Kalinin et al. BMC Neurology (2017) 17:177 DOI 10.1186/s12883-017-0958-3
RESEARCH ARTICLE
Open Access
The hemorrhagic transformation index score: a prediction tool in middle cerebral artery ischemic stroke Mikhail N. Kalinin1,2* , Dina R. Khasanova1,2 and Murat M. Ibatullin1,3
Abstract Background: We aimed to develop a tool, the hemorrhagic transformation (HT) index (HTI), to predict any HT within 14 days after middle cerebral artery (MCA) stroke onset regardless of the intravenous recombinant tissue plasminogen activator (IV rtPA) use. That is especially important in the light of missing evidence-based data concerning the timing of anticoagulant resumption after stroke in patients with atrial fibrillation (AF). Methods: We retrospectively analyzed 783 consecutive MCA stroke patients. Clinical and brain imaging data at admission were recorded. A follow-up period was 2 weeks after admission. The patients were divided into derivation (DC) and validation (VC) cohorts by generating Bernoulli variates with probability parameter 0.7. Univariate/multivariate logistic regression, and factor analysis were used to extract independent predictors. Validation was performed with internal consistency reliability and receiver operating characteristic (ROC) analysis. Bootstrapping was used to reduce bias. Results: The HTI was composed of 4 items: Alberta Stroke Program Early CT score (ASPECTS), National Institutes of Health Stroke Scale (NIHSS), hyperdense MCA (HMCA) sign, and AF on electrocardiogram (ECG) at admission. According to the predicted probability (PP) range, scores were allocated to ASPECTS as follows: 10–7 = 0; 6–5 = 1; 4–3 = 2; 2–0 = 3; to NIHSS: 0–11 = 0; 12–17 = 1; 18–23 = 2; >23 = 3; to HMCA sign: yes = 1; to AF on ECG: yes = 1. The HTI score varied from 0 to 8. For each score, adjusted PP of any HT with 95% confidence intervals (CI) was as follows: 0 = 0.027 (0.011–0.042); 1 = 0.07 (0.043–0.098); 2 = 0.169 (0.125–0.213); 3 = 0.346 (0.275–0.417); 4 = 0.571 (0.474–0.668); 5 = 0.768 (0.676–0.861); 6 = 0.893 (0.829–0.957); 7 = 0.956 (0.92–0.992); 8 = 0.983 (0.965–1.0). The optimal cutpoint score to differentiate between HT-positive and negative groups was 2 (95% normal-based CI, 1–3) for the DC and VC alike. ROC area/ sensitivity/specificity with 95% normal-based CI for the DC and VC were 0.85 (0.82–0.89)/0.82 (0.73–0.9)/0.89 (0.8–0.97) and 0.83 (0.78–0.88)/0.8 (0.66–0.94)/0.87 (0.73–1.0) respectively. McDonald’s categorical omega with 95% bias-corrected and accelerated CI for the DC and VC was 0.81 (0.77–0.84) and 0.82 (0.76–0.86) respectively. Conclusions: The HTI is a simple yet reliable tool to predict any HT within 2 weeks after MCA stroke onset regardless of the IV rtPA use. Keywords: Stroke, Middle cerebral artery, Complication, Hemorrhage, Prognosis, Hemorrhagic transformation
* Correspondence:
[email protected] 1 Department of Neurology and Neurosurgery for Postgraduate Training, Kazan State Medical University, Kazan, Russia 2 Department of Neurology, Interregional Clinical Diagnostic Center, 12A Karbyshev St, Kazan 420101, Russia Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Kalinin et al. BMC Neurology (2017) 17:177
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Table 3 Baseline Characteristics in the DC and VC
Table 1 Variables with Missing Values Missing, n (%)
Valid, n
Cholesterol, total
107 (13.7)
676
LVEF
80 (10.2)
703
AST
61 (7.8)
722
Bilirubin, total
55 (7)
728
Fibrinogen
41 (5.2)
742
Albumin
37 (4.7)
746
Protein, total
18 (2.3)
765
Sodium
11 (1.4)
772
Potassium
10 (1.3)
773
Prothrombin time
5 (0.6)
778
ALT
4 (0.5)
779
Urea
2 (0.3)
781
Hematocrit
2 (0.3)
781
Hemoglobin
1 (0.1)
782
Note: ALT stands for Alanine transaminase, AST Aspartate transaminase, and LVEF Left ventricular ejection fraction (echocardiography, Simpson method)
Background Hemorrhagic transformation (HT), either asymptomatic (AHT) or symptomatic (SHT), is considered to be a notorious complication of acute ischemic stroke (AIS), associated with limited treatment options and long-term adverse outcomes [1]. It seems reasonable that efforts should be directed towards preventing HT before it occurs. Fortunately, it is more predictable than other types of intracranial hemorrhage. In AIS patients, the incidence of HT induced by intravenous recombinant tissue plasminogen activator (IV rtPA) is reported to be 4.5–39.6% for AHT and 5.2–7.3% for SHT. In contrast, the rate of spontaneous AHT and SHT ranges from 13% to 43% and from 0.6% to 20% respectively [2, 3]. Although the proportion of AIS patients treated with IV rtPA is relatively small (4.7–21.4%) [4], the majority of authors have focused on searching HT
DC (n = 535)
VC (n = 248)
pValue
Age (y)
71 (60–78)
69 (61–77)
0.924
DBP (mm Hg)
90 (80–100)
100 (80–100)
0.025
Height (m)
1.65 (1.6–1.72)
1.65 (1.58–1.71) 0.063
Male sex, n (%)
289 (54)
125 (50.4)
0.346
Clinical data, median (IQR)
NIHSS
8 (4–16)
8 (4–16)
0.574
Pulse rate (bpm)
78 (74–83)
78 (74–85)
0.155
SBP (mm Hg)
160 (140–180)
160 (140–180)
0.19
Time from onset (h)
5.5 (2–11)
6 (2.5–11)
0.265
Temperature (°C)
36.6 (36.4–36.6) 36.6 (36.5–36.6) 0.194
Weight (kg)
78 (68–88)
76.7 (68–85)
0.476
212 (39.6)
109 (44)
0.252
Stroke cause, n (%) Large-artery atherosclerosis Cardioembolism
225 (42.1)
101 (40.7)
0.725
Small-vessel occlusion
79 (14.8)
33 (13.3)
0.587
Other determined etiology
7 (1.3)
1 (0.4)
0.241
Undetermined etiology
12 (2.2)
4 (1.6)
0.562
25 (4.7)
8 (3.2)
0.348
Risk factors, n (%) Acute myocardial infarction AF history
210 (39.3)
94 (37.9)
0.719
Alcohol abuse
62 (11.6)
29 (11.7)
0.966
Atherosclerosis
528 (98.7)
248 (100)
0.07
Bleeding history
41 (7.7)
27 (10.9)
0.136
Chronic heart failure
62 (11.6)
28 (11.3)
0.903
Chronic liver failure
5 (0.9)
7 (2.8)
0.045
Chronic renal failure
20 (3.7)
11 (4.4)
0.642
Coronary artery disease
191 (35.7)
89 (35.9)
0.96
Diabetes mellitus
142 (26.5)
69 (27.8)
0.707
Dyslipidemia
216 (40.4)
103 (41.5)
0.759
Hypertension
497 (92.9)
230 (92.7)
0.937
Malignancy
10 (1.9)
4 (1.6)
0.801
Table 2 MI Specification
Seizures at onset
10 (1.9)
3 (1.2)
0.502
Software package
IBM SPSS Statistics, v.24; Armonk, NY
Previous TIA/stroke
221 (41.3)
116 (46.8)
0.151
Random number generator
Mersenne twister
8 (6–9)
8 (6–9)
0.708
Imputation method
Fully conditional specification (MCMC)
HMCA sign
141 (26.4)
66 (26.6)
0.939
Model type
Linear regression, no interaction terms
Leukoaraiosis
347 (64.9)
168 (67.7)
0.429
Number of iterations
100
Left hemispheric stroke
286 (53.5)
122 (49.2)
0.266
Predictors
All collected data, including missing variables
Right hemispheric stroke
234 (43.7)
122 (49.2)
0.154
Restrictions
Extrema of source data
Bihemispheric stroke
15 (2.8)
4 (1.6)
0.314
Number of imputations
15
Quality of MI
No pattern on MCMC convergence charts FMI, RIV, RE (Table 4)
Brain CT, n (%) ASPECTS, median (IQR)
Note: FMI stands for Fraction of missing information, MCMC Markov chain Monte Carlo, RE Relative efficiency, and RIV Relative increase in variance
Blood tests, median (IQR) Albumin (g/L), n = 513/233
41.1 (38.6–43.1) 40.7 (38.8–42.9) 0.612
ALT (IU/L), n = 531/248
20 (14–28)
19 (13.2–29.8)
0.48
Kalinin et al. BMC Neurology (2017) 17:177
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Table 3 Baseline Characteristics in the DC and VC (Continued) AST (IU/L), n = 495/227
24 (19–31)
APTT (s) Bilirubin, total (μmol/L), n = 497/231
23 (19–32)
Table 3 Baseline Characteristics in the DC and VC (Continued)
0.939
HI-1
32 (28.8–35.3)
31.9 (28.7–34.5) 0.299
HI-2
82 (15.3)
38 (15.3)
0.999
11.5 (8.3–17)
11.5 (8–16.1)
0.699
PH-1
9 (1.7)
4 (1.6)
0.944
PH-2
13 (2.4)
14 (5.6)
0.022
Cholesterol, total (mmol/L), n = 467/209
5.1 (4.3–5.9)
5.2 (4.3–6.1)
0.286
Death
34 (6.4)
19 (7.7)
0.499
Creatinine (μmol/L)
90.6 (79.3–106) 90 (77.4–108)
Malignant cerebral edema
32 (6)
14 (5.6)
0.852
Dependency
325 (60.7)
147 (59.3)
0.695
0.851
Fibrinogen (g/L), n = 502/240
3.2 (2.6–4)
3.2 (2.6–4.2)
0.985
Glucose (mmol/L)
6.8 (5.9–8.3)
6.8 (5.9–8.1)
0.998
Hematocrit, n = 534/247
0.43 (0.38–0.46) 0.42 (0.37–0.45) 0.08
Hemoglobin (g/L), n = 535/247
141 (128–153)
139 (124–150)
0.12
INR
1.04 (0.96–1.15) 1.05 (0.98–1.15) 0.361
Platelet count (×109 cells/L)
245 (199–306)
Protein, total (g/L), n = 523/242
67.9 (64.4–71.7) 68.4 (64.7–72.7) 0.159
Potassium (mmol/L), n = 530/243
4 (3.7–4.3)
4 (3.7–4.3)
0.223
PT (s), n = 531/247
12 (10.9–14.8)
12 (11.2–15.3)
0.408
RBC (×1012 cells/L)
4.63 (4.28–4.97) 4.55 (4.14–4.93) 0.032
Sodium (mmol/L), n = 530/242
139.5 (138– 141.3)
139.1 (137– 141)
0.164
Urea (mmol/L), n = 533/248
6 (4.7–7.7)
5.7 (4.6–7.6)
0.403
7.9 (6.5–9.7)
7.6 (6.3–9.5)
0.285
9
WBC (×10 cells/L)
249.5 (201– 301)
0.865
ECG, n (%) AF rhythm
164 (30.7)
77 (31)
0.911
HR (bpm), median (IQR)
79 (67–91)
80 (68–96)
0.157
Normal ECG
26 (4.9)
10 (4)
0.607
Other ECG changes
259 (48.4)
121 (48.8)
0.921
57 (50–60)
57 (50–61)
0.993
Aortic atherosclerosis
462 (86.4)
217 (87.5)
0.661
Cardiomegaly
401 (75)
207 (83.5)
0.008
Normal chest X-ray
28 (5.2)
13 (5.2)
0.996
Pleural effusion
62 (11.6)
20 (8.1)
0.134
Pneumonia
48 (9)
23 (9.3)
0.891
Pulmonary congestion
215 (40.2)
109 (44)
0.32
LVEF (%), n = 486/217, median (IQR)
22 (4.1)
4 (1.6)
0.069
Note: APTT stands for Activated partial thromboplastin time, DBP Diastolic blood pressure, INR International normalized ratio, PT Prothrombin time, RBC Red blood cells, SBP Systolic blood pressure, and WBC White blood cells
predictors coupled with IV rtPA over the past decade. As a result, a variety of predictive clinical scores have emerged [5–9]. On the other hand, there is a lack of tools for making an accurate HT prediction in AIS patients who are not eligible for IV rtPA. That is especially important in the light of missing evidence-based data concerning the timing of anticoagulant resumption after AIS in patients with atrial fibrillation (AF). Recommendations on the initiation of anticoagulation are currently based on consensus opinion, in what is known as the “1–3–6–12 day rule” [10]. Therefore, the two-week timeframe following the AIS onset is the most critical for developing HT. In this instance, an accurate prediction of HT could make a difference in decision making to reinstitute anticoagulation. The middle cerebral artery (MCA) is by far the largest cerebral artery and is the vessel most commonly affected by cerebrovascular accident. Given the background, we aimed to develop a simple and yet reliable instrument called the hemorrhagic transformation index (HTI) to predict any HT within 14 days after AIS onset in the MCA territory regardless of the use of IV rtPA.
Chest X-ray, n (%)
Antithrombotic medication, n (%) Anticoagulant
28 (5.2)
14 (5.6)
0.812
Antiplatelet
390 (73)
201 (81)
0.014
Anticoagulant + antiplatelet
66 (12.3)
17 (6.9)
0.02
IV rtPA
51 (9.5)
16 (6.5)
0.152
Any HT
126 (23.6)
60 (24.2)
0.844
SHT
69 (12.9)
29 (11.7)
0.636
Outcome, n (%)
Methods Patients
Using prospectively collected clinical and radiological databases, we retrospectively identified 783 consecutive patients with AIS in the MCA territory who were admitted to the stroke unit of the Interregional Clinical Diagnostic Center, Kazan, Russia, within 12 h after onset between January 2013 and May 2016. The exclusion criteria were: involvement of other vascular territories; AIS following any surgery or endovascular procedure within 1 month; brain ischemic lesions due to an intracranial tumor, infection, cerebral venous thrombosis, subarachnoid hemorrhage, and arteriovenous malformation/fistula. In total, 1361 AIS patients were admitted over the specified period. The sample was drawn from the local Caucasian population.
Kalinin et al. BMC Neurology (2017) 17:177
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Table 4 Univariate Analysis in the DC Using the MI Dataset Any HT (n = 126)
No HT (n = 409)
OR (95% CI)
p-Value
FMI
RIV
RE
Age (y)
74 (62–79)
70 (60–77)
1.016 (0.998–1.034)
0.077
0
0
1
DBP (mm Hg)
90 (80–100)
90 (80–100)
0.992 (0.979–1.005)
0.217
0
0
1
Height (m)
1.65 (1.6–1.7)
1.66 (1.6–1.73)
0.983 (0.961–1.006)
0.138
0
0
1
Clinical data, median (IQR)
Male sex, n (%)
60 (47.6)
229 (56)
0.715 (0.479–1.066)
0.1
0
0
1
NIHSS
20 (14–23)
6 (3–10)
1.253 (1.206–1.302)