David Tanne

Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: The multicenter rt-PA acute stroke survey

Background—Intravenous recombinant tissue plasminogen activator (rtPA) is an effective therapy for acute ischemic stroke, but it is associated with risk of intracerebral hemorrhage (ICH). Our aim was to identify, in a large cohort of patients, readily available baseline factors that are associated with thrombolysis-related ICH. Methods and Results—In a multicenter retrospective and prospective investigation of individual data from 1205 patients treated in routine clinical practice with intravenous rtPA within 3 hours of stroke symptom onset, 72 patients (6%) developed symptomatic ICH and 86 additional patients (7%) had asymptomatic ICH identified on a routine follow-up CT. In analyses based on clinical variables alone, the main attributes associated with ICH were a history of diabetes mellitus and cardiac disease, increasing stroke severity, advancing age, use of antiplatelet agents other than aspirin before stroke onset, and elevated pretreatment mean blood pressure. In additional analyses that incorporated baseline CT and laboratory findings (in a subset of patients), the main associations were early ischemic CT changes, in particular if exceeding one third of middle cerebral artery territory; increasing stroke severity; diabetes mellitus or elevated serum glucose; and lower platelet counts. Final independent attributes associated with parenchymatous hematoma, defined by purely radiologically based criteria, were similar to those of symptomatic ICH. Conclusions—Readily available factors can identify acute ischemic stroke patients at high and low risk for rtPA-related ICH. These factors require confirmation in a prospective cohort before clinical implementation.

Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study.

BACKGROUND Treatment strategies for acute basilar artery occlusion (BAO) are based on case series and data that have been extrapolated from stroke intervention trials in other cerebrovascular territories, and information on the efficacy of different treatments in unselected patients with BAO is scarce. We therefore assessed outcomes and differences in treatment response after BAO. METHODS The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO between November 1, 2002, and October 1, 2007. Stroke severity at time of treatment was dichotomised as severe (coma, locked-in state, or tetraplegia) or mild to moderate (any deficit that was less than severe). Outcome was assessed at 1 month. Poor outcome was defined as a modified Rankin scale score of 4 or 5, or death. Patients were divided into three groups according to the treatment they received: antithrombotic treatment only (AT), which comprised antiplatelet drugs or systemic anticoagulation; primary intravenous thrombolysis (IVT), including subsequent intra-arterial thrombolysis; or intra-arterial therapy (IAT), which comprised thrombolysis, mechanical thrombectomy, stenting, or a combination of these approaches. Risk ratios (RR) for treatment effects were adjusted for age, the severity of neurological deficits at the time of treatment, time to treatment, prodromal minor stroke, location of the occlusion, and diabetes. FINDINGS 619 patients were entered in the registry. 27 patients were excluded from the analyses because they did not receive AT, IVT, or IAT, and all had a poor outcome. Of the 592 patients who were analysed, 183 were treated with only AT, 121 with IVT, and 288 with IAT. Overall, 402 (68%) of the analysed patients had a poor outcome. No statistically significant superiority was found for any treatment strategy. Compared with outcome after AT, patients with a mild-to-moderate deficit (n=245) had about the same risk of poor outcome after IVT (adjusted RR 0.94, 95% CI 0.60-1.45) or after IAT (adjusted RR 1.29, 0.97-1.72) but had a worse outcome after IAT compared with IVT (adjusted RR 1.49, 1.00-2.23). Compared with AT, patients with a severe deficit (n=347) had a lower risk of poor outcome after IVT (adjusted RR 0.88, 0.76-1.01) or IAT (adjusted RR 0.94, 0.86-1.02), whereas outcomes were similar after treatment with IAT or IVT (adjusted RR 1.06, 0.91-1.22). INTERPRETATION Most patients in the BASICS registry received IAT. Our results do not support unequivocal superiority of IAT over IVT, and the efficacy of IAT versus IVT in patients with an acute BAO needs to be assessed in a randomised controlled trial. FUNDING Department of Neurology, University Medical Center Utrecht.

Initial clinical experience with IV tissue plasminogen activator for acute ischemic stroke: A multicenter survey

Article abstract We assessed initial clinical experience with IV tissue plasminogen activator (t-PA) treatment of acute ischemic stroke in a standardized retrospective survey of hospitals with experienced acute stroke treatment systems. The incidence of symptomatic intracerebral hemorrhage (ICH) was 6% (11 of 189 patients; 95% CI 3 to 11%), similar to that in the National Institute of Neurological Disorders and Stroke (NINDS) t-PA Stroke Study. Deviations from the NINDS protocol guidelines were identified in 30% of patients (56 of 189). The incidence of symptomatic ICH was 11% among patients with protocol deviations as compared with 4% in patients who were treated according to the NINDS protocol guidelines, suggesting that strict adherence to protocol guidelines is prudent.

Reduced incidence of ischemic stroke in patients with severe factor XI deficiency.

Inherited disorders of hemostasis are natural models for investigating mechanisms of thrombosis and development of antithrombotic therapy. Because mice with total factor XI deficiency are protected against ischemic stroke and do not manifest excessive bleeding, we investigated the incidence of ischemic stroke in patients with severe inherited factor XI deficiency. Incidence of ischemic stroke in 115 patients aged 45 years or more with severe factor XI deficiency (activity less than 15 U/dL) was compared with incidence in the Israeli population as estimated from a stroke survey of 1528 patients. Adjustment for major risk factors of stroke (hypertension, diabetes mellitus, hypercholesterolemia, current smoking) was based on comparison of their prevalence in the stroke survey to an Israeli health survey of 9509 subjects. Incidence of myocardial infarction in the factor XI cohort was also recorded. After adjustment for the 4 major risk factors of ischemic stroke, the expected incidence of ischemic stroke was 8.56 compared with one observed (P = .003). The reduced 1:115 incidence of ischemic stroke contrasted with a 19:115 incidence of myocardial infarction, similar to the expected incidence. Thus, severe factor XI deficiency probably is protective against ischemic stroke but not against acute myocardial infarction.

Chronic Kidney Disease and Clinical Outcome in Patients With Acute Stroke

Background and Purpose— Chronic kidney disease (CKD) is increasingly recognized as an independent risk factor for cardiovascular disease and stroke. Our aim was to examine the association between estimated glomerular filtration rate (GFR) and stroke outcome and to assess whether CKD and its severity affect stroke outcome in a large cohort of unselected patients with acute stroke. Methods— We examined the association between baseline estimated GFR and CKD and 1-year outcomes in 821 consecutive patients with acute stroke (ischemic or hemorrhagic). GFR was estimated by 2 methods: the Modification of Diet in Renal Disease and the Mayo Clinic quadratic equation. An estimated GFR rate ≤60 mL/min/1.73 m2 defined CKD. Results— Odds ratios (95% CI) for death across levels of estimated GFR based on both equations were estimated. CKD was present in 36% (n=291) of patients based on the Modification of Diet in Renal Disease equation and 18% (n=147) based on the Mayo Clinic equation. The adjusted ORs for mortality after 1-year based on the Modification of Diet in Renal Disease equation were 0.7 (95% CI, 0.4 to 1.2) associated with GFR 45 to 60 and 3.2 (1.7 to 6.4) associated with GFR 15 to 44 as compared with GFR >60 mL/min/1.73 m2, whereas those based on the Mayo Clinic equation were 2.3 (1.1 to 4.7) and 3.3 (1.6 to 7.1), respectively. The adjusted ORs for Barthel Index ≤75 or death after 1 year were 0.8 (0.5 to 1.5) and 2.1 (0.9 to 4.8) by the Modification of Diet in Renal Disease equation and 1.9 (0.8 to 4.4) and 3.9 (1.5 to 11.0) by the Mayo Clinic equation, respectively. Conclusions— CKD is a strong independent predictor of mortality and poor outcome in patients with acute stroke. The estimation of the prevalence of CKD and of the GFR cutoffs associated with poor outcome depend on the equation used to estimate GFR.

Intravenous tissue plasminogen activator for acute ischemic stroke in patients aged 80 years and older: The tPA stroke survey experience

BACKGROUND AND PURPOSE Intravenous tissue plasminogen activator (tPA) administered within 3 hours of symptom onset is the first available effective therapy for acute ischemic stroke (AIS). Few data exist, however, on its use in very elderly patients. We examined the characteristics, complications, and short-term outcome of AIS patients aged >/=80 years treated with tPA. METHODS Patients aged >/=80 years (n=30) were compared with counterparts aged <80 years (n=159) included in the tPA Stroke Survey, a US retrospective survey of 189 consecutive AIS patients treated with intravenous tPA at 13 hospitals. RESULTS Risk of intracerebral hemorrhage (fatal, symptomatic, and total) was 3%, 3%, and 7% in the elderly age group and 2%, 6%, and 9%, respectively, in their younger counterparts (P=NS for all comparisons). Likelihood of favorable outcome, defined as modified Rankin score 0 to 1, National Institutes of Health Stroke Scale score </=5, or marked improvement by hospital discharge, was comparable between groups (37%, 54%, and 43% versus 30%, 54%, and 43%, respectively; P=NS for all comparisons). Elderly patients were more likely to be treated by stroke specialists (87% versus 60%; P=0.005) and less likely to have an identified protocol deviation (13% versus 33%; P=0.03). Elderly patients were discharged more often to nursing care facilities (17% versus 5%; P=0.003). In logistic regression models there were no differences in odds ratio for favorable or poor outcome, other than tendency for higher in-hospital mortality in elderly patients (odds ratio, 2.8; 95% CI, 0.81 to 9.62; P=0.10). CONCLUSIONS Among AIS patients treated with intravenous tPA, age-related differences in characteristics and disposition were identified. No evidence for withholding tPA treatment for AIS in appropriately selected patients aged >/=80 years was identified.

Relation Between the Metabolic Syndrome and Ischemic Stroke or Transient Ischemic Attack A Prospective Cohort Study in Patients With Atherosclerotic Cardiovascular Disease

Background and Purpose— The combination of risk factors known as the metabolic syndrome is receiving increased attention, but prospective data on the syndromes association with ischemic cerebrovascular events are scarce. We explored the relation of metabolic syndrome versus frank diabetes with first-ever ischemic stroke or transient ischemic attack (TIA) in a large cohort of patients with atherosclerotic cardiovascular disease. Methods— Patients with coronary heart disease, screened for a clinical trial, underwent an extensive medical evaluation and follow-up for cerebrovascular disease over 4.8 to 8.1 years. National Cholesterol Education Program Adult Treatment Panel III criteria were used to define the metabolic syndrome, with body mass index substituted for waist circumference. Patients with previously diagnosed diabetes or with a fasting plasma glucose level >125 mg/dL (≥7.0 mmol/L) were considered diabetic. Results— The study sample comprised 14 284 patients, of which 3703 (26%) fulfilled the criteria for the metabolic syndrome without diabetes and 3500 others (25%) the criteria for diabetes. Adjusting for stroke risk factors, patients with the metabolic syndrome without diabetes exhibited a 1.49-fold increased odds for ischemic stroke or TIA (95% confidence interval [CI], 1.20 to 1.84), whereas those with frank diabetes had a 2.29-fold increased odds (95% CI, 1.88 to 2.78). The relative odds for ischemic stroke or TIA, associated with presence of the metabolic syndrome per se, were 1.39 (95% CI, 1.10 to 1.77) in men but 2.10 (95% CI, 1.26 to 3.51) in women. Although all components of the metabolic syndrome were associated with increased risk for ischemic stroke or TIA, impaired fasting glucose and hypertension were the strongest predictors of risk. Conclusions— The presence of the metabolic syndrome, even without diabetes, in patients with pre-existing atherosclerotic vascular disease identifies patients at increased risk for ischemic stroke or TIA. The suggestion of more pronounced risk associated with the metabolic syndrome in women deserves further assessment in other cohorts.

Kidney function is associated with the rate of cognitive decline in the elderly

Objective: We tested the hypothesis that impaired kidney function in the elderly is associated with a more rapid rate of cognitive decline. Methods: Baseline serum was used to calculate estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease formula, for 886 elderly without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. Kidney function was also dichotomized into impairment or no impairment based on eGFR < or ≥60 mL/min/1.73 m2. Structured cognitive testing was performed at baseline and at annual evaluations, using a battery of 19 cognitive tests summarized into global cognition and 5 cognitive domains. Results: In mixed-effects models adjusted for age, sex, and education, a lower eGFR at baseline was associated with a more rapid rate of cognitive decline (estimate 0.0008, SE <0.001, p = 0.017). The increased rate of cognitive decline associated with a 15-mL/min/1.73 m2 lower eGFR at baseline (approximately 1 SD) was similar to the effect of being 3 years older at baseline. Impaired kidney function at baseline was associated with a more rapid rate of cognitive decline (estimate −0.028, SE <0.009, p = 0.003). The increased rate of cognitive decline associated with impaired kidney function at baseline was approximately 75% the effect of ApoE4 allele on the rate of cognitive decline. Baseline kidney function was associated with declines in semantic memory, episodic memory, and working memory but not visuospatial abilities or perceptual speed. Conclusion: Impaired kidney function is associated with a more rapid rate of cognitive decline in old age.

Predictors of good outcome after intravenous tPA for acute ischemic stroke

Background: Thrombolytic therapy for acute ischemic stroke with IV alteplase is increasingly well established in North America but not elsewhere. Baseline factors that altered the response to alteplase were not identified by the National Institute of Neurological Disorders and Stroke tPA Stroke Study Group. Methods: The authors gathered information from centers in the United States, Canada, and Germany on 1,205 patients with acute ischemic stroke treated with IV alteplase. The purpose was to identify independent factors that were predictive of good outcome using multivariable logistic regression modelling. The modified Rankin Scale score was dichotomized into good outcome (mRS 0 to 1) and poor outcome (mRS >1) as the primary outcome measure. Results: In relative order of decreasing magnitude, milder baseline stroke severity, no history of diabetes mellitus, normal CT scan, normal pretreatment blood glucose level, and normal pretreatment blood pressure were independent predictors of good outcome among patients treated with IV alteplase for acute ischemic stroke. Confounding was observed among history of diabetes mellitus, CT scan appearance, baseline serum glucose level, and blood pressure, suggesting important relationships among these variables. Conclusions: Several factors were independently predictive of good outcome among patients with acute ischemic stroke treated with alteplase. These results require further confirmation before clinical implementation.

High-Density Lipoprotein Cholesterol and Risk of Ischemic Stroke Mortality A 21-Year Follow-up of 8586 Men From the Israeli Ischemic Heart Disease Study

BACKGROUND AND PURPOSE While there is overwhelming evidence relating low levels of HDL cholesterol (HDL-C) with coronary heart disease, the association with cerebrovascular disease is not clear. The aim of the present report was to assess the association between HDL-C levels and ischemic stroke mortality obtained from a long-term follow-up in the Israeli Ischemic Heart Disease Study. METHODS The subjects of this report are 8586 men, tenured civil servants and municipal employees, aged 42 years or older at the time of HDL-C measurements in 1965. They were followed up for mortality for 21 years. Death due to cerebrovascular disease included the International Classification of Disease, 9th Revision, codes 430 to 438, of which presumed ischemic stroke included codes 433 to 438. RESULTS During the 21-year follow-up, 295 men died from cerebrovascular events, of which 241 deaths were due to presumed ischemic stroke. Individuals subsequently experiencing a fatal ischemic stroke had a marginally lower age-adjusted mean HDL-C (1.05 mmol/L) and a significantly lower (P < .001) age-adjusted mean percentage of serum cholesterol contained in the HDL fraction (%HDL) (19.3%) than counterparts surviving the follow-up period (1.06 mmol/L and 20.6%, respectively). Decreasing age-adjusted rates of ischemic stroke mortality were observed with increasing %HDL: 14.6, 14.0, and 11.8 per 10,000 person-years in the low, middle, and upper tertiles of %HDL, respectively. In multivariate analysis, a low concentration of HDL-C appeared to be significantly predictive of ischemic stroke mortality. The relative risk associated with a 5% decrease of %HDL was 1.18 (95% confidence interval, 1.03 to 1.34). Men at the lower tertile of HDL-C levels experienced a 1.32-fold increase of covariate-adjusted ischemic stroke mortality risk compared with counterparts at the upper tertile. CONCLUSIONS In this prospective study of middle-aged and elderly men from a healthy, working population, we have demonstrated an independent negative association between HDL-C and ischemic stroke mortality during a long-term (21-year) follow-up.