Worse Outcome in Stroke Patients Treated with rt-PA Without Early Reperfusion: Associated Factors

Translational Stroke Research, Nov 2017

Based on preclinical studies suggesting that recombinant tissue plasminogen activator (rt-PA) may promote ischemic brain injuries, we investigated in patients the possible risk of worse clinical outcome after rt-PA treatment as a result of its inability to resolve cerebral ischemia. Here, we designed a cohort study using a retrospective analysis of patients who received treatment with intravenous (4.5-h window) or intraarterial rt-PA, without or with thrombectomy. Controls were consecutive patients who did not receive recanalization treatment, who met all inclusion criteria. As a marker of reperfusion, we defined the variable of early neurological improvement as the difference between the score of the National Institute of Health Stroke Scale (NIHSS) (at admission and 24 h). The main variable was worsening of the patient’s functional situation in the first 3 months. To compare quantitative variables, we used Student’s t test or the Mann-Whitney test. To estimate the odds ratios of each independent variable in the patient’s worsening in the first 3 months, we used a logistic regression model. We included 1154 patients; 577 received rt-PA, and 577 served as controls. In the group of patients treated with rt-PA, 39.4% who did not present clinical reperfusion data developed worsening within 3 months after stroke compared with 3.5% of patients with reperfusion (P < 0.0001). These differences were not significant in the control group. In summary, administration of rt-PA intravenously or intraarterially without reperfusion within the first 24 h may be associated with a higher risk of functional deterioration in the first 3 months.

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Worse Outcome in Stroke Patients Treated with rt-PA Without Early Reperfusion: Associated Factors

Worse Outcome in Stroke Patients Treated with rt-PA Without Early Reperfusion: Associated Factors Ramón Iglesias-Rey 0 1 2 3 4 Manuel Rodríguez-Yáñez 0 1 2 3 4 Emilio Rodríguez-Castro 0 1 2 3 4 José Manuel Pumar 0 1 2 3 4 Susana Arias 0 1 2 3 4 María Santamaría 0 1 2 3 4 Iria López-Dequidt 0 1 2 3 4 Pablo Hervella 0 1 2 3 4 Clara Correa-Paz 0 1 2 3 4 Tomás Sobrino 0 1 2 3 4 Denis Vivien 0 1 2 3 4 Francisco Campos 0 1 2 3 4 Mar Castellanos 0 1 2 3 4 José Castillo 0 1 2 3 4 0 Inserm, Inserm, UMR-S U1237, Physiopathology and Imaging of Neurological diseases, GIP Cyceron, Caen Normandie University , 14073 Caen , France 1 Department of Neuroradiology, Clinical University Hospital, Universidade de Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS) , 15706 Santiago de Compostela , Spain 2 Clinical Neurosciences Research Laboratory, Department of Neurology, Clinical University Hospital, Universidade de Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS) , 15706 Santiago de Compostela , Spain 3 Department of Neurology, Biomedical Research Institute, University Hospital A Coruña , 15006 Corunna , Spain 4 CHU de Caen, Department of Clinical Research, Caen University Hospital , 14000 Caen , France Based on preclinical studies suggesting that recombinant tissue plasminogen activator (rt-PA) may promote ischemic brain injuries, we investigated in patients the possible risk of worse clinical outcome after rt-PA treatment as a result of its inability to resolve cerebral ischemia. Here, we designed a cohort study using a retrospective analysis of patients who received treatment with intravenous (4.5-h window) or intraarterial rt-PA, without or with thrombectomy. Controls were consecutive patients who did not receive recanalization treatment, who met all inclusion criteria. As a marker of reperfusion, we defined the variable of early neurological improvement as the difference between the score of the National Institute of Health Stroke Scale (NIHSS) (at admission and 24 h). The main variable was worsening of the patient's functional situation in the first 3 months. To compare quantitative variables, we used Student's t test or the Mann-Whitney test. To estimate the odds ratios of each independent variable in the patient's worsening in the first 3 months, we used a logistic regression model. We included 1154 patients; 577 received rt-PA, and 577 served as controls. In the group of patients treated with rt-PA, 39.4% who did not present clinical reperfusion data developed worsening within 3 months after stroke compared with 3.5% of patients with reperfusion (P < 0.0001). These differences were not significant in the control group. In summary, administration of rt-PA intravenously or intraarterially without reperfusion within the first 24 h may be associated with a higher risk of functional deterioration in the first 3 months. Blood-brain barrier; Critical care; Hemorrhage transformation; Ischemic stroke; Prognosis Introduction Stroke is the second leading cause of death in developed countries, the second leading cause of dementia, and the leading cause of major disability in adults, with an increasing incidence because of the progressive aging of the population in such countries. Since 1995, despite its complications, recombinant tissue plasminogen activator (rt-PA) administered intravenously alone or subsequently in combination with intraarterial administration or with mechanical thrombectomy is the only drug treatment for acute ischemic stroke [ 1–7 ]. Besides the unquestionable benefit from its thrombolytic activity, consistent evidence has accumulated on the neurotoxic effect of rt-PA both in vitro and in vivo, including in experimental models of cerebral ischemia [ 8–14 ]. Mechanisms by which rt-PA causes these neurotoxic effects have not been fully elucidated, mainly due to their multifactorial and time-dependent activity. The clinical evidence on the neurotoxicity associated with rt-PA treatment following ischemic stroke is still debated, and it is of crucial importance to reduce risks after administration of the thrombolytic agent for a better patient management [ 15, 16 ]. In the present work, we thus decided to set-up a clinical study based on the hypothesis that rt-PA could be a BJanus^ drug. Our hypothesis was based on two possible scenarios: (1) If the thrombolytic activity of rt-PA is effective and cerebral ischemia rapidly resolved, the blood-brain barrier remains intact with the rt-PA maintained within the vascular compartment, thus leading to a better clinical outcome; (2) if the rt-PA cannot play its thrombolytic action thus leading to a prolonged cerebral ischemia, rt-PA could then enhance damages of the blood-brain barrier and of the cerebral parenchyma, thus leading to a worse clinical outcome [17]. Materials and Methods Study Design A retrospective cohort study (n = 1154) was designed using a prospective registry of acute ischem (...truncated)


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Ramón Iglesias-Rey, Manuel Rodríguez-Yáñez, Emilio Rodríguez-Castro, José Manuel Pumar, Susana Arias, María Santamaría, Iria López-Dequidt, Pablo Hervella, Clara Correa-Paz, Tomás Sobrino, Denis Vivien, Francisco Campos, Mar Castellanos, José Castillo. Worse Outcome in Stroke Patients Treated with rt-PA Without Early Reperfusion: Associated Factors, Translational Stroke Research, 2017, pp. 1-9, DOI: 10.1007/s12975-017-0584-9