Emerging Therapy Critiques Section Editors: Gustavo Saposnik, MD, and Daniel Stribian, MD, PhD
Desmoteplase After Ischemic Stroke in Patients With Occlusion or High-Grade Stenosis in Major Cerebral Arteries Perttu J. Lindsberg, MD, PhD; Valeria Caso, MD, PhD
T
he beneficial effects of intravenous thrombolysis in ischemic stroke, reperfusion and improved outcome, have been directly correlated to time from onset to treatment. Recanalization of occluded intracranial arteries by tissue-type plasminogen activator (alteplase) has been shown to be effective only for the first few hours after symptom onset. Measured by transcranial Doppler monitoring, the effect of alteplase decreases over time, and treatment delay beyond 4.5 hours predicts lack of recanalization, especially in distal occlusions.1 Will the more fibrin-specific and longer acting fibrinolytics correct this problem in patients admitted beyond the accepted thrombolysis time window of ≤3 to 4.5 hours? A recent report by Albers et al2 provided the outcomes of patients treated with intravenous desmoteplase to reverse occlusion or high-grade stenosis of major cerebral arteries (Desmoteplase in Acute Ischemic Stroke [DIAS]-3 trial) but failed to give support to this idea. This first prospective, randomized, controlled phase 3 trial was designed to detect a possible benefit of a single intravenous bolus of 90 µg/kg of desmoteplase given 3 to 9 hours after onset in patients with confirmed major artery occlusion without substantial ischemic damage.2 Desmoteplase failed to improve functional outcomes at 90 days. It did not increase the rates of symptomatic brain hemorrhage, symptomatic brain edema, and death. On the other hand, significant (nominal P1/3 of the middle cerebral artery territory or >1/2 of the anterior cerebral artery or posterior cerebral artery territories. Other exclusion criteria were parenchymal hyperintensity on fluid-attenuated inversion recovery, T2*, or echo-planar imaging-T2 images or marked hypodensity on CT as indicators of subacute infarction or enhancement with morphological features suggesting that the lesion is >9 hours old. In the rating of the full analysis cohort (n=473), the centralized imaging committee had to exclude 8% (36) of the patients because of a lack of qualifying occlusion, another 8% (40) for ischemic lesion size >1/3 of the middle cerebral artery territory, 3% (12) for the presence of intracranial or subarachnoid hemorrhage, and finally 3% (16) for hyperintensity on fluid-attenuated inversion recovery or marked CT hypodensity.2 Similar difficulties in applying study imaging criteria congruently by study investigators and central imaging committees are not exceptional. In a recent study on thrombectomy performed within 8 hours of symptom onset in ischemic stroke (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within 8 Hours of Symptom Onset [REVASCAT]), investigators observed discrepancies between central and investigator-adjudicated Alberta Stroke Program Early Computed Tomography Scores and vascular occlusion sites. Centrally adjudicated imaging studies had shown that 25% of patients had Alberta Stroke Program Early Computed Tomography Scores of ≤6 and 9% had occlusions in the M2 segment; both were
Received November 14, 2015; final revision received January 9, 2016; accepted January 11, 2016. From the Research Programs, Molecular Neurology, Biomedicum Helsinki, and Clinical Neurosciences, Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland (P.J.L.); and Stroke Unit, Department of Internal and Cardiovascular Medicine, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy (V.C.). Correspondence to Perttu J. Lindsberg, MD, PhD, Clinical Neurosciences, Neurology, Helsinki University Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland. E-mail [email protected] (Stroke. 2016;47:00-00. DOI: 10.1161/STROKEAHA.115.011495.) © 2016 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.115.011495
Downloaded from http://stroke.ahajournals.org/ at CONS CALIFORNIA DIG LIB on February 17, 2016 1
2 Stroke March 2016 exclusion criteria.4 Clearly, this problem undermines the investigational success by degrading the effective sample sizes and calls for increased consideration in every future study where detailed imaging study entry criteria are important. Patient selection by imaging modality has also been reported to play a role in detecting treatment effect in a planned post hoc subgroup analysis.2 The improved response to desmoteplase in patients with
Desmoteplase After Ischemic Stroke in Patients With Occlusion or High-Grade Stenosis in Major Cerebral Arteries Perttu J. Lindsberg, MD, PhD; Valeria Caso, MD, PhD
T
he beneficial effects of intravenous thrombolysis in ischemic stroke, reperfusion and improved outcome, have been directly correlated to time from onset to treatment. Recanalization of occluded intracranial arteries by tissue-type plasminogen activator (alteplase) has been shown to be effective only for the first few hours after symptom onset. Measured by transcranial Doppler monitoring, the effect of alteplase decreases over time, and treatment delay beyond 4.5 hours predicts lack of recanalization, especially in distal occlusions.1 Will the more fibrin-specific and longer acting fibrinolytics correct this problem in patients admitted beyond the accepted thrombolysis time window of ≤3 to 4.5 hours? A recent report by Albers et al2 provided the outcomes of patients treated with intravenous desmoteplase to reverse occlusion or high-grade stenosis of major cerebral arteries (Desmoteplase in Acute Ischemic Stroke [DIAS]-3 trial) but failed to give support to this idea. This first prospective, randomized, controlled phase 3 trial was designed to detect a possible benefit of a single intravenous bolus of 90 µg/kg of desmoteplase given 3 to 9 hours after onset in patients with confirmed major artery occlusion without substantial ischemic damage.2 Desmoteplase failed to improve functional outcomes at 90 days. It did not increase the rates of symptomatic brain hemorrhage, symptomatic brain edema, and death. On the other hand, significant (nominal P1/3 of the middle cerebral artery territory or >1/2 of the anterior cerebral artery or posterior cerebral artery territories. Other exclusion criteria were parenchymal hyperintensity on fluid-attenuated inversion recovery, T2*, or echo-planar imaging-T2 images or marked hypodensity on CT as indicators of subacute infarction or enhancement with morphological features suggesting that the lesion is >9 hours old. In the rating of the full analysis cohort (n=473), the centralized imaging committee had to exclude 8% (36) of the patients because of a lack of qualifying occlusion, another 8% (40) for ischemic lesion size >1/3 of the middle cerebral artery territory, 3% (12) for the presence of intracranial or subarachnoid hemorrhage, and finally 3% (16) for hyperintensity on fluid-attenuated inversion recovery or marked CT hypodensity.2 Similar difficulties in applying study imaging criteria congruently by study investigators and central imaging committees are not exceptional. In a recent study on thrombectomy performed within 8 hours of symptom onset in ischemic stroke (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within 8 Hours of Symptom Onset [REVASCAT]), investigators observed discrepancies between central and investigator-adjudicated Alberta Stroke Program Early Computed Tomography Scores and vascular occlusion sites. Centrally adjudicated imaging studies had shown that 25% of patients had Alberta Stroke Program Early Computed Tomography Scores of ≤6 and 9% had occlusions in the M2 segment; both were
Received November 14, 2015; final revision received January 9, 2016; accepted January 11, 2016. From the Research Programs, Molecular Neurology, Biomedicum Helsinki, and Clinical Neurosciences, Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland (P.J.L.); and Stroke Unit, Department of Internal and Cardiovascular Medicine, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy (V.C.). Correspondence to Perttu J. Lindsberg, MD, PhD, Clinical Neurosciences, Neurology, Helsinki University Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland. E-mail [email protected] (Stroke. 2016;47:00-00. DOI: 10.1161/STROKEAHA.115.011495.) © 2016 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.115.011495
Downloaded from http://stroke.ahajournals.org/ at CONS CALIFORNIA DIG LIB on February 17, 2016 1
2 Stroke March 2016 exclusion criteria.4 Clearly, this problem undermines the investigational success by degrading the effective sample sizes and calls for increased consideration in every future study where detailed imaging study entry criteria are important. Patient selection by imaging modality has also been reported to play a role in detecting treatment effect in a planned post hoc subgroup analysis.2 The improved response to desmoteplase in patients with
