Sami Curtze

Off-Label Thrombolysis Is Not Associated With Poor Outcome in Patients With Stroke

Background and Purpose— Numerous contraindications included in the license of alteplase, most of which are not based on scientific evidence, restrict the portion of patients with acute ischemic stroke eligible for treatment with alteplase. We studied whether off-label thrombolysis was associated with poorer outcome or increased rates of symptomatic intracerebral hemorrhage compared with on-label use. Methods— All consecutive patients with stroke treated with intravenous thrombolysis from 1995 to 2008 at the Helsinki University Central Hospital were registered (n=1104). After excluding basilar artery occlusions (n=119), the study population included 985 patients. Clinical outcome (modified Rankin Scale 0 to 2 versus 3 to 6) and symptomatic intracerebral hemorrhage according to 3 earlier published criteria were analyzed with a logistic regression model adjusting for 21 baseline variables. Results— One or more license contraindications to thrombolysis was present in 51% of our patients (n=499). The most common of these were age >80 years (n=159), mild stroke National Institutes of Health Stroke Scale score <5 (n=129), use of intravenous antihypertensives prior to treatment (n=112), symptom-to-needle time >3 hours (n=95), blood pressure >185/110 mm Hg (n=47), and oral anticoagulation (n=39). Age >80 years was the only contraindication independently associated with poor outcome (OR, 2.18; 95% CI, 1.27 to 3.73) in the multivariate model. None of the contraindications were associated with an increased risk of symptomatic intracerebral hemorrhage. Conclusions— Off-license thrombolysis was not associated with poorer clinical outcome, except for age >80 years, nor with increased rates of symptomatic intracerebral hemorrhage. The current extensive list of contraindications should be re-evaluated when data from ongoing randomized trials and observational studies become available.

SMASH-U: A Proposal for Etiologic Classification of Intracerebral Hemorrhage

Background and Purpose— The purpose of this study was to provide a simple and practical clinical classification for the etiology of intracerebral hemorrhage (ICH). Methods— We performed a retrospective chart review of consecutive patients with ICH treated at the Helsinki University Central Hospital, January 2005 to March 2010 (n=1013). We classified ICH etiology by predefined criteria as structural vascular lesions (S), medication (M), amyloid angiopathy (A), systemic disease (S), hypertension (H), or undetermined (U). Clinical and radiological features and mortality by SMASH-U (Structural lesion, Medication, Amyloid angiopathy, Systemic/other disease, Hypertension, Undetermined) etiology were analyzed. Results— Structural lesions, namely cavernomas and arteriovenous malformations, caused 5% of the ICH, anticoagulation 14%, and systemic disease 5% (23 liver cirrhosis, 8 thrombocytopenia, and 17 various rare conditions). Amyloid angiopathy (20%) and hypertensive angiopathy (35%) were common, but etiology remained undetermined in 21%. Interrater agreement in classifying cases was high (&kgr;, 0.89; 95% CI, 0.82–0.96). Patients with structural lesions had the smallest hemorrhages (median volume, 2.8 mL) and best prognosis (3-month mortality 4%), whereas anticoagulation-related ICHs were largest (13.4 mL) and most often fatal (54%). Overall, median ICH survival was 5½ years, varying strongly by etiology (P<0.001). After adjustment for baseline characteristics, patients with structural lesions had the lowest 3-month mortality rates (OR, 0.06; 95% CI, 0.01–0.37) and those with anticoagulation (OR, 1.9; 1.0–3.6) or other systemic cause (OR, 4.0; 1.6–10.1) the highest. Conclusions— In our patients, performing the SMASH-U classification was feasible and interrater agreement excellent. A plausible etiology was determined in most patients but remained elusive in one in 5. In this series, SMASH-U based etiology was strongly associated with survival.

Causes of Death and Predictors of 5-Year Mortality in Young Adults After First-Ever Ischemic Stroke The Helsinki Young Stroke Registry

Background and Purpose— Data on mortality and its prognostic factors after an acute ischemic stroke in young adults are scarce and based on relatively small heterogeneous patient series. Methods— We analyzed 5-year mortality data of all consecutive patients aged 15 to 49 with first-ever ischemic stroke treated at the Department of Neurology, Helsinki University Central Hospital, from January 1994 to September 2003. We followed up the patients using data from the mortality registry of Statistics Finland. We used life table analyses for calculating mortality risks. Kaplan–Meier method allowed comparisons of survival between clinical subgroups. We used the Cox proportional hazard model for identifying predictors of mortality. Stroke severity was measured using the National Institutes of Health Stroke Scale and the Glasgow Coma Scale. Results— Among the 731 patients (mean age, 41.5±7.4 years; 62.8% males) followed, 78 died. Cumulative mortality risks were 2.7% (95% CI, 1.5% to 3.9%) at 1 month, 4.7% (3.1% to 6.3%) at 1 year, and 10.7% (9.9% to 11.5%) at 5 years with no gender difference. Those ≥45 years of age had lower probabilities of survival. Among the 30-day survivors (n=711), stroke caused 21%, cardioaortic and other vascular causes 36%, malignancies 12%, and infections 9% of the deaths. Malignancy, heart failure, heavy drinking, preceding infection, type 1 diabetes, increasing age, and large artery atherosclerosis causing the index stroke independently predicted 5-year mortality adjusted for age, gender, relevant risk factors, stroke severity, and etiologic subtype. Conclusions— Despite the overall low mortality after an ischemic stroke in young adults, several recognizable subgroups had substantially increased risk of death in the long term.

Lifestyle Risk Factors for Ischemic Stroke and Transient Ischemic Attack in Young Adults in the Stroke in Young Fabry Patients Study

Background and Purpose— Although many stroke patients are young or middle-aged, risk factor profiles in these age groups are poorly understood. Methods— The Stroke in Young Fabry Patients (sifap1) study prospectively recruited a large multinational European cohort of patients with cerebrovascular events aged 18 to 55 years to establish their prevalence of Fabry disease. In a secondary analysis of patients with ischemic stroke or transient ischemic attack, we studied age- and sex-specific prevalences of various risk factors. Results— Among 4467 patients (median age, 47 years; interquartile range, 40–51), the most frequent well-documented and modifiable risk factors were smoking (55.5%), physical inactivity (48.2%), arterial hypertension (46.6%), dyslipidemia (34.9%), and obesity (22.3%). Modifiable less well-documented or potentially modifiable risk factors like high-risk alcohol consumption (33.0%) and short sleep duration (20.6%) were more frequent in men, and migraine (26.5%) was more frequent in women. Women were more often physically inactive, most pronouncedly at ages <35 years (18–24: 38.2%; 25–34: 51.7%), and had high proportions of abdominal obesity at age 25 years or older (74%). Physical inactivity, arterial hypertension, dyslipidemia, obesity, and diabetes mellitus increased with age. Conclusions— In this large European cohort of young patients with acute ischemic cerebrovascular events, modifiable risk factors were highly prevalent, particularly in men and older patients. These data emphasize the need for vigorous primary and secondary prevention measures already in young populations targeting modifiable lifestyle vascular risk factors. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00414583.

Outcome by Stroke Etiology in Patients Receiving Thrombolytic Treatment. Descriptive Subtype Analysis

Background and Purpose— Treating ischemic stroke with thrombolytic therapy is effective and safe, but limited data exist on its efficacy and safety in different etiologic subtypes. Methods— Patients with acute ischemic stroke treated with intravenous thrombolysis between 1995 and 2008 at our hospital were classified according to the Trial of ORG 10172 in Acute Stroke Treatment criteria based on diagnostic evaluation. Clinical outcome of the stroke subtypes by 3-month modified Rankin Scale was compared by multivariate logistic regression. A good outcome was defined as modified Rankin Scale ≤2. Symptomatic intracranial hemorrhage was defined according to both National Institute of Neurological Disorders and Stroke and European Cooperative Acute Stroke Study criteria. Results— Of the 957 eligible patients, 41% (389) had cardioembolisms, 23% (217) large-artery atherosclerosis, and 11% (101) small-vessel disease (SVD). A good outcome was more common in SVD than in the other subtypes. Patients with SVD were more often male (64% versus 54%), had a lower baseline National Institutes of Health Stroke Scale score, lower mortality rate, and experienced no symptomatic intracranial hemorrhage. Patients with SVD had a prior stroke more often (20% versus 11%), whereas hypertension, diabetes, hypercholesterolemia, and transient ischemic attacks were equally distributed in all subtypes. Patients with SVD had a better outcome even after adjusting for baseline National Institutes of Health Stroke Scale and glucose level, age, and hyperdense artery sign (OR, 1.81; 1.01 to 3.23). In the adjusted multivariate model, other etiologic groups showed no significant correlation to good outcome. Conclusions— Patients with SVD were spared from bleeding complications and had the best outcome even after adjustment for confounding factors.

The CAVE Score for Predicting Late Seizures After Intracerebral Hemorrhage

Background and Purpose— Seizures are a common complication of intracerebral hemorrhage (ICH). We developed a novel tool to quantify this risk in individual patients. Methods— Retrospective analysis of the observational Helsinki ICH Study (n=993; median follow-up, 2.7 years) and the Lille Prognosis of InTra-Cerebral Hemorrhage (n=325; 2.2 years) cohorts of consecutive ICH patients admitted between 2004 and 2010. Helsinki ICH Study patients’ province-wide electronic records were evaluated for early seizures occurring within 7 days of ICH and among 7-day survivors (n=764) for late seizures (LSs) occurring >7 days from ICH. A Cox regression model estimating risk of LSs was used to derive a prognostic score, validated in the Prognosis of InTra-Cerebral Hemorrhage cohort. Results— Of the Helsinki ICH Study patients, 109 (11.0%) had early seizures within 7 days of ICH. Among the 7-day survivors, 70 (9.2%) patients developed LSs. The cumulative risk of LSs was 7.1%, 10.0%, 10.2%, 11.0%, and 11.8% at 1 to 5 years after ICH, respectively. We created the CAVE score (0–4 points) to estimate the risk of LSs, with 1 point for each of cortical involvement, age <65 years, volume >10 mL, and early seizures within 7 days of ICH. The risk of LSs was 0.6%, 3.6%, 9.8%, 34.8%, and 46.2% for CAVE scores 0 to 4, respectively. The c-statistic was 0.81 (0.76–0.86) and 0.69 (0.59–0.78) in the validation cohort. Conclusions— One in 10 patients will develop seizures after ICH. The risk of this adverse outcome can be estimated by a simple score based on baseline variables.

Post-Thrombolytic Hyperglycemia and 3-Month Outcome in Acute Ischemic Stroke

Background: Treating hyperglycemia in acute ischemic stroke may be beneficial, but knowledge on its prognostic value and optimal target glucose levels is scarce. We investigated the dynamics of glucose levels and the association of hyperglycemia with outcomes on admission and within 48 h after thrombolysis. Methods: We included 851 consecutive patients with acute ischemic stroke treated with intravenous thrombolysis in the Helsinki University Central Hospital during 1998–2008. Outcome measures were unfavorable 3- month outcome (3–6 on the modified Rankin Scale), death, and symptomatic intracerebral hemorrhage (sICH) according to NINDS criteria. Hyperglycemia was defined as a blood glucose level of ≧8.0 mmol/l. Four groups were identified based on (a) admission and (b) peak glucose levels 48 h after thrombolysis: (1) persistent normoglycemia (baseline plus 48-hour normoglycemia), (2) baseline hyperglycemia (48-hour normoglycemia), (3) 48-hour hyperglycemia (baseline normoglycemia), and (4) persistent hyperglycemia (baseline plus 48-hour hyperglycemia). Results: 480 (56.4%) of our patients (median age 70 years; onset-to-needle time 199 min; National Institutes of Health Stroke Scale score 9), had persistent normoglycemia, 59 (6.9%) had baseline hyperglycemia, 175 (20.6%) had 48-hour hyperglycemia, while persistent hyperglycemia appeared in 137 (16.1%) patients. Persistent and 48-hour hyperglycemia independently predicted unfavorable outcome [odds ratio (OR) = 2.33, 95% confidence interval (CI) = 1.41–3.86, and OR = 2.17, 95% CI = 1.30–3.38, respectively], death (OR = 6.63, 95% CI = 3.25–13.54, and OR = 3.13, 95% CI = 1.56–6.27, respectively), and sICH (OR = 3.02, 95% CI = 1.68–5.43, and OR = 1.89, 95% CI = 1.04–3.43, respectively), whereas baseline hyperglycemia did not. Conclusions: Hyperglycemia (≧8.0 mmol/l) during 48 h after intravenous thrombolysis of ischemic stroke is strongly associated with unfavorable outcome, sICH, and death.

White Matter Lesions Double the Risk of Post-Thrombolytic Intracerebral Hemorrhage

Background and Purpose— Cerebral white matter lesions (WMLs), a surrogate for small-vessel disease, are common in patients with stroke and may be related to an increased intracranial bleeding risk after intravenous thrombolysis in acute ischemic stroke. We aimed to investigate the risk of symptomatic intracerebral hemorrhage (sICH) in the presence of WMLs in a large cohort of ischemic stroke patients treated with intravenous thrombolysis. Methods— We included 2485 consecutive patients treated with intravenous thrombolysis at the Helsinki University Central Hospital. WMLs were scored according to 4 previously published computed tomography visual rating scales from all baseline head scans. A sICH was classified according to the European Cooperative Acute Stroke Study II criteria. The associations of sICH with nominal, ordinal, and continuous variables were analyzed in a univariate binary regression model and adjusted in multivariate binary regression models. Results— In univariate and multivariate regression analyses, all 4 tested visual WML rating scales (as continuous variables or dichotomized at different cutoff points) were associated with increased risk of sICH. In binary analyses, WML doubled the bleeding risk: the odds ratios of all 4 visual rating scales ranged from 2.22 (95% confidence interval, 1.49–3.30) to 2.70 (1.87–3.90) in univariable and from 2.00 (1.26–3.16) to 2.62 (1.71–4.02) in multivariable analyses. The multivariable-adjusted odds ratio for the association of high load of WMLs with remote parenchymal hemorrhage was 4.11 (2.38–7.10). Conclusions— WMLs visible on computed tomography are associated with a more than doubled risk of sICH in patients treated with intravenous thrombolysis for acute ischemic stroke.

Validation of the DRAGON Score in 12 Stroke Centers in Anterior and Posterior Circulation

Background and Purpose— The DRAGON score predicts functional outcome in the hyperacute phase of intravenous thrombolysis treatment of ischemic stroke patients. We aimed to validate the score in a large multicenter cohort in anterior and posterior circulation. Methods— Prospectively collected data of consecutive ischemic stroke patients who received intravenous thrombolysis in 12 stroke centers were merged (n=5471). We excluded patients lacking data necessary to calculate the score and patients with missing 3-month modified Rankin scale scores. The final cohort comprised 4519 eligible patients. We assessed the performance of the DRAGON score with area under the receiver operating characteristic curve in the whole cohort for both good (modified Rankin scale score, 0–2) and miserable (modified Rankin scale score, 5–6) outcomes. Results— Area under the receiver operating characteristic curve was 0.84 (0.82–0.85) for miserable outcome and 0.82 (0.80–0.83) for good outcome. Proportions of patients with good outcome were 96%, 93%, 78%, and 0% for 0 to 1, 2, 3, and 8 to 10 score points, respectively. Proportions of patients with miserable outcome were 0%, 2%, 4%, 89%, and 97% for 0 to 1, 2, 3, 8, and 9 to 10 points, respectively. When tested separately for anterior and posterior circulation, there was no difference in performance (P=0.55); areas under the receiver operating characteristic curve were 0.84 (0.83–0.86) and 0.82 (0.78–0.87), respectively. No sex-related difference in performance was observed (P=0.25). Conclusions— The DRAGON score showed very good performance in the large merged cohort in both anterior and posterior circulation strokes. The DRAGON score provides rapid estimation of patient prognosis and supports clinical decision-making in the hyperacute phase of stroke care (eg, when invasive add-on strategies are considered).

Intravenous Thrombolysis in Patients Dependent on the Daily Help of Others Before Stroke

Background and Purpose— We compared outcome and complications in patients with stroke treated with intravenous thrombolysis (IVT) who could not live alone without help of another person before stroke (dependent patients) versus independent ones. Methods— In a multicenter IVT-register–based cohort study, we compared previously dependent (prestroke modified Rankin Scale score, 3–5) versus independent (prestroke modified Rankin Scale score, 0–2) patients. Outcome measures were poor 3-month outcome (not reaching at least prestroke modified Rankin Scale [dependent patients]; modified Rankin Scale score of 3–6 [independent patients]), death, and symptomatic intracranial hemorrhage. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (OR [95% confidence interval]) were calculated. Results— Among 7430 IVT-treated patients, 489 (6.6%) were dependent and 6941 (93.4%) were independent. Previous stroke, dementia, heart, and bone diseases were the most common causes of preexisting dependency. Dependent patients were more likely to die (ORunadjusted, 4.55 [3.74–5.53]; ORadjusted, 2.19 [1.70–2.84]). Symptomatic intracranial hemorrhage occurred equally frequent (4.8% versus 4.5%). Poor outcome was more frequent in dependent (60.5%) than in independent (39.6%) patients, but the adjusted ORs were similar (ORadjusted, 0.95 [0.75–1.21]). Among survivors, the proportion of patients with poor outcome did not differ (35.7% versus 31.3%). After adjustment for age and stroke severity, the odds of poor outcome were lower in dependent patients (ORadjusted, 0.64 [0.49–0.84]). Conclusions— IVT-treated stroke patients who were dependent on the daily help of others before stroke carry a higher mortality risk than previously independent patients. The risk of symptomatic intracranial hemorrhage and the likelihood of poor outcome were not independently influenced by previous dependency. Among survivors, poor outcome was avoided at least as effectively in previously dependent patients. Thus, withholding IVT in previously dependent patients might not be justified.