Asymptomatic Hemorrhagic Transformation after Acute Ischemic Stroke: Is It Clinically Innocuous? Chunyan Lei, MD,* Bo Wu, MD, PhD,*† Ming Liu, MD, PhD,*† and Yanchao Chen, MD*

Background: Whether asymptomatic hemorrhagic transformation (HT) is clinically innocuous, that is, unassociated with clinically detectable neurologic deterioration, remains an open question. To explore this, we examined whether asymptomatic HT affects long-term poor outcome and risk of stroke recurrence. Methods: We consecutively and prospectively enrolled patients with acute ischemic stroke who were admitted to our hospital. Based on clinical and imaging data, patients were diagnosed as having asymptomatic HT, symptomatic HT, or not HT, and the 3 groups were compared in terms of basic clinical characteristics, poor outcome, and stroke recurrence. We constructed Kaplan–Meier survival curves and compared groups by means of log rank tests for significant difference. Results: Of the 1789 patients enrolled, 143 (8.0%) presented with asymptomatic HT, 25 (1.4%) presented with symptomatic HT. These patients with were more likely to be female, to have experienced atrial fibrillation, and to have higher National Institute of Health Stroke Scale score on stroke than were patients without HT. After adjusting for other confounding factors, the risk of poor outcome was significantly higher among those with asymptomatic HT and symptomatic HT than among those without HT. Moreover, patients with asymptomatic HT and symptomatic HT showed a significantly lower cumulative 1-year survival rate than did those without HT (P , .001). The patients showed similar rates of cumulative stroke recurrence at 1 year (P 5 .673). Conclusions: Asymptomatic HT and symptomatic HT after acute ischemic stroke worsened long-term clinical outcomes, although it did not affect risk of stroke recurrence. These findings suggest that asymptomatic HT should not be considered clinically innocuous. Key Words: Ischemic stroke—asymptomatic hemorrhagic transformation—poor outcome—recurrence. Ó 2014 by National Stroke Association

From the *Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, Chengdu; and †State Key Laboratory of Human Disease Biotherapy and Ministry of Education, Department of Neurology, West China Hospital, Sichuan University, Chengdu, P. R. China. Received May 28, 2014; revision received June 18, 2014; accepted June 25, 2014. This research was supported by the Science and Technology Support Program of the Department of Science and Technology of Sichuan Province (2012FZ0006) and National Natural Science Foundation of China, China (81371283, 81371282). B.W. and M.L. are co-corresponding authors. Address correspondence to Bo Wu, MD, PhD, Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, No 37 Guo Xue Xiang, Chengdu 610041, Sichuan Province, P. R. China. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.06.024

Hemorrhagic transformation (HT) is considered a complication of acute ischemic stroke in the presence or absence of thrombolytic treatment, and it may be response to the ischemic event.1,2 HT occurs when vascular integrity is lost and neurovascular homeostasis is disrupted after acute ischemic stroke. HT is referred to as symptomatic when the extravasation aggravates neurologic function, which can occur after mechanical compression, ischemic stroke, and other injuries.2-4 In fact, symptomatic HT in victims of acute ischemic stroke can counteract the ability of thrombolytic therapies to ameliorate nervous deterioration. As a result, numerous studies have examined the mechanism, risk factors, and outcomes of stroke patients with HT.3,5-11 HT can also occur in an asymptomatic form. Although asymptomatic HT is detectable by the same imaging

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techniques as symptomatic HT, it has traditionally been considered clinically innocuous because it does not appear to affect functional outcomes of patients with acute ischemic stroke.5 As a result, asymptomatic HT is not so well studied as the symptomatic form, and risk factors for asymptomatic HT have not been defined. This relative neglect of asymptomatic HT has started to change, stimulated by recent studies that have called its innocuous nature into question. These studies have used the modified Rankin Scale (MRS) to examine short-term functional outcomes in patients of acute ischemic stroke treated or not with recombinant tissue plasminogen activator.12-14 Although results of these studies suggest that prognosis of patients with asymptomatic HT may not be benign, only 1 study confirmed that patients with asymptomatic HT compared with those without HT had significant worse functional outcome.12 The present study aimed to take advantage of a largescale, long-term prospective database of patients with acute ischemic stroke in China to identify risk factors of asymptomatic HT as well as to examine the influence of asymptomatic HT on long-term recovery and recurrence of hemorrhagic and ischemic stroke.

Subjects and Methods Patients and Evaluation This study was conducted using prospective data from the Chengdu Stroke Registry, which has been described previously.15 This registry project was approved by the Scientific Research Department of West China Hospital, Sichuan University, and the study protocol conformed to local and international standards of research ethics. Informed consent was obtained from subjects or their guardians. Patients in the present study were prospectively and consecutively enrolled after being admitted to our hospital between 1 January, 2009, and 31 May, 2012, within 7 days of first stroke onset.

Patient Grouping and Workup In addition to the baseline computed tomography (CT) scan, one or more scan (CT or magnetic resonance imaging [MRI]) was performed at the time of any clinical worsening, or within 1 week after stroke. The presence of HT on brain images was determined independently by 2 neurologists blinded to clinical data (inter-rater reliability, k 5 .85). When there was disagreement, a third neurologist also blinded to clinical data was consulted, and a consensus decision was reached. Asymptomatic HT was defined as the presence of a low-signal area (diameter $5 mm) within acute ischemic lesion on follow-up T2images or the presence of any degree of hyperdensity showing a typical vascular distribution within the lowattenuation infarction area on the follow-up CT image

coupled with the absence of HT-associated neurologic deterioration based on clinical judgment. Neurologic deterioration was defined as a 2-point increase in the overall score on the National Institute of Health Stroke Scale (NIHSS) after stroke or a 1-point increase on only the motor items of the NIHSS or a 1-point increase on the level of consciousness item of the NIHSS or the presence of any new neurologic symptoms or signs that could not be attributed to factors other than stroke.5,8,16 HT was classified according to the EuropeanAustralian Acute Stroke Study system as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH) on the basis of MRI scan results. HI was defined as the presence of isolated and confluent petechial staining of infarcted tissue, without an associated mass effect. PH was defined as the presence of a homogeneous high-attenuation lesion with mass effect occupying the infarcted area or the presence of any hemorrhaging outside the infarcted area.6

Data Collection and Follow-up Baseline information was collected at stroke on age, gender, initial stroke severity assessed using the NIHSS, and stroke risk factors (hypertension, diabetes mellitus, current smoking, alcohol intake). Disability was defined as an MRS score of 3-5. Experienced stroke neurologists blinded to relevant patient data calculated MRS scores. Stroke deaths were confirmed directly by contact with family members. Outcomes data were collected by telephone every 3 months after discharge until May 2013.

Statistical Analysis Results were reported as percentages, means 6 standard deviation, or odds ratios with 95% confidence intervals, as appropriate. The c2 or Fisher exact tests were used to compare group data for categorical variables. Student t test and the Mann–Whitney U test were used to compare group data for continuous variables as appropriate. Two-sided values of P less than .05 were considered statistically significant. All statistical analyses were performed using SPSS (version 16; IBM, Chicago, IL). Variables identified as significant in the univariate analysis (P # .05) were used in forward stepwise multivariate regression to examine their independent contributions to risk of asymptomatic HT. Cumulative survival and recurrence rates were estimated by the Kaplan–Meier product limit method, and log rank tests were used to assess the significance of intergroup differences.

Results Baseline Characteristics and Risk Factors of Asymptomatic HT Of the 1990 patients with ischemic stroke admitted to our hospital during the enrollment period, 226 (13.4%) were excluded. Reasons for exclusion were as follows:

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incomplete neuroimaging workups (n 5 22), loss to follow-up (n 5 162), and receiving recombinant tissue plasminogen activator (rt-PA)) therapy (n 5 17). None of the patients enrolled in the Registry during the study period had received endovascular treatment within 7 days of ischemic stroke onset. The baseline characteristics of the 179 patients (9.2%) lost to follow-up did not differ significantly from those of the patients included in the final analysis. The final study population was 1789 patients (1074 men, 60.3%) with a mean age at stroke onset of 63.43 6 14.03 years. In the final population, 143 patients (8.0%) had asymptomatic HT, of which 108 cases were HI and 35 were PH; 25 (1.4%) patients had symptomatic HT. Baseline characteristics of stroke patients with or without HT are compared in Table 1. Patients with HT were more likely to be female, a history of atrial fibrillation, and higher initial NIHSS score. Patients with HT had higher rates

of respiratory tract infection, urinary tract infection, electrolyte disturbance, gastrointestinal bleeding, and anticoagulation therapy after stroke. They were also more likely to have lower levels of total cholesterol and low-density lipoprotein (LDL). In contrast, levels of triglycerides and high-density lipoprotein varied significantly with absence of HT.

Poor Outcome at 3 Months and 1 Year The proportion of poor outcome in patients with asymptomatic HT was 41.1% at 3 months after stroke and 35.6% at 1 year after stroke; the proportion of poor outcome in patients with symptomatic HT was 60.0% at 3 months after stroke and 56.2% at 1 year after stroke; both proportion of poor outcomes were significantly higher than the corresponding proportion of 33.2% (P , .001) and 30.4% (P , .001) for patients without HT.

Table 1. Baseline characteristics of acute ischemic stroke patients

Variable Age, mean 6 SD, y Male, n (%) Hypertension, n (%) Diabetes mellitus, n (%) Atrial fibrillation, n (%) Current smoking, n (%) Alcohol intake, n (%) NIHSS score, mean 6 SD Systolic BP, mean 6 SD, mm Hg Diastolic BP, mean 6 SD, mm Hg Glucose, mean 6 SD, mmol/L Total cholesterol, mean 6 SD, mmol/L Triglyceride, mean 6 SD, mmol/L HDL, mean 6 SD, mmol/L LDL, mean 6 SD, mmol/L Stroke subtype, n (%) Large artery atherosclerosis Small artery occlusion Cardioembolism Other determined Undetermined Stroke-related complications, n (%) Respiratory tract infection Urinary tract infection Intestinal infection Epilepsy Electrolyte disturbance Gastrointestinal bleeding Stroke recurrence Antiplatelet therapy after stroke onset Anticoagulation therapy after stroke

Asymptomatic HT, N 5 143

Symptomatic HT, N 5 25

No HT, N 5 1621

P value

64.69 6 14.65 72 (50.3) 73 (51.05) 22 (15.4) 36 (25.2) 43 (30.07) 28 (19.58) 8.28 6 6.93 139.90 6 25.15 81.79 6 14.14 6.84 6 2.50 4.23 6 1.01 1.41 6 .84 1.36 6 .37 2.41 6 .86

66.28 6 13.49 9 (36.0) 13 (52.0) 4 (16.0) 10 (40.0) 7 (28.0) 4 (16.0) 10.04 6 3.67 144.25 6 20.95 83.44 6 12.53 6.79 6 1.67 4.33 6 1.25 1.35 6 .82 1.48 6 .49 2.61 6 .95

63.19 6 13.96 996 (61.4) 856 (52.8) 288 (17.8) 107 (6.6) 514 (31.7) 337 (20.8) 6.08 6 6.16 143.65 6 43.64 83.66 6 14.52 6.61 6 2.88 4.45 6 1.04 1.54 6 .84 1.26 6 .61 2.65 6 .91

.024 ,.001 .124 .490 ,.001 .312 .225 .003 .225 .340 .629 .053 .124 ,.001 .011

497 (30.70) 354 (21.80) 181 (11.20) 40 (2.50) 549 (33.90)

5 (20.0) 0 (.0) 16 (64.0) 0 (.0) 4 (16.0)

31 (21.7) 3 (2.10) 56 (39.20) 1 (.70) 52 (36.40)

.058

47 (32.90) 13 (9.10) 1 (.70) 3 (2.10) 8 (5.60) 6 (4.20) 7 (4.90) 126 (88.10) 12 (8.40)

12 (.48) 3 (12.0) 0 (.0) 1 (4.0) 2 (8.0) 2 (8.0)

266 (16.40) 34 (2.10) 1 (.10) 14 (.90) 43 (2.70) 20 (1.20) 105 (6.50) 1505 (92.80) 77 (4.80)

,.001 ,.001 .116 .040 .013 ,.001

20 (80.0) 5 (20.0)

.002 ,.001

Abbreviations: BP, blood pressure; HDL, high-density lipoprotein; HT, hemorrhagic transformation; LDL, low-density lipoprotein; NIHSS, National Institute of Health Stroke Scale; SD, standard deviation.

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The proportion of poor outcome was also higher for the individual asymptomatic HT subtypes than for patients without any HT, at both 3 months (HI: 39.8%; PH: 46.1%; P , .01) and 1 year (HI: 34.9%; PH: 38.6 %; P , .01). These results indicated greater risk of poor outcome in the presence of asymptomatic HT and symptomatic HT at both 3 months and 1 year. Moreover, this elevated risk was still significant after adjusting the data for age, gender, atrial fibrillation, NIHSS score, total cholesterol, high-density lipoprotein, LDL, stroke subtype, respiratory tract infection, urinary tract infection, electrolyte disturbance, gastrointestinal bleeding, and antiplatelet therapy after stroke onset on stroke (Table 2). Moreover, 1-year survival curves showed a significantly lower cumulative survival rate for patients with asymptomatic HT and symptomatic HT than for patients without asymptomatic HT (P , .001, log rank test; Fig 1).

Stroke Recurrence at 1 Year By 1 year after stroke, stroke had recurred in 113 patients. Among patients without HT, 3 suffered intracerebral hemorrhagic stroke, 3 suffered strokes of unclear subtype, and 93 suffered ischemic stroke. In the group with asymptomatic HT, 1 experienced stroke of unclear subtype and 6 experienced ischemic stroke. In the group with symptomatic HT, 1 experienced ischemic stroke. Kaplan–Meier estimation of cumulative stroke recurrence rate showed similar rates for patients with 3 groups (asymptomatic HT: 6.5%; symptomatic HT: 4.0%; without HT: 4.9%; P 5 .673, log rank test; Fig 2).

Discussion Among patients who suffered acute ischemic stroke, we found that the risk of poor outcome for patients with asymptomatic HT was 1.51-fold higher at 3 months and 1.44-fold higher at 1 year than for patients without any HT; for patients with symptomatic HT was 2.42-fold higher at 3 months and 2.25-fold higher at 1 year than for patients without any HT. Patients with asymptomatic HT and symptomatic HT also showed a significantly lower cumulative survival rate. These findings suggest

that clinical outcomes after acute ischemic stroke are likely to be worse in the presence of asymptomatic HT and symptomatic HT than in its absence. Moreover, the asymptomatic HT should be paid more attention as well as symptomatic HT. Our finding of a greater risk of poor outcome among patients with asymptomatic HT confirms and extends previous work. A recent study in which the investigators assessed disability in ischemic stroke patients using the MRS in an ordinal manner reported a greater frequency of disability at 3 months in the group with asymptomatic HT than in the group without it.12 We obtained a similar result at both 3 months and 1 year, suggesting that asymptomatic HT affects not only short-term but also long-term clinical outcomes. The blood extravasation related to HT is associated with defects in the integrity and homeostasis of the neurovasculature, which can disrupt the selective permeability of the blood–brain barrier. HT can also aggravate ischemia-induced oxidative stress, leukocyte infiltration, vascular activation, and inflammatory response due to the toxicity of blood components. The combination of these factors contributes to the clinical outcomes in patients with asymptomatic or symptomatic HT.2,3,6 It has been suggested that the formation of new circulatory pathways after acute ischemic infarction may lead to collateral circulation reperfusion, which may help explain the onset of HT.2,6 Ironically, such formation of new circulatory pathways may also decrease the risk of stroke recurrence. Our finding that asymptomatic HT did not significantly affect cumulative stroke recurrence rates out to 1 year does not support this suggestion. We speculate that asymptomatic HT may be associated with small artery formation rather than large artery formation. Some risk factors for HT, such as lower levels of cholesterol and LDL,9 and absolute elevated blood pressure,10 that are also associated with intracerebral hemorrhage,17,18 raising the possibility that asymptomatic HT increases the risk of recurrence of intracerebral hemorrhage after acute ischemic stroke. However, we found that none of the patients with asymptomatic HT and 3 patients without asymptomatic HT experienced

Table 2. OR and 95% CI for poor outcome of acute ischemic stroke patients Asymptomatic HT

Poor outcome 3-month 1-year

Overall

HI subtype

PH subtype

Symptomatic HT

1.51 (1.11-2.54) 1.44 (1.09-2.3)

1.22 (1.03-1.83) 1.18 (1.01-1.67)

1.91 (1.33-2.95) 1.78 (1.25-2.81)

2.42 (1.75-3.89) 2.25 (1.51-3.45)

Adjusted ORs were calculated after adjusting for age, gender, atrial fibrillation, NIHSS score, Total cholesterol, HDL, LDL, Stroke subtype, respiratory tract infection, urinary tract infection, electrolyte disturbance, gastrointestinal bleeding, antiplatelet therapy after stroke onset on stroke.

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Figure 1. Kaplan–Meier 1-year survival curves for acute ischemic stroke patients (P , .001, log rank test).

intracerebral hemorrhage after acute ischemic cerebral infarction. This suggests that asymptomatic HT may not increase the risk of intracerebral hemorrhage; so antithrombotic therapy may still be administered to patients with asymptomatic HT after blood absorption. Our study suggests that lower levels of total cholesterol and LDL increase risk of asymptomatic HT. Similarly, previous studies have linked lower LDL levels to increased risk of symptomatic HT19 and low levels of LDL and total cholesterol to increased risk of both symptomatic and asymptomatic HT after acute ischemic stroke.9,19,20 A systematic review confirmed these findings by showing that risk of HT was associated with low total and LDL cholesterol levels at baseline.11 Adequate cholesterol levels may be important for maintaining the integrity of

Figure 2. Kaplan–Meier estimates of cumulative stroke recurrence rates for acute ischemic stroke patients (P 5 .673, log rank test).

cerebral small vessels. In this way, lower levels of total cholesterol and LDL may increase risk of HT. Our study suggests that previous work on HT risk factors, which has focused on aggregate analysis of both asymptomatic and symptomatic HT or on symptomatic HT only, seems to apply to asymptomatic HT as well. The findings in this study should be interpreted with some caution, given that it was performed in a single hospital; so it may not accurately reflect what would happen in the general population. Another limitation is that some patients, because of contraindications or economic restrictions, were analyzed only by CT scan instead of MRI, which is more sensitive for detecting HT. Thus we cannot exclude a certain degree of selection bias because of failure to include eligible patients.

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Asymptomatic hemorrhagic transformation after acute ischemic stroke: is it clinically innocuous?

Whether asymptomatic hemorrhagic transformation (HT) is clinically innocuous, that is, unassociated with clinically detectable neurologic deterioratio...
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