Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem Cell Trial of Recovery EnhanceMent After Stroke (STEMS) Pilot Randomized, Controlled Trial (ISRCTN 16784092)

Background and Purpose - Loss of motor function is common after stroke and leads to significant chronic disability. Stem cells are capable of self-renewal and of differentiating into multiple cell types, including neurones, glia, and vascular cells. We assessed the safety of granulocyte-colony-stimulating factor (G-CSF) after stroke and its effect on circulating CD34 stem cells. Methods - We performed a 2-center, dose-escalation, double-blind, randomized, placebo-controlled pilot trial (ISRCTN 16784092) of G-CSF (6 blocks of 1 to 10 g/kg SC, 1 or 5 daily doses) in 36 patients with recent ischemic stroke. Circulating CD34 stem cells were measured by flow cytometry; blood counts and measures of safety and functional outcome were also monitored. All measures were made blinded to treatment. Results - Thirty-six patients, whose mean SD age was 768 years and of whom 50% were male, were recruited. G-CSF (5 days of 10 g/kg) increased CD34 count in a dose-dependent manner, from 2.5 to 37.7 at day 5 (area under curve, P0.005). A dose-dependent rise in white cell count (P0.001) was also seen. There was no difference between treatment groups in the number of patients with serious adverse events: G-CSF, 7/24 (29%) versus placebo 3/12 (25%), or in their dependence (modified Rankin Scale, median 4, interquartile range, 3 to 5) at 90 days. Conclusions - ”G-CSF is effective at mobilizing bone marrow CD34 stem cells in patients with recent ischemic stroke. Administration is feasible and appears to be safe and well tolerated. The fate of mobilized cells and their effect on functional outcome remain to be determined. (Stroke. 2006;37:2979-2983.)

Predicting long-term outcome after acute ischemic stroke: a simple index works in patients from controlled clinical trials

Background and Purpose—An early and reliable prognosis for recovery in stroke patients is important for initiation of individual treatment and for informing patients and relatives. We recently developed and validated models for predicting survival and functional independence within 3 months after acute stroke, based on age and the National Institutes of Health Stroke Scale score assessed within 6 hours after stroke. Herein we demonstrate the applicability of our models in an independent sample of patients from controlled clinical trials. Methods—The prognostic models were used to predict survival and functional recovery in 5419 patients from the Virtual International Stroke Trials Archive (VISTA). Furthermore, we tried to improve the accuracy by adapting intercepts and estimating new model parameters. Results—The original models were able to correctly classify 70.4% (survival) and 72.9% (functional recovery) of patients. Because the prediction was slightly pessimistic for patients in the controlled trials, adapting the intercept improved the accuracy to 74.8% (survival) and 74.0% (functional recovery). Novel estimation of parameters, however, yielded no relevant further improvement. Conclusions—For acute ischemic stroke patients included in controlled trials, our easy-to-apply prognostic models based on age and National Institutes of Health Stroke Scale score correctly predicted survival and functional recovery after 3 months. Furthermore, a simple adaptation helps to adjust for a different prognosis and is recommended if a large data set is available. (Stroke. 2008;39:000-000.)

Relationship between hyperacute blood pressure and outcome after ischemic stroke: data from the VISTA Collaboration

Background and Purpose—High blood pressure (BP) is associated independently with poor outcome after acute ischemic stroke, although in most analyses “baseline” BP was measured 24 hours or more postictus, and not during the hyperacute period. Methods—Analyses included 1722 patients in hyperacute trials (recruitment 8 hours) from the Virtual Stroke International Stroke Trial Archive (VISTA) Collaboration. Data on BP at enrolment and after 1, 2, 16, 24, 48, and 72 hours, neurological impairment at 7 days (NIHSS), and functional outcome at 90 days (modified Rankin scale) were assessed using logistic regression models, adjusted for confounding variables; results are for 10-mm Hg change in BP. Results—Mean time to enrolment was 3.7 hours (range 1.0 to 7.9). High systolic BP (SBP) was significantly associated with increased neurological impairment (odds ratio, OR 1.06, 95% confidence interval, 95% CI 1.01 to 1.12), and poor functional outcome; odds ratios for both increased with later BP measurements made at up to 24 hours poststroke. Smaller (versus larger) declines in SBP over the first 24 hours were significantly associated with poor NIHSS scores (OR 1.16, 95% CI 1.05 to 1.27) and functional outcome (OR 1.23, 95% CI 1.13 to 1.34). A large variability in SBP was also associated with poor functional outcome. Conclusions—High SBP and large variability in SBP in the hyperacute stages of ischemic stroke are associated with increased neurological impairment and poor functional outcome, as are small falls in SBP over the first 24 hours.

Effect of telmisartan on functional outcome, recurrence, and blood pressure in patients with acute mild ischemic stroke: a PRoFESS subgroup analysis

Background and Purpose—High blood pressure (BP) is common in acute ischemic stroke and associated independently with a poor functional outcome. However, the management of BP acutely remains unclear because no large trials have been completed. Methods—The factorial PRoFESS secondary stroke prevention trial assessed BP-lowering and antiplatelet strategies in 20 332 patients; 1360 were enrolled within 72 hours of ischemic stroke, with telmisartan (angiotensin receptor antagonist, 80 mg/d, n647) vs placebo (n713). For this nonprespecified subgroup analysis, the primary outcome was functional outcome at 30 days; secondary outcomes included death, recurrence, and hemodynamic measures at up to 90 days. Analyses were adjusted for baseline prognostic variables and antiplatelet assignment. Results—Patients were representative of the whole trial (age 67 years, male 65%, baseline BP 147/84 mm Hg, small artery disease 60%, NIHSS 3) and baseline variables were similar between treatment groups. The mean time from stroke to recruitment was 58 hours. Combined death or dependency (modified Rankin scale: OR, 1.03; 95% CI, 0.84–1.26; P0.81; death: OR, 1.05; 95% CI, 0.27–4.04; and stroke recurrence: OR, 1.40; 95% CI, 0.68–2.89; P0.36) did not differ between the treatment groups. In comparison with placebo, telmisartan lowered BP (141/82 vs 135/78 mmHg, difference 6 to 7 mmHg and 2 to 4 mmHg; P0.001), pulse pressure (3 to 4 mmHg; P0.002), and rate-pressure product (466 mmHg.bpm; P0.0004). Conclusion—Treatment with telmisartan in 1360 patients with acute mild ischemic stroke and mildly elevated BP appeared to be safe with no excess in adverse events, was not associated with a significant effect on functional dependency, death, or recurrence, and modestly lowered BP.

Effect of nitric oxide donors on blood pressure and pulse pressure in acute and subacute stroke

High blood pressure (BP), pulse pressure (PP), and rate pressure product (RPP) areeach associated independently with a poor outcome in acute ischemic stroke. Whereas nitric oxide (NO) donors, such as glyceryl trinitrate (GTN), lower blood pressure in acute ischemic stroke, their effect on other hemodynamic measures is not known. We performed a systematic review of the effects of NO donors on systemic hemodynamic measures in patients with acute/subacute stroke. Randomized controlled trials were identified from searches of the Cochrane Library, Pubmed, and Embase. Information on hemodynamic measures, including systolic BP (SBP), diastolic BP (DBP), and heart rate, were assessed, and hemodynamic derivatives of these were calculated: PP (PP SBP DBP), mean arterial pressure (MAP DBP PP/3), mid blood pressure (MBP (SBP DBP)/2), pulse pressure index (PPI PP/MAP), and RPP (RPP SBP HR). The effect of treatment on hemodynamic measures was calculated as the weighted mean difference (WMD) between treated and control groups with adjustment for baseline. Results: Three trials involving 145 patients were identified; 93 patients received the NO donor, GTN, and 52 control. As compared with placebo, GTN significantly reduced SBP (WMD -9.80 mmHg, p< 0.001), DBP (WMD -4.43 mmHg, p<0.001), MAP (WMD -6.41 mmHg, p< 0.001), MBP (WMD -7.33 mmHg,p<0.001), PP (WMD -6.11 mmHg, p<0.001 ) and PPI (WMD -0.03, p=0.04 ). 3 GTN increased HR (WMD +3.87 bpm, p<0.001) and non-significantly lowered RPP (WMD -323 mmHg.bpm, p=0.14). Conclusion: The NO donor GTN reduces BP, PP and other derivatives in acute and subacute stroke whilst increasing heart rate.

Telmisartan to prevent recurrent stroke and cardiovascular events

Background Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin–angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin–angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke. Methods In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes. Results The median interval from stroke to randomization was 15 days. During a mean followup of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P = 0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P = 0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P = 0.10). Conclusions Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)

Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke

Background Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens — aspirin plus extendedrelease dipyridamole (ASA–ERDP) versus clopidogrel. Methods In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. Results A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA–ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA–ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA–ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA–ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). Conclusions The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA–ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

The relationship between baseline blood pressure and computed tomography findings in acute stroke: data from the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST)

Background and Purpose—High blood pressure (BP) is present in 80% of patients with acute ischemic stroke and is independently associated with poor outcome. There are few data examining the relationship between admission BP and acute CT findings. Methods—TAIST was a randomized controlled trial assessing 10 days of treatment with tinzaparin versus aspirin in 1489 patients with acute ischemic stroke (48 hr) with admission BP of 220/120 mm Hg. CT brain scans were performed before randomization and after 10 days. The relationships between baseline BP and adjudicated CT findings were assessed. Odds ratios per 10 mm Hg change in BP were calculated. Results—Higher systolic BP (SBP) was associated with abnormal CT scans because of independent associations with chronic changes of leukoariosis (OR, 1.12; 95% CI, 1.05–1.17) and old infarction (OR, 1.12; 95% CI, 1.06 –1.17) at baseline, and signs of visible infarction at day 10 (OR, 1.06; 95% CI, 1.00 –1.13). A lower SBP was associated with signs of acute infarction (OR, 0.94; 95% CI, 0.89–0.99). Hemorrhagic transformation, dense middle cerebral artery sign, mass effect, and cerebral edema at day 10 were not independently associated with baseline BP. Conclusion—Although high baseline BP is independently associated with a poor outcome after stroke, this was not shown to be through an association with increased hemorrhagic transformation, cerebral edema, or mass effect; trial design may be suboptimal to detect this. Higher SBP is associated with visible infarction on day 10 scans. The influence of changing BP in acute stroke on CT findings is still to be ascertained.

Dipyridamole plus aspirin versus aspirin alone in the secondary prevention after TIA or stroke: a meta-analysis by risk

Objectives: Our aim was to study the effect of combination therapy with aspirin and dipyridamole (A+D) over aspirin alone (ASA) in secondary prevention after transient ischemic attack or minor stroke of presumed arterial origin and to perform subgroup analyses to identify patients that might benefit most from secondary prevention with A+D. Data sources: The previously published meta-analysis of individual patient data was updated with data from ESPRIT (N=2,739); trials without data on the comparison of A+D versus ASA were excluded. Review methods: A meta-analysis was performed using Cox regression, including several subgroup analyses and following baseline risk stratification. Results: A total of 7,612 patients (5 trials) were included in the analyses, 3,800 allocated to A+D and 3,812 to ASA alone. The trial-adjusted hazard ratio for the composite event of vascular death, non-fatal myocardial infarction and non-fatal stroke was 0.82 (95% confidence interval 0.72-0.92). Hazard ratios did not differ in subgroup analyses based on age, sex, qualifying event, hypertension, diabetes, previous stroke, ischemic heart disease, aspirin dose, type of vessel disease and dipyridamole formulation, nor across baseline risk strata as assessed with two different risk scores. A+D were also more effective than ASA alone in preventing recurrent stroke, HR 0.78 (95% CI 0.68 – 0.90). Conclusion: The combination of aspirin and dipyridamole is more effective than aspirin alone in patients with TIA or ischemic stroke of presumed arterial origin in the secondary prevention of stroke and other vascular events. This superiority was found in all subgroups and was independent of baseline risk. ---------------------------7dc3521430776 Content-Disposition: form-data; name="c14_creators_1_name_family" Halkes

The Virtual International Stroke Trials Archive

Background and Purpose - Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. Methods - Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. Results - ”Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on 15 000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 6912 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials. Conclusions - This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning. (Stroke. 2007;38:1905-1910.)