical use. The size
of the block and the random sequence will be select by the statistician and will be unknown
to the investigators and medical staff caring for the patients. Randomization will be
performed immediately before catheter treatment of the bifurcation lesion.
5. PROCEDURES BY VISIT
5.1. Patient Enrollment
All potential subjects should be consented prior to performing any study related procedures.
The investigator or representative will explain the nature and scope of the study, potential
risks and benefits of participation, and answer questions for the patient and/or legally
authorized representative. If the patient agrees to participate, the informed consent must
be signed and dated; a copy must be provided to the patient or legally authorized
representative.
Baseline data to be collected will include demographics , angiograophic and clinical
parameters.
5.2. Laboratory Assessments
- ECG prior to procedure and between 12 hours and 24 hours post-procedure or before
hospital discharge
- CK and CKMB and Troponin T prior to procedure and 8 hours, 16 hours and 24 hours
post-procedure
5.3. Concomitant Medications
All subjects receive the medication regimen listed below. All medications administered
should be recorded in the subjects medical record.
Prior to Procedure Aspirin At least 400 mg per os Clopidogrel 600 mg loading dose or
Prasugrel 60 mg loading dose
During Procedure IV Heparin For angioplasty bolus 100 I.U./ kg/ KG IC Nitroglycerin 100 -
200 mcg prior to baseline and post intervention angiograms
Post-Procedure Aspirin At least 100 mg per day indefinitely Clopidogrel 75 mg per day for at
least 6 months or Prasugrel 10 mg or 5 mg/die for at least 6 months as per clinical
indication
Glycoprotein IIb/IIIa inhibitors (Abciximab) can be used only for bail out.
5.4. Coronary Angiography and Intervention
5.4.1. Angiography
Using standard procedures for angioplasty, an introducer sheath of at least 6 French will be
introduced and the heparin bolus will be administered. After introduction of the guiding
catheter and following intra-coronary injection of nitroglycerin, baseline angiography of
the vessel will be performed in at least two best views that show the target lesion free of
foreshortening or vessel overlap, using a 6 French or larger guiding catheter.
5.4.2. Lesion / Vessel Pre-treatment
For any patients with multiple lesions requiring treatment at the time of the index
procedure, lesions outside the target vessel must be treated first successfully.
The target lesion in the main branch will be crossed with an intracoronary guide wire of
0.014 inch diameter and a second guide wire is passed into the side branch to protect the
access. The choice of the appropriate guide wires is up to the discretion of the operator.
After successful passage with the guide wires the lesion in the main branch should be
pre-dilated with an appropriately sized balloon. Predilatation of the side branch before
stenting of the main branch is up to the discretion of the operator.
5.4.3. Stenting Procedure and Stenting Technique
Among the many approaches to bifurcation stenting, we chose techniques that avoid
non-stented gaps at the orifice of the side branch with minimal stent distortion or stent
overlap in the carina region or the proximal segment of the main branch. Both techniques the
provisional T-stenting as well the Culotte-stenting provide complete coverage of the side
branch ostium. Final 'kissing balloon' dilatation should be performed in all patients
irrespective of whether they were assigned to T-stenting or Culotte-stenting.
Stents should be selected long enough to cover the lesions completely. If more than one
stent is needed to cover the lesion in the main or side branch completely, it is recommended
to overlap the stents 1 - 2 mm. The aim should be to reach a diameter stenosis < 10% without
proximal and distal dissections. Post dilatation may be performed at the operators
discretion. Pre or post dilatation technique should avoid balloon injury to any segment of
the vessel that will not be entirely covered by the drug eluting stent including the
patients with provisional side branch stenting following an unsatisfactory result after
balloon angioplasty.
T-stenting:
Both vessels have to be wired. Lesion preparation in the main vessel and side branch may be
undertaken according to operator preference. After lesion preparation, the main branch is
stented first.
After placement of the stent in the main branch, rewiring and predilatation of the side
branch, the second stent in the side branch is advanced and an additional balloon is placed
in the main branch at the orifice of the side branch. Then, the stent in the side branch is
positioned, taking care that the marker band and about the first half millimetre of the
stent are within the main branch stent. When the optimal position of the side-branch stent
is achieved, the side-branch stent is deployedby a kissing balloon manoeuvre, first
inflating the side-branch balloon with the stent and immediately afterwards the main branch
balloon.
Culotte stent technique:
Both vessels have to be wired. Lesion preparation in the main vessel and side branch may be
undertaken according to operator preference. After lesion preparation, the side branch have
be stented first.
The first stent is placed from main branch into the side branch side branch, covering the
entire diseased segment with a wire jailed in the main vessel. The main vessel is rewired
through the stent struts, and after removal of the jailed wire, is dilated with a balloon to
separate stent struts. The side branch wire is then removed (to prevent metal-to-metal jail)
and the main vessel is stented covering the proximal and distal segment. The side-branch is
re-wired and high pressure (e.g. 20 atm) individual inflations are made in each vessel at
the bifurcation point to ensure good stent strut separation. Finally a lower pressure
kissing inflation is made. For both the high pressure individual and lower pressure final
kissing inflations, balloon sizing should be in accordance with the diameter of the vessel
itself.
Further treatment to proximal or distal aspects of the main vessel or side branch can be
continued at the discretion of the operator. At any stage, proximal or distal dissections
may be treated as required with further stent implantations. At any stage, post-dilatations
may be undertaken to optimise stent expansion.
Irrespective of the assigned treatment, glyceryl trinitrate is injected intra-coronarily at
the completion of the procedure and final angiography of the vessel is performed in the two
optimal views that were chosen at baseline.
5.4.4. Stent type
Any approved type of drug-eluting stent can be used at the operator's discretion.
5.5. Follow-up Procedures
All patients enrolled in the study will be required to complete 30 days, 6 months, one, two,
three and fiv -years follow-up to evaluate long-term results.
5.5.1. 30 Days (± 5 days) Post Procedure (Telephone contact)
The assessment will include angina status (according to the Canadian Cardiovascular Society
Classification of angina), all adverse events, all concomitant medications and any
interventional treatment that occurred since the the index procedure.
5.5.2. Angiographic Follow-Up 9 Months (± 14 days) Post Procedure
As part of current routine clinical practice, all patients will undergo repeat angiography
at 9 months after the index procedure. Angiographies will be performed as described in
Section 5.4.1.
All films, including unscheduled angiograms, will be analysed to the angiographic core
laboratory.
. 5.5.3. At 30 days, 6,12, 24. 36 and 60 Months (± 30 days) post Procedure (Telephone
contact or contact with family doctor)
The assessment will include angina, all adverse events, all concomitant medications and any
interventional treatment that occurred since the previous contact.
5.5.4 Quantitave coronary angiography:
For quantitative coronary angiography, angiograms obtained at baseline, at completion of the
intervention and at 9 month follow-up will be analysed with using a computer based system
dedicated to bifurcation analysis (Qangio XA, version7.0, Medis, Leiden, Netherlands),
according to the standard operating procedure of our angiographic core laboratory.
Quantitative angiographic measurements will be obtained of the three segments of the
bifurcation lesion: the proximal and distal segment of the main branch and the side branch.
We will perform measurements in the stented portion of the vessel (in-stent) and in the
distal or proximal 5 mm margin (edge). In-segment analyses will comprise the in-stent and
the edge area.
In addition, the bifurcation angle from the analysis system will be estimated.
6. SAFETY ISSUES
All serious adverse events must be reported to the ethic committee.
These include any complication that:
results in death is life-threatening results in persistent and significant disability or
incapacity.
7. SAMPLE SIZE ESTIMATION
The study is designed to have a 90% power to detect a 25% relative reduction of the primary
endpoint by Culotte technique as compared with T stenting at a significance level of 0.05.
Assuming percent diameter stenosis in the side branch of 30±23 % at follow-up (ref. 10), a
sample size of 133 patients in each arm is obtained. The study will include 150 patients in
each arm, to allow for losses to angiographic follow-up.
