E. Clarke Haley

Recommendations for the management of patients with unruptured intracranial aneurysms: A statement for healthcare professionals from the Stroke Council of the American Heart Association.

Aneurysmal subarachnoid hemorrhage (SAH) has a 30-day mortality rate of 45%, with approximately half the survivors sustaining irreversible brain damage.1 On the basis of an annual incidence of 6 per 100 000, ≈15 000 Americans will have an aneurysmal SAH each year. Population-based incidence rates vary considerably from 6 to 16 per 100 000, with the highest rates reported from Japan and Finland.2 3 4 5 Approximately 5% to 15% of stroke cases are secondary to ruptured saccular aneurysms. Although the prevention of hemorrhage has been advocated as the most effective strategy aimed at lowering mortality rates,6 the optimal management of patients with unruptured intracranial aneurysms (UIAs) remains controversial. Management decisions require an accurate assessment of the risks of various treatment options compared with the natural history of the condition. The natural history of UIAs and treatment outcomes are influenced by (1) patient factors, such as previous aneurysmal SAH, age, and coexisting medical conditions; (2) aneurysm characteristics, such as size, location, and morphology; and (3) factors in management, such as the experience of the surgical team and the treating hospital. These many influences have contributed to considerable variability in the reported risks for aneurysmal SAH and the treatment of UIAs. There are no prospective randomized trials of treatment interventions versus conservative management to date, and it is possible that no such studies will be carried out in the future. According to a classification system suggested by Cook et al,7 randomized clinical trials with low likelihoods of false-positive and false-negative errors provide the highest level of evidence (level I) that can be applied to a clinical recommendation. Randomized trials with high likelihoods of false-negative and positive errors provide level II evidence. Level III evidence is generated with nonrandomized concurrent cohort comparisons between contemporaneous patients who did and …

Medical and Neurological Complications of Ischemic Stroke Experience From the RANTTAS Trial

BACKGROUND AND PURPOSE Medical and neurological complications after acute ischemic stroke may adversely impact outcome and in some cases may be preventable. Limited data exist regarding the frequency of such complications occurring in the first days after the ictus and the relationship of these complications to outcome. Our objective was to identify the types, severity, and frequency of medical and neurological complications following acute ischemic stroke and to determine their role in mortality and functional outcome. METHODS Rates of serious (life-threatening) and nonserious medical and neurological complications and mortality were derived from the placebo limb of the Randomized Trial of Tirilazad Mesylate in Acute Stroke (RANTTAS) database (n=279). Complications were correlated with clinical outcome using logistic regression techniques. RESULTS Of all patients, 95% had at least one complication. The most common serious medical complication was pneumonia (5%), and the most common serious neurological complication was new cerebral infarction or extension of the admission infarction (5%). The 3-month mortality was 14%; 51% of these deaths were attributed primarily to medical complications. Outcome was significantly worse in patients with serious medical complications, after adjustment for baseline imbalances, as measured by the Barthel Index (odds ratio [OR], 6.1; 95% confidence interval [CI], 2.5 to 15.1) and by the Glasgow Outcome Scale (OR, 11.6; 95% CI, 4.3 to 30.9). After death was discounted, serious medical complications were associated with severe disability at 3 months as determined by the Glasgow Outcome Scale (OR, 4.4; 95% CI, 1.3 to 14.8). CONCLUSIONS Medical complications that follow ischemic stroke not only influence mortality but may influence functional outcome.

Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial

BACKGROUND The IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial. METHODS We used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2-3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0-2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration. FINDINGS Of 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0·85 [95% CI 0·77-0·94]; adjusted relative risk 0·88 [0·80-0·98]). INTERPRETATION Delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials. FUNDING US National Institutes of Health and National Institute of Neurological Disorders and Stroke.

Recommendations for the Management of Patients With Unruptured Intracranial Aneurysms A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association

Aneurysmal subarachnoid hemorrhage (SAH) has a 30-day mortality rate of 45%, with approximately half the survivors sustaining irreversible brain damage.1 On the basis of an annual incidence of 6 per 100 000, ≈15 000 Americans will have an aneurysmal SAH each year. Population-based incidence rates vary considerably from 6 to 16 per 100 000, with the highest rates reported from Japan and Finland.2 3 4 5 Approximately 5% to 15% of stroke cases are secondary to ruptured saccular aneurysms. Although the prevention of hemorrhage has been advocated as the most effective strategy aimed at lowering mortality rates,6 the optimal management of patients with unruptured intracranial aneurysms (UIAs) remains controversial. Management decisions require an accurate assessment of the risks of various treatment options compared with the natural history of the condition. The natural history of UIAs and treatment outcomes are influenced by (1) patient factors, such as previous aneurysmal SAH, age, and coexisting medical conditions; (2) aneurysm characteristics, such as size, location, and morphology; and (3) factors in management, such as the experience of the surgical team and the treating hospital. These many influences have contributed to considerable variability in the reported risks for aneurysmal SAH and the treatment of UIAs. There are no prospective randomized trials of treatment interventions versus conservative management to date, and it is possible that no such studies will be carried out in the future. According to a classification system suggested by Cook et al,7 randomized clinical trials with low likelihoods of false-positive and false-negative errors provide the highest level of evidence (level I) that can be applied to a clinical recommendation. Randomized trials with high likelihoods of false-negative and positive errors provide level II evidence. Level III evidence is generated with nonrandomized concurrent cohort comparisons between contemporaneous patients who did and …

Infarct Volume as a Surrogate or Auxiliary Outcome Measure in Ischemic Stroke Clinical Trials

BACKGROUND AND PURPOSE Reduction in infarct volume is the standard measure of therapeutic success in animal stroke models. Reduction in infarct volume has been advocated as a biological surrogate or auxiliary outcome measure for human stroke clinical trials to replace or supplement deficit, disability, and global clinical scales. However, few studies have investigated correlations between infarct volume and clinical end points in acute ischemic stroke patients. METHODS CT scans at days 6 to 11 were acquired prospectively in 191 fully eligible patients enrolled in the Randomized Trial of Tirilazad Mesylate in Patients With Acute Stroke (RANTTAS). Patients were enrolled within 6 hours of onset of stroke in any vessel distribution. Infarct volume was measured by operator-assisted computerized planimetry. RESULTS One hundred thirty-two patients had visible new supratentorial infarcts, with median infarct volume of 28.0 cm3 (interquartile range, 9.0 to 93.0 cm3). Fifty-nine patients had no visible new infarct. Correlations with standard 3-month outcome scales and mortality were as follows: Barthel Index, r=0.43; Glasgow Outcome Scale, r=0.53; National Institutes of Health Stroke Scale, r=0.54; mortality, r=0.31. For visible infarcts alone, correlations were as follows: BI, r=0.46; GOS, r=0.59; NIHSS, r=0.56; mortality, r=0.32. CONCLUSIONS Subacute CT infarct volume correlates moderately with 3-month clinical outcome as assessed by widely used neurological and functional assessment scales. The modesty of this linkage constrains the use of infarct volume as a surrogate end point in ischemic stroke clinical trials.

Hypertension and Its Treatment in the NINDS rt-PA Stroke Trial

BACKGROUND AND PURPOSE We examined the frequency, course, and treatment of hypertension in the NINDS rt-PA Stroke Trial. METHODS Blood pressure (BP) was measured at the time of admission, at randomization, and then 36 times during the first 24 hours after randomization. Patients with a systolic BP of >185 mm Hg and a diastolic BP of >110 mm Hg at admission were defined as hypertensive before randomization, and those with a systolic BP of >180 mm Hg or a diastolic BP of >105 mm Hg within the first 24 hours after randomization were defined as hypertensive after randomization. Standardized clinical assessments were conducted at 24 hours and at 3 months. Post hoc analyses were conducted to evaluate the association of antihypertensive therapy with clinical outcomes. RESULTS Of the 624 patients, 121(19%) had hypertension on admission and 372 (60%) had hypertension in the 24 hours after randomization. The use of antihypertensive therapy before randomization (tPA 9%, placebo 9%) and after randomization (tPA 24%, placebo 29%) was similar between placebo- and tPA-treated patients. No adverse effects of prerandomization antihypertensive therapy on 3-month favorable outcome were detected for either the placebo- or tPA-treated groups. For placebo patients with hypertension in the 24 hours after randomization, clinical outcome measures were similar for those patients who did and did not receive antihypertensive therapy after randomization (P > or = 0.26); antihypertensive therapy was not associated with declines in BP (P = 0.44) or with abrupt declines (P = 0.14). Those tPA patients who were hypertensive after randomization and received antihypertensive therapy were less likely to have a favorable outcome at 3 months (P < 0.01) than those who were hypertensive and did not receive antihypertensive therapy. CONCLUSIONS The frequency of hypertension and the use of antihypertensive therapy were similar between the tPA and placebo groups in the NINDS rt-PA Stroke Trial. In the placebo group, antihypertensive therapy was not associated with less favorable outcomes at 3 months; postrandomization antihypertensive therapy was associated with less favorable outcomes for the tPA patients who were hypertensive. However, because of the nonrandomized use of antihypertensive therapy and the many post hoc comparisons leading to type 1 errors, the significance of this observation is unclear. Careful attention to BP and gentle management remain warranted for stroke patients treated with tPA.

A Predictive Risk Model for Outcomes of Ischemic Stroke

BACKGROUND AND PURPOSE The great variability of outcome seen in stroke patients has led to an interest in identifying predictors of outcome. The combination of clinical and imaging variables as predictors of stroke outcome in a multivariable risk adjustment model may be more powerful than either alone. The purpose of this study was to determine the multivariable relationship between infarct volume, 6 clinical variables, and 3-month outcomes in ischemic stroke patients. METHODS Included in the study were 256 eligible patients from the Randomized Trial of Tirilazad Mesylate in Acute Stroke (RANTTAS). Six clinical variables and 1-week infarct volume were the prespecified predictor variables. The National Institutes of Health Stroke Scale, Barthel Index, and Glasgow Outcome Scale were the outcomes. Multivariable logistic regression techniques were used to develop the model equations, and bootstrap techniques were used for internal validation. Predictive performance of the models was assessed for discrimination with receiver operator characteristic (ROC) curves and for calibration with calibration curves. RESULTS The predictive models had areas under the ROC curve of 0.79 to 0.88 and demonstrated nearly ideal calibration curves. The areas under the ROC curves were statistically greater (P<0.001) with both clinical and imaging information combined than with either alone for predicting excellent recovery and death or severe disability. CONCLUSIONS Combined clinical and imaging variables are predictive of 3-month outcome in ischemic stroke patients. Demonstration of this relationship with acute clinical variables and 1-week infarct information supports future attempts to predict 3-month outcome with all acute variables.

Predicting Major Neurological Improvement With Intravenous Recombinant Tissue Plasminogen Activator Treatment of Stroke

Background and Purpose— In the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study, major neurological improvement within 24 hours (MNI) occurred significantly more frequently with recombinant tissue plasminogen activator (rtPA) treatment than with placebo. We explored the relationship between MNI and 3-month favorable outcome and sought clinical predictors of MNI. Methods— Data from 312 rtPA-treated patients from the NINDS trial were used to assess the ability of MNI to predict favorable outcome at 3 months as defined by a modified Rankin Scale score of 0 to 1. Next, a multivariable predictive model was developed for MNI within the same data set. Clinical variables examined included age, time to treatment (TTT), diabetes, pretreatment glucose, baseline National Institutes of Health Stroke Scale score, pretreatment blood pressure, history of atrial fibrillation, weight >100 kg, and a dense artery sign. Finally, this model was used to forecast into the placebo group of the NINDS trial to assess the uniqueness of the predictors in the rtPA-treated group. Results— MNI had a positive predictive value and negative predictive value of 0.70 for predicting favorable 3-month outcome. Only age [odds ratio (OR), 0.68; 95% confidence interval (CI), 0.47 to 0.99] and TTT (OR, 0.56; 95% CI, 0.34 to 0.91) appear to be independently associated with MNI. The model performed only moderately well (area under the receiver-operating characteristic curve, 0.66). Age (OR, 0.67; 95% CI, 0.45 to 0.99) but not TTT was associated with MNI in the placebo group. Conclusions— MNI may be a useful surrogate for thrombolytic activity and is predictive of favorable 3-month outcome. When rates of MNI in different populations of stroke patients treated with thrombolysis are compared, adjustments for age and TTT may be necessary.

Blood pressure during the first minutes of focal cerebral ischemia

STUDY OBJECTIVE To determine whether blood pressure declines spontaneously during the first minutes and hours of focal cerebral ischemia. DESIGN Multiple blood pressure measurements as part of an urgent stroke therapy trial (treatment within 90 minutes of stroke onset). SETTING Thirteen hospitals in three metropolitan communities. PARTICIPANTS Sixty-nine patients (mean age, 65 +/- 9 years) with acute ischemic stroke who were participants in a phase I urgent stroke therapy trial of recombinant tissue plasminogen activator. MAIN OUTCOME MEASURE Blood pressures recorded at the scene of stroke by life-squad personnel, in the emergency department, and in the ICU. RESULTS The mean time from stroke onset to the time of first blood pressure measurement was 19 +/- 13 minutes. Twenty-four of the 69 patients in the urgent stroke therapy trial had an initial systolic blood pressure of at least 160 mm Hg. Of these, 23 had a significant decline in systolic and diastolic blood pressure during the first 90 minutes after the onset of stroke (mean change in systolic pressure, -29 +/- 22 mm Hg, P < .001; mean change in diastolic pressure, -10 +/- 14 mm Hg, P < .01). No patients received antihypertensive therapy during the time in which the decline in blood pressure was noted. CONCLUSION Mildly or moderately elevated blood pressure frequently declines spontaneously during the first minutes and hours of focal cerebral ischemia and generally does not require urgent pharmacologic treatment.

Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke. Results of a Prematurely Terminated Randomized Clinical Trial

Background and Purpose— Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA. Methods— The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a “best” dose of tenecteplase to carry forward. Once a “best” dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. Results— The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established. Conclusion— This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.