Richard M. Zweifler

A Randomized Efficacy Trial of Citicoline in Patients With Acute Ischemic Stroke

BACKGROUND AND PURPOSEnCiticoline (cytidine-5-diphosphocholine; CDP-choline) may reduce central nervous system ischemic injury by stabilizing cell membranes and reducing free radical generation. A previous dose-comparison trial in patients with acute stroke found that 500 mg of citicoline appeared to improve neurological outcome with minimal side effects.nnnMETHODSnThe current trial was a 33-center, randomized, double-blind, efficacy trial in 394 patients comparing placebo (n=127) with citicoline (n=267) (500 mg po daily) for 6 weeks, with a 6-week posttreatment follow-up period. Patients with acute (24 hours) ischemic strokes clinically assessed to be in the middle cerebral artery territory with National Institutes of Health Stroke Scale (NIHSS) > or = 5 were enrolled.nnnRESULTSnMean time to treatment was 12 hours, and mean age was 71 for placebo and 70 for citicoline. Although mean baseline NIHSS were similar for both groups, there was a higher percentage of placebo patients with NIHSS <8 (34% vs 22%; P<0.01). The incidence and type of side effects were similar between the groups. The planned primary analysis (logistic regression: 5 categories Barthel) failed the proportional odds assumption and was rendered unreliable. There were no between-group differences seen on the planned secondary assessment analyses at 90 days, including the Barthel Index > or = 95 at 12 weeks (last observation carried forward: placebo 40%; citicoline 40%) or mortality rate (placebo 18%; citicoline 17%). However, post hoc analyses in a subgroup of patients with baseline NIHSS > or = 8 found that citicoline-treated patients were more likely to have a full recovery (Barthel > or = 95): placebo 21%; citicoline 33%; P=0.05; whereas no difference was seen in patients with baseline NIHSS<8 (placebo 77%; citicoline 69%; P>0.1.nnnCONCLUSIONSnThe results of this study indicate that citicoline was safe but ineffective in improving the outcome of patients with acute ischemic stroke who were enrolled in this trial. Post hoc analyses indicate that there may be a subgroup of patients with moderate to severe strokes who would benefit.

Statin Treatment and Stroke Outcome in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial

Background and Purpose— Laboratory experiments suggest statins reduce stroke severity and improve outcomes. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial was a placebo-controlled, randomized trial designed to determine whether treatment with atorvastatin reduces strokes in subjects with recent stroke or transient ischemic attack (n=4731). We analyzed SPARCL trial data to determine whether treatment favorably shifts the distribution of severities of ischemic cerebrovascular outcomes. Methods— Severity was assessed with the National Institutes of Health Stroke Scale, Barthel Index, and modified Rankin Scale score at enrollment (1 to 6 months after the index event) and 90 days poststroke in subjects having a stroke during the trial. Results— Over 4.9 years, strokes occurred in 576 subjects. There were reductions in fatal, severe (modified Rankin Scale score 5 or 4), moderate (modified Rankin Scale score 3 or 2), and mild (modified Rankin Scale score 1 or 0) outcome ischemic strokes and transient ischemic attacks and an increase in the proportion of event-free subjects randomized to atorvastatin (P<0.001 unadjusted and adjusted). Results were similar for all outcome events (ischemic and hemorrhagic, P<0.001 unadjusted and adjusted) with no effect on outcome hemorrhagic stroke severity (P=0.174 unadjusted, P=0.218 adjusted). If the analysis is restricted to those having an outcome ischemic stroke (ie, excluding those having a transient ischemic attack or no event), there was only a trend toward lesser severity with treatment based on the modified Rankin Scale score (P=0.0647) with no difference based on the National Institutes of Health Stroke Scale or Barthel Index. Conclusion— The present exploratory analysis suggests that the outcome of recurrent ischemic cerebrovascular events might be improved among statin users as compared with nonusers.

The Impact of Intensive Patient Education on Clinical Outcome in a Clinic-Based Migraine Population

Objective.—To determine whether the addition of patient education to routine medical management improves the clinical status of migraine patients and reduces their utilization of healthcare resources.

Design, Progress and Challenges of a Double-Blind Trial of Warfarin versus Aspirin for Symptomatic Intracranial Arterial Stenosis

Background and Relevance: Atherosclerotic stenosis of the major intracranial arteries is an important cause of transient ischemic attack (TIA) or stroke. Of the 900,000 patients who suffer a TIA or stroke each year in the USA, intracranial stenosis is responsible for approximately 10%, i.e. 90,000 patients. There have been no prospective trials evaluating antithrombotic therapies for preventing recurrent vascular events in these patients. The main objective of this trial is to compare warfarin [International Normalized Ratio (INR) 2–3] with aspirin (1,300 mg/day) for preventing stroke (ischemic and hemorrhagic) and vascular death in patients presenting with TIA or stroke caused by stenosis of a major intracranial artery. Study Design: Prospective, randomized, double-blind, multicenter trial. The sample sizerequired will be 403 patients per group, based on stroke and vascular death rates of 33% per 3 years in the aspirin group vs. 22% per 3 years in the warfarin group, a p value of 0.05, power of 80%, a 24% rate of ‘withdrawal of therapy’, and a 1% rate of ‘lost to follow-up’. Conduct of Trial: Patients with TIA or nondisabling stroke caused by ≧50% stenosis of a major intracranial artery documented by catheter angiography are randomized to warfarin or aspirin. Patients are contacted monthly by phone and examined every 4 months until a common termination date. Mean follow-up in the study is expected to be 3 years. Conclusion: This study will determine whether warfarin or aspirin is superior for patients with symptomatic intracranial arterial stenosis. Furthermore, it will identify patients whose rate of ischemic stroke in the territory of the stenotic intracranial artery on best medical therapy is sufficiently high to justify a subsequent trial comparing intracranial angioplasty/stenting with best medical therapy in this subset of patients.

Magnesium Sulfate Increases the Rate of Hypothermia Via Surface Cooling and Improves Comfort

Background and Purpose— Therapeutic hypothermia shows promise as a treatment for acute stroke. Surface cooling techniques are being developed but, although noninvasive, they typically achieve slower cooling rates than endovascular methods. We assessed the hypothesis that the addition of intravenous MgSO4 to an antishivering pharmacological regimen increases the cooling rate when using a surface cooling technique. Methods— Twenty-two healthy volunteers were studied. Hypothermia was induced using a surface technique with a target tympanic temperature (Ttym) of 34.5°C (target range 34 to 35°C). Subjects received 1 of the following pharmacological regimens: (1) meperidine monotherapy (n=5); (2) meperidine plus buspirone, 30 to 60 mg PO administered at the time of initiation of cooling (n=4); (3) meperidine and ondansetron, 8 to 16 mg IV administered as an 8 mg bolus at the time of initiation of cooling with an optional second dose after 4 hours as needed for nausea (n=5); or (4) meperidine, ondansetron, and MgSO4, 4 to 6 g IV bolus followed by 1 to 3 g per hour infusion (n=8). Thermal comfort was evaluated with a 100-mm-long visual analog scale. Results— More subjects who received MgSO4 were vasodilated during hypothermia induction (7 of 8 [88%] versus 4 of 14 [29%]; P=0.024). MgSO4 (coefficient −17.265; P=0.039), weight (1.838, 0.001), and the initial 2-hour meperidine dose (0.726, 0.003) were found to significantly impact the time to achieve Ttym of 35°C. Subjects who received MgSO4 had significantly higher mean comfort scores than those who did not (48±15 versus 38±12; P<0.001). Conclusions— Administration of intravenous MgSO4 increases the cooling rate and comfort when using a surface cooling technique.

Progress in shivering control

Hypothermia is a potent neuroprotectant and induced hypothermia holds great promise as a therapy for acute neuronal injury. Thermoregulatory responses, most notably shivering, present major obstacles to therapeutic temperature management. A review of thermoregulatory physiology and strategies aimed at controlling physiologic responses to hypothermia is presented.

Prevalence and Prognosis of Coexistent Asymptomatic Intracranial Stenosis

Background and Purpose— There are limited data on the prevalence and prognosis of asymptomatic intracranial stenosis (AIS). Methods— Baseline cerebral angiograms and MR angiograms were used to determine AIS (50% to 99%) coexistent to symptomatic intracranial stenosis for patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease study. Results— Coexisting AIS were detected in 18.9% (n=14/74) of patients undergoing 4-vessel cerebral angiography and 27.3% (n=65/238) of patients undergoing MR angiogram. During a mean follow-up period of 1.8 years, no ischemic strokes were attributable to an AIS on cerebral angiography and 5 ischemic strokes (5.9%, 95% CI: 2.1% to 12.3%) occurred in the AIS territory on MR angiogram (risk at 1 year=3.5%, 95% CI: 0.8% to 9.0%). Conclusions— Whereas the prevalence of coexisting AIS (50% to 99%) in patients with symptomatic stenosis is high, the risk of stroke from these asymptomatic stenoses is low.

Management of acute stroke.

Stroke ranks as the third leading cause of death and the most common cause of permanent disability in adults. Timely recognition and treatment is imperative to reduce stroke-related morbidity and mortality. Patients with acute ischemic stroke should be evaluated for administration of intravenous tissue plasminogen activator (t-PA); those who do not qualify for t-PA should receive aspirin therapy in the absence of a contraindication. In all stroke patients, intravenous hydration with normal saline should be administered, hypoxia should be corrected with supplemental oxygen, and hyperglycemia and fever should be treated aggressively. Blood pressure management should be individualized on the basis of stroke pathophysiology and specific treatment plan (e.g., planned thrombolysis) following published guidelines. Evaluation of stroke etiology should be undertaken, and the results should be used to guide secondary stroke prevention efforts.

Coronary Heart Disease Risk in Patients With Stroke or Transient Ischemic Attack and No Known Coronary Heart Disease Findings From the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial

Background and Purpose— Noncoronary forms of atherosclerosis (including transient ischemic attacks or stroke of carotid origin or >50% stenosis of the carotid artery) are associated with a 10-year vascular risk of >20% and are considered as a coronary heart disease (CHD) -risk equivalent from the standpoint of lipid management. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial included patients with stroke or transient ischemic attack and no known CHD regardless of the presence of carotid atherosclerosis. We evaluated the risk of developing clinically recognized CHD in SPARCL patients. Methods— A total of 4731 patients (mean age, 63 years) was randomized to 80 mg/day atorvastatin placebo. The rates of major coronary event, any CHD event, and any revascularization procedure were evaluated. Results— After 4.9 years of follow-up, the risks of a major coronary event and of any CHD end point in the placebo group were 5.1% and 8.6%, respectively. The rate of outcome of stroke decreased over time, whereas the major coronary event rate was stable. Relative to those having a large vessel-related stroke at baseline, those having a transient ischemic attack, hemorrhagic stroke, small vessel stroke, or a stroke of unknown cause had similar absolute rates for a first major coronary event and for any CHD event; transient ischemic attack, small vessel, and unknown cause groups had lower absolute revascularization procedure rates. Major coronary event, any CHD event, and any revascularization procedure rates were similarly reduced in all baseline stroke subtypes in the atorvastatin arm compared with placebo with no heterogeneity between groups. Conclusion— CHD risk can be substantially reduced by atorvastatin therapy in patients with recent stroke or transient ischemic attack regardless of stroke subtype.

Implementation of a Stroke Code System in Mobile, Alabama: Diagnostic and Therapeutic Yield

BACKGROUND AND PURPOSEnThere is now therapy of proven benefit for acute ischemic stroke. Successful interventional therapy for stroke patients requires implementation of a system that facilitates rapid triage and diagnostic evaluation.nnnMETHODSnWe initiated a 24-hour, 7-day-per-week stroke code system at the University of South Alabama Hospitals and prospectively collected data from the first 100 patients whose clinical presentations triggered this system.nnnRESULTSnSeventy-eight patients (78%) had acute ischemic stroke. Of the remaining 22, 9 had evidence of intracerebral hemorrhage. The most common nonstroke diagnosis was seizure (n = 5). Forty-eight of the 87 stroke patients (55%) presented within 6 hours of stroke onset (40/78 = 51% of the ischemic stroke patients), and 35 of the 87 (40%) presented within 3 hours of onset (28/78 = 36% of the ischemic stroke patients). Thirty-one (31% of the group overall; 40% of the ischemic stroke patients) were eligible for acute therapy. Twenty-five of these eligible patients were entered into a treatment study, 4 declined participation, and 2 were treated with open-label tissue plasminogen activator.nnnCONCLUSIONSnImplementation of a stroke code system may result in a high yield of patients with acute stroke and relatively few stroke mimickers. A significant proportion of all cases generated will be eligible for acute treatment under current experimental protocols or with tissue plasminogen activator, but the majority will not.