Association between Time and Severe Hypoperfusion with Risk of Hemorrhagic Transformation in Stroke Patients

Introduction: Perfusion imaging studies show a substantially increased risk of hemorrhagic transformation (HT) in severely hypoperfused tissue. Preclinical evidence indicates that ischemic damage is influenced not only by the degree of hypoperfusion but also by the duration of exposure to that hypoperfused state. We aim to investigate the association of time and severe hypoperfusion with parenchymal hematoma (PH) in ischemic stroke and explore whether there is a combined effect of the two variables on PH. Methods: Data are from the ESCAPE-NA1 trial, which evaluated the effect of nerinetide in large vessel occlusion patients treated with thrombectomy. This study included patients with some degree of recanalization (expanded Thrombolysis in Cerebral Infarct [eTICI] >0) and available baseline CT perfusion. Severe hypoperfusion was defined as at least 1mL volume of relative cerebral blood flow (rCBF)<20%. We assess 24-hour imaging for the presence of PH, according to Heidelberg bleeding criteria. Univariable and multivariable logistic regression analyses, including interaction terms, were used to assess the effect of time and severe hypoperfusion on outcomes. Results: Out of 1105 patients from ESCAPE-NA1, 396 (35.8%) were included. The median age was 70 years (IQR=59.8-79.2), 202 (51%) were females, and 50 (12.6%) experienced PH. Onset-to-imaging time (adjusted OR 1.04 [95%CI=1.01-1.06] per 15-minute increase) and the presence of severe hypoperfusion (adjusted OR 2.87 [95%CI=1.47-5.63]) were the only variables associated with PH in multivariable analysis. No significant interaction effect of time and severe hypoperfusion on PH was found. The presence of severe hypoperfusion had a negative predictive value of 98% and a positive predictive value of 39.4% for predicting PH in patients presenting within three hours and after six hours from symptom onset, respectively. Conclusion: Both severe hypoperfusion and time affect the risk of hemorrhagic transformation. However, the interaction between these two variables was not statistically significant, indicating that their effects on hemorrhagic transformation risk are not dependent on each other. Analyzing these variables may help identify patients with a leaky, severely compromised blood-brain barrier in the ischemic core—a “leaky core.”