Stroke Treatment Trials Research Articles

Abstract 101: Prehospital Study Enrollment Enables Initiation of Neuroprotective Agent for Acute Stroke in Hyperacute Time Windows

Background: As “time lost is brain lost” in acute ischemic stroke, earlier start of therapy will maximize access of promising drugs to salvageable brain tissue. We hypothesized that prehospital treatment initiation would accelerate treatment delivery of neuroprotective agent in a prehospital randomized clinical trial. Methods: We analyzed research treatment initiation times in consecutive patients enrolled in the NIH Field Administration of Stroke Therapy – Magnesium (FAST-MAG) Phase 3 clinical trial. In FAST-MAG, patients with suspected acute stroke within 2 hours of onset are randomized to paramedic initiation of magnesium sulfate or placebo in 358 participating ambulances and 59 receiving hospitals. Results: Among 1486 patients, mean age was 69 (SD13.7), 42% were female, median pretreatment Los Angeles Motor Scale score was 4, and final diagnosis was acute cerebral ischemia in 71.9%, intracranial hemorrhage in 24.4%, and stroke mimic in 3.7%. Figure 1 shows the distribution of values for time from onset (last known well) to treatment (OTT). Clustering of experimental treatment start times at the maximum permitted time window, common in in-hospital stroke trials, was not seen in this cohort with prehospital care mandated early transports. Across all patients, the median OTT was 49.0 minutes. 73.5% of patients were treated within the first 60 minutes of onset (the “golden hour”) and 10.8% within the first 30 minutes of onset. Mean time from paramedic arrival on scene to start of treatment was 23.0 (SD 7.6) minutes, and 4.3% of patients were treated within 10 minutes of medic arrival (the “platinum ten minutes”). Conclusions: Prehospital initiation enables start of experimental neuroprotective therapy in times previously not achievable in acute stroke treatment trials. Nearly three-quarters of patients can be treated within the golden hour and more than one in ten within the first 30 minutes of onset.

The Totaled Health Risks in Vascular Events (THRIVE) Score Predicts Ischemic Stroke Outcomes Independent of Thrombolytic Therapy in the NINDS tPA Trial

To date, no ischemic stroke outcome prediction scores have been validated for use in the setting of both endovascular and non-endovascular stroke treatments. The Totaled Health Risks in Vascular Events (THRIVE) score has been previously validated in patients undergoing endovascular stroke treatment, and we hypothesized that it would perform similarly well in patients receiving intravenous tissue plasminogen activator (tPA) or no acute therapy. We compared the performance of the THRIVE score between patients in the National Institutes of Neurological Disorders and Stroke (NINDS) tPA trial and patients in the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trials of endovascular stroke treatment. The predictive performance of the THRIVE score was compared using receiver operator characteristic (ROC) curve analysis. In the NINDS cohort, separate analyses were also performed for patients receiving tPA versus those receiving placebo. ROC curve analysis revealed a good prediction of outcomes across the range of THRIVE scores in both the NINDS and MERCI datasets. As we have previously found in the MERCI datasets, the THRIVE score, which encompasses the National Institutes of Health Stroke Scale (NIHSS) score, age, and chronic disease burden, was a better predictor of outcomes than NIHSS and age alone in the NINDS trial dataset. THRIVE score and tPA administration both strongly predicted outcome, but these effects were statistically independent. The THRIVE score provides accurate prediction of long-term neurologic outcomes in patients with acute ischemic stroke regardless of treatment modality. Both the THRIVE score and tPA administration predict outcome, but the THRIVE score does not influence the impact of tPA on outcome, and tPA administration does not influence the impact of THRIVE score on outcome.

Safety and Effectiveness of Endovascular Treatment after 6 Hours of Symptom Onset in Patients with Anterior Circulation Ischemic Stroke: A Matched Case Control Study

Endovascular treatment within 6 hours of symptom onset appears to be beneficial in carefully selected patients with ischemic stroke. It is unclear whether endovascular treatment beyond 6 hours of symptom onset is safe and efficacious. Over a 6-year period, 52 patients with acute ischemic stroke in the anterior circulation underwent emergent endovascular thrombolytic infusion and mechanical thrombectomy after 6 hours of symptom onset at 3 institutions. Their outcomes were compared to 52 placebo-treated patients matched by baseline National Institutes of Health Stroke Scale (NIHSS) score and nonlacunar anterior circulation location from the Trial of Org 10172 in Acute Stroke Treatment trial using a 1:1 ratio. Univariate and multivariate analyses were performed comparing the rates of symptomatic intracerebral hemorrhage, early neurologic improvement, favorable outcome at 7 days or discharge, and in-hospital mortality between the 2 groups. After adjustment for gender, time interval between symptom onset to treatment, hypertension, hyperlipidemia, and history of cigarette smoking, rates of neurologic improvement at 24 hours (odds ratio [OR] 1.15; 95% confidence interval [CI] 0.43-3.1) and favorable outcome at 7 days or discharge (OR 1.39; 95% CI 0.47-4.05) were similar in the 2 groups. No differences in the rates of symptomatic intracerebral hemorrhage or death were found after adjusting for potential confounders. In an analysis limited to only those patients who underwent computed tomographic perfusion or magnetic resonance imaging before receiving endovascular treatment, the rate of favorable outcome at 7 days or discharge was similar between patients who underwent endovascular treatment and control patients (35.7% v 32.1%; P = .77). We did not observe any evidence of benefit in halting neurologic worsening or improving outcomes among patients undergoing endovascular treatment for treatment of an anterior circulation ischemic stroke after 6 hours of symptom onset. Strong evidence of both the safety and efficacy of emergent endovascular treatment when administered to patients with stroke in the anterior circulation is needed.

How baseline severity affects efficacy and safety outcomes in acute ischemic stroke intervention trials

Baseline severity of stroke may be an important predictor of efficacy and safety outcomes in acute stroke intervention trials. This summary explores definitions of baseline variables and outcomes used to measure stroke severity, efficacy, and safety. In addition, the discussion here reviews select acute ischemic stroke intravenous thrombolytic studies, such as the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study and European Cooperative Acute Stroke Studies, select neuroprotectant and endovascular clot retrieval device studies, and large cooperative databases, such as the Virtual International Stroke Trials Archive and Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry, to explore relationships between baseline stroke severity and other possible factors associated with efficacy and safety outcomes. The NIH Stroke Scale and modified Rankin scale will be featured as major stroke outcome measures, based on frequency of use and reliability, familiarity, adaptability, and comparability.

Stroke Severity May Impact Speed of Diagnosis & Thrombolysis (P04.058)

Objective: To demonstrate that clinical severity affects speed of diagnosis and treatment of acute ischemic stroke. Background Prior stroke treatment trials demonstrate that earlier thrombolysis leads to greater benefit; however, recent data suggests that less than 1/3 of stroke patients had door-to-needle times Design/Methods: Retrospectively, all acute ischemic stroke patients who received IV rt-PA alone were identified in our stroke database. Patients who received IA rt-PA or mechanical thromboembolectomy were excluded from analysis. Door-to-needle times and NIHSS scores at admission and discharge were identified. Statistical analysis was done using the Mann-Whitney test and a regression model for adjustment of admission NIHSS score severity. Results: IV rt-PA alone was given to 112 AIS patients; 8 lacked discharge NIHSS scores, so 104 were included for analysis. Fifty received IV rt-PA within 60 minutes, 54 after 60 minutes. Mean admission NIHSS scores were 11.2 and 8.8 (p=0.016) for the 60min groups, respectively. The mean improvements in NIHSS scores at discharge were 6.9 and 5.1 (p=0.606), respectively. When the same data set was dichotomized at a target of 80 minutes, the admission scores were 10.6 ( 80min, n=24) (p=0.142). The mean improvements in NIHSS scores for this time dichotomization were 6.8 and 3.0 (p=0.033), respectively. Conclusions: Our experience suggests that greater stroke severity is associated with earlier diagnosis and treatment. When stroke severity on admission is adjusted, the data shows a greater degree of improvement for patients who are treated earlier, confirming prior reports in the literature. Our data may also suggest that less severe stroke cases may present more of a diagnostic challenge, which may delay treatment; however, further review of nation-wide data is necessary to fully answer this question. Disclosure: Dr. Nair has nothing to disclose. Dr. Wang has nothing to disclose. Dr. McNeil has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Jahnel has received personal compensation for activities with Genetech as a Consultant. Dr. Stapel has nothing to disclose. Dr. Stapel has nothing to disclose. Dr. Stapel has nothing to disclose. Dr. Stapel has nothing to disclose. Dr. Beck has nothing to disclose. Dr. Alanis has nothing to disclose. Dr. Talkad has received personal compensation for activities with Genentech, Inc. as a speaker. Dr. Wang has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc. and Boehringer Ingelheim Pharmaceuticals, Inc.

Abstract 3309: Enrolling the Oldest Old is Achievable in Acute Stroke Clinical Trials

Background: Acute stroke clinical trials have frequently excluded the very elderly, leading to a lack of data regarding therapy effect in this rapidly growing population. We sought to describe the frequency and characteristics of the oldest old (patients aged 80-95) enrolled in an ongoing multicenter prehospital treatment trial, the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) study. Methods: FAST-MAG is a phase 3, NIH-funded, randomized, double-blind study of field-administered magnesium sulfate vs. placebo in stroke patients enrolled within 2 hours of symptom onset. All patients who were not disabled prestroke up to age 95 are eligible for enrollment. Results: Among the first 1207 subjects enrolled in FAST-MAG, 353 (29%) were >= 80 and 42 (4%) were >= 90 years old. Compared with younger trial subjects, individuals >=80 years old had higher mean age (85 v 63, p<0.0001), were more often women (53% vs. 38%, P<0.0001), less often Hispanic ethnicity (13% v 27%, p<0.0001), more often racially white (87% v 76%, p<0.0001), and were less likely to have intracerebral hemorrhage (15% v 28%, p<0.0001). However, the very elderly had similar stroke deficit severity (NIHSS 11 v 11, p=0.65) and were evaluated by paramedics (mean 37 v 37 min) and arrived in the ED (73 v 71 min, p=0.65) at similar time points. In the field, the very elderly had similar SBP (160 v 158, p=0.59) but lower DBP (78 v 86, p<0.0001). Medical history variables distinguishing the very elderly from younger patients were higher frequency of HTN (87% vs. 77%, P<0.0001), atrial fibrillation (40% vs. 17%, p<0.0001), coronary artery disease (27% vs 18%, p<0.0001), and lower tobacco use (4% vs 23%, p<0.0001). Rates of TPA use among cerebral ischemia patients did not differ between the very elderly and younger patients (31% v 28%, p=0.507). The subgroup of extremely old patients, aged 90-95, were similar to patients aged 80-89, except there were no smokers, and even higher proportions were women (69%), non-Hispanic (91%) and white (93%). Conclusions: The very elderly can account for nearly 3 in 10 patients enrolled in a hyperacute stroke treatment trial. The oldest old have distinct clinical characteristics, indicating that their inclusion is in clinical trials is important for study results to be widely generalizable to clinical practice.

Optimal end points for acute stroke therapy trials: best ways to measure treatment effects of drugs and devices.

Over the past decade, analysis of completed actual trials, model population studies, and theoretical work have improved approaches to selecting and analyzing end points in acute stroke treatment trials. Narrative review. Because stroke affects persons in their biological, functional, social, and experiential dimensions, measures of impairment, disability, handicap, and quality of life are all desirable in pivotal trials, with disability being most important. Scales that are valid, reliable, responsive, and easy to administer are preferred; consequently, the modified Rankin Scale has become the most widely used single clinical efficacy measure. Because stroke cripples and kills, most outcome scales array patient outcome in ordered ranks, spread over the entire range from normal to disabled to dead. Generally, shift analysis, analyzing all health state transitions concurrently, is the most efficient analytic technique to detect treatment effects, with sliding dichotomy less efficient and fixed dichotomy least efficient, unless treatment effects strongly cluster at 1 or a few health state transitions that can be prespecified. Test statistics must also take into account interpretability, ie, how well they can be converted into metrics capturing all outcomes the intervention might alter in proportion to the degree they are valued by the patient; full ordinal analysis is most informative, sliding dichotomy is intermediately informative, and fixed dichotomy is least informative regarding this global outcome. Stroke trial power and interpretation can be substantially enhanced by adherence to the principles delineated in this review. Full ordinal and sliding dichotomy analysis will most often be advantageous compared with fixed dichotomous approaches.

Simultaneous Ring Voice-over-Internet Phone System Enables Rapid Physician Elicitation of Explicit Informed Consent in Prehospital Stroke Treatment Trials

Background: Cellular phone conversations between on-scene patients or their legally authorized representatives (LARs) and off-scene enrolling physician-investigators require immediate and reliable connection systems to obtain explicit informed research consent in prehospital treatment trials. Methods: The NIH Field Administration of Stroke Therapy – Magnesium (FAST-MAG) Trial implemented a voice-over-internet protocol (VOIP) simultaneous ring system (multiple investigator cell phones called simultaneously and first responder connected to call) to enable physician-investigators to elicit consent immediately from competent patients or LARs encountered by 228 ambulances enrolling patients in a multicenter prehospital stroke trial. For 1 month, the number, origin, duration, and yield of enrolling line calls were monitored prospectively. Results: Six investigators were connected to 106 enrolling line calls, with no identified unanswered calls. Thirty-five percent of new patient calls yielded an enrollment. The most common reasons for non-enrollment were last known well >2 h (n = 7) and uncon sentable patient without LAR available (n = 7). No non-enrollments were directly attributable to the VOIP system. In enrollments, consent was provided by the patient in 67% and a LAR in 33%. The duration of enrollment calls (mean ± SD: 8.4 ± 2.5 min, range 6–14) was longer than non-enrollment calls (5.5 ± 3.5, range 2–13; p < 0.001). The median interval from last known well to study agent start was 46 min, and 70% were enrolled within 60 min of onset. Conclusions: The simultaneous ring system was reliable and effective, permitting enrollment of a substantial number of patients within the first hour after stroke onset. VOIP cellular networks with simultaneous ring are a preferred means of facilitating consent in prehospital treatment trials.

Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study

Treatment strategies for acute basilar artery occlusion (BAO) are based on case series and data that have been extrapolated from stroke intervention trials in other cerebrovascular territories, and information on the efficacy of different treatments in unselected patients with BAO is scarce. We therefore assessed outcomes and differences in treatment response after BAO. The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO between November 1, 2002, and October 1, 2007. Stroke severity at time of treatment was dichotomised as severe (coma, locked-in state, or tetraplegia) or mild to moderate (any deficit that was less than severe). Outcome was assessed at 1 month. Poor outcome was defined as a modified Rankin scale score of 4 or 5, or death. Patients were divided into three groups according to the treatment they received: antithrombotic treatment only (AT), which comprised antiplatelet drugs or systemic anticoagulation; primary intravenous thrombolysis (IVT), including subsequent intra-arterial thrombolysis; or intra-arterial therapy (IAT), which comprised thrombolysis, mechanical thrombectomy, stenting, or a combination of these approaches. Risk ratios (RR) for treatment effects were adjusted for age, the severity of neurological deficits at the time of treatment, time to treatment, prodromal minor stroke, location of the occlusion, and diabetes. 619 patients were entered in the registry. 27 patients were excluded from the analyses because they did not receive AT, IVT, or IAT, and all had a poor outcome. Of the 592 patients who were analysed, 183 were treated with only AT, 121 with IVT, and 288 with IAT. Overall, 402 (68%) of the analysed patients had a poor outcome. No statistically significant superiority was found for any treatment strategy. Compared with outcome after AT, patients with a mild-to-moderate deficit (n=245) had about the same risk of poor outcome after IVT (adjusted RR 0.94, 95% CI 0.60-1.45) or after IAT (adjusted RR 1.29, 0.97-1.72) but had a worse outcome after IAT compared with IVT (adjusted RR 1.49, 1.00-2.23). Compared with AT, patients with a severe deficit (n=347) had a lower risk of poor outcome after IVT (adjusted RR 0.88, 0.76-1.01) or IAT (adjusted RR 0.94, 0.86-1.02), whereas outcomes were similar after treatment with IAT or IVT (adjusted RR 1.06, 0.91-1.22). Most patients in the BASICS registry received IAT. Our results do not support unequivocal superiority of IAT over IVT, and the efficacy of IAT versus IVT in patients with an acute BAO needs to be assessed in a randomised controlled trial. Department of Neurology, University Medical Center Utrecht.

Use of neuroimaging in acute stroke trials

In the last few years, the development of reperfusion techniques in the treatment of acute ischemic stroke has transformed the concept of a noncurable, nonurgent illness to one of the most emergent no-time-to-waste diseases. However, this time dependence hampers the spreading of treatment to a wider patient population. The new neuroimaging techniques for acute stroke aim to increase the number of eligible patients by extending the window through tissue viability rather than time, and to better select those who will safely benefit from thrombolysis in this extended time window. This article summarizes the neuroimaging techniques available currently and describes the new developments in acute stroke treatment trials.

Who will participate in acute stroke trials?

Despite the high incidence of acute stroke, only a minority of patients are enrolled in acute stroke treatment trials. We aimed to identify factors associated with participation in clinical trials of novel therapeutic agents for acute stroke. Prospective survey of patients with acute stroke <72 hours from onset. A structured interview was administered to the patient or primary decision-maker. If offered participation in an actual acute treatment trial, questions focused on decisions about that trial; otherwise a similar mock trial was proposed. The primary outcome was whether the subject agreed to participate in the proposed trial. A total of 200 subjects (47% patients, 53% proxies) completed the survey: mean age 63 +/- 14 years, 47% women, 44% white, 50% black. A real acute trial was offered to 22%; others were offered a mock trial. Overall, 57% (95% confidence interval: 50%-64%) of respondents stated they would participate in the proposed acute treatment trial. There were no differences with respect to age, sex, race, educational level, self-assessed stroke severity or stroke type, vascular risk factors, or comorbidities. Misconceptions about key research concepts were found in 50% but did not impact participation. Participation was associated with the perceived risk of the proposed trial intervention (p < 0.001), prior general attitudes about research (p < 0.001), and influences attributed to family, religion, and other personal beliefs (p < 0.001). Patients were more likely to participate than proxy decision-makers (p = 0.04). Demographic factors, clinical factors, and prior knowledge about research have little impact on the decision to participate in acute stroke clinical trials. Preexisting negative attitudes and external influences about research strongly inhibit participation. Patients are more inclined to participate than their proxy decision-makers.

To Phase 3 or Not to Phase 3?

See related article, pages 1803–1810. Decisions to progress new chemical entities, biologicals, or new treatment modalities into Phase 3 are usually based on small Phase 2 studies that are designed to assess safety and to explore efficacy.1–3 Based on these Phase 2 safety studies, both large and small companies have launched large Phase 3 programs that include 2 concurrently run studies, ie, Stroke-Acute Ischemic NXY Treatment (SAINT) I and SAINT II ASP I and Ancrod Stroke Program (ASP) II. When Phase 3 studies have failed to demonstrate efficacy for the whole population under study, subgroup analysis to identify patients who may have benefited from treatment has led to additional Phase 3, subsequently negative studies.4 In part as a result of this approach, the number of failed studies for treatment of acute ischemic stroke, especially for neuroprotection, has become legendary. In this issue, Mandava and Kent5 present a model to predict if the results of a single study are different from a pooled control population. The model calculates expected outcome using a pooled control population and the ±95% “prediction interval surfaces” using the baseline variables of the National Institutes of Health Stroke Scale and age. The outcome variables assessed in the model are mortality and the 90-day modified Rankin …

A Method to Determine Stroke Trial Success Using Multidimensional Pooled Control Functions

Many early phase trials in stroke have not been subsequently confirmed. Randomization balance in baseline factors that influence outcome are difficult to achieve and may be partly responsible for misleading early results. We hypothesized that comparison with an outcome function derived from a large number of pooled control arms would mitigate these randomization problems and provide a reliable predictor for decision-making before proceeding to later phase trials. We developed such a model and added a novel feature of generation of multidimensional 95% prediction surfaces by which individual studies could be compared. We performed a proof-of-principle study with published clinical trials, determining whether our method correctly identified known outcomes. The control arms from all randomized, controlled trials for acute stroke with >or=10 subjects, including baseline National Institute of Health Stroke Scale, age, and 3-month outcomes published between 1994 and May 2008, were identified. A Matlab program (PPREDICTS) was written to generate outcome functions based on these parameters. Published treatment trials were compared with these 95% intervals to determine whether it successfully identified positive and negative trials. Models of mortality and functional outcome were successfully generated (mortality: R(2)=0.69; functional outcome, modified Rankin Scale 0 to 2: R(2)=0.81; both P<0.0001). The National Institute of Neurological Diseases and Stroke intravenous recombinant tissue plasminogen activator trial and 3 studies yet to be subjected to Phase III study had modified Rankin Scale 0 to 2 outcomes above the 95% prediction interval. Sixteen treatment arm outcomes fell within prediction surface bounds. This group included 2 major trials, Stroke-Acute Ischemic NXY Treatment and Abciximab Emergent Stroke Treatment Trial, that initially appeared promising but went on to negative Phase III results. This proof-of-principle analysis confirmed all positive and negative clinical stroke trial results and identified some promising therapies. The use of a pooled standard treatment group function combined with statistical bounds may improve selection of early studies for further study. This method may be applicable to any condition in which baseline factors influence outcome and at any stage of the development process.

Expediting MRI-Based Proof-of-Concept Stroke Trials Using an Earlier Imaging End Point

Before Phase III trials of acute stroke therapies, proof-of-concept MRI trials are increasingly used to gauge the likelihood of success. Given that animal models use infarct volume as the end point, Phase II trials have aimed to translate the findings using infarct growth. These trials could be expedited if subacute diffusion-weighted imaging lesion volume replaced late T2-weighted lesion volume as the primary end point. In the Echoplanar Imaging Thrombolytic Evaluation Trial, patients with acute ischemic stroke presenting within 3 to 6 hours were randomized to tissue plasminogen activator or placebo. We assessed correlations between acute (Day 1), subacute (Day 3 to 5) as well as late (Day 90) lesion volumes and clinical outcome (National Institutes of Health Stroke Scale). We compared lesion growth between placebo- and tissue plasminogen activator-treated patients. All 3 scans were performed in 72 of 101 patients (32 tissue plasminogen activator, 40 placebo). Median time to subacute imaging was 3 days (interquartile range, 2 to 4) and 90 days (interquartile range, 90 to 95) for the late scan. Increase in lesion volume from acute to subacute scans was smaller in the tissue plasminogen activator group compared with the placebo group (6.77 mL; interquartile range, 2.30 to 49.10; versus 30.00 mL; interquartile range, 7.19 to 85.93; P=0.03). Subsequent shrinkage did not reveal significant treatment effects. Correlation coefficient between acute and late lesion volumes was 0.81 (P<0.01). Subacute and late lesion volumes were strongly correlated (rho=0.94, P<0.01). Correlation coefficient for acute, subacute, and late lesion volume and late National Institutes of Health Stroke Scale score was 0.64 (P<0.01), 0.81 (P<0.01), and 0.77 (P<0.01), respectively. These findings suggest that subacute imaging at Day 3 after thrombolysis is an appropriate imaging end point for proof-of-concept MRI-based stroke treatment trials and can replace later MRI measurements.

Extending Acute Trials to Remote Populations

Methods to increase recruitment into acute stroke trials are needed. The purposes of this study were to evaluate the safety and acceptability of initiating acute stroke trials during early helicopter evacuation and to test an intervention to facilitate informed consent. A randomized, controlled trial was done with patients with acute stroke who were transferred by helicopter to the University of Iowa Hospitals and Clinics from February 2007 to January 2008. The intervention to be evaluated was the use of fax and a telephone call to the patient/surrogate ahead of helicopter arrival at the outside emergency department. The aim was to improve the rate of subsequent consent (primary outcome) for a pilot trial of a potentially beneficial, low-risk medical intervention (ranitidine) to prevent aspiration pneumonitis. Consenting eligible patients received the infusion during the flight to University of Iowa Hospitals and Clinics. One hundred patients were enrolled. Consent rate was 54% in the intervention group and 50% in the control group (P=0.69). However, the consent rate was higher (69%) when prearrival communications between the coinvestigator and potential subjects were successful (P=0.04). This approach resulted in an average gain of 59 minutes as compared with initiating recruitment on arrival to University of Iowa Hospitals and Clinics. Enrollment into stroke intervention trials is feasible during helicopter transportation from a community hospital emergency department to a tertiary stroke center. This underused resource may improve trial efficiency by enabling and expediting participation of remote populations currently excluded from research. Consent rates might be further improved by communication strategies that are more successful in reaching patients at outside emergency departments.

The International Stroke Conference 2008 New Orleans, Louisiana February 20-22, 2008

The International Stroke Conference 2008 New Orleans, Louisiana February 20-22, 2008

Methods and processes for the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial

Treatment group imbalances in baseline stroke severity in the NINDS intravenous t-PA for acute stroke treatment trial led to controversy regarding the efficacy of tissue plasminogen activator (t-PA) in the treatment of acute ischemic stroke. Describe the steps used to independently re-evaluate this trial. NIH appointed an independent multidisciplinary committee that gained access to the original data. We undertook analyses of t-PA efficacy accounting for this imbalance, as well as analyses to identify subgroups that experienced additional harm or benefit from t-PA. Analyses of time from stroke onset to treatment (OTT), blood pressure, and intracerebral hemorrhage are given as illustrations. Despite subgroup imbalances in baseline stroke severity, when t-PA was administered to acute ischemic stroke patients according to study protocol, there was a statistically significant and clinically important benefit of t-PA treatment resulting in a higher likelihood of having a favorable clinical outcome at 3 months. Moreover, we were unable to identify subgroups of patients between which t-PA treatment effect differed, albeit these analyses had low power. These data failed to support the NINDS investigators' conclusion that effect of t-PA therapy diminished with increasing values of OTT within the protocol-specified 3 h time limit. In addition, the blood pressure measurements were highly variable and inconsistently determined so as to be too unreliable for inclusion in analysis. With new NIH requirements for data-sharing, the frequency of re-analysis of clinical trial data may increase substantially. This re-evaluation provides a blueprint for future re-evaluations of other trials. These best practices include re-analysis of the study data, after suitable replication, by an independent multidisciplinary committee, including a skilled statistical programmer analyst. Primary investigators should address significant errors determined in such re-analyses.

Outcomes Validity and Reliability of the Modified Rankin Scale: Implications for Stroke Clinical Trials

The modified Rankin scale (mRS), a clinician-reported measure of global disability, is widely applied for evaluating stroke patient outcomes and as an end point in randomized clinical trials. Extensive evidence on the validity of the mRS exists across a large but fragmented literature. As new treatments for acute ischemic stroke are submitted for agency approval, an appreciation of the mRS's attributes, specifically its relationship to other stroke evaluation scales, would be valuable for decision-makers to properly assess the impact of a new drug on treatment paradigms. The purpose of this report is to assemble and systematically assess the properties of the mRS to provide decision-makers with pertinent evaluative information. A Medline search was conducted to identify reports in the peer-reviewed medical literature (1957-2006) that provide information on the structure, validation, scoring, and psychometric properties of the mRS and its use in clinical trials. The selection of articles was based on defined criteria that included relevance, study design and use of appropriate statistical methods. Of 224 articles identified by the literature search, 50 were selected for detailed assessment. Inter-rater reliability with the mRS is moderate and improves with structured interviews (kappa 0.56 versus 0.78); strong test-re-test reliability (kappa=0.81 to 0.95) has been reported. Numerous studies demonstrate the construct validity of the mRS by its relationships to physiological indicators such as stroke type, lesion size, perfusion and neurological impairment. Convergent validity between the mRS and other disability scales is well documented. Patient comorbidities and socioeconomic factors should be considered in properly applying and interpreting the mRS. Recent analyses suggest that randomized clinical trials of acute stroke treatments may require a smaller sample size if the mRS is used as a primary end point rather than the Barthel Index. Multiple types of evidence attest to the validity and reliability of the mRS. The reported data support the view that the mRS is a valuable instrument for assessing the impact of new stroke treatments.

Impact of Stroke Syndrome and Stroke Severity on the Process of Consent in the Third International Stroke Trial

Background: Obtaining informed consent for a patient’s participation in a randomized trial of treatment for use in a medical emergency may be achieved in a variety of ways. We sought to assess the process of consent and to evaluate the influence of the patient’s neurological deficit on the method used to obtain consent in the first 300 patients recruited into the Third International Stroke Trial (IST-3). Methods: IST-3 is the first large-scale randomized controlled trial of intravenous thrombolysis in acute ischaemic stroke. The clinician could use one of four procedures to recruit the patient: written consent, witnessed consent, assent, or a waiver of consent. The patient’s neurological deficits were recorded at baseline. We analysed the relationship between the neurological deficits at baseline and the consent procedure. Results: The method of consent used was written consent in 71 subjects (24%), witnessed verbal consent in 30 subjects (10%), assent by a relative in 197 subjects (66%), and waiver of consent in 2 subjects (1%). Patients with severe neurological deficits (as measured either by their stroke syndrome or their lower predicted probability of being alive and independent at 6 months) were more likely to be recruited by assent. Patients able to give written consent had less severe strokes. Conclusions: Patients with non-lacunar hemispheric stroke syndromes or with a more severe neurological deficit were less likely to give written consent. Excluding such patients from acute stroke treatment trials would eliminate many otherwise eligible subjects, who have a poor predicted outcome without treatment and yet might benefit from acute treatments such as thrombolysis. Flexible consent procedures developed for IST-3 have made it feasible to recruit the target population.

MR DWI does not substitute for stroke severity scores in predicting stroke outcome

The accurate prediction of outcome following stroke is of great importance. In the clinical arena, accurate outcome prediction can enable physicians to be involved in informed discussions with the patient and caregivers, to accurately define treatment goals, to objectively balance the risks and benefits of treatment options, and to make early decisions about later discharge. There also has been great interest in applying predictive models to the design and analysis of acute stroke treatment trials. Predictors measured at baseline, such as the initial NIH Stroke Scale (NIHSS), can identify patients with good, intermediate, or poor prognosis if untreated. Trials will then enroll only those with intermediate prognosis under the assumption that these are most likely to show benefit.1–3 Although logical and attractive, the validity of this approach remains to be proven.2 Furthermore, a priori restriction of eligibility by baseline predictors of outcome could result in the failure to detect a benefit that is present in all patients. The efficacy of IV tissue plasminogen activator (tPA) is not affected by baseline NIHSS.4 More recently, the baseline NIHSS has been used to define the criteria for a beneficial clinical outcome.3 Instead of selecting a single criterion for all patients, such as a modified Rankin Scale score (mRS) of 0 to 1, the criterion for those with a higher baseline NIHSS and a worse prognosis is liberalized to include mRS 0 to 2. Whether this approach …