Symptomatic Hemorrhagic Complications in Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III Clinical Trial (CLEAR III): A Posthoc Root-Cause Analysis

• Published in: Neurosurgery Vol. 83; no. 6; pp. 1260 - 1268
• Main Authors: Fam, Maged D, Stadnik, Agnieszka, Zeineddine, Hussein A, Girard, Romuald, Mayo, Steven, Dlugash, Rachel, McBee, Nichol, Lane, Karen, Mould, W Andrew, Ziai, Wendy, Hanley, Daniel, Awad, Issam A
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.12.2018; Copyright by the Congress of Neurological Surgeons; Wolters Kluwer Health, Inc
• Subjects: Aged; Aged, 80 and over; Cerebral Intraventricular Hemorrhage - chemically induced; Cerebral Intraventricular Hemorrhage - drug therapy; Clinical trials; Clinical Trials, Phase III as Topic; Double-Blind Method; Female; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - adverse effects; Hemorrhage; Humans; Intraventricular hemorrhage; Male; Middle Aged; Neurosurgery; Research—Human—Clinical Studies; Risk Factors; Root Cause Analysis; Thrombolytic Therapy - adverse effects; Thrombolytic Therapy - methods; Tissue plasminogen activator; Tissue Plasminogen Activator - administration & dosage; Tissue Plasminogen Activator - adverse effects; Treatment Outcome; Maryland; Intraventricular hemorrhage; Rebleeding; Complications; Thrombolysis; Hemorrhage
• ISSN: 0148-396X; 1524-4040; 1524-4040
• DOI: 10.1093/neuros/nyx587

Abstract BACKGROUND As intraventricular thrombolysis for intraventricular hemorrhage (IVH) has developed over the last 2 decades, hemorrhagic complications have remained a concern despite general validation of its safety in controlled trials in the Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-IVH) program. OBJECTIVE To analyze factors associated with symptomatic bleeding following IVH with and without thrombolysis in conjunction with the recently completed CLEAR III trial. METHODS We reviewed safety reports on symptomatic bleeding events reported during the first year after randomization among subjects enrolled in the CLEAR III trial. Clinical and imaging data were retrieved through the trial database as part of ongoing quality and safety monitoring. A posthoc root-cause analysis was performed to identify potential factors predisposing to rebleeding in each case. Cases were classified according to onset of rebleeding (during dosing, early after dosing and delayed), the pattern of bleeding, and treatment rendered (alteplase vs saline). RESULTS Twenty subjects developed a secondary symptomatic intracranial hemorrhage constituting 4% of subjects. Symptomatic rebleeding events occurred during the dosing protocol (n = 9, 67% alteplase), early after the protocol (n = 5, 40% alteplase), and late (n = 6, 0% alteplase). Catheter-related hemorrhages were the most common (n = 7, 35%) followed by expansion or new intraventricular (n = 6, 30%) and intracerebral (n = 5, 25%) hemorrhages. Symptomatic hemorrhages during therapy resulted from a combination of treatment- and patient-related factors and were at most partially attributable to alteplase. Rebleeding after the dosing protocol primarily reflected patients’ risk factors. CONCLUSION Intraventricular thrombolysis marginally increases the overall risk of symptomatic hemorrhagic complications after IVH, and only during the treatment phase.