Transcript Post procedure

COBRA- Investigators meeting- Oct 06,2010 Bologna
COBRA- Investigators meeting- Oct 06,2010 Bologna
WHY Cobra?
• Very few papers in the literature concerning Anticoagulation and
Antiplatelet protocols Pre/Per/Post Aneurysms embolization !
• Protocols very different from one center to another!
• Attempt to establish guidelines by WFITN failed
• Thrombo-embolic (TE) and Intra-operative Rupture (IOR) main
cause of clinical complication !
• More and more stents , flow diverters are used !
Clarity
Study
COBRA- Investigators
meetingOct 06,2010 Bologna
782 Consecutive ruptured aneurysms
• TE: 12.5%
– Permanent morbidity: 2.9%
– Death: 0.9%
• IOR: 4.3%
– Permanent morbidity: 0.6%
– Death: 0
• Postop. Rebleeding (30 Days): 0.7%
– Permanent morbidity: 0.1%
– Death: 0.5%
Atena
Study
COBRA- Investigators
meetingOct 06,2010 Bologna
739 Consecutive unruptured
aneurysms in 649 Patients
• TE: 7.1%
• IOR: 2.6%
COBRA- Investigators meeting- Oct 06,2010 Bologna
• Investigator initiated and designed, european,
multicenter trial
• Two Studies:
– Cobra ruptured aneurysms randomized study on
808 Patients
– Cobra Unruptured aneurysms registry on 400
Patients
COBRA- Investigators meeting- Oct 06,2010 Bologna
COBRA Ruptured aneurysms
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
PRIMARY AIM AND HYPOTHESIS
• Primary Aim: To determine whether antiplatelet therapy
(500mg IV ASA) during embolization
•
Decrease the risk of perioperative thromboembolic events
(TE)
• Without increasing risk and clinical outcome of intraoperative
rupture, early rebleeding, and ventricular drainage related
hemorrhages.
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
STUDY DESIGN
• Patients with ruptured aneurysms will be randomized (1:1) in
25 sites to:
Embolization without
OR
with intraoperative antiplatelet therapy (IV ASA 500mg)
• After the treatment, no antiplatelet medication will be given.
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
PRIMARY ENDPOINTS
• Any perioperative TE within 72 hours enrollment
– Intraoperative: clotting on DSA
– Postoperative:
• CT/ MRI/DSA in case of neurological deficit
• MRI at 24 to 72 hours (diffusion + Flair)
• Classified : No clinical consequence / TIA (<24 H) / Stroke / Death
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
SAMPLE SIZE ESTIMATES
• The projected rate of the primary endpoint (any perioperative TE within
72 hours) in the “No ASA arm” will be 15%.
• The sample size calculation based on 50% relative risk reduction in
primary endpoint with ASA (from 15.0% to 7.5%).
• With probability of Type I Error = 0.05 and power = 0.90, the required
sample size is a total of 368 patients in each group. To include the risk of
protocol violations, the sample size will be 404 patients in each group.
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
Clinical Secondary Endpoints
• TE within 30 days
• Risk and Consequence of IOR
• Early rebleeding (30 days)
• Rate and clinical consequences of ventricular drainage related
hemorrhage.
• Complications related to SAH ( vasospasm and hydrocephalus)
• Morbidity and mortality at hospital discharge and 30 days (GOS, mRs)
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
Technical Secondary Endpoints
• Postop. aneurysm occlusion evaluated on postop. DSA by an
independent core lab using the 3 grades Montreal scale
• Recanalization rate at one year: evaluated by an independent core
lab in a sub-group of 250 patients.
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
INCLUSION CRITERIA
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•
•
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Patient with an aneurysm ruptured less than one week prior
Patient older than 18 years
WFNS grade 1, 2 or 3
Patient willing and able to return for all follow-up visits required by
the protocol
• Patient understands the purpose and requirements of the study,
and has provided informed consent
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
EXCLUSION CRITERIA
• Parenchymal hematoma ( Intraventricular SAH is not an exclusion criteria).
• Patients with multiple aneurysms if the ruptured aneurysm is not
identified
• Dissecting or fusiform aneurysms
• Aneurysms associated with an arteriovenous malformation
• Intracranial tumor (except meningioma)
• Aneurysms already treated by endovascular or neurosurgical technique
route
• Patients already treated for another aneurysm
• Patientsto be treated for multiple aneurysms during one procedure
• Patients to be treated with stents or flow diverters
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
EXCLUSION CRITERIA
•
•
•
•
•
Patients with a stroke in the month before the treatment
Patients protected by the law
Pregnant or nursing women
Allergy or contraindication to aspirin, heparin, local or general anesthesia
History of life-threatening allergy to contrast dye. If not life threatening
and can be effectively pretreated, patient can be enrolled at physician’s
discretion
• Active peptic ulcer disease, major systemic hemorrhage within 30 days,
active bleeding diathesis, platelets < 100,000, hematocrit < 30, INR > 1.5,
clotting factor abnormality that increases the risk of bleeding
• Major surgery within previous 30 days
• Enrollment in another study that would conflict with the current study
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
RANDOMIZATION
•
Before randomization, the site coordinator has to control that the patient meets all eligibility
criteria and the patient (or his family) has signed informed consent.
•
The site coordinator will create a file for the patient on the web database. The site coordinator will
fulfilled demographic and anatomic data as well as eligibility criteria. Randomization will be
automatically performed through the database.
•
As precise anatomic data are needed for enrollment this step has to take place after diagnostic
angiography.
•
If endovascular treatment is performed immediately after diagnostic angiography, the site
coordinator has to fill the web database before starting the endovascular treatment.
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
COILING PROCEDURE: Peri-operative medications
• Pre-procedure: No ASA treatment.
• Intra-procedure:
– Patients randomized in the group “ASA” will receive aspirin 500 mg IV
after first coil deposition.
– Patients randomized in the group “NO ASA” will receive no anti-platelet
treatment.
– All patients will receive heparin. After femoral puncture, a bolus of
intravenous heparin weight adjusted (50 UI / kg) followed by a continuous
IV administration of 30 UI/kg/h.
– IIb / IIIa inhibitors agents will be used if needed in case of TE
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
COILING PROCEDURE: Peri-operative medications
• Post-procedure:
– No ASA
– Heparin is reversed at the end of the procedure with protamine
sulfate 60UI/kg.
– Heparin is reintroduced 2H after, approximately at 10 UI/kg/h and
adapted to maintain the ACT between x 2 and 3 of normal.
– At 48 H heparin is stopped, followed by subcutaneous low
molecular weight heparin at a prophylactic dose for one week.
COBRAInvestigators
meeting- Oct
06,2010 Bologna
COBRA
Ruptured
aneurysms
• COILING PROCEDURE: Techniques
• Anesthesia / Arterial Access
• General anesthesia.
• Use of closure device is authorized.
• Procedure Steps
• Aneurysms must be treated using TARGET coils (Boston Scientific).
All types of TARGET coils are authorized. Other coils are authorized
for no more than 10% length.
• The remodeling technique (Balloon assisted coiling) is authorized.
• Stenting is not authorized.
• Flow diverters are not authorized.
COBRA- Investigators meeting- Oct 06,2010 Bologna
Clinical follow-up
•
Patients will be evaluated preoperatively, postoperatively, at hospital discharge, and at 1 month,
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Clinical evaluations will be performed by a member of the neurovascular blinded to whether the
patient received aspirin, but not by the treating physician.
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Preoperatively: WFNS and GCS
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Postoperatively: GCS, mRs
Anatomic follow-up
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Anatomic follow-up will be performed by DSA at the end of procedure and by DSA and/or MRA at
one year (250 patients).
•
Anatomic evaluation will be performed by an independent core lab (2 neuroradiologists):
evaluation with Montreal scale
COBRA- Investigators meeting- Oct 06,2010 Bologna
ADVERSE EVENTS: Definitions
The following definitions for adverse events will be used during the trial:
•
Adverse Event (AE): Any unfavorable and unintended sign , symptom or disease that occurs to a
subject while enrolled in a clinical investigation. Adverse device event (ADE): Any unfavorable and
unintended sign, symptom or disease related to the study device
•
Serious Adverse Event (SAE): A serious adverse event is any medical experience regardless of its
relationship to the study protocol that occurs during subject enrollment in this trial that results in any
of the following: (1) inpatient hospitalization or prolongation of a hospitalization; (b) persistent or
significant disability/incapacity; (c) death of the study subject, or (d) necessitates an intervention to
prevent a permanent impairment of a body function or permanent damage to a body structure.
•
Serious Adverse Device Event (SADE) Any SAE related to the study device.
•
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or any lifethreatening problem or death caused by or associated with a device, if that effect, problem or death
was not previously identified in nature, severity or degree of incidence in the investigational plan or
IDE application (including a supplementary plan or application), or any other unanticipated serious
problem associated with a device that related to the rights, safety or welfare of subjects.
COBRA- Investigators meeting- Oct 06,2010 Bologna
Safety Oversight Processes:
•
Data Safety Monitoring Board (DSMB)
– A Data Safety Monitoring Board (DSMB) will meet approximately every six months to
review the progress of this study (e.g enrollment, site performance, meeting risk
factor targets) as well as data on the safety of both treatment arms.
– Before the study begins, the DSMB (in consultation with the study statisticians and
principal investigator) will decide on the frequency and timing of interim efficacy
analyses.
– One treatment arm is defined as more efficacious if the rate of thromboembolic
complications is lowered by more than 70% compared to the other arm.
– One treatment arm is defined as unsafe if the rate of death is increased by more than
50% compared to the other arm.
– Additionally, the DSMB may recommend modifications of to the protocol if a
reversible safety issue is identified.
COBRA- Investigators meeting- Oct 06,2010 Bologna
Safety Oversight Processes:
• Independent Medical Monitor
– All SAEs will be forwarded to the Statistical Coordinating Center. They will then
be relayed to the Independent Medical Monitor (IMM) for review and for the
required reporting.
– CRO will query sites to obtain complete information for serious adverse events
and report results to independent medical monitor.
• Principal Investigators
– Drs. Pierot and Cognard will be informed of the DSMB’s every 200 patients of
study performance and safety and any other safety issues detected by the
IMM.
COBRA- Investigators meeting- Oct 06,2010 Bologna
Reporting obligations
•
All adverse events with and without clinical effect will be registered in the database.
•
All serious adverse events will be registered in the database and forwarded to the
Independent Medical Monitor.
Malfunction, device failures as well as unanticipated adverse device events will be reported
to each countries medical device vigilance center, according to national regulations. UADE
will be reported to the manufacturer and study PIs within 24 hours
•
Complaints will be reported to the Boston Scientific regional complaints handling centers as
Target coils is an approved device.
COBRA- Investigators meeting- Oct 06,2010 Bologna
EVALUATION OF END POINTS AND COMPLICATIONS
• All TE occurring during or in the 30 days following the treatment will be reported
whatever the clinical outcome. Any intravascular clot occurring during the
endovascular treatment will be described: clot at the neck of the aneurysm, parent
artery occlusion, distal emboli.
• Modalities of treatment of the TE will have to be described (no treatment, medical
treatment, endovascular treatment)
• Clinical consequences of the TE will have to be described: No clinical symptoms /
TIA / Permanent deficit / Death
• 24 to 72 hours after the endovascular treatment, MRI examination will be
performed (diffusion, FLAIR) and Patients will be classified in two groups : No
diffusion abnormalities / Diffusion abnormalities
COBRA- Investigators meeting- Oct 06,2010 Bologna
EVALUATION OF END POINTS AND COMPLICATIONS
•
All intraoperative rupture occurring during the treatment will be reported whatever the
clinical outcome (exit of the tip of the coil or the microcatheter outside the limit of the
aneurysmal sac and/or extravasation of contrast media).
•
Clinical consequences of the intra-operative rupture will have to be described in 3
categories:
– no clinical symptoms
– permanent deficit
– death
COBRA- Investigators meeting- Oct 06,2010 Bologna
EVALUATION OF END POINTS AND COMPLICATIONS
•
All early rebleedings occurring during the month following the treatment will have to be
reported.
•
Clinical consequences of the early rebleeding will have to be described in 3 categories:
– no clinical symptoms
– permanent deficit
– Death
•
Modalities of treatment will be described:
– hematoma evacuation
– ventricular shunting
– aneurysm clipping
– aneurysm recoiling
COBRA- Investigators meeting- Oct 06,2010 Bologna
EVALUATION OF END POINTS AND COMPLICATIONS
Bleedings related to ventricular shunting will be evaluated.
• In case of pre-embolization shunting, CT will be performed in the 24/72 hours following
the endovascular treatment.
• In case of post-embolization shunting placed in the week following the endovascular
treatment, a CT will be performed within the 72h.
All deaths occurring during the treatment and the month following the treatment will be
reported. The cause of death will be classified in 3 groups:
• related to a treatment complication: TE, intraoperative rupture, early rebleeding
• related to SAH complication: delayed ischemia (vasospasm), hydrocephalus
• related to SAH
COBRA- Investigators meeting- Oct 06,2010 Bologna
COBRA Unruptured aneurysms
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
• The primary objective:
To determine the rate and clinical consequences of TE, IOR and postprocedure bleeding in patients with unuptured aneurysms treated by
coiling with double preoperative antiplatelet premedication (ASA +
clopidogrel).
• Primary Hypothesis
A preoperative antiplatelet therapy can be safely used in the
endovascular treatment of unruptured aneurysms with a rate of
thromboembolic events and intraoperative rupture similar or lower
compared to ATENA patients
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
• PRIMARY ENDPOINTS
• Rate and clinical outcome of perioperative thromboembolic events
(within 72 hours after treatment)
• Asymptomatic events (depicted intraoperatively by angiography
and postoperatively by MRI) and symptomatic events (TIA, stroke,
death) will be recorded. A postoperative MRI will be performed to
depict ischemic lesions on diffusion imaging.
• 400 patients
• Up to 25 actively enrolling sites in the Europe
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
• Clinical Secondary Endpoints
• Rate and clinical outcome of thromboembolic events occurring
within 30 days after enrollment.
• Rate and clinical outcome of intraoperative rupture.
• Rate and clinical consequences of post-procedure bleeding at 1
Year.
• Morbidity and mortality at hospital discharge and at one month
(Glasgow Outcome Scale, Modified Rankin Scale
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
• Technical Secondary Endpoints
• Postoperative aneurysm occlusion: will be evaluated on a
postoperative DSA or MRA performed before hospital discharge by
an independent core lab using the 3 grades Montreal scale (total
occlusion, neck remnant, aneurysm remnant).
• Recanalization rate at one year: will be evaluated by an
independent core lab by comparing one year DSA or MRA and
postoperative DSA or MRA. Recanalization is defined as any
increase of aneurysmal contrast filling at one year
• A subgroup analysis will be conducted according to the technique
used to treat the patient (coiling, remodelling, stenting).
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
• Medico-Economic Endpoint
• A medico-economic study will be conducted to determine the inhospital costs of the endovascular management of unruptured
aneurysms. This analysis will be conducted in a sub-group of 40
patients in two centers (Reims, Toulouse).
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
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Inclusion criteria
Patient with unruptured aneurysm
Patient older than 18 years
Aneurysm <= 15mms
Patient is willing and able to return for all follow-up visits required
by the protocol
• Patient understands the purpose and requirements of the study,
can make him/herself understood, and has provided informed
consent
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
• Exclusion criteria
•
•
•
•
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Intracranial hemorrhage in the 30 days before treatment
Dissecting or fusiform aneurysms
Aneurysms associated with an arteriovenous malformation
Intracranial tumor (except meningioma)
Aneurysms already treated by endovascular or neurosurgical route
Patients already treated for another aneurysm
Patients treated for multiple aneurysms during one procedure
Patients treated with flow diverters
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
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Patients protected by the law
Patients with stroke in the month before the treatment
Pregnant or nursing women
Allergy or contraindication to aspirin, clopidogrel, heparin, local or general
anesthesia
History of life-threatening allergy to contrast dye. If not life threatening and can be
effectively pretreated, patient can be enrolled at physician’s discretion
Active peptic ulcer disease, major systemic hemorrhage within 30 days, active
bleeding diathesis, platelets < 100,000, hematocrit < 30, INR > 1.5, clotting factor
abnormality that increases the risk of bleeding
Major surgery within previous 30 days or planned in the next 90 days after
enrollment
Enrollment in another study that would conflict with the current study
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
• Informed consent
All participants (or family) must provide written informed consent to
participate, which must be cosigned by a study investigator and
witness. The original signed informed consent form is placed in the
participant’s study binder, one copy is given to the participant, and
another copy is put in the participant’s medical record.
• Enrollment of participants
Inclusion will be consecutive in each center for patients who meet the
entrance criteria and accept to participate and sign consent. Once
the consent is completed, the patient will be enrolled.
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
• Pre-procedure
• ASA 150 (or 160) mg per day x 7 days, and clopidogrel 75 mg per day x 7
days
• Intra procedure
• Heparin: After femoral puncture, a bolus of iIV heparin weight adjusted (50
UI / kg) will be given followed by a continuous IV administration of 30
UI/kg/h.
• IIb / IIIa inhibitors agents, if needed in case of intra-luminal thrombosis
developing during the procedure.
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
• Post procedure
• ASA 150 (or 160) mg per day during 30 days
• In case of stenting ASA 150 (or 160) mg / day + clopidogrel 75mg / day
during 3 months followed by at least nine months treatment with aspirin
only.
• Heparin is reversed at the end of the procedure with protamine sulfate
60UI/kg. Heparin is reintroduced two hours after the procedure,
approximately at 10 UI/kg/h and adapted to maintain the activated clotting
time (ACT) between x 2 and 3 of normal.
• At 48 hours heparin is interrupted, followed by subcutaneous low molecular
weight heparin at a prophylactic dose.
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
• Aneurysms must be treated using TARGET coils (Boston Scientific).
All types of TARGET coils are authorized. Other coils are authorized
for no more than 10% length.
• The remodeling technique (Balloon assisted coiling) is authorized.
• Stenting is authorized (all stents authorized for aneurysm
treatment).
• Flow diverters are not authorized.
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
Follow up Procedure
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Post procedure
Clinical evaluation
Anatomic assessment
All adverse events
Hospital discharge
Clinical evaluation
All adverse events
30 days post procedure (+/- 7 days)
Clinical evaluation
All adverse events
1 year post procedure (+/- 90 days)
Clinical evaluation
Anatomic assessment
All adverse events
COBRAInvestigators
meeting- Octaneurysms
06,2010 Bologna
COBRA
Unruptured
Angiographic Follow up
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DSA at the end of procedure and by DSA and/or MRA at one year.
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Per exams, 6 views will be provided: frontal, lateral and working view, unsubstracted
non injected and substracted injected
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Anatomic evaluation will be performed by an independent core lab (2
neuroradiologists):
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Evaluation with Montreal scale at post procedure
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Aneurysm occlusion and recanalization rate at one year
COBRA- Investigators meeting- Oct 06,2010 Bologna
The answers from a Questionnaire
sent to potential investigators!!!
22/62 answers
COBRA- Investigators meeting- Oct 06,2010 Bologna
• Germany: 2/8
– C. Tashner, J. Fielher
• UK: 2/7
– D Mitra, J Byrne
• Sweden: 2/2
– M. Cronquist, M. Soederman
• Spain: 2/10
– M Pumar,F Ballenilla
• France: 14/35
– X Leclerc, H Brunel, J Sedat, F Ricolfi, L Spelle, P Courthéoux, D
Herbreteau, J Berge, S gallas, X Barreau, H Desal, R Beaujeux, J Moret, D
Trystram
COBRA- Investigators meeting- Oct 06,2010 Bologna
COBRA Questionnaire: Are you using Tranexamic acid in case of SAH?
COBRA- Investigators meeting- Oct 06,2010 Bologna
COBRA Questionnaire: when do you start heparinotherapy during EVT
of ruptured aneurysms? (1 double answer)
COBRA- Investigators meeting- Oct 06,2010 Bologna
COBRA Questionnaire: what is your usual heparin regimen? (1 double
answer)
COBRA- Investigators meeting- Oct 06,2010 Bologna
COBRA Questionnaire: do you reverse heparin at the end of the
procedure?
COBRA- Investigators meeting- Oct 06,2010 Bologna
COBRA Questionnaire: Postoperative protocol for heparin
COBRA- Investigators meeting- Oct 06,2010 Bologna
COBRA Questionnaire: Postoperative operative aspirin? (1 double
response)
COBRA- Investigators meeting- Oct 06,2010 Bologna
COBRA Questionnaire: COBRA protocol feasible in your centre?
COBRA- Investigators meeting- Oct 06,2010 Bologna
The comments, questions we have had from potential Investigators:
• Why only Target Coils?
• Heparin Intraoperative regimen ?
• When starting heparin ?
• Heparin reversal?
• Modalities of administration (bolus, continuous, both)
• Heparin Post-operative regimen ?
– Heparin
– LMWH
• Post-operative ASA ?