1. COBRA- Investigators meeting- Oct 06,2010 Bologna

2. 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 !

3. COBRA- Investigators meeting- Oct 06,2010 Bologna 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% Clarity Study 782 Consecutive ruptured aneurysms

4. COBRA- Investigators meeting- Oct 06,2010 Bologna TE: 7.1% IOR: 2.6% Atena Study 739 Consecutive unruptured aneurysms in 649 Patients

5. 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

6. COBRA- Investigators meeting- Oct 06,2010 Bologna COBRA Ruptured aneurysms

7. COBRA- Investigators meeting- Oct 06,2010 Bologna 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. COBRA Ruptured aneurysms

8. COBRA- Investigators meeting- Oct 06,2010 Bologna 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. COBRA Ruptured aneurysms

9. COBRA- Investigators meeting- Oct 06,2010 Bologna 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 COBRA Ruptured aneurysms

10. COBRA- Investigators meeting- Oct 06,2010 Bologna 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. COBRA Ruptured aneurysms

11. COBRA- Investigators meeting- Oct 06,2010 Bologna 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) COBRA Ruptured aneurysms

12. COBRA- Investigators meeting- Oct 06,2010 Bologna 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. COBRA Ruptured aneurysms

13. COBRA- Investigators meeting- Oct 06,2010 Bologna INCLUSION CRITERIA 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 COBRA Ruptured aneurysms

14. COBRA- Investigators meeting- Oct 06,2010 Bologna 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 COBRA Ruptured aneurysms

15. COBRA- Investigators meeting- Oct 06,2010 Bologna 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 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 COBRA Ruptured aneurysms

16. COBRA- Investigators meeting- Oct 06,2010 Bologna 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. COBRA Ruptured aneurysms

17. COBRA- Investigators meeting- Oct 06,2010 Bologna 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 COBRA Ruptured aneurysms

18. COBRA- Investigators meeting- Oct 06,2010 Bologna 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. COBRA Ruptured aneurysms

19. COBRA- Investigators meeting- Oct 06,2010 Bologna 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 Ruptured aneurysms

20. COBRA- Investigators meeting- Oct 06,2010 Bologna Clinical follow-up Patients will be evaluated preoperatively, postoperatively, at hospital discharge, and at 1 month, Clinical evaluations will be performed by a member of the neurovascular blinded to whether the patient received aspirin, but not by the treating physician. Preoperatively: WFNS and GCS Postoperatively: GCS, mRs Anatomic follow-up 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

21. 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 life- threatening 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.

22. 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.

23. 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.

24. 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.

25. 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

26. 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

27. 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

28. 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

29. COBRA- Investigators meeting- Oct 06,2010 Bologna COBRA Unruptured aneurysms

30. COBRA- Investigators meeting- Oct 06,2010 Bologna The primary objective: To determine the rate and clinical consequences of TE, IOR and post- procedure 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 COBRA Unruptured aneurysms

31. COBRA- Investigators meeting- Oct 06,2010 Bologna 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 COBRA Unruptured aneurysms

32. COBRA- Investigators meeting- Oct 06,2010 Bologna 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 COBRA Unruptured aneurysms

33. COBRA- Investigators meeting- Oct 06,2010 Bologna 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). COBRA Unruptured aneurysms

34. COBRA- Investigators meeting- Oct 06,2010 Bologna Medico-Economic Endpoint A medico-economic study will be conducted to determine the in- hospital 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). COBRA Unruptured aneurysms

35. COBRA- Investigators meeting- Oct 06,2010 Bologna 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 COBRA Unruptured aneurysms

36. COBRA- Investigators meeting- Oct 06,2010 Bologna Exclusion criteria 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 COBRA Unruptured aneurysms

37. COBRA- Investigators meeting- Oct 06,2010 Bologna 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 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 COBRA Unruptured aneurysms

38. COBRA- Investigators meeting- Oct 06,2010 Bologna 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. COBRA Unruptured aneurysms

39. COBRA- Investigators meeting- Oct 06,2010 Bologna 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. COBRA Unruptured aneurysms

40. COBRA- Investigators meeting- Oct 06,2010 Bologna 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. COBRA Unruptured aneurysms

41. COBRA- Investigators meeting- Oct 06,2010 Bologna 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. COBRA Unruptured aneurysms

42. COBRA- Investigators meeting- Oct 06,2010 Bologna Follow up Procedure 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 COBRA Unruptured aneurysms

43. COBRA- Investigators meeting- Oct 06,2010 Bologna Angiographic Follow up DSA at the end of procedure and by DSA and/or MRA at one year. Per exams, 6 views will be provided: frontal, lateral and working view, unsubstracted non injected and substracted injected Anatomic evaluation will be performed by an independent core lab (2 neuroradiologists): Evaluation with Montreal scale at post procedure Aneurysm occlusion and recanalization rate at one year COBRA Unruptured aneurysms

44. COBRA- Investigators meeting- Oct 06,2010 Bologna The answers from a Questionnaire sent to potential investigators!!! 22/62 answers

45. 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

46. COBRA- Investigators meeting- Oct 06,2010 Bologna COBRA Questionnaire: Are you using Tranexamic acid in case of SAH?

47. COBRA- Investigators meeting- Oct 06,2010 Bologna COBRA Questionnaire: when do you start heparinotherapy during EVT of ruptured aneurysms? (1 double answer)

48. COBRA- Investigators meeting- Oct 06,2010 Bologna COBRA Questionnaire: what is your usual heparin regimen? (1 double answer)

49. COBRA- Investigators meeting- Oct 06,2010 Bologna COBRA Questionnaire: do you reverse heparin at the end of the procedure?

50. COBRA- Investigators meeting- Oct 06,2010 Bologna COBRA Questionnaire: Postoperative protocol for heparin

51. COBRA- Investigators meeting- Oct 06,2010 Bologna COBRA Questionnaire: Postoperative operative aspirin? (1 double response)

52. COBRA- Investigators meeting- Oct 06,2010 Bologna COBRA Questionnaire: COBRA protocol feasible in your centre?

53. 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 ?