Original Paper Received: January 26, 2015 Accepted: March 23, 2015 Published online: May 14, 2015
Cerebrovasc Dis 2015;40:3–9 DOI: 10.1159/000381866
Thrombolysis for Acute Minor Stroke: Outcome and Barriers to Management Results from the RESUVAL Stroke Network
Chloé Laurencin a, f Frédéric Philippeau b, f Karine Blanc-Lasserre c, f Anne-Evelyne Vallet d, f Serkan Cakmak e, f Laura Mechtouff a, f Tae-Hee Cho a, f Thomas Ritzenthaler a, f Elodie Flocard f Magali Bischoff f Carlos El Khoury f Norbert Nighoghossian a, f Laurent Derex a, f
a Department
of Neurology, Stroke Unit, Neurological Hospital, University of Lyon, Lyon, b Department of Neurology, Stroke Unit, Hospital of Bourg-en-Bresse, Bourg-en-Bresse, c Department of Neurology, Stroke Unit, Hospital of Valence, Valence, d Department of Neurology, Stroke Unit, Hospital of Vienne, Vienne, e Department of Neurology, Stroke Unit, Hospital of Villefranche-sur-Saône, Villefranche-sur-Saône, f RESUVAL Stroke Network, Lyon, France
Abstract Background: We evaluated the management, outcome and haemorrhagic risk in a cohort of ischaemic stroke patients with mild symptoms treated with intravenous tissue plasminogen activator (tPA) within the first 4.5 h. Methods: We analysed data from a prospective stroke thrombolysis registry. A total of 1,043 patients received tPA between 2010 and 2014 in the 5 stroke units of the RESUVAL stroke network (Rhône Valley, France). Among them, 170 patients had a National Institute of Health Stroke Scale (NIHSS) score ≤4 (minor group: MG) before tPA and 873 patients had a NIHSS score >4. Results: A high rate (77%) of excellent outcome (3-month-modified Rankin Scale score ≤1) was observed in the MG. No symptomatic intracerebral haemorrhage occurred and the rate of any haemorrhagic transformation was 5%. Fifty-four percent of the MG patients had visible arterial occlusion before tPA. Patients of the MG were less likely to be transported by Emergency Medical Services and to be di-
© 2015 S. Karger AG, Basel 1015–9770/15/0402–0003$39.50/0 E-Mail [email protected] www.karger.com/ced
rectly admitted to the stroke unit or to imaging. Median delays from onset to admission, from admission to imaging and from onset to tPA were longer in the MG. Conclusion: Our data provided evidence of safety and suggested potential benefit of thrombolysis in patients with NIHSS score ≤4. A majority of these patients exhibited arterial occlusion before thrombolysis. Most often, patients with mild stroke are not given priority in terms of the mode of transport, direct admission to stroke unit and rapid imaging, resulting in an increased delay from onset to thrombolysis. Health system improvements are needed to provide all suspected stroke victims equal access to imaging and treatment on an emergency basis. © 2015 S. Karger AG, Basel
Introduction
Mild stroke symptoms represent one of the main reasons for not using intravenous (IV) tissue plasminogen activator (tPA) in time-eligible acute ischemic stroke (AIS) patients [1, 2]. Clinicians refrain from using IV tPA in this Laurent Derex, MD, PhD Department of Neurology Stroke Unit, Neurological Hospital, University of Lyon 59 Boulevard Pinel, FR–69003 Lyon (France) E-Mail laurent.derex @ chu-lyon.fr
Downloaded by: NYU Medical Center Library 128.122.253.228 - 5/21/2015 1:45:37 AM
Key Words Stroke · Thrombolysis · Minor stroke
Methods We retrospectively analysed data from an observational prospective thrombolysis registry of individual data collected between October 2010 and January 2014. The data came from a regional emergency stroke network in the Rhône Valley, France (RESUVAL stroke network) with 5 stroke units (one academic stroke unit and 4 non-academic stroke units), covering a population of 3 million people. Data from all patients treated with thrombolysis for stroke in the Rhône Valley region were included, with regular audit performed on site to ensure completeness of data. This network focuses on dense regional stroke unit coverage and on the establishment of a standardised protocol for pre-hospital management with high priority of Emergency Medical Services (EMS) dispatching, emergency transport and neurologist pre-notification of the arrival of a suspected stroke victim. Admission to stroke unit, multimodal MRI and CT are available around the clock. Intravenous tPA is administered within the first 4 h and 30 min after stroke onset by a senior neurologist with stroke expertise. The RESUVAL thrombolysis registry contains baseline demographic and stroke-related data as well as imaging information and outcome parameters for each stroke patient. To ensure high data quality, immediate data entry is obligatory on admission and during the 3 months follow-up visit. Study Population In our study, minor ischemic stroke (MIS) was defined as an admission NIHSS score ≤4 in accordance with previous studies [3]. All patients were treated with IV tPA within the first 4.5 h. Patients treated with intra-arterial thrombolysis or thrombectomy were excluded from this analysis. Clinical Data Regarding pre-hospital management, the following data were systematically collected: rate and time of EMS call, mode of transport (ambulance of the EMS, private ambulance, Fire Department ambulance, or private vehicle), symptoms onset to search for medical help, symptoms onset to admission, admission to brain imag-
4
Cerebrovasc Dis 2015;40:3–9 DOI: 10.1159/000381866
ing, and admission to thrombolysis delays. When the time of symptoms onset was unknown, stroke onset was defined as the time the patient was last seen in a normal condition. The NIHSS score was assessed by a certified senior neurologist immediately before thrombolysis, at day 1 and at 3 months during a follow-up visit. The functional outcome was assessed using the modified Rankin Scale (mRS) at 3 months during a follow-up visit by a trained or certified senior neurologist. An excellent outcome was defined as 3-month-mRS score ≤1. A good outcome was defined as 3-month-mRS score ≤2. Stroke etiology was classified using the Trial of Org 10172 in Acute Stroke Treatment criteria after a complete diagnostic work-up [4]. Imaging Data Intravenous tPA was administered after multimodal brain MRI or CT was performed. When pre-treatment vascular imaging was performed, symptomatic cerebral arterial occlusion was evaluated. Proximal arterial occlusion was defined as the occlusion of the basilar artery, vertebral artery, proximal middle cerebral artery (M1) and internal carotid artery. Distal arterial occlusion was defined as the occlusion of the M2, M3 and M4 segments of the middle cerebral artery, the anterior cerebral artery and the posterior cerebral artery. When a proximal and a distal occlusion were observed, the patient was assigned to the proximal arterial occlusion group. Control CT scan was performed in all surviving patients (between 24 and 36 h after tPA was administered) to rule out intracranial bleeding. Intracerebral hemorrhages after thrombolysis were classified according to the ECASS criteria. Symptomatic hemorrhage was defined according to ECASS-III criteria (intracerebral hemorrhage combined with clinical deterioration of ≥4 points on NIHSS, or death) [5]. Statistical Analysis The quantitative variables were presented by their rate (%), and the continuous data by their median and interquartile range. The test of Shapiro was used to test the ‘normality’ of the continuous variables. The non-parametric Mann-Whitney test was used to compare the continuous variables and the χ2 test was used to compare the quantitative variables. A 0.05 threshold was considered statistically significant. All data were processed using the statistical environment R, version 2.14.1.
Results
Between October 2010 and January 2014, a total of 1,043 AIS patients received IV tPA in the 5 stroke units of our regional stroke network. Among them, 170 patients had a NIHSS score ≤4 (minor group: MG) before tPA administration and 873 patients had a NIHSS score >4 (non minor group: NMG). Demographic and Baseline Clinical Data Patients of the MG were younger than patients of the NMG (median age: 67 [58–79] and 74 [63–81], respectively, p < 0.001) (table 1). Laurencin et al.
Downloaded by: NYU Medical Center Library 128.122.253.228 - 5/21/2015 1:45:37 AM
setting because of uncertainty about the clinical benefit and fear of hemorrhagic complications. The exclusion of patients with mild stroke symptoms is not based on scientific evidence as these patients were either excluded or underrepresented in randomized thrombolysis trials. The objective of our study was to evaluate the clinical outcome and hemorrhagic risk in a prospective cohort of AIS patients with mild stroke symptoms on admission treated with IV tPA and describe pre-treatment vascular imaging patterns, causes of stroke and modalities of prehospital and in-hospital management in this subset of patients. We compared AIS patients with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤4 with those patients (NIHSS score >4) who received IV tPA during the same period in our regional stroke network.
Table 1. Baseline characteristics of patients
Clinical data Age, years, median [IQR] Male sex, n (%) Baseline NIHSS score, median [IQR] Baseline SBP, mm Hg, median [IQR] Baseline DBP, mm Hg, median [IQR] Glycemia, mmol/l, median [IQR] Imaging data, % Brain MRI performed Brain CT performed Visible arterial occlusion Proximal arterial occlusion* Distal arterial occlusion*
MG (n = 170)
NMG (n = 873)
p
67 [58–79] 112 (66) 3 [2–4] 151 [135–164] 80 [73–83] 6.1 [5.3–7.0]
74 [63–81] 463 (53) 12 [8–17] 148 [132–165] 80 [70–90] 6.5 [5.7–7.7]
Cerebrovasc Dis 2015;40:3–9 DOI: 10.1159/000381866
Thrombolysis for Acute Minor Stroke: Outcome and Barriers to Management Results from the RESUVAL Stroke Network
Chloé Laurencin a, f Frédéric Philippeau b, f Karine Blanc-Lasserre c, f Anne-Evelyne Vallet d, f Serkan Cakmak e, f Laura Mechtouff a, f Tae-Hee Cho a, f Thomas Ritzenthaler a, f Elodie Flocard f Magali Bischoff f Carlos El Khoury f Norbert Nighoghossian a, f Laurent Derex a, f
a Department
of Neurology, Stroke Unit, Neurological Hospital, University of Lyon, Lyon, b Department of Neurology, Stroke Unit, Hospital of Bourg-en-Bresse, Bourg-en-Bresse, c Department of Neurology, Stroke Unit, Hospital of Valence, Valence, d Department of Neurology, Stroke Unit, Hospital of Vienne, Vienne, e Department of Neurology, Stroke Unit, Hospital of Villefranche-sur-Saône, Villefranche-sur-Saône, f RESUVAL Stroke Network, Lyon, France
Abstract Background: We evaluated the management, outcome and haemorrhagic risk in a cohort of ischaemic stroke patients with mild symptoms treated with intravenous tissue plasminogen activator (tPA) within the first 4.5 h. Methods: We analysed data from a prospective stroke thrombolysis registry. A total of 1,043 patients received tPA between 2010 and 2014 in the 5 stroke units of the RESUVAL stroke network (Rhône Valley, France). Among them, 170 patients had a National Institute of Health Stroke Scale (NIHSS) score ≤4 (minor group: MG) before tPA and 873 patients had a NIHSS score >4. Results: A high rate (77%) of excellent outcome (3-month-modified Rankin Scale score ≤1) was observed in the MG. No symptomatic intracerebral haemorrhage occurred and the rate of any haemorrhagic transformation was 5%. Fifty-four percent of the MG patients had visible arterial occlusion before tPA. Patients of the MG were less likely to be transported by Emergency Medical Services and to be di-
© 2015 S. Karger AG, Basel 1015–9770/15/0402–0003$39.50/0 E-Mail [email protected] www.karger.com/ced
rectly admitted to the stroke unit or to imaging. Median delays from onset to admission, from admission to imaging and from onset to tPA were longer in the MG. Conclusion: Our data provided evidence of safety and suggested potential benefit of thrombolysis in patients with NIHSS score ≤4. A majority of these patients exhibited arterial occlusion before thrombolysis. Most often, patients with mild stroke are not given priority in terms of the mode of transport, direct admission to stroke unit and rapid imaging, resulting in an increased delay from onset to thrombolysis. Health system improvements are needed to provide all suspected stroke victims equal access to imaging and treatment on an emergency basis. © 2015 S. Karger AG, Basel
Introduction
Mild stroke symptoms represent one of the main reasons for not using intravenous (IV) tissue plasminogen activator (tPA) in time-eligible acute ischemic stroke (AIS) patients [1, 2]. Clinicians refrain from using IV tPA in this Laurent Derex, MD, PhD Department of Neurology Stroke Unit, Neurological Hospital, University of Lyon 59 Boulevard Pinel, FR–69003 Lyon (France) E-Mail laurent.derex @ chu-lyon.fr
Downloaded by: NYU Medical Center Library 128.122.253.228 - 5/21/2015 1:45:37 AM
Key Words Stroke · Thrombolysis · Minor stroke
Methods We retrospectively analysed data from an observational prospective thrombolysis registry of individual data collected between October 2010 and January 2014. The data came from a regional emergency stroke network in the Rhône Valley, France (RESUVAL stroke network) with 5 stroke units (one academic stroke unit and 4 non-academic stroke units), covering a population of 3 million people. Data from all patients treated with thrombolysis for stroke in the Rhône Valley region were included, with regular audit performed on site to ensure completeness of data. This network focuses on dense regional stroke unit coverage and on the establishment of a standardised protocol for pre-hospital management with high priority of Emergency Medical Services (EMS) dispatching, emergency transport and neurologist pre-notification of the arrival of a suspected stroke victim. Admission to stroke unit, multimodal MRI and CT are available around the clock. Intravenous tPA is administered within the first 4 h and 30 min after stroke onset by a senior neurologist with stroke expertise. The RESUVAL thrombolysis registry contains baseline demographic and stroke-related data as well as imaging information and outcome parameters for each stroke patient. To ensure high data quality, immediate data entry is obligatory on admission and during the 3 months follow-up visit. Study Population In our study, minor ischemic stroke (MIS) was defined as an admission NIHSS score ≤4 in accordance with previous studies [3]. All patients were treated with IV tPA within the first 4.5 h. Patients treated with intra-arterial thrombolysis or thrombectomy were excluded from this analysis. Clinical Data Regarding pre-hospital management, the following data were systematically collected: rate and time of EMS call, mode of transport (ambulance of the EMS, private ambulance, Fire Department ambulance, or private vehicle), symptoms onset to search for medical help, symptoms onset to admission, admission to brain imag-
4
Cerebrovasc Dis 2015;40:3–9 DOI: 10.1159/000381866
ing, and admission to thrombolysis delays. When the time of symptoms onset was unknown, stroke onset was defined as the time the patient was last seen in a normal condition. The NIHSS score was assessed by a certified senior neurologist immediately before thrombolysis, at day 1 and at 3 months during a follow-up visit. The functional outcome was assessed using the modified Rankin Scale (mRS) at 3 months during a follow-up visit by a trained or certified senior neurologist. An excellent outcome was defined as 3-month-mRS score ≤1. A good outcome was defined as 3-month-mRS score ≤2. Stroke etiology was classified using the Trial of Org 10172 in Acute Stroke Treatment criteria after a complete diagnostic work-up [4]. Imaging Data Intravenous tPA was administered after multimodal brain MRI or CT was performed. When pre-treatment vascular imaging was performed, symptomatic cerebral arterial occlusion was evaluated. Proximal arterial occlusion was defined as the occlusion of the basilar artery, vertebral artery, proximal middle cerebral artery (M1) and internal carotid artery. Distal arterial occlusion was defined as the occlusion of the M2, M3 and M4 segments of the middle cerebral artery, the anterior cerebral artery and the posterior cerebral artery. When a proximal and a distal occlusion were observed, the patient was assigned to the proximal arterial occlusion group. Control CT scan was performed in all surviving patients (between 24 and 36 h after tPA was administered) to rule out intracranial bleeding. Intracerebral hemorrhages after thrombolysis were classified according to the ECASS criteria. Symptomatic hemorrhage was defined according to ECASS-III criteria (intracerebral hemorrhage combined with clinical deterioration of ≥4 points on NIHSS, or death) [5]. Statistical Analysis The quantitative variables were presented by their rate (%), and the continuous data by their median and interquartile range. The test of Shapiro was used to test the ‘normality’ of the continuous variables. The non-parametric Mann-Whitney test was used to compare the continuous variables and the χ2 test was used to compare the quantitative variables. A 0.05 threshold was considered statistically significant. All data were processed using the statistical environment R, version 2.14.1.
Results
Between October 2010 and January 2014, a total of 1,043 AIS patients received IV tPA in the 5 stroke units of our regional stroke network. Among them, 170 patients had a NIHSS score ≤4 (minor group: MG) before tPA administration and 873 patients had a NIHSS score >4 (non minor group: NMG). Demographic and Baseline Clinical Data Patients of the MG were younger than patients of the NMG (median age: 67 [58–79] and 74 [63–81], respectively, p < 0.001) (table 1). Laurencin et al.
Downloaded by: NYU Medical Center Library 128.122.253.228 - 5/21/2015 1:45:37 AM
setting because of uncertainty about the clinical benefit and fear of hemorrhagic complications. The exclusion of patients with mild stroke symptoms is not based on scientific evidence as these patients were either excluded or underrepresented in randomized thrombolysis trials. The objective of our study was to evaluate the clinical outcome and hemorrhagic risk in a prospective cohort of AIS patients with mild stroke symptoms on admission treated with IV tPA and describe pre-treatment vascular imaging patterns, causes of stroke and modalities of prehospital and in-hospital management in this subset of patients. We compared AIS patients with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤4 with those patients (NIHSS score >4) who received IV tPA during the same period in our regional stroke network.
Table 1. Baseline characteristics of patients
Clinical data Age, years, median [IQR] Male sex, n (%) Baseline NIHSS score, median [IQR] Baseline SBP, mm Hg, median [IQR] Baseline DBP, mm Hg, median [IQR] Glycemia, mmol/l, median [IQR] Imaging data, % Brain MRI performed Brain CT performed Visible arterial occlusion Proximal arterial occlusion* Distal arterial occlusion*
MG (n = 170)
NMG (n = 873)
p
67 [58–79] 112 (66) 3 [2–4] 151 [135–164] 80 [73–83] 6.1 [5.3–7.0]
74 [63–81] 463 (53) 12 [8–17] 148 [132–165] 80 [70–90] 6.5 [5.7–7.7]
