Impact of heart rate on admission on mortality and morbidity in acute ischaemic stroke patients - results from VISTA.

BACKGROUND AND PURPOSE: Elevated heart rate (HR) is associated with worse outcomes in patients with cardiovascular disease. Its predictive value in acute stroke patients is less well established. We investigated the effects of HR on admission in acute ischaemic stroke patients. METHODS: Using the Virtual International Stroke Trials Archive (VISTA) database, the association between HR in acute stroke patients without atrial fibrillation and the pre-defined composite end-point of (recurrent) ischaemic stroke, transient ischaemic attack (TIA), myocardial infarction (MI) and vascular death within 90 days was analysed. Pre-defined secondary outcomes were the composite end-point components and any death, decompensated heart failure and degree of functional dependence according to the modified Rankin Scale after 90 days. HR was analysed as a categorical variable (quartiles). RESULTS: In all, 5606 patients were available for analysis (mean National Institutes of Health Stroke Scale 13; mean age 67 years; mean HR 77 bpm; 44% female) amongst whom the composite end-point occurred in 620 patients (11.1%). Higher HR was not associated with the composite end-point. The frequencies of secondary outcomes were 3.2% recurrent stroke (n = 179), 0.6% TIA (n = 35), 1.8% MI (n = 100), 6.8% vascular death (n = 384), 15.0% any death (n = 841) and 2.2% decompensated heart failure (n = 124). Patients in the highest quartile (HR> 86 bpm) were at increased risk for any death [adjusted hazard ratio (95% confidence interval) 1.40 (1.11-1.75)], decompensated heart failure [adjusted hazard ratio 2.20 (1.11-4.37)] and worse modified Rankin Scale [adjusted odds ratio 1.29 (1.14-1.52)]. CONCLUSIONS: In acute stroke patients, higher HR (>86 bpm) is linked to mortality, heart failure and higher degree of dependence after 90 days but not to recurrent stroke, TIA or MI.

Post-stroke cognitive decline: an update and perspectives for clinical research.

The close relationship between stroke and dementia is an important health issue. Ischaemic stroke can facilitate the onset of vascular dementia as well as aggravate pre-existing cognitive decline. The onset of cognitive decline may become manifest immediately following the onset of ischaemic stroke, but often there is a delay in the development of cognitive decline after a stroke. This delay can be seen as a therapeutic time window allowing interventions to be applied to preserve cognition following stroke. Both neurodegenerative and vascular mechanisms are activated and probably result in overlapping processes within the neurovascular unit. This review focuses on the incidence and prevalence of cognitive decline following stroke, predisposing stroke aetiologies, pre-stroke decline, imaging factors and biomarkers. Outcomes are discussed in relation to timing of assessment and neuropsychological tests used for evaluation of cognitive decline in ischaemic stroke patients. Including such tests in routine evaluations of stroke patients after some weeks or months is recommended. Finally, an outlook on ongoing and planned intervention trials is added and some recommendations for future research are proposed.

Dipyridamole-induced headache and lower recurrence risk in secondary prevention of ischaemic stroke: a post hoc analysis.

BACKGROUND AND PURPOSE: Our objective was to investigate the association between recurrent stroke risk and headache induced by extended-release dipyridamole (ER-DP) when administered alone or with low-dose aspirin (ASA+ER-DP). METHODS: This was a post hoc analysis of prospectively collected data on recurrent stroke risk and headache as an adverse event or reason for treatment discontinuation from the PRoFESS (N = 20,332) and ESPS2 (N = 6602) trials. Hazard ratios (HRs) for recurrent stroke were calculated using the Cox model. RESULTS: In PRoFESS, the 2.5-year recurrent stroke risk in patients receiving ASA+ER-DP was 8.2% in those with headache within 7 days of starting treatment and 9.4% in those without [HR 0.85, 95% confidence interval (CI) 0.73-0.98; P = 0.03]. Recurrent stroke risk was 5.0% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.2% in those who did not (HR 0.52, 95% CI 0.35-0.77; P = 0.001). No such difference was observed in clopidogrel-treated patients. In ESPS2, risk of recurrent stroke was 6.2% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.8% in patients who did not (HR 0.62, 95% CI 0.31-1.27; P = 0.19) and 7.3% in patients who discontinued ER-DP due to headache by day 90 versus 13.2% in those who did not (HR 0.53, 95% CI 0.27-1.04; P = 0.06). CONCLUSIONS: Patients taking ASA+ER-DP in PRoFESS who developed headache had significantly reduced stroke recurrence risk versus those without headache. Similar (non-significant) findings for ASA+ER-DP and ER-DP in ESPS2 suggest that dipyridamole-induced headache may reflect better cerebrovascular function.

Progesterone and cerebral ischaemia: the relevance of ageing.

Cerebral stroke is a leading cause of long-term disability and a major cause of death in the developed world. The total incidence of stroke is projected to rise substantially over the next 20 years as a result of the rising elderly population. Although age is one of the most significant prognostic markers for poor outcome after stroke, very few experimental studies have been conducted in aged animals. Importantly, sex differences in both vulnerability to stroke and outcome after cerebral ischaemia have frequently been reported and attributed to the action of steroid hormones. Progesterone is a candidate neuroprotective factor for stroke, although the majority of pre-clinical studies have focused on using young, healthy adult animals. In terms of cerebral stroke, males and postmenopausal females represent the groups at highest risk of cerebral stroke and these categories can be modelled using either aged or ovariectomised female animals. In this review, we discuss the importance of conducting experimental studies in aged animals compared to young, healthy animals, as well as the impact this has on experimental outcomes. In addition, we focus on reviewing the studies that have been conducted to date examining the neuroprotective potential of progesterone in aged animals. Importantly, the limited studies that have been conducted in aged animals do lend further support to progesterone as a therapeutic option after ischaemic stroke that warrants further investigation.

Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke?

BACKGROUND: Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. METHODS: We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran-Mantel-Haenszel test. RESULTS: Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43-1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1·31; 95% confidence interval 1·18-1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1·01; 95% CI 0·90-1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. CONCLUSION: Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment.

Emulating multicentre clinical stroke trials: a new paradigm for studying novel interventions in experimental models of stroke.

The recent meta-analysis of NXY-059 in experimental stroke models using individual animal data found the drug to be an effective neuroprotective agent. However, the failure of translation of both this compound and many others from preclinical studies to the clinic indicates that new approaches must be used in drug discovery so that animal models become more reflective of the clinical situation, and studies using animal models of stroke mimic the design of studies performed in humans, as far as possible. In this review, we suggest that a fundamental paradigm shift is needed away from performing preclinical studies in individual laboratories to performing them in an organised group of independent laboratories. Studies should be run by a steering committee and should be supported by a coordinating centre, external data monitoring committee and outcome adjudication committee. This structure will mimic the practice of multicentre clinical trials. By doing so, future studies will minimise potential sources of bias including randomisation, concealment of allocation, blinding of surgery and outcome assessment and ensure publication of all data. It is likely that individual studies will involve increased heterogeneity and therefore will need to be larger. However, regular independent monitoring of data will allow development of interventions to be ceased immediately if neutral or negative data are obtained. The additional costs involved should be seen as reasonable when compared with the resources that would have been expended in running a clinical trial that subsequently proved negative.

Effects of NXY-059 in experimental stroke: an individual animal meta-analysis.

BACKGROUND AND PURPOSE: Disodium 2,4-disulphophenyl-N-tert-butylnitrone (NXY-059) was neuroprotective in experimental stroke models but ineffective in a large clinical trial. This first-ever individual animal meta-analysis was used to assess the preclinical studies. EXPERIMENTAL APPROACH: Studies were obtained from AstraZeneca and PubMed searches. Data for each animal were obtained from the lead author of each study and/or AstraZeneca. Published summary data were used if individual data were not available. Infarct volume and motor impairment were standardized to reflect different species and scales. Standardized mean difference (SMD), coefficients from multilevel models and 95% confidence intervals (95% CI) are presented. KEY RESULTS: Fifteen studies (26 conditions, 12 laboratories) involving rats (544), mice (9) and marmosets (32) were identified (NXY-059: 332, control: 253) with individual data for 442 animals. Four studies were unpublished. Studies variably used randomization (40%), blinding of surgeon (53%) and outcome assessor (67%). NXY-059 reduced total (SMD -1.17, 95% CI -1.50 to -0.84), cortical (SMD -2.17, 95% CI -2.99 to -1.34) and subcortical (-1.43, 95% CI -2.20 to -0.86) lesion volume; efficacy was seen in transient, permanent and thrombotic ischaemia, up to 180 min post occlusion. NXY-059 reduced motor impairment (SMD -1.66, 95% CI -2.18 to -1.14) and neglect. Evidence for performance, attrition and publication bias was present. CONCLUSIONS AND IMPLICATIONS: NXY-059 was neuroprotective in experimental stroke although bias may have resulted in efficacy being overestimated. Efficacy in young, healthy, male animals is a poor predictor of clinical outcome. We suggest the use of preclinical meta-analysis before initiation of future clinical trials.

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

OBJECTIVES: To study the effect of combination therapy with aspirin and dipyridamole (A+D) over aspirin alone (ASA) in secondary prevention after transient ischaemic attack (TIA) 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 7612 patients (five trials) were included in the analyses, 3800 allocated to A+D and 3812 to ASA alone. The trial-adjusted hazard ratio (HR) for the composite event of vascular death, non-fatal myocardial infarction and non-fatal stroke was 0.82 (95% confidence interval (CI) 0.72 to 0.92). HRs did not differ in subgroup analyses based on age, sex, qualifying event, hypertension, diabetes, previous stroke, ischaemic 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 to 0.90). CONCLUSION: The combination of aspirin and dipyridamole is more effective than aspirin alone in patients with TIA or ischaemic 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.

Should data monitoring committees assess efficacy when considering safety in trials in acute stroke?

BACKGROUND: The primary role of a trial's data monitoring committee (DMC) is to ensure the safety of enrolled patients. In stroke trials, safety is monitored typically by comparing death and stroke-specific events between treatment groups. DMCs may also have the remit for monitoring efficacy depending on the aims of the trial. We hypothesised that functional outcome at the end of follow-up, a measure of efficacy, is also a powerful measure of safety and tested this in a systematic review. METHODS: Acute stroke trials with a negative outcome or which were stopped prematurely on the grounds of safety were sought systematically from searches of electronic databases and published reviews. Information on early and late death, impairment and functional outcome, and the presence of a DMC, were recorded for each trial. The results for each outcome measure were ranked within each trial to determine which was most statistically efficient in detecting hazard. RESULTS: Fourteen trials were included. The most efficient outcomes for detecting hazard were late death or disability, six trials; early death, four trials (two of which tested thrombolysis); late death, three trials and late death or impairment, one trial. Early death was insensitive to hazard in all six trials where late death or dependency was most sensitive. Two trials (both phase II) did not report the presence of a DMC. CONCLUSIONS: Functional outcome at end of follow-up can be sensitive to hazard and should be included in all assessments of safety in stroke trials, whether or not efficacy itself is being assessed.

Amphetamine increases blood pressure and heart rate but has no effect on motor recovery or cerebral haemodynamics in ischaemic stroke: a randomized controlled trial (ISRCTN 36285333).

Amphetamine enhances recovery after experimental ischaemia and has shown promise in small clinical trials when combined with motor or sensory stimulation. Amphetamine, a sympathomimetic, might have haemodynamic effects in stroke patients, although limited data have been published. Subjects were recruited 3-30 days post-ischaemic stroke into a phase II randomized (1:1), double-blind, placebo-controlled trial. Subjects received dexamphetamine (5 mg initially, then 10 mg for 10 subsequent doses with 3- or 4-day separations) or placebo in addition to inpatient physiotherapy. Recovery was assessed by motor scales (Fugl-Meyer (FM)), and functional scales (Barthel index (BI) and modified Rankin score (mRS)). Peripheral blood pressure (BP), central haemodynamics and middle cerebral artery blood flow velocity were assessed before, and 90 min after, the first two doses. Thirty-three subjects were recruited, aged 33-88 (mean 71) years, males 52%, 4-30 (median 15) days post stroke to inclusion. Sixteen patients were randomized to placebo and seventeen to amphetamine. Amphetamine did not improve motor function at 90 days; mean (s.d.) FM 37.6 (27.6) vs control 35.2 (27.8) (P=0.81). Functional outcome (BI, mRS) did not differ between treatment groups. Peripheral and central systolic BP, and heart rate (HR), were 11.2 mm Hg (P=0.03), 9.5 mm Hg (P=0.04) and 7 beats per minute (P=0.02) higher, respectively, with amphetamine, compared with control. A nonsignificant reduction in myocardial perfusion (BUI) was seen with amphetamine. Other cardiac and cerebral haemodynamics were unaffected. Amphetamine did not improve motor impairment or function after ischaemic stroke but did significantly increase BP and HR without altering cerebral haemodynamics.

Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke.

BACKGROUND: Colony stimulating factors (CSFs), also called haematopoietic growth factors, regulate bone marrow production of circulating red and white cells, and platelets. They have been shown to be neuroprotective in experimental stroke. Some CSFs also mobilise the release of bone marrow stem cells into the circulation. OBJECTIVES: To assess the effects of CSFs on functional outcome and haematology measures in patients with acute or subacute stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched November 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1985 to June 2006), EMBASE (1985 to June 2006), and Science Citation Index (1985 to June 2006). In an attempt to identify further published, unpublished and ongoing trials we contacted manufacturers and principal investigators of trials (last contacted 2006). We also searched reference lists of relevant articles and reviews. SELECTION CRITERIA: Unconfounded randomised controlled trials recruiting patients with acute or subacute ischaemic or haemorrhagic stroke were included. CSFs included stem cell factor (SCF), erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF, CSF-1), and thrombopoietin (TPO), or analogues of these. The primary outcome was functional outcome (assessed as combined death or disability and dependency using scales such as the modified Rankin Scale or Barthel Index) at the end of the trial. Secondary outcomes included safety at the end of treatment (death, impairment, deterioration, extension or recurrence), death at the end of follow up, and haematology measures (blood counts at or around day seven after treatment commenced). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. Study authors were contacted for additional information. MAIN RESULTS: No large trials were identified. EPO therapy was associated with a non-significant reduction in neurological impairment in one small trial (n = 40 participants) but had no significant effect on haematological measures. G-CSF was associated with a non-significant reduction in combined death and dependency in two small trials (n = 46 participants) although there was substantial heterogeneity in this result. G-CSF significantly elevated white cell count in three trials (n = 91). Further small trials of EPO and G-CSF are ongoing. AUTHORS' CONCLUSIONS: No large trials of EPO, G-CSF or other colony stimulating factors have been performed and it is too early to know whether CSFs improve functional outcome.

Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke.

BACKGROUND: Colony stimulating factors (CSFs), also called haematopoietic growth factors, regulate bone marrow production of circulating red and white cells, and platelets. They have been shown to be neuroprotective in experimental stroke. Some CSFs also mobilise the release of bone marrow stem cells into the circulation. OBJECTIVES: We systematically assessed the effects of CSFs on functional outcome and haematology measures in patients with acute or subacute stroke enrolled into randomised controlled trials. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched February 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005), MEDLINE (1985 to March 2006), EMBASE (1985 to November 2005), and Science Citation Index (1985 to November 2005). In an attempt to identify further published, unpublished and ongoing trials we contacted manufacturers and principal investigators of trials (last contacted 2005). We also searched reference lists of relevant articles and reviews. SELECTION CRITERIA: Unconfounded randomised controlled trials recruiting patients with acute or subacute ischaemic or haemorrhagic stroke were included. CSFs included stem cell factor (SCF), erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF, CSF-1), and thrombopoietin (TPO), or analogues of these. The primary outcome was functional outcome (assessed as combined death or disability and dependency using scales such as the modified Rankin Scale or Barthel Index) at the end of the trial. Secondary outcomes included safety at the end of treatment (death, impairment, deterioration, extension or recurrence), death at the end of follow up, and haematology measures (blood counts at or around day seven after treatment commenced). DATA COLLECTION AND ANALYSIS: Data on measures by intention to treat (where available) were collected and analysed as dichotomous or continuous outcomes, as relevant, using random-effects models. Heterogeneity was assessed. MAIN RESULTS: No large trials were identified. EPO therapy was associated with a non-significant reduction in neurological impairment in one small trial (n = 40 participants) but had no significant effect on haematological measures. Further small trials of EPO and G-CSF are ongoing. AUTHORS' CONCLUSIONS: No large trials of EPO, G-CSF or other colony stimulating factors have been performed and it is too early to know whether CSFs improve functional outcome.

Significant variation in mortality and functional outcome after acute ischaemic stroke between Western countries: data from the tinzaparin in acute ischaemic stroke trial (TAIST).

BACKGROUND: The medical care of patients with acute stroke varies considerably between countries. This could lead to measurable differences in mortality and functional outcome. OBJECTIVE: To compare case mix, clinical management, and functional outcome in stroke between 11 countries. METHODS: All 1484 patients from 11 countries who were enrolled into the tinzaparin in acute ischaemic stroke trial (TAIST) were included in this substudy. Information collected prospectively on demographics, risk factors, clinical features, measures of service quality (for example, admission to a stroke unit), and outcome were assessed. Outcomes were adjusted for treatment assignment, case mix, and service relative to the British Isles. RESULTS: Differences in case mix (mostly minor) and clinical service (many of prognostic relevance) were present between the countries. Significant differences in outcome were present between the countries. When assessed by geographical region, death or dependency were lower in North America (odds ratio (OR) adjusted for treatment group only = 0.52 (95% confidence interval, 0.39 to 0.71) and north west Europe (OR = 0.54 (0.37 to 0.78)) relative to the British Isles; similar reductions were found when adjustments were made for 11 case mix variables and five service quality measures. Similarly, case fatality rates were lower in North America (OR = 0.44 (0.30 to 0.66)) and Scandinavia (OR = 0.50 (0.33 to 0.74)) relative to the British Isles, whether crude or adjusted for case mix and service quality. CONCLUSIONS: Both functional outcome and case fatality vary considerably between countries, even when adjusted for prognostic case mix variables and measures of good stroke care. Differing health care systems and the management of patients with acute stroke may contribute to these findings.

Pentoxifylline, propentofylline and pentifylline for acute ischaemic stroke.

BACKGROUND: Methylxanthine derivatives are vasodilators. They also inhibit platelet aggregation and thromboxane A2 synthesis, decrease the release of free radicals and may be neuroprotective. NOTE: This review covers an area where no active research is taking place. It will be updated if relevant information becomes available, e.g. on completion of an appropriate study. OBJECTIVES: To assess the effect of intravenous or oral methylxanthines (pentoxifylline, propentofylline, or pentifylline) in patients with acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched November 2003). For the first version, we also searched EMBASE (1980 to 1999), MEDLINE (1966 to 1999), Science Citation Index (1981 to 1999) and the Ottawa Stroke Trials Registry. We also contacted the manufacturers of methylxanthines and the principal investigators of the identified trials. SELECTION CRITERIA: Randomised trials comparing pentoxifylline, propentofylline or pentifylline with placebo or control in patients with definite or presumed acute ischaemic stroke. Trials were included if treatment was started within one week of stroke onset. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria. Trial quality was assessed. MAIN RESULTS: Five trials were included. Four trials tested pentoxifylline in 763 people, and one tested propentofylline in 30 people. No trials of pentifylline were found. The odds of early death (within four weeks) was non-significantly reduced in patients given a methylxanthine drug as compared with those given placebo (odds ratio (OR) 0.64, 95% confidence interval (CI) 0.41 to 1.02). This non-significant trend to less deaths was due mainly to one pentoxifylline trial that found a highly significant reduction in early deaths. Two trials reported early death or disability and found a non-significant reduction (OR 0.49, 95% CI 0.20 to 1.20). There was no significant difference in late death (beyond four weeks), as reported in the propentofylline trial involving 30 patients, although the confidence interval was wide (OR 0.70, 95% CI 0.13 to 3.68). Data for neurological impairment and disability were not in a form suitable for analysis. Data on quality of life, stroke recurrence, thromboembolism and bleeding were not reported. REVIEWERS' CONCLUSIONS: There is not enough evidence to assess adequately the effectiveness and safety of methylxanthines after acute ischaemic stroke.

Prostacyclin and analogues for acute ischaemic stroke.

BACKGROUND: Prostacyclin is an agent with a number of effects on platelets, blood vessels and nerve cells which might improve outcome after acute ischaemic stroke. NOTE: This review covers an area where no active research is taking place. It will be updated if relevant information becomes available, e.g. on completion of an appropriate study. OBJECTIVES: The objective of this review was to assess the effect of prostacyclin or analogues on survival in people with acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched November 2003). For the first version, we also searched EMBASE (1980 to 1999), MEDLINE (1966 to 1999), Science Citation Index (1981 to 1999) and the Ottawa Stroke Trials Registry. We also contacted the manufacturers of prostacyclin and the principal investigators of the identified trials. SELECTION CRITERIA: Randomised trials comparing prostacyclin or analogues with placebo or control. Trials where people were entered within one week of stroke onset were included. DATA COLLECTION AND ANALYSIS: Information on the methods of randomisation, blinding, analysis, the number of patients randomised, dose and timing of prostacyclin or analogue, patient withdrawals, the number of deaths occurring in each trial, and trial quality, were collected and assessed. MAIN RESULTS: Five trials involving 191 people were included. Six early deaths (within four weeks) occurred with prostacyclin, and nine with placebo (odds ratio (OR) 0.63, 95% confidence interval (CI) 0.22 to 1.85). One trial of 32 patients reported late deaths (by 10 to 18 months) in 50% of patients in each group. REVIEWERS' CONCLUSIONS: Too few patients have been studied in randomised trials to allow conclusions to be drawn about the effect of prostacyclin treatment on survival of people with acute stroke.

Theophylline, aminophylline, caffeine and analogues for acute ischaemic stroke.

BACKGROUND: Theophylline causes potent cerebral vasoconstriction which decreases blood flow in the non-ischaemic areas of the brain and increases collateral blood flow surrounding the ischaemic region. NOTE: This review covers an area where no active research is taking place. It will be updated if relevant information becomes available, e.g. on completion of an appropriate study. OBJECTIVES: The objective of this review was to assess the effect of theophylline and its analogues, aminophylline and caffeine, in people with confirmed or presumed acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched November 2003). For the first version, we also searched EMBASE (1980 to 1999), MEDLINE (1966 to 1999) and Science Citation Index (1981 to 1999). We also contacted the principal investigators of the identified trials. SELECTION CRITERIA: Randomised trials of theophylline or an analogue compound compared with placebo or control in people with confirmed or presumed acute ischaemic stroke. Trials were included if treatment was started within one week of stroke onset. DATA COLLECTION AND ANALYSIS: Three reviewers applied the inclusion criteria, assessed trial quality and extracted data for the first version. The review was updated by one reviewer. MAIN RESULTS: Two trials involving just 119 patients were included; 6 studies were excluded. Trial quality was good. Both of the trials tested aminophylline. Analysis was by intention-to-treat where possible. No significant difference was shown in early case fatality (within four weeks) between aminophylline and placebo although the confidence intervals were wide (odds ratio [OR] 1.12, 95% confidence interval [CI] 0.49 to 2.56). There was no significant difference for early death and deterioration (OR 0.87, 95% CI 0.41 to 1.88). Death or disability was not significantly reduced by treatment based on 73 patients in one trial (OR 0.64, 95% CI 0.24 to 1.68). Data for late death and disability were not in a form suitable for analysis. No data on quality of life were available. REVIEWERS' CONCLUSIONS: There is not enough evidence to assess whether theophylline or its analogues, e.g. aminophylline, are safe and improve outcome in people with acute ischaemic stroke.

The potential of nitric oxide therapeutics in stroke.

The therapeutic modulation of the nitric oxide (NO) system has generated considerable interest as a new way for managing many disease processes. In stroke, a useful strategy is to increase NO availability and thereby exploit its beneficial antiplatelet, antiatherosclerotic, haemodynamic and neuroprotective properties. Pharmacologically, this can be achieved by providing NO substrate, using NO donors or by upregulating nitric oxide synthase. Alternatively, one can reduce NO availability by inhibiting NO synthase and thereby limiting its pro-inflammatory and neurotoxic properties. This article reviews developments in NO-related therapeutics for treatment of stroke, with a particular emphasis on compounds that are in the clinical research and development pipeline. Although the routine use of NO therapeutics for the prevention or treatment of stroke cannot currently be recommended, we are evidently at an exciting stage in their pharmacological development. Definitive randomised controlled trials in stroke patients are required as a matter of urgency.

The effect of tirilazad mesylate on infarct volume of patients with acute ischemic stroke.

The authors investigated whether the lack of effect of tirilazad on clinical outcome in patients with acute ischemic stroke is explained by failure of tirilazad to reduce infarct volume. Overall, tirilazad had no significant effect on infarct volume. In the subgroups of male patients and of those with a cortical infarct, tirilazad significantly reduced infarct volume. These effects were reduced to nonsignificant trends after adjustment for imbalances in baseline characteristics. In conclusion, early treatment of patients with tirilazad has no effect on infarct volume.