TicAgreLor Versus Placebo to Prevent Cerebral ISCHemia in anEuRysmal Low Grade SAH A Double Blinded Randomised Controlled Study

After aSAH, ischemic complications such as peri-procedural TEE and DCI prevalence are as high as 15 and 30% of the patients respectively. They are the main causes of disability in patients who survive the initial bleeding. The diagnoses of TEE and DCI may be difficult in patients experiencing high grade aSAH contrariwise to low grade where clinical exam and reliable imaging of brain ischemia could be performed. In addition, TEE/DCI dramatically impact the prognosis of these patients who had no/minor initial deficit. Platelet activation and thrombo-inflammatory mechanisms play a critical role in the pathophysiology of TEE and DCI through multiple pathways. Several APD have been evaluated to mitigate TEE/DCI risk with heterogeneous results. A recent metanalysis suggested that APD could reduce TEE incidence by 13 %. Interestingly patients receiving mono or dual APD just before aneurysmal repair did not experience an increased hemorrhagic risk. Regarding DCI, aspirin failed to demonstrate any benefit in an European randomized controlled trial while 3 recent meta-analyses suggested that APD use may be associated with a relative risk reduction of 40-50%. Hence, in the absence of positive trials no APD use is not recommended for the management of aSAH. Compared to previous APD used in aSAH, Ticagrelor, a reversible P2Y12 receptor inhibitor, has a promising profile to control TEE/ DCI: stronger and shorter antiplatelet action as well as vasodilatory and anti-inflammatory effects.

Two hundred and seventy-four patients will be randomized 1:1 in Ticagrelor or placebo group within 72hrs of aneurysm rupture in a multicentre prospective double-blind, parallel group study. Ticagrelor/placebo will be administered orally just before the endovascular treatment of the aneurysm with a loading dose of 180 mg, followed by 90 mg twice a day during 2 weeks. We will assess a composite primary end point based on the occurrence of ischemic complications: peri-procedural asymptomatic and symptomatic TEE and/or neurological deterioration due to DCI. During the first 24H, TEE is defined by clotting or arterial occlusion on angiography during endovascular procedure and/or 24hrs-MRI infarctions and/or neurological deterioration defined by the worsening ≥2pts from baseline on NIHSS performed immediately after the intervention, then every 6 hours. From day 2 to 15, multi daily clinical monitoring using NIHSS will be performed to assess the occurrence of neurological deterioration due to DCI, defined as worsening ≥2pts on NIHSS, lasting for at least 2hrs. A brain imaging- MRI recommended- is needed in the case of neurological deterioration to confirm its ischemic mechanism. Rescue therapies for DCI will be feasible according to a decisional algorithm. Systematic MRI will be performed within the 24hrs of the endovascular procedure and 15 days after randomization in order to detect, confirm and quantify cerebral infarcts. At 3 months, visit will include functional outcome with the mRS and the GOSE, cognitive functions with the Montreal Cognitive Assessment (MoCA) and quality of life using EQ-5D. Any hemorrhagic complication related to SAH (rebleeding during the procedure, hydrocephalus requiring ventricular drain, intracerebral hemorrhage) other major bleedings and side effects of the treatment such as dyspnea will be carefully monitored and reported.

Inclusion criteria

• Age 18 - 80 years old
• Low grade aneurysmal subarachnoid hemorrhage defined by a WFNS 1-3
• Aneurysmal treatment planned to be completed within 72 h after rupture
• Sacciform aneurysm diameter ≥ 4 mm
• Ruptured aneurysm treatable by endovascular, endo-saccular technic (stent and flow diverters are not allowed). If the aneurysm responsible of the SAH is difficult to identify, several aneurysms that may be related to the SAH can be treated during the procedure.
• Affiliated person or beneficiary of a social security scheme.
• Free, informed and written consent signed by the participant or truthworthy/proxy representative and the investigator (at the latest on the day of inclusion and before any examination required by the research).

Exclusion criteria

• Poor grade aSAH defined as WFNS 4 and 5
• Fusiform, dissecting, thrombosed aneurysms and aneurysm associated with brain arteriovenous malformation
• Associated unruptured aneurysm requiring treatment within 3 months
• History of intracranial hemorrhage within the past 6 months
• Intraparenchymal hematoma associated with SAH -Ongoing antiplatelet drug
• Acute symptomatic hydrocephalus or ventricular derivation
• Intra-ventricular hemorrhage on admission CT scan, filling >50% of both lateral ventricles and 3rd and 4th ventricles
• Pre aSAH mRS ≥
• Active pathological bleeding and notably recent extra cranial hemorrhage (within previous 30 days), gastrointestinal hemorrhage within the past 6 months, or major surgery within 30 days
• Other contra-indications to Ticagrelor: hypersensitivity to the active substance or to any of the excipients,
• Severe hepatic or kidney failure,
• Concomitant administration of strong CYP3A4 inhibitors(for ex ketoconazole, clarithromycine, nefazodone, ritonavir and atazanavir) drugs that interfered with P-glycoprotein transporter
• Respiratory failure, asthma , obstructive broncho-pneumopathy
• Pregnant and breastfeeding women
• Patients under guardianship or other legal protection, deprived of their liberty by judicial or administrative decision