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What Is the Risk of Symptomatic Intracerebral Hemorrhage in Patients With Stroke Mimics Who Receive Intravenous Thrombolytics?
ANNALS OF EMERGENCY MEDICINE
DECEMBER 2015
Systematic Review Snapshot TAKE-HOME MESSAGE In studies of thrombolysis for ischemic stroke, some subjects receiving the drug for conditions mimicking stroke experienced intracranial hemorrhage, although this was less frequent than in patients treated for true stroke. DATA SOURCES The authors searched MEDLINE and SCOPUS, with last search on September 13, 2014; the search combined Medical Subject Heading terms and key words for stroke mimics, stroke misdiagnosis, thrombolysis, and tissue plasminogen activator. The metaanalysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.1 STUDY SELECTION Prospective and retrospective observational studies reporting the use of intravenous thrombolytics in stroke mimics were eligible, with no language restrictions. Case reports and studies with overlapping data were excluded; however, sample size was not used as an exclusion criterion. DATA EXTRACTION AND SYNTHESIS Two authors independently extracted all data for safety of intravenous thrombolytics in stroke mimics and acute ischemic stroke and reported results as standardized means. For each study, the number of events in patients receiving intravenous thrombolytics with stroke mimic and acute ischemic stroke was identified and a risk ratio
Volume 66, no. 6 : December 2015
What Is the Risk of Symptomatic Intracerebral Hemorrhage in Patients With Stroke Mimics Who Receive Intravenous Thrombolytics? EBEM Commentators
Brit J. Long, MD Department of Emergency Medicine SAUSHEC Fort Sam Houston, TX
Alex Koyfman, MD Department of Emergency Medicine UT Southwestern Medical Center/Parkland Memorial Hospital Dallas, TX
Results Outcomes for stroke mimic versus ischemic stroke treated with thrombolysis. Outcome Symptomatic intracranial hemorrhage Favorable functional outcome
Number of Studies (Subjects)
Risk Ratio (95% CI)
Heterogeneity, I2 (%)
9 (392)
0.3 (0.1–0.8)
No (0)
4 (206)
2.8 (2.1–3.7)
Yes (82)
CI, Confidence interval.
Commentary Female sex, lower presentation NIH Stroke Scale (NIHSS), and younger age were correlated with patients with stroke mimic, and hypertension and atrial fibrillation were more common in acute ischemic stroke (AIS) patients. Acute ischemic strokes are commonly observed in the emergency department,5 as are nonvascular conditions resembling stroke,6 with
a published range of 5% to 31% among patients with stroke suspected initially.7 With quality improvement efforts focused on decreasing door-to-needle time, the risk of inadvertently administering intravenous thrombolytics to a patient with a stroke mimic may increase.8 This review suggests that the risk of symptomatic intracranial hemoorhage (sICH) with intravenous thrombolytics is lower among patients with stroke mimic Annals of Emergency Medicine 611
Systematic Review Snapshot
calculated. The primary outcome was safety in intravenous thrombolytics administration, with symptomatic intracranial hemoorhage and oral edema as outcomes. Favorable functional outcome was defined as a modified Rankin Scale score of 0 to 1 at hospital discharge. Baseline characteristics between the groups were also compared. For each study, a predefined 10-point quality control was used to address biases, categorized as high, low, or unclear according to recommendations by Higgins et al.2 Unavailable study data were categorized as unclear risk of bias. Overall risk ratio for pooled studies was computed with a random-effects model, with heterogeneity assessed by Cochran Q and I2.3 Publication bias was assessed with funnel plot and the Egger test for asymmetry.4
compared with those with AIS but is not zero. Indeed, if the baseline event rate of sICH is presumed to be close to zero, causing sICH in 1 of 200 stroke mimics is concerning. Moreover, publication and reporting bias seem likely to tip in the direction of underreporting cases of erroneous treatment with thrombolysis, leading to harm, and the selective sICH measure (as compared to incident intracranial hemorrhage) in the setting of neurologic deficits is conservative, potentially
612 Annals of Emergency Medicine
underestimating the rate of harms. Thus, it seems intuitively likely that this review’s estimate represents the lowest end of a credible range. In summary, the rate of sICH in patients with stroke mimic who receive intravenous thrombolytics is low in published data, although this estimate may be lower than that observed in clinical practice.9 Patients with stroke mimics generally were younger, were women, and had lower NIHSS scores. Fully functional outcome was 3-fold more likely for patients with stroke mimic compared with that for AIS patients. However, the risk of causing harm to even 1 patient given intravenous thrombolytics in the setting of a stroke mimic is concerning, and physicians must strongly weigh the risks and benefits of providing them. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshot (SRS) series. The source for this systematic review snapshot is: Tsivgoulis G, Zand R, Katsanos AH, et al. Safety of intravenous thrombolysis in stroke mimics: prospective 5-year study and comprehensive meta-analysis. Stroke. 2015;46:1281-1287. 1. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation
2.
3.
4.
5.
6.
7.
8.
9.
and elaboration. J Clin Epidemiol. 2009;62: e1-e34. Higgins JP, Altman DG, Gøtzsche PC, et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343: d5928. Deeks JJ, Higgins JP, Altman DG. Chapter 9: analysing data and undertaking metaanalyses. Cochrane Handbook for Systematic Reviews of Interventions Web site. Available at: http://handbook.cochrane.org/chapter_ 9/9_analysing_data_and_undertaking_meta_ analyses.htm. Updated March 2011. Accessed February 4, 2014. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-634. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-e322. Lioutas VA, Sonni S, Caplan LR. Diagnosis and misdiagnosis of cerebrovascular disease. Curr Treat Options Cardiovasc Med. 2013;15:276-287. Merino JG, Luby M, Benson RT, et al. Predictors of acute stroke mimics in 8187 patients referred to a stroke service. J Stroke Cerebrovasc Dis. 2013;22: e397-e403. Jauch EC, Saver JL, Adams HP Jr, et al; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870-947. Zinkstok SM, Engelter ST, Gensicke H, et al. Safety of thrombolysis in stroke mimics: results from a multicenter cohort study. Stroke. 2013;44:1080-1084.
Michael Brown, MD, MSc, Alan Jones, MD, and David Newman, MD, serve as editors of the SRS series.
Volume 66, no. 6 : December 2015
DECEMBER 2015
Systematic Review Snapshot TAKE-HOME MESSAGE In studies of thrombolysis for ischemic stroke, some subjects receiving the drug for conditions mimicking stroke experienced intracranial hemorrhage, although this was less frequent than in patients treated for true stroke. DATA SOURCES The authors searched MEDLINE and SCOPUS, with last search on September 13, 2014; the search combined Medical Subject Heading terms and key words for stroke mimics, stroke misdiagnosis, thrombolysis, and tissue plasminogen activator. The metaanalysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.1 STUDY SELECTION Prospective and retrospective observational studies reporting the use of intravenous thrombolytics in stroke mimics were eligible, with no language restrictions. Case reports and studies with overlapping data were excluded; however, sample size was not used as an exclusion criterion. DATA EXTRACTION AND SYNTHESIS Two authors independently extracted all data for safety of intravenous thrombolytics in stroke mimics and acute ischemic stroke and reported results as standardized means. For each study, the number of events in patients receiving intravenous thrombolytics with stroke mimic and acute ischemic stroke was identified and a risk ratio
Volume 66, no. 6 : December 2015
What Is the Risk of Symptomatic Intracerebral Hemorrhage in Patients With Stroke Mimics Who Receive Intravenous Thrombolytics? EBEM Commentators
Brit J. Long, MD Department of Emergency Medicine SAUSHEC Fort Sam Houston, TX
Alex Koyfman, MD Department of Emergency Medicine UT Southwestern Medical Center/Parkland Memorial Hospital Dallas, TX
Results Outcomes for stroke mimic versus ischemic stroke treated with thrombolysis. Outcome Symptomatic intracranial hemorrhage Favorable functional outcome
Number of Studies (Subjects)
Risk Ratio (95% CI)
Heterogeneity, I2 (%)
9 (392)
0.3 (0.1–0.8)
No (0)
4 (206)
2.8 (2.1–3.7)
Yes (82)
CI, Confidence interval.
Commentary Female sex, lower presentation NIH Stroke Scale (NIHSS), and younger age were correlated with patients with stroke mimic, and hypertension and atrial fibrillation were more common in acute ischemic stroke (AIS) patients. Acute ischemic strokes are commonly observed in the emergency department,5 as are nonvascular conditions resembling stroke,6 with
a published range of 5% to 31% among patients with stroke suspected initially.7 With quality improvement efforts focused on decreasing door-to-needle time, the risk of inadvertently administering intravenous thrombolytics to a patient with a stroke mimic may increase.8 This review suggests that the risk of symptomatic intracranial hemoorhage (sICH) with intravenous thrombolytics is lower among patients with stroke mimic Annals of Emergency Medicine 611
Systematic Review Snapshot
calculated. The primary outcome was safety in intravenous thrombolytics administration, with symptomatic intracranial hemoorhage and oral edema as outcomes. Favorable functional outcome was defined as a modified Rankin Scale score of 0 to 1 at hospital discharge. Baseline characteristics between the groups were also compared. For each study, a predefined 10-point quality control was used to address biases, categorized as high, low, or unclear according to recommendations by Higgins et al.2 Unavailable study data were categorized as unclear risk of bias. Overall risk ratio for pooled studies was computed with a random-effects model, with heterogeneity assessed by Cochran Q and I2.3 Publication bias was assessed with funnel plot and the Egger test for asymmetry.4
compared with those with AIS but is not zero. Indeed, if the baseline event rate of sICH is presumed to be close to zero, causing sICH in 1 of 200 stroke mimics is concerning. Moreover, publication and reporting bias seem likely to tip in the direction of underreporting cases of erroneous treatment with thrombolysis, leading to harm, and the selective sICH measure (as compared to incident intracranial hemorrhage) in the setting of neurologic deficits is conservative, potentially
612 Annals of Emergency Medicine
underestimating the rate of harms. Thus, it seems intuitively likely that this review’s estimate represents the lowest end of a credible range. In summary, the rate of sICH in patients with stroke mimic who receive intravenous thrombolytics is low in published data, although this estimate may be lower than that observed in clinical practice.9 Patients with stroke mimics generally were younger, were women, and had lower NIHSS scores. Fully functional outcome was 3-fold more likely for patients with stroke mimic compared with that for AIS patients. However, the risk of causing harm to even 1 patient given intravenous thrombolytics in the setting of a stroke mimic is concerning, and physicians must strongly weigh the risks and benefits of providing them. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshot (SRS) series. The source for this systematic review snapshot is: Tsivgoulis G, Zand R, Katsanos AH, et al. Safety of intravenous thrombolysis in stroke mimics: prospective 5-year study and comprehensive meta-analysis. Stroke. 2015;46:1281-1287. 1. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation
2.
3.
4.
5.
6.
7.
8.
9.
and elaboration. J Clin Epidemiol. 2009;62: e1-e34. Higgins JP, Altman DG, Gøtzsche PC, et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343: d5928. Deeks JJ, Higgins JP, Altman DG. Chapter 9: analysing data and undertaking metaanalyses. Cochrane Handbook for Systematic Reviews of Interventions Web site. Available at: http://handbook.cochrane.org/chapter_ 9/9_analysing_data_and_undertaking_meta_ analyses.htm. Updated March 2011. Accessed February 4, 2014. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-634. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-e322. Lioutas VA, Sonni S, Caplan LR. Diagnosis and misdiagnosis of cerebrovascular disease. Curr Treat Options Cardiovasc Med. 2013;15:276-287. Merino JG, Luby M, Benson RT, et al. Predictors of acute stroke mimics in 8187 patients referred to a stroke service. J Stroke Cerebrovasc Dis. 2013;22: e397-e403. Jauch EC, Saver JL, Adams HP Jr, et al; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870-947. Zinkstok SM, Engelter ST, Gensicke H, et al. Safety of thrombolysis in stroke mimics: results from a multicenter cohort study. Stroke. 2013;44:1080-1084.
Michael Brown, MD, MSc, Alan Jones, MD, and David Newman, MD, serve as editors of the SRS series.
Volume 66, no. 6 : December 2015