Accuracy of predictive scores of hemorrhagic transformation in patients with acute ischemic stroke

Andrade, João Brainer Clares de; Mohr, Jay Preston; Ahmad, Muhammad; Lima, Fabricio Oliveira; Barros, Levi Coelho Maia; Silva, Gisele Sampaio

doi:10.1590/0004-282X-ANP-2021-0091

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Article • Arq. Neuro-Psiquiatr. 80 (5) • May 2022 • https://doi.org/10.1590/0004-282X-ANP-2021-0091 copy

Accuracy of predictive scores of hemorrhagic transformation in patients with acute ischemic stroke

Acurácia de escores preditivos de transformação hemorrágica em pacientes com isquemia cerebral aguda

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Background:

Hemorrhagic transformation (HT) is a complication in ischemic strokes, regardless of use of reperfusion therapy (RT). There are many predictive scores for estimating the risk of HT. However, most of them include patients also treated with RT. Therefore, this may lead to a misinterpretation of the risk of HT in patients who did not undergo RT.

Objective:

We aimed to review published predictive scores and analyze their accuracy in our dataset.

Methods:

We analyzed the accuracy of seven scales. Our dataset was derived from a cohort of 1,565 consecutive patients from 2015 to 2017 who were admitted to a comprehensive stroke center. All patients were evaluated with follow-up neuroimaging within seven days. Comparison of area under the curve (AUC) was performed on each scale, to analyze differences between patients treated with recombinant tissue plasminogen activator (tPA) and those without this treatment.

Results:

Our dataset provided enough data to assess seven scales, among which six were used among patients with and without tPA treatment. HAT (AUC 0.76), HTI (0.73) and SEDAN (0.70) were the most accurate scores for patients not treated with tPA. SPAN-100 (0.55) had the worst accuracy in both groups. Three of these scores had different cutoffs between study groups.

Conclusions:

The predictive scores had moderate to fair accuracy for predicting HT in patients treated with tPA. Three scales were more accurate for predicting HT in patients not treated with tPA. Through standardizing these characteristics and including more patients not treated with RT in a large multicenter series, accurate predictive scores may be created.

Keywords:
Ischemic Stroke; Precision Medicine

Scales	Variables	Type of HT	Criteria	Neuroimaging technique	Time elapsed until follow-up neuroimaging
HTI⁴4 Kalinin MN, Khasanova DR, Ibatullin MM. The hemorrhagic transformation index score: a prediction tool in middle cerebral artery ischemic stroke. BMC Neurol. 2017 Sep 7;17(1):177. https://doi.org/10.1186/s12883-017-0958-3 https://doi.org/10.1186/s12883-017-0958-...	ASPECTS, Atrial Fibrillation on ECG, NIHSS, INR (1.26–1.82 and ≤1.25) and hyperdense middle cerebral artery sign	Any	ECASS I	CT only	7–14 days
HAT⁹9 Lou M, Safdar A, Mehdiratta M, Kumar S, Schlaug G, Caplan L, et al. The HAT Score: a simple grading scale for predicting hemorrhage after thrombolysis. Neurology. 2008 Oct;71(18):1417-23. https://doi.org/10.1212/01.wnl.0000330297.58334.dd https://doi.org/10.1212/01.wnl.000033029...	Diabetes mellitus or blood glucose on admission (>200 mg/dL), NIHSS (15–19 or >19) and presence of early visible hypodensity on initial head CT scan (regarding involvement of 1/3 of MCA area)	SHT	NINDS	CT or MRI	24–48 h
SEDAN¹⁰10 Strbian D, Engelter S, Michel P, Meretoja A, Sekoranja L, Ahlhelm FJ, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol. 2012 Jan;71:634-41. https://doi.org/10.1161/STROKEAHA.113.003806 https://doi.org/10.1161/STROKEAHA.113.00...	Age (>75 years), NIHSS (≥10), early infarct signs on initial CT scan, hyperdense middle cerebral artery sign and blood glucose on admission (145-216 and >216 mg/dL)	SHT	ECASS II	CT or MRI	24 h
iSCORE¹¹11 Saposnik G, Guzik AK, Reeves M, Ovbiagele B, Johnston SC. Stroke prognostication using age and NIH Stroke Scale: SPAN-100. Neurology. 2013 Jan;80(1):21-8. https://doi.org/10.1212/WNL.0b013e31827b1ace https://doi.org/10.1212/WNL.0b013e31827b...	Age, atrial fibrillation on ECG, chronic heart failure, NIHSS/Canadian neurological scale, preadmission disability, renal dialysis or cancer, male sex, clinical stroke subtype (lacunar or non-lacunar) and blood glucose on admission (≥135 mg/dL)	Any	ECASS II and NINDS	NA	NA
SPAN-100³⁰30 Saposnik G, Fang J, Kapral MK, Tu JV, Mamdani M, Austin P, et al. The iScore predicts effectiveness of thrombolytic therapy for acute ischemic stroke. Stroke. 2012 Feb;43(5):1315-22. https://doi.org/10.1161/STROKEAHA.111.646265 https://doi.org/10.1161/STROKEAHA.111.64...	Age and NIHSS on admission	Any	NINDS	CT only	36 h
HeRS³¹31 Marsh EB, Llinas RH, Schneider AL, Hillis AE, Lawrence E, Dziedzic P, et al. Predicting hemorrhagic transformation of acute ischemic stroke. Medicine (Baltimore). 2016 Jan;95(2):e2430. https://doi.org/10.1097/MD.0000000000002430 https://doi.org/10.1097/MD.0000000000002...	Age, infarct volume and glomerular filtration rate	Any	ECASS II	MRI only	Seven days
SITS-SICH³²32 Mazya M, Egido JA, Ford GA, Lees KR, Mikulik R, Toni D, et al. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: safe Implementation of Treatments in Stroke (SITS) symptomatic intracerebral hemorrhage risk score. Stroke. 2012 Jun;43(6):1524-31. https://doi.org/10.1161/STROKEAHA.111.644815 https://doi.org/10.1161/STROKEAHA.111.64...	Age (≥72 years), antiplatelet (aspirin alone or aspirin + clopidogrel), history of arterial hypertension, NIHSS (7–12 and ≥13), stroke onset to treatment time (≥180 min), SBP (≥146 mmHg), weight (≥95 kg) and blood glucose on admission (≥180 mg/dL)	SHT	SITS-MOST	CT or MRI	22–36 h
MSS³³33 Cucchiara B, Tanne D, Levine SR, Demchuk AM, Kasner S. A risk score to predict intracranial hemorrhage after recombinant tissue plasminogen activator for acute ischemic stroke. J Stroke Cerebrovasc Dis. 2008 Nov-Dec;17(6):331-3. https://doi.org/10.1016/j.jstrokecerebrovasdis.2008.03.012 https://doi.org/10.1016/j.jstrokecerebro...	Age (≥60 years), NIHSS (≥10), blood glucose (>150 mg/dl) and platelet count less than 150,000/mm³	Any	NINDS	CT only	Up to 36 h
GRASPS³⁴34 Menon BK, Saver JL, Prabhakaran S, Reeves M, Liang L, Olson DM, et al. Risk score for intracranial hemorrhage in patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Stroke. 2012 Sep;43(9):2293-9. https://doi.org/10.1161/STROKEAHA.112.660415 https://doi.org/10.1161/STROKEAHA.112.66...	Age, ethnicity (Asian or non-Asian), male sex, NIHSS, SBP and blood glucose on admission	SHT	NINDS	CT or MRI	Up to 36 h
THRIVE³⁵35 Flint AC, Cullen SP, Faigeles BS, Rao VA. Predicting long-term outcome after endovascular stroke treatment: the totaled health risks in vascular events score. AJNR Am J Neuroradiol. 2010 Aug;31(7):1192-6. https://doi.org/10.3174/ajnr.A2050 https://doi.org/10.3174/ajnr.A2050...	Age (≤59, 60–79, ≥80), NIHSS on admission (≤10, 11–20, ≥21) and comorbidities (arterial hypertension, diabetes mellitus or atrial fibrillation)	SHT or intraparenchymal hematoma type 2	NINDS and SITS	CT only	72 h

Scale	AUC – original derivation cohort	AUC – original validation cohort	Points (range)	Cutoff point	Patients not treated with RT included?	Overall prevalence of HT, %	Prevalence of SHT, %	Sample size
HTI⁴4 Kalinin MN, Khasanova DR, Ibatullin MM. The hemorrhagic transformation index score: a prediction tool in middle cerebral artery ischemic stroke. BMC Neurol. 2017 Sep 7;17(1):177. https://doi.org/10.1186/s12883-017-0958-3 https://doi.org/10.1186/s12883-017-0958-...	0.85 (0.82–0.89)	0.83 (0.78–0.88)	0–8	2	Yes	23.8	12.5	783
SPAN-100³⁰30 Saposnik G, Fang J, Kapral MK, Tu JV, Mamdani M, Austin P, et al. The iScore predicts effectiveness of thrombolytic therapy for acute ischemic stroke. Stroke. 2012 Feb;43(5):1315-22. https://doi.org/10.1161/STROKEAHA.111.646265 https://doi.org/10.1161/STROKEAHA.111.64...	0.72 (0.63–0.76)	0.59 (0.53–0.65)	0–1	100	Yes	9.9	NA	624
SEDAN¹⁰10 Strbian D, Engelter S, Michel P, Meretoja A, Sekoranja L, Ahlhelm FJ, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol. 2012 Jan;71:634-41. https://doi.org/10.1161/STROKEAHA.113.003806 https://doi.org/10.1161/STROKEAHA.113.00...	0.77 (0.71–0.83)	0.82 (0.76–0.87)^* * Validation performed by other authors4;	0–5	^ There is not a single cutoff;	No	NA	7	1,813^£ £ Including validation cohort;
GRASPS³⁴34 Menon BK, Saver JL, Prabhakaran S, Reeves M, Liang L, Olson DM, et al. Risk score for intracranial hemorrhage in patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Stroke. 2012 Sep;43(9):2293-9. https://doi.org/10.1161/STROKEAHA.112.660415 https://doi.org/10.1161/STROKEAHA.112.66...	0.70 (0.68–0.73)	0.68 (0.66–0.74)	0–101	45–101^ There is not a single cutoff;	No	NA	4.8	10,242
HAT⁹9 Lou M, Safdar A, Mehdiratta M, Kumar S, Schlaug G, Caplan L, et al. The HAT Score: a simple grading scale for predicting hemorrhage after thrombolysis. Neurology. 2008 Oct;71(18):1417-23. https://doi.org/10.1212/01.wnl.0000330297.58334.dd https://doi.org/10.1212/01.wnl.000033029...	0.74 (0.65– 0.79)	0.82 (0.77–0.88)^* * Validation performed by other authors4;	0-5	4	No	20	7	400
MSS³³33 Cucchiara B, Tanne D, Levine SR, Demchuk AM, Kasner S. A risk score to predict intracranial hemorrhage after recombinant tissue plasminogen activator for acute ischemic stroke. J Stroke Cerebrovasc Dis. 2008 Nov-Dec;17(6):331-3. https://doi.org/10.1016/j.jstrokecerebrovasdis.2008.03.012 https://doi.org/10.1016/j.jstrokecerebro...	0.68 (0.67–0.72)	0.72 (0.67–0.77)^* * Validation performed by other authors4;	0-4	3	No	NA	6	1205
SITS-SICH³²32 Mazya M, Egido JA, Ford GA, Lees KR, Mikulik R, Toni D, et al. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: safe Implementation of Treatments in Stroke (SITS) symptomatic intracerebral hemorrhage risk score. Stroke. 2012 Jun;43(6):1524-31. https://doi.org/10.1161/STROKEAHA.111.644815 https://doi.org/10.1161/STROKEAHA.111.64...	0.71^* ***** Confidence interval is not available;	0.69^* ***** Confidence interval is not available;	0-12	3	No	NA	7.4^¥ ¥ Per NINDS classification;	31,627^£ £ Including validation cohort;
iSCORE¹¹11 Saposnik G, Guzik AK, Reeves M, Ovbiagele B, Johnston SC. Stroke prognostication using age and NIH Stroke Scale: SPAN-100. Neurology. 2013 Jan;80(1):21-8. https://doi.org/10.1212/WNL.0b013e31827b1ace https://doi.org/10.1212/WNL.0b013e31827b...	NA	0.83 (0.79–0.87)^* * Validation performed by other authors4;	0–180^α α The final score ranges from the patients’ age; AUC: area under the curve; GRASPS: get with the guidelines-stroke SICH risk; HAT: hemorrhage after thrombolysis; HTI: hemorrhagic transformation index score; iScore: ischemic stroke predictive risk score; MSS: multicenter rt-PA stroke survey group score; SEDAN: blood sugar [glucose] on admission, early infarct signs and [hyper] dense cerebral artery sign on admission computed tomography [CT] head scan, age, and NIHSS; SITS-SICH: safe implementation of treatments in stroke (SITS) symptomatic intracerebral hemorrhage risk score; SPAN-100: stroke prognostication using age and NIH stroke scale; HeRS: hemorrhage risk stratification score; THRIVE: totaled health risks in vascular events; HT: hemorrhagic transformation; SHT: symptomatic hemorrhagic transformation; NA: not available.	>140	No	12.4	6.9	1,696
HeRS³¹31 Marsh EB, Llinas RH, Schneider AL, Hillis AE, Lawrence E, Dziedzic P, et al. Predicting hemorrhagic transformation of acute ischemic stroke. Medicine (Baltimore). 2016 Jan;95(2):e2430. https://doi.org/10.1097/MD.0000000000002430 https://doi.org/10.1097/MD.0000000000002...	0.701^* ***** Confidence interval is not available;	0.81 (0.75–0.86)^* * Validation performed by other authors4;	-	^ There is not a single cutoff;	Yes	22	NA	345
THRIVE³⁵35 Flint AC, Cullen SP, Faigeles BS, Rao VA. Predicting long-term outcome after endovascular stroke treatment: the totaled health risks in vascular events score. AJNR Am J Neuroradiol. 2010 Aug;31(7):1192-6. https://doi.org/10.3174/ajnr.A2050 https://doi.org/10.3174/ajnr.A2050...	0.63^* ***** Confidence interval is not available;	NA	0–9	2–3^ There is not a single cutoff;	Yes	6.0	1.6	6,483^£ £ Including validation cohort;

Scale	Number of patients not treated with RT	AUC	Cutoff point	Sensitivity/specificity, %	Number of patients treated with RT	AUC	Cutoff point	Sensitivity/specificity, %	p-value^* * Comparing the values for the area under the curve between the groups of patients;
HAT⁹9 Lou M, Safdar A, Mehdiratta M, Kumar S, Schlaug G, Caplan L, et al. The HAT Score: a simple grading scale for predicting hemorrhage after thrombolysis. Neurology. 2008 Oct;71(18):1417-23. https://doi.org/10.1212/01.wnl.0000330297.58334.dd https://doi.org/10.1212/01.wnl.000033029... ,^£ £ Patients not treated with tPA were not included in the original cohort; AUC: area under the curve; GRASPS: get with the guidelines-stroke SICH risk; HAT: hemorrhage after thrombolysis; HTI: hemorrhagic transformation index score; iScore: ischemic stroke predictive risk score; MSS: multicenter rt-PA stroke survey group score; SEDAN: blood sugar [glucose] on admission, early infarct signs and [hyper] dense cerebral artery sign on admission computed tomography [CT] head scan, age, and NIHSS; SITS-SICH: safe implementation of treatments in stroke (SITS) symptomatic intracerebral hemorrhage risk score; SPAN-100: stroke prognostication using age and NIH stroke scale; HeRS: hemorrhage risk stratification score; THRIVE: totaled health risks in vascular events; RT: reperfusion therapy; NA: not available.	988	0.76 (0.72–0.80)	2	88.4/54.2	577	0.68 (0.62–0.73)	3	51.2/80.1	0.01
HTI⁴4 Kalinin MN, Khasanova DR, Ibatullin MM. The hemorrhagic transformation index score: a prediction tool in middle cerebral artery ischemic stroke. BMC Neurol. 2017 Sep 7;17(1):177. https://doi.org/10.1186/s12883-017-0958-3 https://doi.org/10.1186/s12883-017-0958-...	413	0.73 (0.68–0.79)	5	83/54.8	NA	NA	NA	NA	-
SEDAN¹⁰10 Strbian D, Engelter S, Michel P, Meretoja A, Sekoranja L, Ahlhelm FJ, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol. 2012 Jan;71:634-41. https://doi.org/10.1161/STROKEAHA.113.003806 https://doi.org/10.1161/STROKEAHA.113.00... ,^£ £ Patients not treated with tPA were not included in the original cohort; AUC: area under the curve; GRASPS: get with the guidelines-stroke SICH risk; HAT: hemorrhage after thrombolysis; HTI: hemorrhagic transformation index score; iScore: ischemic stroke predictive risk score; MSS: multicenter rt-PA stroke survey group score; SEDAN: blood sugar [glucose] on admission, early infarct signs and [hyper] dense cerebral artery sign on admission computed tomography [CT] head scan, age, and NIHSS; SITS-SICH: safe implementation of treatments in stroke (SITS) symptomatic intracerebral hemorrhage risk score; SPAN-100: stroke prognostication using age and NIH stroke scale; HeRS: hemorrhage risk stratification score; THRIVE: totaled health risks in vascular events; RT: reperfusion therapy; NA: not available.	988	0.70 (0.66–0.74)	3	61.6/72.8	577	0.71 (0.67–0.76)	3	57.3/75.1	0.81
THRIVE³⁵35 Flint AC, Cullen SP, Faigeles BS, Rao VA. Predicting long-term outcome after endovascular stroke treatment: the totaled health risks in vascular events score. AJNR Am J Neuroradiol. 2010 Aug;31(7):1192-6. https://doi.org/10.3174/ajnr.A2050 https://doi.org/10.3174/ajnr.A2050...	988	0.66 (0.62–0.70)	4	75.8/54.4	577	0.70 (0.66–0.75)	5	53.8/74.6	0.20
GRASPS³⁴34 Menon BK, Saver JL, Prabhakaran S, Reeves M, Liang L, Olson DM, et al. Risk score for intracranial hemorrhage in patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Stroke. 2012 Sep;43(9):2293-9. https://doi.org/10.1161/STROKEAHA.112.660415 https://doi.org/10.1161/STROKEAHA.112.66... ,^£ £ Patients not treated with tPA were not included in the original cohort; AUC: area under the curve; GRASPS: get with the guidelines-stroke SICH risk; HAT: hemorrhage after thrombolysis; HTI: hemorrhagic transformation index score; iScore: ischemic stroke predictive risk score; MSS: multicenter rt-PA stroke survey group score; SEDAN: blood sugar [glucose] on admission, early infarct signs and [hyper] dense cerebral artery sign on admission computed tomography [CT] head scan, age, and NIHSS; SITS-SICH: safe implementation of treatments in stroke (SITS) symptomatic intracerebral hemorrhage risk score; SPAN-100: stroke prognostication using age and NIH stroke scale; HeRS: hemorrhage risk stratification score; THRIVE: totaled health risks in vascular events; RT: reperfusion therapy; NA: not available.	943	0.64 (0.59–0.68)	70	68/55.3	568	0.68 (0.63–0.73)	74	61.5/68.7	0.22
MSS³³33 Cucchiara B, Tanne D, Levine SR, Demchuk AM, Kasner S. A risk score to predict intracranial hemorrhage after recombinant tissue plasminogen activator for acute ischemic stroke. J Stroke Cerebrovasc Dis. 2008 Nov-Dec;17(6):331-3. https://doi.org/10.1016/j.jstrokecerebrovasdis.2008.03.012 https://doi.org/10.1016/j.jstrokecerebro... ,^£ £ Patients not treated with tPA were not included in the original cohort; AUC: area under the curve; GRASPS: get with the guidelines-stroke SICH risk; HAT: hemorrhage after thrombolysis; HTI: hemorrhagic transformation index score; iScore: ischemic stroke predictive risk score; MSS: multicenter rt-PA stroke survey group score; SEDAN: blood sugar [glucose] on admission, early infarct signs and [hyper] dense cerebral artery sign on admission computed tomography [CT] head scan, age, and NIHSS; SITS-SICH: safe implementation of treatments in stroke (SITS) symptomatic intracerebral hemorrhage risk score; SPAN-100: stroke prognostication using age and NIH stroke scale; HeRS: hemorrhage risk stratification score; THRIVE: totaled health risks in vascular events; RT: reperfusion therapy; NA: not available.	584	0.60 (0.54–0.65)	2	70.7/44	134	0.60 (0.50–0.71)	2	80.6/58.2	0.95
SPAN-100³⁰30 Saposnik G, Fang J, Kapral MK, Tu JV, Mamdani M, Austin P, et al. The iScore predicts effectiveness of thrombolytic therapy for acute ischemic stroke. Stroke. 2012 Feb;43(5):1315-22. https://doi.org/10.1161/STROKEAHA.111.646265 https://doi.org/10.1161/STROKEAHA.111.64...	988	0.55 (0.51–0.60)	73	67.4/41.1	577	0.63 (0.58–0.68)	73	78.9/35.7	0.80

Comparison	Patients not treated with RT	Patients treated with RT
Comparison	p-value	p-value
HAT×SEDAN	0.25	0.65
HAT×GRASPS	<0.001	0.67
HAT×SPAN-100	<0.001	0.10
HAT×THRIVE	0.03	0.67
HAT×MSS	<0.001	0.07
HAT×HTI	0.54	-
HTI×SEDAN	0.68	-
HTI×GRASPS	0.001	-
HTI×SPAN-100	<0.001	-
HTI×MSS	0.01	-
HTI×THRIVE	0.09	-
SEDAN×GRASPS	0.004	0.96
SEDAN×SPAN-100	<0.001	0.18
SEDAN×THRIVE	0.09	0.80
SEDAN×MSS	0.002	0.13
GRASPS×SPAN-100	<0.001	0.09
GRASPS×THRIVE	0.27	0.86
GRASPS×MSS	0.94	0.14
SPAN-100×THRIVE	<0.001	0.07
SPAN-100×MSS	<0.001	0.77
THRIVE×MSS	0.06	0.10

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[1] Correspondence: João Brainer Clares de Andrade; Email: joao.brainer@unifesp.br.