Demaerschalk, Bart M.

Background and Purpose— Previous studies of multiple-day dosing with the defibrinogenating agent, ancrod, in acute ischemic stroke yielded conflicting results but suggested that a brief dosing regimen might improve efficacy and safety. The Ancrod Stroke Program was designed to test this concept in subjects beginning ancrod or placebo within 6 hours of the onset of acute ischemic stroke. Methods— Five hundred subjects with acute ischemic stroke who could begin receiving study material within 6 hours of symptom onset were infused intravenously with either ancrod (0.167 IU/kg per hour) or placebo over 2 or 3 hours. The primary efficacy outcome was a dichotomized, modified Rankin score at 90 days with less stringent cut-points for higher prestroke modified Rankin score and pretreatment NIHSS total score (“responder analysis”). Safety variables included mortality, major bleeding, and intracranial hemorrhage. Results— Although the desired changes in fibrinogen level were seen in >90% of ancrod subjects, interim analysis for futility led to the study being halted for lack of efficacy. Positive responder status in the interim dataset was seen in 39.6% of ancrod subjects and 37.2% of placebo subjects ( P =0.47). Ninety-day mortality did not differ between the 2 groups (ancrod, 15.6%; placebo, 14.1%; P =0.32), and the incidence of symptomatic intracranial hemorrhage within the first 72 hours, although not significantly different in ancrod compared to placebo subjects ( P =0.19), was approximately twice as high (3.9% vs 2.0%; P =0.19). Conclusion— These results demonstrate that intravenous ancrod starting within 6 hours after symptom onset in a broad selection of subjects with ischemic stroke did not improve their outcome and revealed a trend to increased bleeding despite successful efforts to achieve rapid initial defibrinogenation and avoid prolonged hypofibrinogenemia.

Background and Purpose— Detection of an intracardiac shunt is frequently sought during the evaluation of patients with cryptogenic ischemic stroke and agitated saline intravenous injection, or “bubble study” (BS), is performed in most cases. We present the first attempt to identify the clinical features in patients who had cerebral ischemic events with BS. Methods— Using a list serve established by the American Academy of Neurology, a member posted a question regarding the safety of BS in patients with patent foramen ovale. A standardized questionnaire was used to gather data about patients with cerebral ischemic events, details of each case were reviewed, and the findings pooled. Results— Five patients with ischemic complications of BS (all female, aged 42 to 90 years) were identified from 4 institutions, 3 ischemic strokes and 2 transient ischemic attacks. Events occurred either during or within 5 minutes of BS. Early brain MRIs confirmed acute infarction in 3, including one who had transient symptoms. MRI infarct volumes were small, and deficits were mild in those who developed stroke. Diagnostic evaluation revealed a patent foramen ovale alone in one case, a pulmonary arteriovenous malformation in one case, and a patent foramen ovale and/or pulmonary shunt in 3 cases. Conclusions— Ischemic cerebrovascular complications can occur in patients who undergo BS and are associated with the presence of cardiac or pulmonary shunts. The true incidence and degree of disability remains unknown, and further study is indicated to assess the impact of technical differences in BS methodology. Novel methods to promote physician communication such as the use of electronic list serves may reduce barriers to reporting of drug, technique, or device complications and should be explored to identify rare complications that otherwise will likely go unappreciated.

Background and Purpose— Epidemiological studies have found strong correlations between elevated plasma fibrinogen levels and both ischemic stroke incidence and stroke mortality. Little is known about the influence of fibrinogen levels on functional stroke outcome. Methods— Placebo data from the Stroke Treatment with Ancrod Trial (STAT) and European Stroke Treatment with Ancrod Trial (ESTAT) were analyzed. Fibrinogen levels were determined within 3 hours (STAT) or 6 hours (ESTAT) of stroke onset and at preset intervals throughout 5 days of intravenous infusions. Barthel Index scores at 90 days quantified functional outcomes. The association between initial fibrinogen levels and functional outcomes was evaluated using a multiple logistic regression analysis. Results— Fibrinogen levels increased gradually over the first 24 hours from a pretreatment median value of 340 mg/dL to a 24-hour median value of 376 mg/dL. In a univariate analysis, the proportion of patients with good functional outcome decreased with increasing quartiles of initial fibrinogen levels in both STAT (36.0% to 26.2%) and ESTAT (53.8% to 24.8%). In a multifactorial analysis, the same trend was observed. Patients with initial fibrinogen levels <450 mg/dL had better outcomes in both studies; the difference (42.0% versus 21.6%) was significant in ESTAT ( P =0.0006), even when corrected for age and initial stroke severity. Conclusion— The independent association of higher initial fibrinogen levels with poor outcome needs to be verified using a larger acute stroke dataset. Even in the present small populations, the apparent association of these 2 variables suggests that treatments designed to reduce fibrinogen levels could potentially be important in treating acute ischemic stroke.

The recent “Advanced Neuroimaging for Acute Stroke Treatment” meeting on September 7 and 8, 2007 in Washington DC, brought together stroke neurologists, neuroradiologists, emergency physicians, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), industry representatives, and members of the US Food and Drug Administration (FDA) to discuss the role of advanced neuroimaging in acute stroke treatment. The goals of the meeting were to assess state-of-the-art practice in terms of acute stroke imaging research and to propose specific recommendations regarding: (1) the standardization of perfusion and penumbral imaging techniques, (2) the validation of the accuracy and clinical utility of imaging markers of the ischemic penumbra, (3) the validation of imaging biomarkers relevant to clinical outcomes, and (4) the creation of a central repository to achieve these goals. The present article summarizes these recommendations and examines practical steps to achieve them.

Background and Purpose— In 1998, 2947 patients in metropolitan Phoenix were hospitalized for acute cerebral infarction. Only 2 of the 26 regional hospitals satisfied criteria for primary stroke center (PSC) designation. Fewer than 1% of patients with ischemic stroke received tissue plasminogen activator for thrombolysis. We sought to develop and evaluate the effectiveness of a metropolitan prehospital emergency medical system for effectively identifying and transporting patients with acute stroke to a matrix of predesignated PSCs and increasing to 20% the proportion of all such patients receiving tissue plasminogen activator. Methods— The American Stroke Association Phoenix Operation Stroke partnered with the Arizona Emergency Medical Systems in 1998 to 1999 to list goals and objectives, identify key stakeholders, and develop committees to address community education, emergency medical system training, and PSC designation. Results— Over 8 years, emergency medical system personnel were trained to identify and transport patients with acute stroke to PSCs, 8 hospitals met PSC criteria, the metropolitan matrix of PSCs became operational (in 2003), and 18% of patients with acute ischemic stroke received thrombolysis. Conclusions— It is feasible to develop and operationalize a successful metropolitan-wide matrix of PSCs to accommodate emergency medical system-identified and transported patients with acute stroke in a 9000-square-mile region with a population of 3.5 million people.

Background and Purpose— Intravenous tissue plasminogen activator (tPA) is an economically worthwhile but underused treatment option for acute ischemic stroke. We sought to identify the extent of tPA use in Canadian medical centers and the potential savings associated with increased use nationally and by province. Methods— We determined the nationwide annual incidence of ischemic stroke from the Canadian Institute of Health Information. The proportion of all ischemic stroke patients who received tPA was derived from published data. Economic analyses that report the expected annual cost savings of tPA were consulted. The analysis was conducted from the perspective of a universal health care system during 1 year. We estimated cost-savings with incrementally (eg, 2%, 4%, 6%, 8%, 10%, 15%, and 20%) increased use of tPA for acute ischemic stroke nationally and provincially. Results— The current average national tPA utilization is 1.4%. For every increase of 2 percentage points in utilization, $757 204 (Canadian) could possibly be saved annually (95% CI maximum loss of $3 823 992 to a maximum savings of $2 201 252). With a 20% rate, >$7.5 million (Canadian) could be saved nationwide the first year. Conclusions— We estimate that even small increases in the proportion of all Canadian ischemic stroke patients receiving tPA could result in substantial realized savings for Canada’s health care system.

Background and Purpose— Thrombolysis for acute ischemic stroke saves societal costs, but hospitals that practice acute stroke care appear to shoulder the burden of the cost, which exceeds reimbursement. With creation of the diagnosis-related group (DRG) 559, the US Centers for Medicare and Medicaid Services pays hospitals approximately US $6000 more per case when thrombolysis is administered. We sought to determine the total cost of, and reimbursement for, acute stroke treatment with thrombolysis at a single stroke center and the economic impact of DRG 559. Methods— Between September 2001 and December 2004, we collected data on all patients with acute stroke who received thrombolysis. We identified all hospital costs and reimbursement per patient. Financial results were expressed as a cost-reimbursement ratio: average total cost to average total reimbursement per patient. We then reanalyzed data using the projected Medicare hospital reimbursement with DRG 559. Results— Sixty-seven patients with stroke (mean age, 72 years) were treated (mean length of stay, 4.4 days; mean stroke severity, National Institutes of Health Stroke Scale score of 15; and symptomatic intracranial hemorrhage rate, 7%). The cost-reimbursement ratio was 1.41 (95% CI=0.98 to 2.28) before DRG 559 and estimated to be 0.82 (95% CI=0.66 to 0.97) after DRG 559. Conclusions— Our hospital costs have traditionally exceeded Medicare reimbursement for the acute care of thrombolyzed patients with ischemic stroke, but with DRG 559, a new economically favorable cost-reimbursement ratio for hospitals will be established.