Isradipine in patients with acute ischaemic cerebral infarction. An overview of the ASCLEPIOS Programme. The effects of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure, cerebral and cardiac hemodynamics, and plasma nitric oxide levels in acute stroke. [Use of prostacyclin in patients with ischemic stroke. A double-blind method II]. Low dose beta blockade in acute stroke ("BEST" trial): an evaluation. Bendrofluazide fails to reduce elevated blood pressure levels in the immediate post-stroke period. A randomized, double-blind, placebo-controlled pilot trial of intravenous magnesium sulfate in acute stroke. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Effect of nimodipine on blood pressure in acute ischemic stroke in humans. Controlled safety study of a hemoglobin-based oxygen carrier, DCLHb, in acute ischemic stroke. Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Nimodipine in acute ischemic stroke: a double-blind controlled study. Flunarizine in acute ischemic stroke: a pilot study. [The effectiveness of piracetam in acute cerebral ischemia in the human. A clinical controlled double-blind study of piracetam/10% dextran 40 versus 10% dextran 40/placebo]. Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke. Towards a model stroke trial. The single-centre naftidrofuryl study. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke. The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. A pilot randomized trial of induced blood pressure elevation: effects on function and focal perfusion in acute and subacute stroke. Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography. Placebo-controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction. A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke. Double-blind study of nimodipine in non-severe stroke. Lisinopril for the treatment of hypertension within the first 24 hours of acute ischemic stroke and follow-up. A randomised, controlled pilot study to investigate the potential benefit of intervention with insulin in hyperglycaemic acute ischaemic stroke patients. Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial. Intravenous prostacyclin in acute nonhemorrhagic stroke: a placebo-controlled double-blind trial. Transdermal glyceryl trinitrate lowers blood pressure and maintains cerebral blood flow in recent stroke.
Calcium-related mechanisms are an integral part of metabolic reactions during acute cerebral infarction. In an animal model of stroke, the calcium antagonist isradipine was shown to protect neurons against ischaemia. In order to improve the neurological and functional outcome of human stroke patients, a randomised, double-blind, placebo-controlled multicentre study was started in up to 600 patients with acute ischaemic brain infarction. Since early treatment is considered to be of great importance, patients must be recruited no more than 12 hours after stroke onset. Medical, ECG, laboratory, neurological and functional evaluations are conducted for up to 90 days after stroke. High blood pressure in acute stroke is common and appears to be associated with a poor outcome. Lowering blood pressure might therefore improve outcome, provided that cerebral perfusion is not compromised. We assessed the effects of glyceryl trinitrate (GTN) on cerebral and systemic hemodynamic measures in acute stroke. Ninety patients with acute ischemic or hemorrhagic stroke were randomized within 72 hours of ictus to transdermal GTN given daily for 10 days (either 5 mg, 5 mg for 4 days then 10 mg, or 10 mg) or control. Twenty-four hour blood pressure monitoring, middle cerebral artery blood velocity, cardiac output, augmentation index, and plasma nitric oxide levels were each measured at baseline and then on days 1, 4, 5, and 10. The primary outcome was blood pressure on day 1. We found that GTN lowered mean peripheral arterial blood pressure on day 1 by 5.3% to 6.7% in a dose dependent manner as compared with control (mean, SD): control, 108.8 (15.1) mmHg; 5 mg, 102.5 (13.9) mmHg; 5/10 mg, 103.4 (14.9) mmHg; 10 mg, 101.5 (12.6) mmHg; (P = .005). Increasing the dose from 5 to 10 mg on day 5 resulted in an overall reduction in blood pressure of 11.4% as compared with leaving the dose at 5 mg (P = .006). GTN reduced peripheral pulse pressure, central aortic blood pressure, pulse pressure, and augmentation index on day 1. Middle cerebral artery blood velocity and pulsatility index in the affected hemisphere, cardiac output, systemic peripheral resistance, and plasma nitric oxide levels were not altered by GTN. Treatment with GTN was associated with headache: control 0 (0%), GTN 9 (15%) (P = .027); no negative effect on end-of-treatment death or deterioration, or 3 month death or dependency was discernable. GTN reduced peripheral blood pressure in a dose-dependent fashion in patients with acute stroke at day 1 and also reduced central blood pressure and augmentation index. In contrast, GTN did not alter middle cerebral artery blood velocity or pulsatility index in the affected hemispheres, suggesting that cerebral blood flow did not change. A trial assessing the effect of lowering blood pressure with GTN on safety and functional outcome in patients with acute stroke is now warranted. Thirty patients with acute ischaemic stroke were allocated randomly into a group treated with prostacyclin and a group receiving placebo. The treatment was started 24 to 72 hours after the onset of stroke. Prostacyclin sodium (Wellcome, U.K. or Chinoin, HPR) or its solvent (glycine buffer) were administered intravenously once daily during 2 weeks in 6-hour infusions. Prostacyclin was infused at rates of 2.5-5.0 ng/kg/min. Statistically significant improvement appeared from the second day on in the prostacyclin group, and only from the eighth day on in the placebo group. However, the final improvement was not statistically different between these groups. The beta blocker stroke ("BEST") trial was designed to see if the apparent protective effect of propranolol on cerebral function in patients with subarachnoid haemorrhage applied also to patients suffering from acute stroke. Three hundred and two conscious patients with clinically diagnosed hemispheric strokes sustained within the past 48 hours were randomly assigned to receive atenolol, propranolol, or matching placebo capsules for three weeks. More early deaths occurred among the patients allocated to receive beta blockers, but this was largely explained by differences in the initial characteristics of the patients among the different treatment groups. By contrast, the outcome in a further 60 patients, who had been taking beta blockers at the time of their stroke but were otherwise similar to the patients in the trial, was considerably better, suggesting that prior treatment with beta blockers might be protective. The search for an effective medical treatment for acute stroke must continue. The approach used here, in which neurological outcome was assessed in a modest number of patients with a view to proceeding subsequently to a full scale trial of functional outcome, allows practical benefits of a treatment to be evaluated under realistic conditions and an ineffective treatment to be eliminated without undue cost. Blood pressure (BP) levels, beat-to-beat blood pressure variability, dynamic cerebral autoregulation and cardiac baroreceptor sensitivity are frequently abnormal following acute stroke and are associated with an adverse short- and long-term prognosis. Thiazide diuretics are effective antihypertensive agents in preventing primary and secondary stroke, but their hypotensive and cerebral autoregulatory effects in the immediate post-stroke period have not been studied.
                Thirty-seven hypertensive neuroradiologically proven ischaemic stroke patients were randomized in a double-blind, placebo controlled, parallel group study to bendrofluazide 2.5 mg daily or matching placebo, within 96 h of stroke onset, for a 7-day period. Casual and non-invasive beat-to-beat arterial BP levels, cerebral blood flow velocity, ECG and transcutaneous carbon dioxide levels were measured within 70 +/- 20 h of cerebral infarction and again 7 days later. Dynamic cerebral autoregulatory indices, pulse interval, BP variability and cardiac baroreceptor sensitivity were also calculated.
                Small, non-significant falls were seen in casual and beat-to-beat BP levels over the 7-day period in both active and placebo-treated patients with no differences between treatments. No significant changes were seen in dynamic cerebral autoregulation or in cardiac baroreceptor sensitivity during the follow-up in either group.
                Following acute ischaemic stroke, the standard dose of bendrofluazide at 2.5 mg daily in this study sample did not lower systemic BP levels over the subsequent 7-day period. There was no evidence that bendrofluazide significantly altered cerebral autoregulation or improved cardiac baroreceptor sensitivity post-ictus. Bendrofluazide appears to be an ineffective hypotensive agent at the standard dosage in the initial post-stroke period.
                Copyright 2005 S. Karger AG, Basel. Magnesium ions act as endogenous vasodilators of the cerebral circulation and act pharmacologically as noncompetitive antagonists of the N-methyl-D-aspartate receptor by virtue of their role as endogenous voltage-sensitive blockers of the ion channel. The preclinical efficacy of magnesium has been demonstrated in standard models of stroke.
                Sixty patients were randomized to magnesium sulfate (8 mmol IV over 15 minutes and 65 mmol over 24 hours) or placebo within 12 hours of clinically diagnosed middle cerebral artery stroke. Pulse, blood pressure, and serum magnesium levels were monitored. Primary outcome was death or significant functional impairment (Barthel Index score < 60) at 3 months.
                Magnesium was well tolerated, with no significant adverse effects and no change in blood pressure or pulse rate. Laboratory and electrocardiographic variables did not differ significantly between placebo- and magnesium-treated groups. Serum magnesium rose from 0.76 mmol/L to 1.42 mmol/L over 24 hours and remained significantly higher than in the placebo group at 48 hours. Thirty percent of magnesium-treated and 40% of placebo-treated patients were dead or disabled (Barthel Index score < 60) at 3 months (P = .42). There was a decrease in the number of early deaths in the magnesium-treated group (P = .066, log-rank test).
                Magnesium sulfate is well tolerated after acute stroke and has no deleterious hemodynamic effects at this dose. Further trials are required to determine efficacy. Hyperglycaemia after acute stroke is a common finding that has been associated with an increased risk of death. We sought to determine whether treatment with glucose-potassium-insulin (GKI) infusions to maintain euglycaemia immediately after the acute event reduces death at 90 days.
                Patients presenting within 24 h of stroke onset and with admission plasma glucose concentration between 6.0-17.0 mmol/L were randomly assigned to receive variable-dose-insulin GKI (intervention) or saline (control) as a continuous intravenous infusion for 24 h. The purpose of GKI infusion was to maintain capillary glucose at 4-7 mmol/L, with no glucose intervention in the control group. The primary outcome was death at 90 days, and the secondary endpoint was avoidance of death or severe disability at 90 days. Additional planned analyses were done to determine any differences in residual disability or neurological and functional recovery. The trial was powered to detect a mortality difference of 6% (sample size 2355), with 83% power, at the 5% two-sided significance level. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN 31118803)
                The trial was stopped due to slow enrolment after 933 patients were recruited. For the intention-to-treat data, there was no significant reduction in mortality at 90 days (GKI vs control: odds ratio 1.14, 95% CI 0.86-1.51, p=0.37). There were no significant differences for secondary outcomes. In the GKI group, overall mean plasma glucose and mean systolic blood pressure were significantly lower than in the control group (mean difference in glucose 0.57 mmol/L, p<0.001; mean difference in blood pressure 9.0 mmHg, p<0.0001).
                GKI infusions significantly reduced plasma glucose concentrations and blood pressure. Treatment within the trial protocol was not associated with significant clinical benefit, although the study was underpowered and alternative results cannot be excluded. Nimodipine is currently under investigation for the treatment of acute stroke. Although relatively specific for the cerebrovasculature, acute reductions in blood pressure after a dose may adversely affect neurologic outcome. We studied 29 consecutive acute ischemic stroke patients treated with placebo (n = 9) or either 120 (n = 10) or 240 (n = 10) mg/day of nimodipine. Blood pressure was recorded before and 30 and 60 minutes after a dose for the first 8 days. Ten neurologic physicians were asked to predict the treatment group (placebo or drug) of randomly selected patients based on blood pressure results. Only those patients on 240 mg/day of nimodipine had significant decreases in blood pressure after a dose (p less than 0.001); however, these were minimal (average 10 mm Hg systolic). Only 26 of 48 treatment predictions (54%) were correct. At the studied doses, nimodipine has a minimal effect on blood pressure in the acute stroke period. Diaspirin cross-linked hemoglobin (DCLHb) is a purified, cell-free human hemoglobin solution. In animal stroke models its use led to a significant reduction in the extent of brain injury. The primary objective of this study was to evaluate the safety of DCLHb in patients with acute ischemic stroke.
                DCLHb or saline was administered to 85 patients with acute ischemic stroke in the anterior circulation, within 18 hours of onset of symptoms, in a multicenter, randomized, single-blind, dose-finding, controlled safety trial, consisting of 3 parts: 12 doses of 25, 50, and 100 mg/kg DCLHb over 72 hours.
                DCLHb caused a rapid rise in mean arterial blood pressure. The pressor effect was not accompanied by complications or excessive need for antihypertensive treatment. Two patients in the 100 mg/kg group had adverse events that were possibly drug related: one suffered fatal brain and pulmonary edema, the other transient renal and pancreatic insufficiency. Multivariate logistic regression analysis showed that a severe stroke at baseline and treatment with DCLHb (OR, 4.0; CI, 1.4 to 12.0) were independent predictors of a worse outcome (Rankin Scale score of 3 to 6) at 3 months.
                Outcome scale scores were worse in the DCLHb group, and more serious adverse events and deaths occurred in DCLHb-treated patients than in control patients. We recommend that additional safety studies be performed, preferably with a second generation, genetically engineered hemoglobin. The Intravenous Nimodipine West European Stroke Trial (INWEST) found a correlation between nimodipine-induced reduction in blood pressure (BP) and an unfavorable outcome in acute stroke. We sought to confirm this correlation with and without adjustment for prognostic variables and to investigate outcome in subgroups with increasing levels of BP reduction.
                Patients with a clinical diagnosis of ischemic stroke (within 24 hours) were consecutively allocated to receive placebo (n=100), 1 mg/h (low-dose) nimodipine (n=101), or 2 mg/h (high-dose) nimodipine (n=94). The correlation between average BP change during the first 2 days and the outcome at day 21 was analyzed.
                Two hundred sixty-five patients were included in this analysis (n=92, 93, and 80 for placebo, low dose, and high dose, respectively). Nimodipine treatment resulted in a statistically significant reduction in systolic BP (SBP) and diastolic BP (DBP) from baseline compared with placebo during the first few days. In multivariate analysis, a significant correlation between DBP reduction and worsening of the neurological score was found for the high-dose group (beta=0.49, P=0. 048). Patients with a DBP reduction of > or =20% in the high-dose group had a significantly increased adjusted OR for the compound outcome variable death or dependency (Barthel Index <60) (n/N=25/26, OR 10. 16, 95% CI 1.02 to 101.74) and death alone (n/N=9/26, OR 4.336, 95% CI 1.131 16.619) compared with all placebo patients (n/N=62/92 and 14/92, respectively). There was no correlation between SBP change and outcome.
                DBP, but not SBP, reduction was associated with neurological worsening after the intravenous administration of high-dose nimodipine after acute stroke. For low-dose nimodipine, the results were not conclusive. These results do not confirm or exclude a neuroprotective property of nimodipine. Nimodipine (BAY e 9736), a new dihydropyridine derivative, has been shown to reduce neurological deficits and mortality induced by acute cerebral ischemia in experimental studies. We investigated the effects of this calcium antagonist in patients with acute ischemic stroke through a randomized, double-blind, parallel-designed trial in which nimodipine was compared with placebo. Forty-one of 54 screened cases were found to fulfil the inclusion criteria (sudden occurrence of a focal neurological deficit secondary to an acute ischemic event in the carotid area diagnosed after a complete neurological work-up) and entered the study. Nineteen of them were treated with nimodipine (40 mg t.i.d. administered for 28 days) and the remaining 22 with placebo, given in identical tablets. In all patients the treatment started within 12 h after the onset of the symptoms. Course and intensity of the neurological deficit were evaluated by the Mathew Scale (slightly modified). Forty patients concluded the trial. Nimodipine was withdrawn in one case following the occurrence of a skin rash whose causative relation with the test drug could not be clarified. Altogether, however, nimodipine was well tolerated and no severe cardiovascular adverse reactions were observed. In terms of efficacy, the scores obtained by the Mathew Scale showed a higher rate of improvement on nimodipine than on placebo, thus indicating that patients receiving the latter drug did not fare as well as those receiving the test medication. Our data suggest that nimodipine may be beneficial in the treatment of acute stroke. Twenty-six patients with acute supratentorial brain infarction were randomly allocated to double-blind intravenous treatment with the calcium entry blocker flunarizine (12 patients) or placebo (14 patients) within 24 h. CT scan excluded other significant pathology. Impaired consciousness and gaze deviation were more common in the placebo group. Three patients in the treated group (25%) were either dead or severely disabled after 6 months, whereas this occurred in 8 of the 14 (57%) control patients, a difference of 32%. This difference is not statistically significant and there is an uneven distribution of important prognostic variables, however, the confidence limits of the difference (-4% and +68%) suggest that there may be a clinically important effect. nan The relationship between high blood pressure and the incidence of stroke is well established. Currently the effects of lowering blood pressure in patients with established cerebrovascular disease is undetermined, and there is continuing concern regarding the treatment of patients soon after a stroke event. Angiotensin-converting enzyme inhibitors maintain cerebral blood flow despite lowering blood pressure in patients with heart failure and otherwise uncomplicated hypertension. We tested the hypothesis that perindopril, an angiotensin-converting enzyme inhibitor with a gradual onset of action and a minimal first-dose hypotensive effect, lowers blood pressure without adversely affecting cerebral blood flow in patients 2 to 7 days after symptoms of cerebral infarction.
                Patients were randomized to receive 15 days of oral perindopril (4 mg) or placebo in a double-blind study. Blood pressure was monitored semiautomatically. Cerebral blood flow was calculated from internal carotid artery and vertebral Doppler ultrasound, supplemented by middle cerebral artery blood velocities.
                Twenty-four patients completed the protocol; four additional patients were withdrawn for reasons unrelated to treatment. Patients on perindopril had a placebo-corrected reduction in blood pressure of 19/11 mm Hg. Blood pressure remained reduced after 2 weeks of treatment. In contrast, total cerebral blood flow was unaffected by perindopril. Neurological symptoms improved similarly in both groups.
                Perindopril was well tolerated and effectively reduced blood pressure without reducing carotid territory blood flow in patients with symptoms of recent cerebral ischemia. It has been questionable whether the lack of proven pharmacological treatments in acute cerebral infarction (ACI) reflects ineffective drugs or only inadequacies in their assessment. The difficulties in developing a rationale for drug therapy in this condition favoured the former, although the latter possibility was supported by re-evaluation of most published trials. In this paper, a plausible rationale, in terms of our current understanding of both the drug and the condition, is expounded for treatment of ACI with naftidrofuryl. Guidelines for the design and conduct of clinical trials in acute stroke are discussed in relation to the particular problems posed: need for early initiation of treatment; need for, and difficulties of, diagnostic confirmation; matching of treatment groups by prognostic indicators of uncertain significance, and requirements for large numbers of patients and long-term follow-up. The practical application of these guidelines is tested in a clinical trial of naftidrofuryl conducted in a single centre on 100 patients with proven diagnoses. Rigorous attention to all aspects of selection, treatment and follow-up, with an explanatory approach to the trial design, was predicted to produce a positive result if the drug was effective. The findings were that naftidrofuryl treatment was associated with no change in death rate but with clinically and statistically significant improvements in neurological recovery and bed-occupancy. Better functional recovery was also noted, so that the trial result was coherent. It was concluded that a beneficial effect had been recorded, and consistency of this outcome with those of previous studies is demonstrated. A case is made for further studies to define exactly the role of this drug in the management of ACI. There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial.
                Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096.
                Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12.7 mL, SD 11.6) than in the intensive group (14.2 mL, SD 14.5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13.3 mm Hg, 95% CI 8.9-17.6 mm Hg; p<0.0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10.8 mm Hg, 95% CI 7.7-13.9 mm Hg; p<0.0001). Mean proportional haematoma growth was 36.3% in the guideline group and 13.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was 1.7 mL (95% CI -0.5 to 3.9, p=0.13). Relative risk of haematoma growth >or=33% or >or=12.5 mL was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -1.0 to 17%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days.
                Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH.
                National Health and Medical Research Council of Australia. Hypertension is a common medical complication in acute stroke and is associated with a poor outcome. However, no large trials have assessed the effect of lowering blood pressure (BP) on outcome, and it remains unclear how BP should be managed in acute stroke. We assessed, in a double-blind randomised controlled trial, whether the nitric oxide (NO) donor glyceryl trinitrate (GTN, a known systemic and cerebral vasodilator), would lower BP and alter platelet function.
                Thirty-seven patients with recent (< 5 days) ischaemic or haemorrhagic stroke were randomised by minimisation to 12 days of daily treatment with transdermal GTN or matching placebo patches. Twenty-four-hour ambulatory BP was measured before and during GTN treatment at days 0, 1 and 8. Platelet aggregation and expression of adhesion molecules were assessed at the same time points. Functional outcome (Rankin scale) and case fatality were assessed at 3 months. Analysis was by intention-to-treat.
                GTN significantly lowered BP by 13.0/5.2 mm Hg at day 1 and 9.3/5.0 mm Hg at day 8. The lesser reduction at day 8 than day 1 suggests that tolerance to GTN was developing. Non-significant falls of 0.9/0.6 and 3.8/0.0 mm Hg occurred at days 1 and 8, respectively, in the placebo group. GTN had no effect on heart rate, or platelet aggregation or expression of platelet adhesion molecules, including glycoproteins Ia, Ib, IIIa and P-selectin. Additionally, GTN did not alter case fatality or dependency, although the study was not powered for these outcomes.
                Transdermal GTN, an NO donor, lowered BP by 5-8%, a clinically significant and relevant, but not excessive, degree in patients with acute stroke. However, GTN had no effect on platelet aggregation or expression of adhesion molecules. Since NO donors increase cerebral blood flow in patients with acute ischaemic stroke, GTN may be an appropriate drug for testing the effect of lowering BP on functional outcome.
                Copyright 2001 S. Karger AG, Basel The Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study was designed to assess the safety of modest blood pressure reduction by candesartan cilexetil in the early treatment of stroke. The study was also designed to provide an estimate of the number of cases required to perform a larger phase III efficacy study.
                Five hundred patients were recruited in a prospective, double-blind, placebo-controlled, randomized, multicenter phase II study.
                This safety trial was stopped prematurely when 342 patients (339 valid) had been randomized because of an imbalance in end points. Demographic data, cardiovascular risk factors, and blood pressure on admission, on study onset, and within the whole study period were not significantly different between the 2 groups. However, the cumulative 12-month mortality and the number of vascular events differed significantly in favor of the candesartan cilexetil group (odds ratio, 0.475; 95% CI, 0.252 to 0.895). There were no significant differences in concomitant medication and in number or type of side effects.
                Although the mechanisms by which angiotensin type 1 (AT1) receptor blockade affects cardiovascular morbidity and mortality are still unresolved, the present study shows that early neurohumoral inhibition has similar beneficial effects in cerebral and in myocardial ischemia. The fact that no cardiovascular or cerebrovascular event occurred as a result of hypotension is of significant clinical importance. When there is need for or no contraindication against early antihypertensive therapy, candesartan cilexetil is a safe therapeutic option according to the ACCESS results. Small, unrandomized studies have indicated that pharmacologically induced blood pressure elevation may improve function in ischemic stroke, presumably by improving blood flow to ischemic, but noninfarcted tissue (which may be indicated by diffusion-perfusion mismatch on MRI). We conducted a pilot, randomized trial to evaluate effects of pharmacologically induced blood pressure elevation on function and perfusion in acute stroke.
                Consecutive series of patients with large diffusion-perfusion mismatch were randomly assigned to induced blood pressure elevation ('treated' patients, n = 9) or conventional management ('untreated' patients, n = 6).
                There were no significant differences between groups at baseline. NIH Stroke Scale (NIHSS) scores were lower (better) in treated versus untreated patients at day 3 (mean 5.6 vs. 12.3; p = 0.01) and week 6-8 (mean 2.8 vs. 9.7; p < 0.04). Treated (but not untreated) patients showed significant improvement from day 1 to day 3 in NIHSS score (from mean 10.2 to 5.6; p < 0.002), cognitive score (from mean 58.7 to 27.9% errors; p < 0.002), and volume of hypoperfused tissue (mean 132 to 58 ml; p < 0.02). High Pearson correlations between the mean arterial pressure (MAP) and accuracy on daily cognitive tests indicated that functional changes were due to changes in MAP.
                Results warrant a full-scale, double-blind clinical trial to evaluate the efficacy and risk of induced blood pressure elevation in selective patients with acute/subacute stroke.
                Copyright 2003 S. Karger AG, Basel To determine if previously hypertensive patients with acute ischemic stroke should be treated with antihypertensive medication in the immediate poststroke period.
                Randomized double-blind, placebo-controlled trial.
                Sixteen consecutive hypertensive patients (four men and 12 women; mean age, 66 years [age range, 46 to 83 years]) with middle cerebral artery infarction within 72 hours of onset and blood pressure between 170 and 220 mm Hg(systolic) and 95 and 120 mm Hg (diastolic).
                Placebo (n = 6), nicardipine hydrochloride (20 mg [n = 5]), captopril (12.5 mg [n = 3]), or clonidine hydrochloride (0.1 mg [n = 2]) given every 8 hours for 3 days.
                Decline in blood pressure, change in cerebral blood flow as measured by single photon emission computed tomography, and clinical change as determined by the National Institutes of Health Stroke Scale.
                Blood pressure fell significantly in both the drug-treated group as a whole and in those patients receiving placebo (P < .001). There was no difference in blood pressure levels between these two groups throughout the study period. Patients receiving nicardipine had a consistently lower pressure than the other groups. A significant negative relationship was noted between the maximum blood pressure fall and improvement in cerebral blood flow. There were four patients whose blood pressure dropped by more than 16% of the baseline value on any 24 hours in the first 3 days. All either failed to increase or actually decreased their cerebral blood flow to the affected area. Three of these patients were treated with nicardipine. There was no significant difference in clinical course between the placebo-and drug-treated groups as a whole.
                Hypertensive ischemic stroke patients with a moderate elevation of blood pressure in the first few days may not require antihypertensive therapy. Nicardipine and possibly other calcium channel blockers may cause an excessive fall in blood pressure and impair cerebral blood flow in these patients and should therefore be used with caution. Nimodipine is a 1,4-dihydropyridine derivative that shows a preferential cerebrovascular activity in experimental animals. Clinical data suggest that nimodipine has a beneficial effect on the neurologic outcome of patients suffering an acute ischemic stroke. Our double-blind placebo-controlled multicenter trial was designed to assess the effects of oral nimodipine on the mortality rate and neurologic outcome of patients with an acute ischemic stroke. One hundred sixty-four patients were randomly allocated to receive either nimodipine tablets (30 mg q.i.d.) or identical placebo tablets for 28 days. Treatment was always started less than or equal to 48 hours after the acute event. The Mathew Scale, slightly modified by Gelmers et al, was used for neurologic assessment. Mortality rate and neurologic outcome after 28 days were used as evaluation criteria. We considered 123 patients to be valid for the analysis of efficacy. Mortality rates did not differ significantly between groups. Neurologic outcome after 28 days of therapy did not differ between groups. However, when only those patients most likely to benefit from any intervention (Mathew Scale sum score of less than or equal to 65 at baseline) were analyzed separately in post hoc-defined subgroups, the nimodipine-treated subgroups showed a significantly better neurologic outcome. This result suggests that some patients with acute ischemic stroke will benefit from treatment with nimodipine tablets. A randomized, double-blind, placebo-controlled multicenter trial was conducted to test the hypothesis that nimodipine would improve the functional outcome in acute ischemic hemispheric stroke.
                A total of 350 patients were randomized to nimodipine 120 mg/d PO or matching placebo for 21 days. Randomization was stratified by onset of therapy, age, and stroke severity. Treatment was begun within 48 hours of onset. The patients had neurological evaluation on admission, on days 1, 7, and 21, and at 3 and 12 months. The primary end points were Rankin grade, neurological score, and mobility at 12 months.
                We did not find any differences in the functional outcome between the treatment groups or between the stratified subgroups. We were also unable in post hoc analyses to find any groups of patients who benefited from nimodipine. During the first month and at 3 months the case-fatality rate was higher in the nimodipine-treated patients than in those on placebo (P = .004 and P = .030, respectively), but at the 1-year follow-up this difference had lost statistical significance. During the first week nimodipine had a statistically significant lowering effect on both systolic (P = .005) and diastolic (P = .013) blood pressure.
                Nimodipine did not improve the functional outcome of acute ischemic hemispheric stroke. The early case-fatality rate was higher in the nimodipine group, possibly due to the blood pressure-lowering effect of nimodipine. We evaluated the effect of nimodipine (30 mg q.i.d. orally for 14 days) on acute ischemic stroke of mild or moderate severity in a unicenter, double-blind, randomized, placebo-controlled pilot study. Treatment had to be started after CT, within 48 h of infarct in patients with a Mathew scale sum score between 50 and 75. The duration of follow-up was 4 months. Eight of the 60 randomized patients were excluded because of incorrect diagnosis. For the remaining 52 patients, 24 were allocated to nimodipine and 28 to placebo. Analysis of variance and covariance and repeated measurements of the Mathew scale scores showed no difference between the two groups, who had continuous and parallel improvement. There was no recurrent stroke, but 1 control died 4 weeks after stroke. Treatment with nimodipine was well tolerated (hypotension: 1 treated patient, 3 controls; bradycardia: 1 treated patient, 2 controls; sGPT increase: 1 treated patient, 1 control). The lack of efficacy of nimodipine in this study may be due to: (1) the neurologic deficit not being severe enough, or (2) the delay before treatment was too long. Hypertension immediately after acute ischemic stroke is associated with impaired morbidity and mortality, although there are few data on antihypertensive use immediately after ictus. This randomized, double-blinded, placebo-controlled, parallel-group study explored the hemodynamic effect and safety of oral lisinopril initiated within 24 h after an ictus.
                Forty hypertensive (systolic blood pressure [BP] >/=140 or diastolic BP >/=90 mm Hg) acute ischemic stroke patients (14 lacunar, 13 partial anterior, 7 total anterior, 6 posterior circulation infarct) were randomized to 5 mg of oral lisinopril (n = 18) or matching placebo (n = 22). Dose was increased to 10 mg (or 2 x placebo) on day 7 if casual systolic BP was >/=140 mm Hg and continued to day 14. After the initial dose, automated BP levels were monitored for 16 h. The BP levels and stroke outcome measures were assessed at day 14, and all patients were followed to day 90.
                At h 4 after the first dose, systolic/diastolic BP change was -20 +/- 21/-6 +/- 10 mm Hg (mean +/- SE) in the lisinopril group and 1 +/- 11/0 +/- 8 mmHg in the placebo group (group differences: systolic BP, P < .05; diastolic BP, P = .07). With a daily dosing regime, systolic BP, mean arterial pressure (MAP), diastolic BP, and pulse pressure (PP) were significantly lower in the lisinopril group compared to the placebo group at day 14 (P < .01). Neurologic and functional measures were similar between groups at follow-up.
                Lisinopril, even at small dosages, is well tolerated and an effective hypotensive agent after acute ischemic stroke, gradually reducing BP by 4 h after oral first-dose administration. Oral lisinopril is now being studied in a larger outcome-based trial in acute hypertensive stroke patients. Hyperglycaemia on presentation with acute ischaemic stroke (AIS) is associated with poor outcome, but intervention is unproven. We investigated the safety and tolerability of one method of glycaemic control.
                Patients within 24 h of AIS and plasma glucose 8-20 mmol/l were randomised to receive either rigorous glycaemic control (RC) or standard management (SM) for 48 h. RC comprised i.v. insulin at a variable rate adjusted for target glucose concentration of 5-8 mmol/l, and intravenous crystalloid. The SM group received intravenous crystalloid alone in an open-label design.
                Thirteen patients were randomised to RC and 12 to SM (age 75 +/- 6.2 years; 40% male; 20% lacunar stroke; time to treatment 8 +/- 6.1 h; plasma glucose 10.6 +/- 0.9 mmol/l; known diabetes 52%; NIHSS 8, range 2-28). The glucose concentration-time curve was reduced in the RC group (AUC 324 +/- 15 versus 385 +/- 28 h.mmol/l, p = 0.04). By 48 h, plasma glucose in both groups was 6.8 +/- 1.1 and 7.5 +/- 1.3 mmol/l respectively, but mean hourly insulin requirements in the RC group had dropped from 3.25 +/- 0.32 units to 1.25 +/- 0.5 units (p < 0.01). One transient episode of hypoglycaemic symptoms occurred in the RC group.
                Glycaemic control with sliding scale insulin for 48 h is feasible and well-tolerated after AIS. Treatment after 48 h may be unnecessary.
                Copyright 2006 S. Karger AG, Basel. Raised blood pressure is common after acute stroke and is associated with an adverse prognosis. We sought to assess the feasibility, safety, and effects of two regimens for lowering blood pressure in patients who have had a stroke.
                Patients who had cerebral infarction or cerebral haemorrhage and were hypertensive (systolic blood pressure [SBP] >160 mm Hg) were randomly assigned by secure internet central randomisation to receive oral labetalol, lisinopril, or placebo if they were non-dysphagic, or intravenous labetalol, sublingual lisinopril, or placebo if they had dysphagia, within 36 h of symptom onset in this double-blind pilot trial. The doses were titrated up if target blood pressure was not reached. Analysis was by intention to treat. This trial is registered with the National Research Register, number N0484128008.
                179 patients (mean age 74 [SD 11] years; SBP 181 [SD 16] mm Hg; diastolic blood pressure [DBP] 95 [SD 13] mm Hg; median National Institutes of Health stroke scale [NIHSS] score 9 [IQR 5-16] points) were randomly assigned to receive labetolol (n=58), lisinopril (n=58), or placebo (n=63) between January, 2005, and December, 2007. The primary outcome--death or dependency at 2 weeks--occurred in 61% (69) of the active and 59% (35) of the placebo group (relative risk [RR] 1.03, 95% CI 0.80-1.33; p=0.82). There was no evidence of early neurological deterioration with active treatment (RR 1.22, 0.33-4.54; p=0.76) despite the significantly greater fall in SBP within the first 24 h in this group compared with placebo (21 [17-25] mm Hg vs 11 [5-17] mm Hg; p=0.004). No increase in serious adverse events was reported with active treatment (RR 0.91, 0.69-1.12; p=0.50) but 3-month mortality was halved (9.7%vs 20.3%, hazard ratio [HR] 0.40, 95% CI 0.2-1.0; p=0.05).
                Labetalol and lisinopril are effective antihypertensive drugs in acute stroke that do not increase serious adverse events. Early lowering of blood pressure with lisinopril and labetalol after acute stroke seems to be a promising approach to reduce mortality and potential disability. However, in view of the small sample size, care must be taken when these results are interpreted and further evaluation in larger trials is needed. The therapeutic efficacy of prostacyclin in nonhemorrhagic cerebral infarction was assessed in a placebo-controlled double-blind trial. A total of 80 patients with stroke onset within 24 hours were randomized into placebo (37 patients) and prostacyclin (43 patients) groups. Demographic data and risk factors were comparable. Patients in the prostacyclin group received a continuous i.v. infusion of prostacyclin at an average rate of 8.5 ng/kg/min for an average of 64 hours. The placebo group received vehicle only in a similar fashion. During treatment hemodynamic changes were more prominent in the patients receiving prostacyclin and included reduction of systolic and diastolic blood pressure and increase in pulse rate. In contrast there was only a slight (but significant) reduction of diastolic blood pressure in the placebo group. Neurologic deficit scores were determined on admission, at Day 3, and at Weeks 1, 2, and 4. Mean neurologic deficit scores upon entry were comparable in the placebo and prostacyclin groups, and a significant improvement in the score for neurologic deficit was noted in both. The placebo group tended to fare better throughout the study, with a significant difference in neurologic deficit score favoring the placebo group at Week 2 (p = 0.0048). Two patients in the placebo and one in the prostacyclin group died. The only difference in adverse reactions was flushing (6 patients in prostacyclin vs. 0 in placebo group, p less than 0.05). The results of this study suggest a lack of therapeutic efficacy of prostacyclin in a defined population of patients with nonhemorrhagic cerebral infarction. High blood pressure (BP) is common in acute stroke and is independently associated with a poor outcome. Lowering BP might improve outcome if it did not adversely affect cerebral blood flow (CBF) or cerebral perfusion pressure. We investigated the effect of glyceryl trinitrate ([GTN] an NO donor) on quantitative CBF, BP, and cerebral perfusion pressure in patients with recent stroke. Eighteen patients with recent (<5 days) ischemic (n=16) or hemorrhagic (n=2) stroke were randomly assigned (2:1) to transdermal GTN (5 mg) or control. CBF (global, hemispheric, arterial territory, and lesion, using xenon computed tomography) and BP (peripheral and central) were measured before and 1 hour after treatment with GTN. The effects of GTN on CBF and BP were adjusted for baseline measurements (ANCOVA). GTN lowered peripheral systolic BP by (mean) 23 mm Hg (95% CI, 2 to 45; P=0.03) and central systolic BP by 22 mm Hg (95% CI, 0 to 44; P=0.048). In contrast, GTN did not alter CBF (mL/min per 100 g): global -1.2 (95% CI, -6.5 to 4.2; P=0.66) and ipsilateral hemisphere -1.4 (95% CI, -7.6 to 4.9; P=0.65) or area of stroke oligemia, penumbra, or core (as defined by critical CBF limits). Contralateral CBF did not change: hemisphere 0 (95% CI, -7 to 6; P=0.96). GTN did not alter cerebral perfusion pressure or zero-filling pressure. Significant reductions in BP after transdermal GTN are not associated with changes in CBF or cerebral perfusion pressure or cerebral steal in patients with recent stroke. Trials need to assess the effect of lowering BP on functional outcome.
There is not enough evidence to evaluate reliably the effect of altering BP on outcome after acute stroke. However, treatment with DCLHb was associated with poor clinical outcomes. Beta receptor antagonists, CCBs, nitric oxide, and prostacyclin each lowered BP during the acute phase of stroke. In contrast, DCLHb increased BP.