CLEAR III TRIAL : UPDATE ON SURGICAL MATTERS THAT MATTER CLEAR Surgical Center Team July 2011
Trial Enrollment Status Updates Insert latest enrollment update chart from most recent CLEAR newsletter
Imaging Studies for Etiology of Intracerebral Intraventricular Hemorrhage
Vascular Lesions and Etiology of ICH/IVH High prevalence in younger patients (up to 50% of cases < 50 years of age) May cause ICH/IVH at any age Distribution of blood and other features on diagnostic CT may suggest, but not totally establish/exclude May include cerebrovascular malformations, aneurysms, arterial dissection, venous occlusive disease, and other vasculopathies
Types of Lesions Delineated on CTA Aneurysms (>2-3mm) Cerebrovascular malformations (arterial, venous, maybe cavernous) Occlusive arterial lesions (Moyamoya, sickle cell arteriopathy) Dilated veins (fistulae)
Types of Lesions Delineated on MR (MRI, MRA, Gadolinium, special sequences)* Many of the same as the CTA Lesser sensitivity than CTA for AVMs and aneurysms Greater sensitivity than CTA for cavernous malformations Tumors Evidence of brain ischemia Hemorrhagic angiopathies * May be performed without Gadolinium if renal failure or allergies
Types of lesions found on Catheter Angiogram Aneurysms and AVMs too small to be seen on CTA/MRA (or to confirm CTA/MRA)
CLEAR Protocol CLEAR III is not designed to test safety/effectiveness of thrombolysis in the setting of known cerebrovascular lesion as the source of hemorrhage Excluding underlying cerebrovascular etiology is a requirement of the CLEAR protocol Investigators are given leeway (options) in choosing appropriate studies for individual case, but looking for and excluding an etiology are REQUIRED.
Take Home Message CTA is advised in EVERY case except: Renal failure Severe allergy MRI/MRA is advised if CTA not done, tumor, ischemia or cavernous angiomas are suspected, or if particular question remains after CTA Catheter angiogram is advised if there is a question on CTA or MRI/MRA (consider catheter angiogram in every young patient <40-50 years of age)
EXAMPLES (REAL CASES FROM FIRST 120 CASES IN CLEAR III) 177 cases were excluded because of vascular etiology among 3197 cases screened
Screen Failures by Category Group Category N % (by group) Vascular* 177 76 % Tumor 26 11 % Radiographically Identifiable Exclusions (n = 234) Midbrain / Infratentorial 13 6 % Severe SAH 9 4 % Hemorrhagic Conversion 9 4 % Non-radiographically Identifiable Exclusions (n = 2963) (other) Ɨ 2963 100 % *Vascular includes aneurysm, AVM, Moyamoya, Dural AV fistula, and other vascular lesions Ɨ (other) age, traumatic injury, pregnancy status, historical mrs score, etc. (current data as of 7/17/2011)
Radiologic Screen Failures by Category
Arteriovenous Malformation 1 51 year old female with suspicious CTA with asymmetric vessels and no clear nidus, so angiogram done revealing an AVM Right lenticulostriate AVM with early draining vein and intra-nidal aneurysm Excluded from CLEAR
Arteriovenous Malformation 2 26 year old, underwent MRI/MRA that did not reveal a definite lesion Catheter angiogram done in view of high likelihood of etiology in young patient Angiogram confirmed small thalamic AVM and treated with embolization. Excluded from CLEAR.
Arteriovenous Malformation 3 61 year old hypertensive female with no definite parenchymal bleed source (primary IVH), had an abnormal CTA
Arteriovenous Malformation 3 Angiogram done confirming an AVM, with feeding artery aneurysm, emergently embolized Excluded from CLEAR; AGE IS NOT A GUARANTEE AGAINST VASCULAR ETIOLOGY
Moyamoya 39 year old with IVH, caudate bleed and hx of cocaine use enrolled without a CTA or other etiologic screen* CTA done after enrollment, and dosing, demonstrated basal arterial occlusions and Moyamoya collaterals Catheter angiogram confirmed diffuse Moyamoya and associated aneurysms. Dosing was stopped in patient and being followed up closely * A protocol deviation
ACom Aneurysm 34 year old patient with ICH and IVH, some basal subarachnoid extension Confirmed ACom aneurysm by angiogram and treated with coiling
Mycotic Aneurysm 50 year old with subtle abnormal contrast enhancement on CTA Mycotic aneurysm confirmed on angiogram and treated with coiling
Etiology of ICH/IVH You will not see if you don t look Help us not miss ANY case where thrombolysis might be unsafe You won t be blamed for screening, but you might regret short cuts
Midbrain Extension and Eligibility Nuances of exclusion criterion
Midbrain extension clarification A minor tail into the rostral midbrain is not an exclusion Thalamic bleeds with apparent midbrain extension that do not have overt midbrin signs (dilated nonreactive pupils, extensor posturing, downward gaze) are eligible for participation in the study. Patients with transient occulomotor dysfunction are eligible for participation. Note: Patients with a posterior fossa ICH or cerebellar hematomas are ineligible. This has been clarified in v3 of the protocol
Indications for first and second EVD placements
First EVD catheter placement indications Acute obstructive hydrocephalus following IVH causing high ICP Even though ICP can be managed medically with sedation and osmotic diuretics, such management is often insufficient to reduce ICP and those settings call for EVD placement Therefore, first catheter placements are often put into the less involved (contralateral) ventricle
Second catheter placement indications Clot producing trapped ventricles Clinically important shifts Pan-ventricular enlargement with effacement/ischemia Typically occurs with larger IVH > 40 ml
Catheter management
Management clarifications During screening If catheter clogs and the patient is in screening for the study, the patient cannot receive t-pa Saline flush is acceptable Use of t-pa during screening excludes patient from participation During dosing If catheter clogs and needs replacement: Try to wait 24 hours prior to removal, unless medically necessary Send post-replacement CT images for SC review
Subject excluded from CLEAR: t-pa given during screening the residents gave rt-pa and thought that was all that was needed to enroll a subject into CLEAR III yea we gave rt-pa to flush the catheter, where does that state that s exclusionary in the protocol? so the neurosurgical team gave rt-pa because they didn t want to place a second catheter and randomize the patient
Take home points for catheter management The use of rt-pa flushes in an EVD are not part of standard of care, and are not an FDA approved indication of rt-pa Intraventricular rt-pa is being tested in this trial, it is the experimental test article, and cannot be used off-protocol in an enrolled or eligible subject
Bleeding expansion/stabilization
IVH stability/expansion Width of the lateral ventricle most compromised by blood clot must not increase by > 2 mm (allowing for movement of blood under influence of gravity) If the clot is not stable (i.e., difference is > 2 mm), a repeat CT scan must be performed at least 12 hours after the scan revealing IVH expansion, and compared to demonstrate further stability/expansion
ICH stability/expansion ICH must be 30 ml on initial presentation Difference must be 5 cc on CT scan repeated for required 6h stability as determined by the (AxBxC)/2 method (total ICH volume must not exceed 35 ml on pre-randomization stability scans) If the clot is not stable (i.e., difference is > 5 ml), a repeat CT scan must be performed at least 12 hours later and compared to the CT scan revealing bleed expansion If the size stabilizes (i.e., enlargement 5 ml) and remains 35 ml, the patient is eligible
Catheter tract stability/expansion Catheter tract bleeding must be < 5 ml on CT scan for stability (including any bleeding at the entry site or along the catheter tract that is 5 mm in diameter seen on any CT slice, is seen on > 2 slices, or is > 5 ml) If a catheter tract hemorrhage is present on the CT scan done after EVD placement and is > 5 ml or > 5 mm, obtain a repeat CT scan 12 hours later. If the size stabilizes (i.e., enlargement < 5 ml or < 5 mm between 2 sequential CT scans), the patient is eligible.
Take home message- stability/expansion Importance of careful scrutinizing of ALL diagnostic and stability scans during screening period and filling out CT scan forms in real time
Research versus best clinical practice A review of the protocol
Best clinical practice Placement of initial EVD for obstructive IVH* Placement of second EVD in cases of casting/trapping/mass effect-shift Daily CT scans to assess clot for first few days after IVH (during test article administration) * Ziai et al., 2009
May be considered research-related Placement of second EVD, when first EVD functions for ICP control, but is otherwise suboptimal for administration of test article (catheter perforations not in ventricle) Required stabilization periods* 6 Hours: Between EVD placement(s) and stability CTs Replacement of catheter Second catheter placed 12 hours: Catheter tract hemorrhage > 5ml (wait 12 hours until next dose is given) 24 Hours: > 2 passes for catheter placement If dosing has begun, any catheter manipulation (removal, 2 nd catheter placement) * May be justified clinically
May be considered research-related What if patient looks good clinically despite obstructive IVH Widely varying practice patterns up front EVD versus EVD if/when patient worsens REMEMBER--- Obstructive IVH is correlated with worse ICH outcome, at all GCS strata; enhanced IVH clearance is the primary intervention being tested in CLEAR III to improve outcome If patient meets inclusion criteria otherwise, frank discussion with family about clinical equipoise Up front EVD is the only opportunity to benefit from potentially enhanced IVH clearance.
Questions?