Remote or Extraischemic Intracerebral Hemorrhage—An Uncommon Complication of Stroke Thrombolysis
Results From the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register
Background and Purpose—Intracerebral hemorrhage after treatment with intravenous recombinant tissue-type plasminogen activator for ischemic stroke can occur in local relation to the infarct, as well as in brain areas remote from infarcted tissue. We aimed to describe risk factors, 3-month mortality, and functional outcome in patients with the poorly understood complication of remote intracerebral hemorrhage, as well as local intracerebral hemorrhage.
Methods—In this study, 43 494 patients treated with intravenous recombinant tissue-type plasminogen activator, with complete imaging data, were enrolled in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) during 2002 to 2011. Baseline data were compared among 970 patients (2.2%) with remote parenchymal hemorrhage (PHr), 2325 (5.3%) with PH, 438 (1.0%) with both PH and PHr, and 39 761 (91.4%) without PH or PHr. Independent risk factors for all hemorrhage types were obtained by multivariate logistic regression.
Results—Previous stroke (P=0.023) and higher age (P<0.001) were independently associated with PHr, but not with PH. Atrial fibrillation, computed tomographic hyperdense cerebral artery sign, and elevated blood glucose were associated with PH, but not with PHr. Female sex had a stronger association with PHr than with PH. Functional independence at 3 months was more common in PHr than in PH (34% versus 24%; P<0.001), whereas 3-month mortality was lower (34% versus 39%; P<0.001).
Conclusions—Differences between risk factor profiles indicate an influence of previous vascular pathology in PHr and acute large-vessel occlusion in PH. Additional research is needed on the effect of pre-existing cerebrovascular disease on complications of recanalization therapy in acute ischemic stroke.
Intracerebral hemorrhage (ICH) is the main complication of treatment with intravenous recombinant tissue-type plasminogen activator (IV-tPA) in acute ischemic stroke. The majority of ICH associated with IV-tPA occurs within or at the margin of ischemic or manifestly infarcted brain tissue.1 Meanwhile, ICH can also appear in tissue without apparent acute ischemia, in brain areas remote from those affected by the initial stroke.2
The European Cooperative Acute Stroke Study (ECASS) introduced a radiological classification of post-thrombolytic cerebral hemorrhage. Hemorrhagic infarcts are categorized into hemorrhagic infarct 1, small petechiae along the margins of an infarct, and hemorrhagic infarct 2, more confluent petechiae within an infarct, without space-occupying effect. Confluent parenchymal hemorrhage (PH) originating in cerebral infarcts may be classified as PH1, <30% of the infarct area, with some mild, local, space-occupying effect, and PH2, >30% of the infarct area, with substantial space-occupying effect.3 Remote PH (PHr), solitary or multiple, is defined as hemorrhages that appear in brain regions without visible ischemic damage, remote from the area of ischemia causing the initial stroke symptoms.4 Cerebral hemorrhage occurs in 0.3% to 0.8% of patients with acute myocardial infarction treated with IV-tPA.5 In patients with ischemic stroke, the incidence of remote cerebral hemorrhage after thrombolysis has been reported at 1.3% to 3.7%.1,2,4 It is currently not known how many patients develop PHr with or without a concomitant infarct-related PH. Mortality rates and functional outcomes for patients with PHr have only been described in a single-center series comprising 7 patients.6 Available stroke thrombolysis literature has extensively covered risk factors for symptomatic ICH; however, this term does not specify the radiological properties of the hematomas.7,8 Symptomatic or not, intra- and extraischemic hemorrhage may be assumed to have at least partially different underlying pathophysiological mechanisms. Despite this, any differences in risk factors for these 2 types of complication in stroke thrombolysis are unknown. It is also not known whether they carry different risk levels of clinical deterioration, death, and poor functional outcome.
The present work aims to report, for the first time to our knowledge, risk factors for PHr and compare them with risk factors for local hemorrhage, secondary to stroke thrombolysis. We also aim to examine early neurological and long-term functional outcome in patients with PHr and PH.
All patients recorded in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) between December 2002 and December 2011 treated with intravenous alteplase (Actilyse; Boehringer-Ingelheim, Germany) were included in this study (n=45 074). The SITS-ISTR is an ongoing, prospective, Internet-based, academic-driven, multinational, observational monitoring register for clinical centers using thrombolysis for the treatment of acute ischemic stroke. The methodology of SITS-ISTR, including procedures for data collection and management, patient identification, and verification of source data, has been described previously.1,9
Patients with PHr (unrelated to current ischemic lesion) or PH (related to current ischemic lesion) were identified on imaging 22 to 36 hours after IV-tPA treatment or earlier if the scan was performed because of clinical deterioration (Figure 1A and 1B). Patients with purely petechial hemorrhagic infarct transformation per the ECASS classification were pooled with patients without any blood on follow-up imaging to form the non-ICH group.4
We collected baseline and demographic characteristics, stroke severity per the National Institutes of Health Stroke Scale (NIHSS), time logistics, medication history, and imaging data on admission and follow-up.
Ethical Approval and Data Monitoring
Need for ethical approval or patient consent for participation in the SITS-ISTR varied among participating countries. Ethical approval and patient consent were obtained in countries that required this; other countries approved the register for conduct as an anonymized audit. The SITS-Monitoring Study (SITS-MOST) data (n=6483)1 are embedded within the SITS-ISTR. The SITS-MOST was approved by the Ethics Committee of the Karolinska Institutet, Stockholm, Sweden, and by the Swedish Medical Products Agency. The SITS International Coordination Office monitored the SITS-ISTR data online and checked individual patient data monthly to identify errors or inconsistencies. For a sample of patients included in SITS-MOST, source data were verified onsite by monitors under the supervision of the national coordinator.
Independent risk factors were identified for PHr and PH. Early neurological deterioration was defined as an increase of ≥4 points in the total NIHSS score at 24 hours from treatment. This level was chosen because it denotes early clinical worsening in the ECASS II and the SITS-MOST definitions of symptomatic ICH in stroke thrombolysis. Rates of mortality were assessed at day 7 and 3-month follow-up for all groups, whereas functional independence (modified Rankin Scale score 0–2) was assessed at 3 months. All assessments of imaging studies and neurological status were performed according to clinical routine at centers participating in SITS-ISTR.
We performed descriptive statistics for baseline clinical, demographic, and imaging data, as well as outcomes, comparing patients with and without pure PHr, pure PH, and concomitant PH and PHr. All baseline variables available in SITS-ISTR were analyzed. For continuous variables, median and interquartile range values were calculated. For categorical variables, we calculated percentage proportions by dividing the number of events by the total number of patients, excluding missing or unknown cases, as done in previous SITS publications.1,9 For the calculation of significance of difference between medians and proportions, we used the Mann–Whitney U test and the Pearson χ2 method, respectively. To avoid variable selection caused by spurious correlations, only variables showing an association with PH or PHr at P≤0.10 level in the univariate analysis were included as potential predictors into the multivariate logistic regression model. In this analysis, variables significant at P<0.05 were regarded as independent risk factors for the respective type of hemorrhage. All analyses were performed using STATISTICA 11 (StatSoft Inc).
A total of 45 079 patients treated with intravenous thrombolysis were recorded in the SITS-ISTR between December 25, 2002, and December 12, 2011, with 95% of the patients enrolled in European centers. Baseline and follow-up radiological data at 22 to 36 hours from the start of IV-tPA were available in 43 494 (96.5%) patients, who were therefore eligible for this study. Among these, 2471 patients (5.7%) were examined by MRI at baseline. Table 1 shows the subtype distribution of all hemorrhage types and combinations in our material. Pure PHr was recorded in 970 patients (2.2%), whereas pure PH occurred in 2325 patients (5.3%). In addition, 438 patients (1.0%) developed concomitant local and remote PH.
Table 2 presents baseline demographic, clinical, laboratory, and radiological characteristics of pure PH and PHr, compared with patients free from any PH. The univariate and multivariate comparisons of patients with concomitant PH and PHr versus the non-ICH group are shown in Tables I and II in the online-only Data Supplement. Patients with pure PHr were older than those with PH and the non-ICH group (median age, 74 versus 72 and 70 years, respectively; both P<0.001). Patients with pure PHr were more frequently women (46% versus 41% for pure PH; P=0.01, and 43% for the non-ICH group; P=0.028). Stroke severity in patients with pure PHr was between the levels seen in pure PH and the non-ICH group (median NIHSS score, 13 versus 16 versus 11; both P<0.001). Pre-tPA systolic blood pressure was higher among patients with PHr compared with PH and the non-ICH group (median, 158 versus 153 versus 150 mm Hg; both P<0.001). Despite having the highest median age, patients with PHr had a lower prevalence of atrial fibrillation (AF; 28.5%) and diabetes mellitus (DM; 16.2%) compared with patients with PH (AF, 34.6%; DM, 23.4%; both P<0.001). The prevalence of any previous stroke was higher in the pure PHr group (16.3%) than in both PH (12.7%; P=0.003) and non-ICH groups (13.0%; P=0.007). Among radiological findings, the hyperdense cerebral artery sign (HCAS) on baseline computed tomography was less common in patients with pure PHr than in those with pure PH (18.2% versus 30.3%; P<0.001). Early infarct signs on baseline computed tomography were also less common in patients with PHr (22.9%) compared with those with PH (28.6%; P<0.001).
Table 3 shows the outcome data. The mortality rate was lower in the PHr group compared with patients with pure PH (18.7% versus 22.7% at 7 days; P=0.012, and 33.9% versus 39.2% at 3 months; P=0.008). Patients with concomitant PH and PHr had the highest mortality (42.8% at 7 days and 62.1% at 3 months; P<0.001 compared with all other groups). For comparison, patients without any PH had mortality rates of 4.9% at 7 days and 12.1% at 3 months (P<0.001 compared with all other groups). The frequency of functional independence (modified Rankin Scale score 0–2) at 3 months was 33.6% in patients with PHr, 24.0% in patients with PH, and 57.9% in the non-ICH group (both P<0.001).
After adjustment for covariance using multivariate logistic regression analysis, baseline NIHSS score, systolic blood pressure, and current aspirin treatment were independently associated with both PHr and PH. In addition to these, higher age and history of nonrecent previous stroke (>3 months before) were associated with pure PHr, whereas AF, HCAS, and blood glucose levels were associated with pure PH (Table 4).
A direct adjusted comparison of independent risk factors for pure PHr and pure PH showed that higher age, female sex, and nonrecent previous stroke shifted the odds toward PHr, whereas higher baseline NIHSS score, higher blood glucose, DM, AF, and HCAS had a stronger association with pure PH (Figure 2).
In this large-scale analysis, we found that PHr makes up for one third of all parenchymal hematomas after intravenous stroke thrombolysis, a fact that is generally not well appreciated (Table 1). This is comparable with a proportion of 27% and 28% in the ECASS I and ECASS II trials, respectively, where placebo patients were included in the calculation, likely leading to a slight underestimation of the percentage in IV-tPA–treated patients.3,4,10 Patients with PHr had the highest median age and highest proportion of female sex of all compared groups. They also had a history of nonrecent previous stroke (>3 months before) more often than patients with local, intraischemic hemorrhage (PH) or those with no hemorrhage. The PHr group had a lower frequency of AF and DM compared with patients with PH and similar rates of other cerebrovascular risk factors, despite being older and having had previous strokes. Stroke severity, frequency of early infarct signs, and HCAS on baseline computed tomography were much lower in the PHr group compared with the PH group.
Consistent with findings from the univariate comparison, the multivariate analysis paints a picture of PH being related to factors associated with large-vessel occlusion, such as higher NIHSS scores, HCAS, and AF. This contrasts with the risk factor profile for PHr, which is associated with previous stroke and higher age, that is, markers of previous cerebrovascular pathology. Despite higher age and more previous strokes in the PHr group, they had no increase in risk factors for cerebral small-vessel disease (hypertension, DM, and smoking) compared with cases with PH. This is in line with the finding that small-vessel disease was diagnosed only rarely in patients with both hemorrhage types.
The weak association of PHr with its 5 independent risk factors, reflected by low adjusted odds ratios (Table 4), raises the suspicion that a mechanism is at play that is not available in our current database. One such mechanism could be cerebral amyloid angiopathy (CAA). This hypothesis gains indirect support from surgical and postmortem studies of spontaneous CAA-related ICH. Here, patients with CAA tend to be older and more often women compared with patients with ICH unrelated to CAA.11–14 The increased prevalence of CAA-related ICH in women corresponds to our finding that female sex has a stronger independent association with PHr than with PH. The cause behind PHr is unlikely to be a common cause of ischemic stroke itself—such underlying pathology is well reflected in the variables recorded in the SITS database. CAA is mainly known for its association with spontaneous lobar ICH and is not known to cause ischemic stroke.15 Therefore, coexisting CAA in patients with ischemic stroke because of other causes would be a contributing mechanism for PHr after intravenous thrombolysis.
An important question can be raised on the possibility of PHr occurring in areas of recent infarction. In our analysis, recent previous stroke (<3 months) was not found to be a risk factor for PHr or PH. Newly published results on recent silent cerebral infarcts on pre-tPA MRI did not show any association with post-tPA hemorrhage.16
Patients with PHr had a worse functional outcome and higher mortality compared with patients free from any PH (Table 3). However, they fared better than those with PH, because 34% of patients with PHr were functionally independent at 3 months, compared with 24% with pure PH. Half (48%) of all local PH were type 2, that is, large with substantial mass effect, compared with PHr, where 67% were type 1, that is, smaller bleeds with mild, local, space-occupying effect (Table 1). Nevertheless, clinical deterioration was equally common with both hemorrhage types. In both PHr and PH groups, 25% of patients had an increase of ≥4 points on the NIHSS scale at 24 hours compared with baseline (Table 3). Thus, despite often being smaller in size, remote hematomas are just as likely as the larger local PH to cause significant neurological deterioration. This is likely because of the fact that the former occurs in functioning, nonischemic brain tissues. Our main explanation for the lower mortality and better functional outcome in patients with PHr compared with those with PH is that the former had a lower baseline stroke severity. Patients with concomitant PH and PHr had the worst clinical outcomes: 3-month mortality at 62% and only 12% remaining functionally independent (modified Rankin Scale score 0–2) at 3 months.
Our study has several limitations. Data were collected via a prospective clinical register; hence, the study has the drawbacks of observational design. Imaging data were read by radiologists at the treating centers, with no independent verification. Nevertheless, the total frequency of PHr in our material (3.2%) is of similar magnitude compared with the National Institute of Neurological Disorders and Stroke (1.3%), ECASS (3.7%), and ECASS II (2.0%), which all had independent, centralized radiological assessment. The SITS-ISTR lacks the option for registering numerous details of radiological investigations, which could be pertinent to the present study, such as previous lesions, white matter disease, and current multifocality of MR diffusion-weighted imaging lesions. As evident from Tables 2 and 3, certain baseline variables in our material have missing data in 5% to 10% of cases. This seems to be a limitation shared by other large observational multicenter stroke databases, because the Get With The Guidelines–Stroke registry also reports proportions of missing baseline data at ≈10%.17,18 Importantly, the SITS-ISTR lacks 3-month follow-up data for mortality in 17% of cases, whereas 3-month functional outcome is missing in 20%. We attempted to mitigate the missing data for 3-month mortality by including 7-day mortality rates, where records are 98% complete. This is justified by the fact that nearly all thrombolysis-related ICH causing clinical deterioration are known to occur <36 hours from treatment.2,19 The SITS-ISTR lacks the option to register the exact number and location of remote hematomas in each patient. Such data would be valuable for our hypothesis on the possible influence of CAA, because, particularly, multifocal remote hematomas in stroke and myocardial infarction thrombolysis have been linked to CAA diagnosed by pathological investigation.20 Information on anatomic location of microbleeds, together with data on the location of subsequent PHr, could aid us in understanding the mechanisms behind the development of this hitherto-unexplained complication of stroke thrombolysis.21 We hope to be able to address this issue in upcoming studies.
The demonstrated differences in risk factor profiles between PHr and PH after stroke thrombolysis suggest that PHr has a stronger association with previous vascular pathology such as previous stroke and possible CAA, compared with local PH, which is more associated with large-vessel occlusion. Patients with PHr have lower mortality and better functional outcome compared with those with PH, largely explained by less severe stroke at baseline in PHr. Local and remote hematomas are equally likely to cause significant early clinical deterioration. Additional studies are needed to elucidate the influence of underlying cerebrovascular disease and its radiological markers on the risk of ICH after stroke thrombolysis.
Scientific Committee of SITS International
Nils Wahlgren (chair), Antoni Dávalos, Gary A. Ford, Martin Grond, Werner Hacke, Michael Hennerici, Markku Kaste, Kennedy R. Lees, R. Mikulik, Risto Roine, Turgut Tatlisumak, Danilo Toni, K.S. Wang.
Scientific Committee of Fighting Stroke (Uppdrag Besegra Stroke)
Nils Wahlgren (chair), Niaz Ahmed, Maaret Castrén, Ulf Eriksson, Jonas Frisén, Ulf Hedin, Staffan Holmin, Åke Sjöholm, Mikael Svensson, Mia von Euler.
We thank all Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) investigators and their centers for their participation. We also pass on our thanks to all patients who participated in SITS-ISTR. Uppsala Clinical Research Centre, Uppsala, Sweden, developed, maintained, and upgraded the software for the SITS register in close collaboration with SITS until September 2010. The current SITS registry is developed, maintained, and upgraded by Zitelab, Copenhagen, Denmark, in close collaboration with SITS. Drs Wahlgren and Ahmed coordinated the study. Dr Mazya performed the statistical analysis. Drs Mazya, Ahmed, and Wahlgren wrote the initial draft of the article. Drs Wahlgren, Ford, and Mikulik were members of the SITS Scientific Committee. Drs Hobohm and Nunes were local coordinators of leading recruiting centres. All authors have read and commented on the first draft, with regard to interpretation of the data and editing of the article, and have seen and approved the final version. Drs Mazya, Ahmed, and Wahlgren have direct access to the original data and vouch for the accuracy and completeness of this report.
Sources of Funding
The Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) is funded by an unrestricted grant from Boehringer Ingelheim, Ferrer, and by a grant from European Union Public Health Executive Authority. Financial support was also provided through the regional agreement on medical training and research (ALF) between Stockholm County Council and the Karolinska Institute. This study is a part of the Fighting Stroke Project (Uppdrag Besegra Stroke) supported by the Swedish Heart and Lung Foundation and Karolinska Institutet; the project is supported by funding from Friends of Karolinska Institutet and Johanniterorden (Swedish Order of St John). The views expressed are those of the authors. Drs Mazya, Wahlgren, and Ahmed had full access to all data in this study and have been responsible for the preparation of this article and its submission for publication.
Dr Ahmed is a senior researcher in Safe Implementation of Treatments in Stroke (SITS) International, which receives a grant from Boehringer Ingelheim and Ferrer for the SITS-Monitoring Study (SITS-MOST)/SITS-International Stroke Thrombolysis Register (SITS-ISTR). Dr Ford has received fees and expenses from Boehringer Ingelheim for educational activities. He has also received fees and expenses from Lundbeck for educational activities. His institution has received grant assistance from Boehringer Ingelheim toward administrative expenses for the coordination of SITS in the United Kingdom, fees for consultancy work, and study payments. Dr Mikulik has received research support from European Regional Development Fund (Project Fakultní Nemocnice U. Sv. Anny–International Clinical Research Center [FNUSA-ICRC], No. CZ.1.05/1.1.00/02.0123). Dr Wahlgren has received expenses from Boehringer Ingelheim for his role as a member of the Steering Committee in relation to the European Cooperative Acute Stroke Study (ECASS) III with alteplase and served as a consultant to Thrombogenics as chairman of the Data and Safety Monitoring Board. SITS International (chaired by Dr Wahlgren) received a grant from Boehringer Ingelheim and Ferrer for the SITS-MOST/SITS-ISTR. His institution has also received grant support toward administrative expenses for the coordination of ECASS III. Dr. Wahlgren has also received lecture fees from Boehringer Ingelheim and Ferrer. The other authors report no conflicts.
Guest Editor for this article was Steven C. Cramer, MD, MMSc.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.004923/-/DC1.
- Received January 22, 2014.
- Revision received March 17, 2014.
- Accepted March 26, 2014.
- © 2014 American Heart Association, Inc.
- 2.↵National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA for ischemic stroke. Stroke. 1997;28:2109–2118.
- Fiorelli M,
- Bastianello S,
- von Kummer R,
- del Zoppo GJ,
- Larrue V,
- Lesaffre E,
- et al
- Trouillas P,
- von Kummer R
- Gore JM,
- Granger CB,
- Simoons ML,
- Sloan MA,
- Weaver WD,
- White HD,
- et al
- Whiteley WN,
- Slot KB,
- Fernandes P,
- Sandercock P,
- Wardlaw J
- Mazya M,
- Egido JA,
- Ford GA,
- Lees KR,
- Mikulik R,
- Toni D,
- et al
- Larrue V,
- von Kummer R R,
- Müller A,
- Bluhmki E
- Gaillard N,
- Schmidt C,
- Costalat V,
- Bousquet JP,
- Heroum C,
- Milhaud D,
- et al
- Menon BK,
- Saver JL,
- Prabhakaran S,
- Reeves M,
- Liang L,
- Olson DM,
- et al
- Messé SR,
- Pervez MA,
- Smith EE,
- Siddique KA,
- Hellkamp AS,
- Saver JL,
- et al