Ancrod for the treatment of acute ischemic brain infarction. The Ancrod Stroke Study Investigators. Erythropoietin therapy for acute stroke is both safe and beneficial. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute Embolic Stroke Trial. Granulocyte colony-stimulating factor for acute ischemic stroke: a randomized controlled trial. A multicentre, double-blind, randomized study to compare the safety and efficacy of once-daily ORG 10172 and twice-daily low-dose heparin in preventing deep-vein thrombosis in patients with acute ischaemic stroke. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. A pilot randomized controlled trial to evaluate the benefit of the cardiac rehabilitation paradigm for the non-acute ischaemic stroke population. AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. A patient decision aid regarding antithrombotic therapy for stroke prevention in atrial fibrillation: a randomized controlled trial.
There is no acute therapy proven to be of benefit for ischemic stroke. Ancrod is a potentially effective therapy because of the advantageous consequences of fibrinogen lowering.
                We studied the safety and efficacy of ancrod in patients with acute ischemic stroke administered within 6 hours of stroke onset. In a double-blind, randomized, placebo-controlled trial 64 patients received intravenous ancrod and 68 received placebo for 7 days. Neurological outcome, disability, and brain infarct volume were measured.
                There was no significant difference in overall mean scores on the Scandinavian Stroke Scale. No increase in bleeding occurred in the ancrod-treated patients. The target reduction of plasma fibrinogen levels of less than 100 mg/dL was achieved in only 15 (23%) of 64 ancrod-treated patients. Those patients with ancrod-induced 6-hour fibrinogen levels 130 mg/dL or less had a marginally significantly better neurological outcome on the Scandinavian Stroke Scale, mortality, and Barthel Index than ancrod-treated patients with higher fibrinogen levels.
                Ancrod appears safe and potentially effective when administered to patients within 6 hours of onset of ischemic stroke. Erythropoietin (EPO) and its receptor play a major role in embryonic brain, are weakly expressed in normal postnatal/adult brain and up-regulated upon metabolic stress. EPO protects neurons from hypoxic/ ischemic injury. The objective of this trial is to study the safety and efficacy of recombinant human EPO (rhEPO) for treatment of ischemic stroke in man.
                The trial consisted of a safety part and an efficacy part. In the safety study, 13 patients received rhEPO intravenously (3.3 X 10(4) IU/50 ml/30 min) once daily for the first 3 days after stroke. In the double-blind randomized proof-of-concept trial, 40 patients received either rhEPO or saline. Inclusion criteria were age <80 years, ischemic stroke within the middle cerebral artery territory confirmed by diffusion-weighted MRI, symptom onset <8 hr before drug administration, and deficits on stroke scales. The study endpoints were functional outcome at day 30 (Barthel Index, modified Rankin scale), NIH and Scandinavian stroke scales, evolution of infarct size (sequential MRI evaluation using diffusion-weighted [DWI] and fluid-attenuated inversion recovery sequences [FLAIR]) and the damage marker S100ss.
                No safety concerns were identified. Cerebrospinal fluid EPO increased to 60-100 times that of nontreated patients, proving that intravenously administered rhEPO reaches the brain. In the efficacy trial, patients received rhEPO within 5 hr of onset of symptoms (median, range 2:40-7:55). Admission neurologic scores and serum S100beta concentrations were strong predictors ofoutcome. Analysis of covariance controlled for these two variables indicated that rhEPO treatment was associated with an improvement in follow-up and outcome scales. A strong trend for reduction in infarct size in rhEPO patients as compared to controls was observed by MRI.
                Intravenous high-dose rhEPO is well tolerated in acute ischemic stroke and associated with an improvement in clinical outcome at 1 month. A larger scale clinical trial is warranted. Patients with acute ischaemic stroke and atrial fibrillation have an increased risk of early stroke recurrence, and anticoagulant treatment with heparins has been widely advocated, despite missing data on the balance of risk and benefit.
                Heparin in Acute Embolic Stroke Trial (HAEST) was a multicentre, randomised, double-blind, and double-dummy trial on the effect of low-molecular-weight heparin (LMWH, dalteparin 100 IU/kg subcutaneously twice a day) or aspirin (160 mg every day) for the treatment of 449 patients with acute ischaemic stroke and atrial fibrillation. The primary aim was to test whether treatment with LMWH, started within 30 h of stroke onset, is superior to aspirin for the prevention of recurrent stroke during the first 14 days.
                The frequency of recurrent ischaemic stroke during the first 14 days was 19/244 (8.5%) in dalteparin-allocated patients versus 17/225 (7.5%) in aspirin-allocated patients (odds ratio=1.13, 95% CI 0.57-2.24). The secondary events during the first 14 days also revealed no benefit of dalteparin compared with aspirin: symptomatic cerebral haemorrhage 6/224 versus 4/225; symptomatic and asymptomatic cerebral haemorrhage 26/224 versus 32/225; progression of symptoms within the first 48 hours 24/224 versus 17/225; and death 21/224 versus 16/225. There were no significant differences in functional outcome or death at 14 days or 3 months.
                The present data do not provide any evidence that LMWH is superior to aspirin for the treatment of acute ischaemic stroke in patients with atrial fibrillation. However, the study could not exclude the possibility of smaller, but still worthwhile, effects of either of the trial drugs. Because granulocyte colony-stimulating factor (G-CSF) has anti-inflammatory and neuroprotective properties and is known to mobilize stem cells, it may be useful in the treatment of acute ischemic stroke. We sought to examine the feasibility, safety and efficacy of using G-CSF to treat acute stroke.
                We conducted a randomized, blinded controlled trial involving 10 patients with acute cerebral infarction (middle cerebral artery territory as documented by the admission MRI) who presented within 7 days of onset and whose scores on the National Institutes of Health Stroke Scale (NIHSS) were between 9 and 20. Patients were assigned to either G-CSF therapy or usual care. The G-CSF group (n = 7) received subcutaneous G-CSF injections (15 microg/kg per day) for 5 days. The primary outcome was percentage changes between baseline and 12-month follow-up in mean group scores on 4 clinical scales: the NIHSS, European Stroke Scale (ESS), ESS Motor Subscale (EMS) and Barthel Index (BI). We also assessed neurologic functioning using PET to measure cerebral uptake of fluorodeoxyglucose in the cortical areas surrounding the ischemic core.
                All of the patients completed the 5-day course of treatment, and none were lost to follow-up. No severe adverse effects were seen in patients receiving G-CSF. There was greater improvement in neurologic functioning between baseline and 12-month follow-up in the G-CSF group than in the control group (NIHSS: 59% change in the mean G-CSF group score v. 36% in the mean control group score, ESS: 33% v. 20%, EMS: 106% v. 58%, BI: 120% v. 60%). Although at 12 months there was no difference between the 2 groups in cerebral uptake of fluorodeoxyglucose in the ischemic core, uptake in the area surrounding the core was significantly improved in the G-CSF group compared with the control group. There was positive correlation between metabolic activity and EMS score following simple linear correlation analysis.
                Our preliminary evidence suggests that using G-CSF as therapy for acute stroke is safe and feasible and leads to improved neurologic outcomes. A multicentre, double-blind, randomized study was performed in 179 patients with acute ischaemic stroke resulting in limb paresis. The purpose was to compare the safety and efficacy of Org 10172 (1250 anti-Xa Units s.c. once daily) and heparin sodium (5000 IU s.c. twice daily) in preventing deep-vein thrombosis (DVT). Prophylaxis started within 72 hours of the onset of stroke and continued for at least 9 days. To detect DVT, patients underwent a daily 125I-fibrinogen leg scanning which, if found positive, was followed by venography. A first computed tomography scan of the brain was performed at screening to rule out cerebral haemorrhage and a second at cessation of treatment to detect any haemorrhagic transformations. At the 2-3-months' follow-up period the patients were examined for signs and symptoms of DVT or pulmonary embolism. On an intention-to-treat analysis, DVT occurred in 14.6% of patients receiving Org 10172 and in 19.8% of those receiving heparin during the treatment period (p = 0.392, NS). Pulmonary embolism was diagnosed in one patient in each group. Major conversion to a symptomatic haemorrhagic brain infarct was found in one patient in each group. Death occurred in 13.5% of patients treated with Org 10172 and in 6.7% of patients treated with heparin (p = 0.135, NS). Deaths were mainly related to pulmonary infection and cerebral oedema, thus considered to be due directly to the clinical status of the patients. 1250 anti-Xa Units of Org 10172 once daily is both safe and as effective as 5000 IU of heparin sodium twice daily given for DVT prophylaxis in patients with acute ischaemic stroke of recent onset. Recombinant tissue-type plasminogen activator (rt-PA) improves outcomes for patients with acute ischemic stroke, but current approved use is limited to within 3 hours of symptom onset. This restricts the number of patients who can be treated, since most stroke patients present more than 3 hours after symptom onset.
                To test the efficacy and safety of rt-PA in patients with acute ischemic stroke when administered between 3 and 5 hours after symptom onset.
                The Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study is a phase 3, placebo-controlled, double-blind randomized study conducted between December 1993 and July 1998, with up to 90 days of follow-up.
                One hundred forty university and community hospitals in North America.
                An intent-to-treat population of 613 acute ischemic stroke patients was enrolled, with 547 of these treated as assigned within 3 to 5 hours of symptom onset. A total of 39 others were treated within 3 hours of symptom onset, 24 were treated more than 5 hours after symptom onset, and 3 never received any study drug.
                Administration of 0.9 mg/kg of rt-PA (n = 272) or placebo (n = 275) intravenously over 1 hour.
                Primary efficacy was an excellent neurologic recovery at day 90 (National Institutes of Health Stroke Scale [NIHSS] score of < or =1); secondary end points included excellent recovery on functional outcome measures (Barthel index, modified Rankin scale, and Glasgow Outcome Scale) at days 30 and 90. Serious adverse events were also assessed.
                In the target population, 32% of the placebo and 34% of rt-PA patients had an excellent recovery at 90 days (P = .65). There were no differences on any of the secondary functional outcome measures. In the first 10 days treatment with rt-PA significantly increased the rate of symptomatic intracerebral hemorrhage (ICH) (1.1% vs 7.0% [P<.001]), a symptomatic ICH (4.7% vs 11.4% [P = .004]), and fatal ICH (0.3% vs 3.0% [P<.001]). Mortality at 90 days was 6.9% with placebo and 11.0% with rt-PA (P = .09). Results in the intent-to-treat population were similar.
                This study found no significant rt-PA benefit on the 90-day efficacy end points in patients treated between 3 and 5 hours. The risk of symptomatic ICH increased with rt-PA treatment. These results do not support the use of intravenous rt-PA for stroke treatment beyond 3 hours. To evaluate risk factor reduction and health-related quality of life following a 10-week cardiac rehabilitation programme in non-acute ischaemic stroke subjects.
                Single-blinded randomized control trial.
                Outpatient rehabilitation.
                Forty-eight community-dwelling ischaemic stroke patients (38 independently mobile, 9 requiring assistance, 1 non-ambulatory) were randomly assigned to intervention or control groups by concealed allocation.
                The trial consisted of a 10-week schedule with measures taken at weeks 1 and 10. Both groups continued usual care (excluding aerobic exercise); intervention subjects attended 16 cycle ergometry sessions of aerobic-training intensity and two stress-management classes.
                Cardiac risk score (CRS); VO(2) (mL O(2)/kg per minute) and Borg Rate of Perceived Exertion (RPE) assessed during a standardized ergometry test; Hospital Anxiety and Depression Scale (HADS); Frenchay Activity Index; Fasting Lipid Profiles and Resting Blood Pressure.
                Group comparison with independent t-tests showed significantly greater improvement at follow-up by intervention subjects than controls in VO(2) (intervention 10.6 +/-1.6 to 12.0 +/- 2.2, control 11.1 +/-1.8 to 11.1 +/-1.9 t=4.734, P<0.001) and CRS (intervention 13.4 +/-10.1 to 12.4 +/-10.5, control 9.4 +/-6.7 to 15.0 +/-6.1 t=-2.537, P<0.05). RPE rating decreased in intervention subjects (13.4 +/-12.2 to 12.4 +/-2.0) and increased in controls (13.8 +/-1.8 to 14.4 +/-1.6); Mann-Whitney U (U = 173.5, P<0.05). Within-group comparison showed significant decrease in the HADS depression subscale in the intervention group alone (5.1 +/-3.4 to 3.0 +/-2.8) (Wilcoxon signed ranks test Z=-3.278, P<0.001).
                Preliminary findings suggest non-acute ischaemic stroke patients can improve their cardiovascular fitness and reduce their CRS with a cardiac rehabilitation programme. The intervention was associated with improvement in self-reported depression. Granulocyte colony-stimulating factor (G-CSF) is a promising stroke drug candidate. The present phase IIa study assessed safety and tolerability over a broad dose range of G-CSF doses in acute ischemic stroke patients and explored outcome data.
                Four intravenous dose regimens (total cumulative doses of 30-180 μg/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch.
                Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions > 14-17 cm³.
                We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points. Decision aids are tools designed to help patients participate in the clinical decision-making process.
                To determine whether use of an audiobooklet (AB) decision aid explaining the results of a clinical trial affected the decision-making process of study participants.
                Randomized controlled trial conducted from May 1997 to April 1998.
                Fourteen centers that participated in the Stroke Prevention in Atrial Fibrillation (SPAF) III trial.
                A total of 287 patients from the SPAF III aspirin cohort study, in which patients with atrial fibrillation and a relatively low risk of stroke received 325 mg/d of aspirin and were followed up for a mean of 2 years.
                At the end of SPAF III, participants were randomized to be informed of the study results with usual care plus use of an AB (AB group) vs usual care alone (control group). The AB included pertinent information to help patients decide whether to continue taking aspirin or switch to warfarin.
                Patients' ability to make choices regarding antithrombotic therapy, and 6-month adherence to these decisions. Their knowledge, expectations, decisional conflict (the amount of uncertainty about the course of action to take), and satisfaction with the decision-making process were also measured.
                More patients in the AB group made a choice about antithrombotic therapy than in the control group (99% vs 94%; P = .02). Patients in the AB group were more knowledgeable and had more realistic expectations about the risk of stroke and hemorrhage (in the AB group, 53%-80% correctly estimated different risks; in the control group, 16%-28% gave correct estimates). Decisional conflict and satisfaction were similar for the 2 groups. After 6 months, a similar percentage of patients were still taking their initial choice of antithrombotic therapy (95% vs 93%; P = .44).
                For patients with atrial fibrillation who had participated in a major clinical trial, the use of an AB decision aid improved their understanding of the benefits and risks associated with different treatment options and helped them make definitive choices about which therapy to take. Further studies are necessary to evaluate the acceptability and impact of decision aids in other clinical settings.
The current evidence is promising but not yet sufficiently robust to support the routine use of fibrinogen depleting agents for the treatment of acute ischaemic stroke. Further trials are needed to determine whether there is worthwhile benefit, and if so, which categories of patients are most likely to benefit.