Report of the Stroke Progress Review Group - September 2006
At NINDS
NINDS Staff
Advisory Council
Labs at NINDS
| Groups at NINDS |
Government
Other NIH Institutes
Government Resources
Other related groups
Organizations
Professional Societies
NINDS is part of the
National Institutes of
Health
Download Adobe Reader
Additional information about Stroke PRG
Table of Contents
Executive Summary
Background
Recommendation
Acute Stroke Treatment
Biology of Repair
Clinical Trials
Cerebral Vascular Biology and Neurovascular Unit
Stroke Epidemiology and Risk Factors
Genetics
Health Services Implementation
CNS Hemorrhage/ICH
Endothelium and Hemostasis
Neurocererovascular Degeneration
Neuroimaging
Neurovascular Protection
OMICs - Genomics, Proteomics, Metabolomics and Bioinformatics
Prevention of First and Recurrent Stroke
Recovery and Rehabilitation Working Group
Vascular Cognitive Impairment
SPRG Meeting Participants
SPRG Meeting Working Group Members
ACUTE STROKE TREATMENT
Co-Chairs: Helmi Lutsep, Patrick Lyden, Jeffrey Saver
Members: Kyra Becker, Jeff Frank, Kama Guluma, Clarke Haley, Michael Hill, Argye Hillis, Rebecca Ichord, Reza Jahan, Tom Kwiatkowski, Brett Meyer, Larry Weshsler
NINDS Liaison: Scott Janis
1. Seminal scientific advances made since 2001. Please indicate if they are linked (or not) to SPRG recommendations.
A. Reperfusion: The restoration of blood flow into ischemic brain remains the only successful treatment for stroke, so far. This therapeutic area was the first priority in the original PRG report, and considerable progress occurred since the Implementation report.
To review the original report: Priority 1: Reperfusion: therapeutic agents that open blood vessels in more patients and that do so better, faster, and more safely, are greatly needed.
Since identification of this priority for acute ischemic stroke treatment in 2002, progress in reperfusion therapies has advanced along several fronts. NINDS funded a dose escalation safety study of tenecteplase that was completed in 2003. Promising results from that experience resulted in funding of a larger Phase 2B study comparing 3 different doses of tenecteplase to each other and to standard treatment with alteplase. Another long-acting and more fibrin specific agent, desmoteplase, underwent preliminary safety testing using MRI-based selection criteria to allow treatment within 3 and 9 hours from stroke onset. Further study of this compound is also now in progress. Early studies examining plasmin, microplasmin, and alfimiprase are underway. A trial of acute treatment with a glycoprotein 2b/3a inhibitor, abciximab, within 5 hours of stroke onset had to be stopped early because of an unfavorable risk/benefit ratio.
NINDS funded trials sought to enhance the efficacy and/or safety of standard fibrinolysis. Phase 2 studies examining combination of glycoprotein 2b/3a inhibitors (CLEAR, ROSIE), a prothrombin inhibitor (argatroban), and hypothermia with standard alteplase or reteplase are in progress or nearing completion. A phase 2 trial of high-frequency transcranial Doppler ultrasound in combination with alteplase (CLOTBUST) showed promising results, and a phase 3 trial has been funded. A trial examining non-focused, low frequency transcranial ultrasound in combination with alteplase (TRUMBI) was stopped early because of excessive intracranial bleeding complications. A phase 3 trial comparing standard dose intravenous alteplase within 3 hours of onset to low dose intravenous alteplase administered within 3 hours followed by intra-arterial recanalization therapies (IA alteplase, IA ultrasound catheter delivered alteplase, or the Merci Retriever), if necessary, within 6 hours has been recently funded by NINDS, after a phase 2 study showed promising results (IMS 2). An industry sponsored phase 3 trial of Ancrod, administered within 6 hours of symptom onset is also in progress.
Progress has been made in extending the time window for reperfusion of imaging to select for treatment late presenting patients still harboring salvageable penumbra. A NINDS-funded trial of MRI screening of patients treated with alteplase in the 3-6 hour time period found that 40-50% of patients exhibit a small infarct, large penumbra pattern and appeared to benefit from therapy (DEFUSE). Imaging selection of patients was also used for the desmetoplase trials (3-9 hour window) and for the ongoing glycoprotein 2b/3a inhibitor plus reteplase therapy trial (time window up to 24 hours) (ROSIE).
Experience continues to accumulate with a number of mechanical devices to disrupt/remove occlusive cerebrovascular thrombi. Techniques explored include transcatheter-applied local ultrasound, laser, or suction devices using the Venturi principle. Various clot retrieval devices including snares, "corkscrews," and others show promise in the removal of occluding thrombus. The U.S. Food and Drug Administration recently approved the MERCI retrieval device specifically for removal of intracranial cerebrovascular clots; however, the agency acknowledged that the efficacy of this approach for stroke treatment has not been proven. A NINDS-funded randomized clinical trial of the MERCI device (MR RESCUE) is under way.
In summary, since the last review, NINDS funded initiatives successfully implemented priority 1, with several new agents and treatment strategies in late-stage development. Further, a few agents that looked promising were found to cause excessive bleeding, allowing investigators not only to winnow the field of candidate therapeutics, but also to gain further insights into the mechanisms of thrombolytic-related hemorrhages.
B. Neuroprotection: The original report listed cytoprotection as Priority 3: Priority 3: Clinical trials and establishing the utility of cytoprotection: a shift is needed from single agent trials to combination trials.
Although a number of clinical trials have reported out since the Implementation report, including one highly promising trial (SAINT 1) there remains no approved effective neuroprotection. Further, NINDS funded initiatives yielded a handful of combination trials, primarily from the SPOTRIAS Network, examining multiple neuroprotective agents, or thrombolysis combined with neuroprotection.
The SAINT I Study, a Phase III prospective randomized controlled trial assessing the benefit of NXY-059 (a putative free radical scavenger manufactured by Astra-Zeneca), showed that neuroprotection remains a viable strategy for the treatment of stroke. In SAINT I, patients who received NXY-059 within 6 hours of the onset of ischemic stroke were more likely to improve than patients who received placebo (odds ratio, 1.20; 95% CI, 1.01 to 1.42). Moreover, among patients who received IV tPA, those treated with NXY-059 were significantly less likely to suffer a hemorrhagic transformation of their infarct, suggesting a vascular protective property to the drug as well. SAINT II, a confirmatory study of NXY-059, failed to confirm these promising findings. .
Cytidyl diphosphocholine, or citicoline, is a naturally occurring nucleoside essential for the formation of phosphatidyl-choline and subsequently for maintenance of membranes. The North American Study of citicoline in stroke failed to show a benefit in the primary end point, but a pooled analysis of patients treated with this drug in multiple trials suggests that it may improve stroke outcome. A large international trial, International Citicoline Trial on Acute Stroke (ICTUS) is currently enrolling patients enrolled within 24 hours of stroke onset. Citicoline was approved in several countries for acute stroke.
The SAINT studies and the citicoline studies are sponsored by the Pharmaceutical Industry. The NIH also funded several ongoing trials of putative neuroprotection agents. Based on animal studies and early pilot studies in humans, high dose albumin soon after stroke onset appeared to be neuroprotective. The results of a Phase II study of Albumin in Acute Stroke (ALIAS) were recently published. In this study, patients treated with 2.05 g/kg of 25% human albumin within 16 hours of stroke onset were significantly more likely to have a better outcome than patients treated with lower doses of human albumin or similar patients in the NINDS tPA study. Based on the findings of this study, a Phase III study of high dose human albumin therapy for patients who can be treated within 5 hours of acute ischemic stroke is underway.
Many neuroprotective agents can safely be given to patients with both ischemic and hemorrhagic stroke. Accordingly, they could be started by paramedics in the ambulance prior to hospital arrival, speeding treatment start. Based on extensive experience with magnesium as an experimental neuroprotective agent in various types of brain injury, it appears to be a logical drug to test in acute stroke. A NINDS-funded pilot study of magnesium administration in field was performed demonstrating the feasibility and safety of magnesium administration in the field, with treatment start accelerated by 2 hours; a NINDS-funded Phase III study, the Field Administration of Stroke Therapy - Magnesium (FAST-Mag) Study, is now recruiting patients with presumed stroke who can receive treatment in the field within 2 hours of symptom onset.{ .
Hypothermia is a promising treatment for stroke given the abundance of animal data on its robust neuroprotective properties and the demonstrated benefits on neurological outcome in patients with cardiac arrest. Feasibility studies of endovascular cooling have been performed. The role of hypothermia in the treatment of acute stroke and it's ability to prolong the time window for intravenous thrombolysis is being evaluated in the Intravascular Cooling in the Treatment of Stroke - Longer tPA window trial, ICTuS-L. ICTuS-L is supported through the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) initiative of NINDS. Patients treated with rt-PA under 3 hours from symptom onset are randomized to cooling or no cooling. Patients presenting within 3 to 6 hours of symptom onset are randomized to cooling or no cooling, with or without rt-PA. The aim of this safety/feasibility study is to establish safety of the combination cooling plus rt-PA prior to a larger efficacy trial. Animal data suggest that the combination of caffeine and ethanol (caffeinol) are neuroprotective; a pilot study showed that this combination was safe in patients with stroke. A study of combinatorial therapy with caffeinol (treatment within 240 minutes) and hypothermia (treatment within 300 minutes) is currently recruiting patients. This study is also funded through the SPOTRIAS program.
In addition to the successes listed previously, seemingly well designed trials conducted since 2002 generated negative results. Repinotan is a serotonin agonist that showed efficacy up to 5 hrs after symptom onset in rodent studies but was not assessed in larger animal models. A phase 3 trial in which the drug was administered within 4.5 hrs of stroke onset and plasma levels were optimized did not show efficacy. ONO-2506 is an astrocyte activation inhibitor that was administered within 6 hrs of stroke onset to patients with cortical strokes. A futility analysis done in May 2005 led to discontinuation of the trial in the United States. Subsequent sub-group analysis identified a potential benefit, and further studies may be organized. YM872 is an AMPA receptor antagonist that was evaluated in two recent phase 2 studies. One included patients within 6 hrs of symptom onset that had moderately severe strokes and assessed lesion size by MRI at 28 days as well as clinical outcome at 90 days. Another study included only those patients that had also received intravenous tPA within 3 hrs of symptom onset. Both trials were stopped in January 2003 for futility and there are no plans to develop this drug further.
SUN N4057 or piclozotan (Daiichi Asubio Pharmaceuticals, Inc.) is a serotonin agonist currently enrolling patients in a phase 2b study. The patients are required to be within 9 hrs of symptom onset (50% within 6 hrs and 50% within 6-9 hrs) and to have a measurable penumbra on magnetic resonance imaging (MRI). This compound is substantially similar to repinotan in mechanism. A neuroprotectant that is in an earlier phase of investigation is TS-011 (Taisho Pharmaceutical Co. Ltd.). This agent blocks the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictor that may contribute to ischemic injury. TS-011 has been shown to reduce infarct size in rats and monkeys and is currently in a phase 1b dosage finding trial in stroke patients. As part of the SPOTRIAS program at Columbia University, a study called Neuroprotection with Statin Therapy for Acute Recovery Trial (Neu-START) is performing a dosage finding trial using lovastatin. Patients are treated within 12 hrs of ischemic stroke onset. A pilot study has been performed evaluating normobaric oxygen in the form of high-flow oxygen therapy delivered via facemask. Patients were within 12 hrs of symptom onset and also had mismatch on MRI. A larger study of normobaric oxygen is supported by the SPOTRIAS program at Massachusetts General Hospital.
In summary, combinations of neuroprotectants, or neuroprotectants plus reperfusion therapy, are likely to have effects above those of each agent alone. Combination therapies elicit great interest for future studies.
C. Stroke centers: In the original report, the need for certified stroke centers was identified as a critical needed resource. Since that report, the Joint Commission for the Accreditation of Health care Organizations (JCAHO) rolled out a national program for Primary Stroke Center Certification following guidelines issued by the Brain Attack Coalition. In September 2006 the JCAHO website listed 252 certified primary stroke centers. In addition, several states, including New York and Massachusetts, have implemented state-run stroke center designation programs using criteria similar to the JCAHO system. Altogether, as of May 2006, seven states with 28% of the American populace had implemented or were in the process of implementing designated Stroke Center systems under which Emergency Medical Services bring key stroke patients directly hospitals that have met minimal standards for acute stroke care. The cadre of certified primary stroke centers provides a ready supply of clinical trial sites; the availability of this trial site pool already makes an impact on the organization of NINDS and pharmaceutical sponsored trials. The Brain Attack Coalition has also released a set of Comprehensive Stroke Center recommendations. A certification program for Comprehensive Stroke Center designation is under review at JCAHO, where an American Heart Association (AHA) committee has been formed to advise JCAHO. Activities include a survey to address how Comprehensive Centers would impact the functioning of primary stroke centers. Further, the AHA Stroke Council has commissioned a writing group to review proposed performance indicators for comprehensive stroke centers.
In addition to identifying the need for stroke center designation, the PRG report mentioned the need for such centers to organize into clinical research consortia or networks. Three such networks (NETT, SPOTRIAS, and the Neurology Clinical Trials Consortium) are described elsewhere in detail.
D. Pediatric stroke: Recent data confirm stroke is a substantial problem in pediatric age group. The safety and efficacy of thrombolysis in children is unknown, and several ad hoc registries are in progress. Data on safety and efficacy of lytics and other therapies in pediatric patients is needed.
E. Emergency Department Investigators and Protocols: The Progress Review Group identified the need to integrate emergency department investigators in collaborative stroke research initiatives a new priority, and considerable gains have been made since 2001. Similar to patients with acute cardiac conditions, patients with acute stroke are initially evaluated and treated by Emergency Medicine personnel, including Emergency Medicine physicians and pre-hospital personnel (EMT's and paramedics). As the outcome of stroke is often determined within a very brief time-frame following the onset of symptoms, interventions in the emergency department, or even prior to emergency department arrival, may provide meaningful benefit. Recent progresses in the development of emergency department investigators as part of large collaborative research initiatives include the following programs:
1) Neurological Emergencies Treatment Trials (NETT) Network: Clinical Coordinating Center (RFA-NS-06-002), Statistical Center (RFA-NS-06-008) and Hubs (RFA-NS-06-009)
The NINDS NETT network creates an infrastructure to promote and conduct clinical trials that will provide new and effective treatments for neurologic emergencies. The key elements of this structure include an interdisciplinary team of emergency physicians, neurologists, neurosurgeons and biostatisticians with specific expertise in the conduct of emergency clinical trials, a hub-and-spoke network design that acknowledges the importance of enrolling patients in both large academic centers and community hospital emergency departments, and a long term network commitment to advancing the national research infrastructure for the interdisciplinary study of emergent illness. In addition to the Network Coordinating Center and the Statistical Data Management Center, up to eleven clinical hub sites will be funded as part of the NETT Network. Each hub site will coordinate activities at 2-10 emergency departments or "spokes". The goals of the NETT Network are: 1) to facilitate high-quality clinical trials in several different types of emergency neurological disorders afflicting adults or children; 2) to encourage collaboration between emergency medicine physicians and neurological disease specialists in trial design and execution; and 3) to facilitate the implementation of new therapies into clinical practice. Once established, the NETT Network is intended to serve as a resource for investigator-initiated clinical research in acute neurological disorders. Following the initial trials funded through this initiative during the development phase, subsequent trials will be funded through traditional NINDS peer-review mechanisms.
2) Field Administration of Stroke Therapy - Magnesium (FAST-MAG) Trial (RO1NS4436). Clinical Coordinating Center: UCLA School of Medicine. Principal Investigator: Jeffery Saver, MD
The FAST-MAG Phase 3 Trial is a multi-center, randomized, placebo-controlled, double-blind, parallel group trial of intravenous magnesium sulfate initiated by paramedics in the field within 2 hours of symptom onset in patients with acute stroke. The primary objective of the study is to evaluate the efficacy and safety of field-initiated magnesium sulfate in improving the long-term functional outcome of patients with acute stroke. The study includes patients within the service area of the Los Angeles County Emergency Medical Services Agency, whose component systems provide pre-hospital care to a population of 9.8 million. Patients with acute stroke are identified in the field by licensed paramedics who have received training in basic and advanced cardiac life support, stroke recognition, and specific procedures relevant to the proposed study. Physician-investigators approve each patient for study entry after cellular phone contact with paramedics. By phone, physician-investigators also elicit informed consent to participate in the study-from patients when the subject is competent and from on-scene legally authorized persons when the subject is not competent. The central aim of this study is to demonstrate that paramedic initiation of the neuroprotective agent magnesium sulfate in the field is an efficacious and safe treatment for acute stroke. Successful conduct of the trial will serve as a pivotal test of the promising neuroprotective agent magnesium sulfate in acute stroke, and will also demonstrate for the first time that field enrollment and treatment of acute stroke patients is a practical and feasible strategy for phase 3 stroke trials, permitting enrollment of greater numbers of patients in hyperacute time windows. An initial pilot trial which enrolled 20 patients was completed on 2002. The current phase III trial has been enrolling patients since January 2005.
3) The Resuscitation Outcomes Consortium (RFA-HL-04-001)
Data Coordinating Center: University of Washington, Seattle, WA
Regional Clinical Centers:
- University of Alabama at Birmingham in Birmingham, AL
- University of Texas Southwestern Medical Center in Dallas, TX
- University of Iowa in Iowa City, IA
- University of Pittsburgh in Pittsburgh, PA
- Oregon Health & Science University in Portland, OR
- University of Ottawa, Ontario and St. Paul's Hospital, University of British Columbia, British Columbia, Canada
- University of California at San Diego in San Diego, CA
- University of Washington, Seattle, WA
- University of Toronto in Toronto, Ontario, Canada
The Resuscitation Outcomes Consortium (ROC) was developed in order to create the network of 10 Regional Clinical Centers (RCCs) above, through which collaborative clinical research in the arena of resuscitation in out-of-hospital cardiac arrest and traumatic brain injury can be efficiently performed by enrolling large numbers of patients (15,000 patients over a 3-year period). The research foci planned for the consortium include the development of new drug therapies, fluid resuscitation in traumatic brain injury, immunomodulation of secondary injury, neuroprotection, bleeding control, alternative cardiopulmonary resuscitation approaches, and new ventilation and oxygenation strategies. The ROC is in the very initial stages of implementation, and the first trials currently slated for initiation include an investigation of hypertonic saline and dextran and neurological outcome in severe traumatic brain injury, and an investigation of early defibrillation and the use of a one-way valve in ventilation in outcome after cardiac arrest. While focal cerebral ischemia (ischemic stroke) is not a defined research focus per se, the mission and activities of the consortium will bring mechanisms and therapies affecting global cerebral ischemia into the forefront of Emergency Medicine research.
F. Telestroke: In the original report, Telemedicine was identified as a needed resource. Since then, the application of telemedicine in acute stroke (so-called Telestroke) has advanced considerably. Over the past 10 years, telemedicine in stroke has evolved from an idealistic dream to a somewhat commonplace reality. The initial question of teleconsultation's feasibility in acute stroke management has been addressed, now allowing for more complex questions of efficacy, safety and future possibilities. The majority of acute stroke victims do not reach the acute care facility within the 3 hour time window mandated for FDA approved rt-PA use. Lack of, or delay in, acute treatment is associated with poorer stroke outcomes. Though nationally the rate of rt-PA treatment varies between 1- 5%, even in established stroke treatment facilities, the rate may only reach 3- 8.5% as shown in the Coverdell Registry. One driving factor resulting in low thrombolytic rates is the lack of specialty expertise available in healthcare shortage areas or in neurologically underserved facilities. In addition to delays in patient arrival and absence of specialty practitioners, there may be hospital delays, due to unfamiliarity with therapies, procedures and protocols, which result in a decreased treatment rate.
The current models of maximizing thrombolytic evaluations have enabled more thrombolytic treatments, but can not be sustained indefinitely nor can they be applied to diffuse geographic regions. Each of these techniques emphasizes an opposite side of the 'hub & spoke' model. The Houston "Mecca Model" relies on patients being quickly transported to a hub facility, while the San Diego "Commando Model" relies on the practitioner being able to quickly drive to the spoke. Telemedicine 'hub & spoke' techniques facilitate 2 way exchanges of patient information and practitioner expertise irrespective of distance.
Telemedicine has been applied to numerous fields of medicine with large degrees of success. Feasibility has been shown in areas such as trauma, psychiatry, cardiology, critical care, neurosurgery, and others. Telemedicine's use has exponentially increased, though clinical efficacy trials have lagged far behind. Roine et. al. published a review noting only 6 randomized, controlled clinical trials of telemedicine out of > 1000 articles assessed. A perception of 'assumed efficacy' and 'minimal harm' likely drive telemedicine's increasingly popular use. In 1999, Levine and Gorman explained both the promises and limitations of telemedicine for use in stroke. Limitations included high cost, lack of reimbursement, lack of clinical standards, scheduling difficulties and time restrictions. Many of these areas have since been addressed though some require further support and championing before telemedicine can be universally applied.
Since 2001, general system designs evolved to include 2-way audio and video capabilities enabling real time face to face conversations with both patient and requesting practitioner. Further requirements include high resolution (400 x 300) capabilities, full screen video abilities, full frame video rate (30 frames per second), synced audio with video, echo cancellation, high data compression and bandwidth, HIPAA compliant security measures, DICOM radiology CT image access and viewing software, and the ability to access a system with minimal, or no delay. To date, technical requirements and clinical protocols have not been standardized. There are currently numerous and varied telemedicine systems in use ranging from 'off the shelf' ISDN bound point to point teleconferencing software to highly complex, site independent, web based access or Internet based systems.
Though there are clearly areas for future development, much of telemedicine's promise has already been realized. Stoke telemedicine's reliability is now well documented both in the United States (Shafqat, Schwamm, Hess, LaMonte, and Meyer) as well as abroad (Wiborg, Handshu, and Audebert). Assessing for clinical deficit using the NIHSS is feasible and reliable with only minimal bedside assistance. Though felt to only be feasible 7 years ago, acute clinical consultation use is now routine in many areas. The TEMPiS- telemedical pilot project for integrative stroke care noted the ability to determine 250 different diagnoses in a 12 month period, with many crosschecked for accuracy, showing that telemedicine can be used for assessing numerous neurologic diagnoses. Another clinical use of telemedicine is in determining telemedicine's ability to more appropriately (either increase or decrease) hospital transfers for neurologic reasons. Investigators in Massachusetts showed that transfers for neurologic reasons were decreased when using telemedicine for stroke. Having telemedicine capabilities may also streamline Life-flight involvement for more rapid or increased hospital transfers, thus facilitating an improved "drip & ship" system.
G. Financial Barriers to Acute Stroke Care: In the original report, reimbursement was listed as a barrier to acute therapy. NINDS, in collaboration with several voluntary health organizations and professional societies, helped draw attention to this considerable issue. In response, DHHS promulgated new regulations, a new DRG, and a new ICD-9 Procedure Code. Until recently DRG assignments for stroke care included only 2 DRGs, DRG 14 (Intracranial Hemorrhage or Cerebral Infarction) and DRG 15 (Nonspecific CVA and Precerebral Occlusion Without Infarction). In 1998 a new code 99.10 was created (Injection or infusion of thrombolytic agent) to identify cases in which a thrombolytic agent was administered. Although this code was to be used for patients with stroke receiving IV tPA, it was not associated with any additional reimbursement.
In 2004, CMS met with representatives from major stroke centers to discuss changes to stroke DRG 14 and 15 related to thrombolytic therapy. They argued that IV tPA administration was a marker for increased stroke severity and that hospital care for such patients was significantly more costly. This increased cost was due to greater utilization of intensive care units, higher diagnostic imaging costs and increased laboratory and pharmacy costs. In addition to higher costs, IV tPA use resulted in improved outcomes for stroke patients. They recommended modification of the stroke DRGs to compensate hospitals for the higher costs associated with care of patients receiving thrombolytic treatment. Higher reimbursements for these patients would encourage hospitals to establish stroke centers to effectively treat acute stroke patients. In response to these recommendations and subsequent supportive public comments, CMS analyzed costs in the MedPAR data regarding patients in DRGs 14 and 15 with and without code 99.10. Charges for patients with code 99.10 in DRG 14 were approximately $16,000 higher than those without this code. As a result, in August 2005 CMS created DRG 559 (Acute Ischemic Stroke with the Use of a Thrombolytic Agent). This became effective in October 2005 and provided an increase in hospital payment from $4,000 to $6000 for DRG 14 to a base rate of $11,578 for DRG 559.
The Merci clot retriever was recently approved by the FDA for removal of thrombus from intracranial arteries in patients with acute stroke. In 2006, CMS in 2006 approved a new ICD-9 Procedure Code, 39.74 - Endovascular removal of obstruction from head and neck vessel(s), to be used in conjunction primarily with the craniotomy DRGs 001 and 543 for ischemic stroke patients treated with the Merci Retriever. The average reimbursement of these DRGs ($17,700 for DRG 1, $22,800 for DRG 543) reflects the higher costs for reasons similar to thrombolytic patients but also the additional expense of angiography suites, catheters and embolectomy devices.
H. Diversity Issues: The previous report identified diversity issues as a potential confound in the interpretation of ongoing clinical trials. Since then, two re-analyses of randomized trials indicated a gender-by-thrombolysis interaction in favor of women: women receive greater benefit from thrombolysis when compared to men for both IV therapy (Kent et al) and IA therapy (Hill et al). Several case series have suggested possible explanations including increased recanalization but this is not uniformly proven. One group, for example, has suggested that clot length is longer in men than women in middle cerebral artery occlusions and that clot volume tends to be larger (Buck et al). Several series also show that women who are untreated have worse outcomes compared to men who are untreated; thrombolysis neutralizes this gender bias resulting in the statistical interaction.
Certain neuroprotective agents may also have gender dependent effects. A selective kappa opioid receptor agonist has provided ischemic neuroprotection in male but not female rats (Chen CH et al). Thus far, clinical neuroprotectant trials in acute stroke have not been powered to look for efficacy differences between men and women. At least one agent, however, the free radical scavenger tirilazad mesylate, has shown poorer functional outcomes in women than in men, likely due to differences in drug metabolism (Tirilazad International Steering Committee).
There are a number of socioeconomic studies which have shown race, socioeconomic status as important prognostic factors in stroke risk, stroke recurrence and access to treatment. Fewer studies address the effects of race on treatment outcome. One group used data from a discharge database of 2594 patients treated with thrombolysis for acute ischemic stroke to assess factors associated with in-hospital mortality. In this patient population, multivariate logistic regression showed that Asian/Pacific Islander race as well as advanced age, congestive heart failure, and atrial fibrillation/flutter independently predicted in-hospital mortality after thrombolysis. No study to date has shown a differential treatment effect by race. While this remains an important social issue, it remains unclear whether differences in biology will show truly differing treatment effects in acute stroke. Further research into race/ethnicity as a predictor of treatment outcome is required.
I. Stroke Mechanisms: Although not specifically singled out in the previous report, in the past 10 years it has become clear that acute stroke trials that include too broad a range of stroke sub-types are underpowered to identify treatment effects in any single sub-group. Therefore, the proper identification of stroke mechanisms assumed larger importance. Arterial ischemic stroke (AIS) can result from atherosclerotic occlusion or critical stenosis of a medium to large artery, embolus from a clot in the heart, embolus from an atherosclerotic plaque in a proximal vessel, paradoxical embolus from a right to left shunt in the heart (or pulmonary AVM), carotid or vertebral dissection, lipohylinosis or microatherosclerosis of small cerebral vessels, or other sources. It is plausible that these different stroke mechanisms would respond differentially to various stroke therapies. However, most randomized controlled trials of treatment for AIS included patients with all of these etiologies. A few limited enrollment to patients with large cortical stroke or lacunar stroke, which are relatively easy to differentiate by clinical presentation and/or conventional MRI. The few trials that have shown efficacy in clinical outcome have included overcome this heterogeneity by enrolling huge numbers of patients to compensate for small mean effect sizes (IST, CAST), testing an agent with a substantial treatment effect (NINDS Study), or by constraining the trial population to a tightly defined subtype (PROACT II). It would be more cost-effective and efficient to identify the stroke subtypes that would be most likely to respond to treatment, or that would be likely to show larger effect sizes.
Several ongoing studies have proposed to develop MR imaging methods to differentiate stroke subtypes that might differentially respond to various interventions. For example, a NINDS funded study, DEFUSE, identified subgroups of patients with AIS, defined by diffusion and perfusion MRI profiles, who were likely to have the best response to intravenous thrombolysis administered 3-6 hours after symptom onset. The NINDS SPOTRIAS Program MR RESCUE trial is identifying MR signatures that identify patients who benefit from endovascular thrombectomy in the 3-8 hour time window. Another NINDS funded study will employ sophisticated MRI techniques to determine quantitative thresholds of specific hemodynamic measures to differentiate critical hypoperfusion from benign oligemia, that might be useful for identifying subgroups of patients who will respond to specific treatments. Similarly, an NINDS funded clinical trial will determine if specific hemodynamic measures of diffusion-perfusion mismatch are useful for determining which patients are most likely to respond to pharmacologically-induced blood pressure elevation within 12 hours of AIS onset, based on earlier published pilot studies by Rordorf, et al. and by Hillis, et al. suggesting that patients with large vessel arterial stenosis may be most likely to show improved function and/or improved perfusion with this intervention. An NINDS funded trial will validate a novel MRI pulse sequence for quantitative CBF in canines and patients with AIS and chronic ischemia. The study will test the hypothesis that qCBF can stratify risks of thrombolysis in patients who would not normally be eligible for thrombolysis. Another trial will seek to improve PWI analysis to identify "tissue at risk". A Phase II clinical trial, ROSIE - ReoPro Retavase Reperfusion of Stroke Safety study - Imaging Evaluation uses MRI criteria, as well as standard criteria, to select patients for a combination of thrombolysis (reteplase) and the platelet GP IIbIIIa antibody, abciximab, up to 24 hours from stroke onset. This study will not, however, determine whether patients who meet MRI criteria will show better response than patients who do not meet MRI criteria. Another NINDS funded trial will develop novel MRI techniques (sodium MRI and pH MRI) to identify patients who might be candidates for reperfusion therapies beyond 3 hours. In addition to MR based studies, an ongoing NINDS-funded study will test the hypothesis that early computed tomography angiography (CTA) can identify patients with specific stroke mechanisms that will respond to specific mechanism- directed therapies. The usefulness of CTA in the early AIS will be evaluated by measuring its positive predictive value, sensitivity, specificity, and reliability, and will compare CTA to current methods of clinical stroke diagnosis in a cohort of 150 patients within 24 hours of onset of AIS. The trial will determine whether CTA is a useful tool for identification of stroke etiology and selection of patients with specific stroke mechanisms for certain mechanism-directed therapies.
References:
| Grant Number | Pi Name | Project Title |
| 5K24NS044848-03 | Albers, Gregory | New MRI techniques for cerebrovascular diseases |
| 1R01NS049395-01A2 | Carroll, Timothy | Improved Measurement of Celebral Perfusion with MRI |
| 5K23NS002147-05 | Kasner, Scott | Early determination of stroke subtype: ct angiography |
| 5R01NS039325 | Albers, Gregory | New mri techniques prior to t-pa therapy after stroke |
| 1R01HL082481 | Culp, William | Ischemic Stroke Treatment with Microbubbles, Clot Lysis |
| 5R01NS038471 | Dunn, Jeffrey | Near infrared/MR system for imaging brain oxygenation |
| 5P41RR015241 | Hillis, Argye | Reperfusion therapy in stroke candidates using mr perfusion & diffusion imaging |
| 5R01NS047607 | Moseley, Michael | Improved PWI Methodology in Acute Clinical Stroke |
| 5P41RR009784 | Moseley, Michael | Clinical mr diffusion & perfusion in clincial hyperacute stroke |
| 2R01HL039810 | Rosen, Bruce | Perfusion Imaging with Magnetic Resonance |
| 5R01NS038477 | Sorensen, Alma | MRI Diffusion/Perfusion Mismatch in Human Acute Stroke |
| 5R01NS038477 | Sorensen, Alma | Mri diffusion/perfusion mismatch in human acute stroke |
| 8R01EB002628 | Thulborn, Keith | Tissue viability in stroke by sodium mr imaging |
| 2R01EB002634 | Van Zijl, Peter | Functional Magnetic Resonance Studies of the Brain |
| 1Z01NS002975 | Warach, Steven | Section on Stroke Diagnostics and Therapeutics |
| 5R01NS042607 | Wityk, Robert | Induced Hypertension for Acute Ischemic Stroke |
| 5R29NS036211 | Wong, Eric | Quantitative magnetic resonance imaging of perfusion |
J. Endpoints: The previous report identified the need for further, rational development of useful stroke trial endpoints as resources.
The 2001 report specifically identified Quality of Life (QOL) instruments as an important needed resource for stroke trials. In the past 5 years, substantial progress in refining and validating stroke-specific QOL scales has occurred, including NINDS-funded studies of the Stroke-Specific Quality of Life Scale and NIA-funded studies of the Stroke Impact Scale. QOL scales incorporate a wider range of patient illness experience in outcome ascertainment and reduce the floor and ceiling effects seen with rater instruments.
Progress has additionally occurred in several other areas of acute stroke trial endpoint analysis. Bayesian techniques have been developed and implemented for identifying the most promising dose in phase 2 trials by utilizing positive (good outcome) and negative (adverse safety outcome) outcomes in real time to select the most informative dose to next be tested, including in the NINDS-supported ROSIE trial. Analyzing the entire range of outcomes ("shift analysis") has been refined and given clinical interpretability. For a disease like stroke that is disabling as well as fatal, incorporating all information from the spectrum of patient outcomes, rather than discarding outcome information by dichotomizing outcome scales, often improves study power. NINDS support has facilitated development of shift analysis (MR RESCUE, FAST-MAG). Baseline severity adjusted endpoint analysis has been refined and implemented in phase 2 and 3 stroke trials, including trials of the a glycoprotein 2b/3a inhibitor, abciximab. By adjusting win criteria to the severity of stroke at entry, this analytic technique increases study power in acute stroke clinical trials.
A variety of useful auxiliary and surrogate biomarkers have been further refined and implemented in phase 2 stroke trials, for more rapid identification of most promising drug dose. Available biomarkers now include the following: 1) For recanalization treatments: transcranial Doppler TIBI scale score, the MR reperfusion ratio, and CTA/MRA noninvasive angiographic assessment of vessel patency (NINDS support of CLOTBUST, DEFUSE); 2) For all acute ischemia treatments: salvage of penumbra defined on diffusion/perfusion MR or CBV/CTP CT imaging (NINDS support of DEFUSE, MR RESCUE); 3) For intracerebral hemorrhage treatment: frequency of hemorrhage expansion on serial CT/MR imaging (NINDS-support of HEME-Surgery, MISTIE, and industry-funded FAST trial).
K. Therapy to improve collateral perfusion: In several places, the original report alluded to devices and strategies that might be used to enhance perfusion into areas of critical blood flow limitation. Many patients with occlusion or critical stenosis of cerebral large arteries do not show recanalization or reperfusion in response to thrombolysis. Some of these patients also fail to show recanalization with embolectomy, angioplasty, or other relatively new interventions aimed to open occluded arteries. In some cases, there are lengthy segments of critical arterial stenosis in the distal internal carotid artery or middle cerebral artery, or both, that cannot be recanalized. Some such patients may show improved perfusion of ischemic tissue by improving collateral circulation.
Temporary induced blood pressure elevation holds promise for improving collateral circulation. This intervention is based on animal studies showing that within the ischemic penumbra, there is a loss of autoregulation, such that increasing systemic blood pressure increases regional cerebral blood flow in ischemic tissue. Recent case series, older series, and a pilot randomized trial have indicated that this intervention may result in improved perfusion and improved function, particularly in patients with large vessel arterial stenosis. An NINDS funded trial (Wytk) is determining whether MR imaging, including DWI and PWI, can identify patients who are most likely to respond to this intervention within 12 hours of stroke onset. In vivo monitoring of norepinephrine-induced blood pressure elevation indicated that increased mean arterial pressure results in an elevation of cerebral perfusion pressure and a selective increase of peak mean flow velocities of the MCA on the affected side
A novel intervention to improve collateral circulation that is currently being studied involves an interventional procedure inflating an intra-aortic balloon to differentially increase blood flow to the ascending aortic artery. The purpose of the Coaxia aortic balloon is to augment cerebral perfusion by occluding 70% of the abdominal aorta below the level of the renal arteries for up to 30 minutes. This reportedly diverts cardiac output to the head and increases cerebral perfusion. This principal has been demonstrated in a pilot randomized prospective study.
L. Medical Devices. Linked to SPRG Recommendations: Randomized trial, MR Rescue, testing efficacy of the Merci Retriever system has been funded by NINDS. The trial also tests the utilization of MRI in selecting patients that may benefit from revascularization therapy in acute stroke.
Not Linked to SPRG Recommendations:
In August 2004, the FDA gave Concentric Medical clearance to market its Merci Retriever system to "remove blood clots from the brain in patients experiencing an ischemic stroke". This approval was granted through the 510(k) process and based on a prospective non-randomized cohort study.{Smith, 2005 #1418} The approval of this device was not linked to SPRG recommendations.
2b. The key unresolved scientific questions identified as such at SPRG in 2001, as well as newly recognized questions.
A. Recanalization. We have not yet found the ideal recanalization therapy. Despite the ongoing trials mentioned above, the need remains to find a way to perform recanalization with minimal risk. Among physicians who are NOT trained in Vascular Neurology, fear of hemorrhage with intravenous fibrinolysis remains the single greatest barrier to implementation of this therapy. Four main avenues may yield success. First, fibrinolytic agents that are safer and more effective are needed. Promising agents include those that are more fibrin specific, such as tenecteplase, desmetoplase, and plasmin-derivatives, ought to produce far less systemic effects, and could cause cerebrovascular thrombolysis with minimal hemorrhage risk. The NINDS funded trial of tenecteplase (Haley) will determine the advantages of this agent. Second, combining fibrinolytic agents with additional drugs active in the coagulation or platelet cascades may improve initial recanalization yield and reduce early reocclusion rates. Further studies of combination recanalization therapies are desirable. Third, combining lytic agents with endothelioprotectants that stabilize the blood brain barrier could reduce the hemorrhage risk. The finding in SAINT 1 that NXY-059 treatment reduced the hemorrhage risk of rt-PA therapy illustrates this approach. Agents active on matrix metalloproteinases show similar promise. Fourth, mechanical recanalization therapies require further development. In the cardiac circulation, primary angioplasty and stenting is superior to pharmacologic recanalization strategies. Primary angioplasty and stenting should be explored for acute cerebral ischemia patients who harbor in situ intracranial atherosclerosis. For patients who have had thromboemboli arrive in the cerebral circulation from a systemic source, clot retrieval, mechanical clot destruction, and other mechanical approaches merit additional development.
B. Neuroprotection. Through continued funding of trials of acute stroke therapy, the NINDS will hopefully help define effective neuroprotective strategies. In particular, combination trials that are difficult and expensive need further NINDS support. Despite the combination trials mentioned above, there remains very little incentive for industry to cooperate in combination trials. Further, the scientific question in such trials is rather trivial, and study sections tend to undervalue pharmacological trials. Nevertheless, the potential public health benefit remains extraordinary, and NINDS should continue to enhance the review process to benefit large combinatorial trials. Statistical methods for improving the efficiency of such investigations exist and should be applied to more stroke clinical trials. Publication bias against negative trials remains an important issue, especially in industry. NINDS in cooperation with an industry roundtable needs to create an environment conducive to the prompt publication of negative trials. Trials designed to exploit and advance the distinctive ability of neuroprotective agents to be given rapidly, before brain imaging, including in the field, should be facilitated. The increasing deployment of recanalization therapy successfully in everyday practice is transforming reperfusion injury from a theoretical to a practical clinical concern. Accordingly, development of neuroprotective agents specifically beneficial against reperfusion injury is now required.
C. Stroke Centers. The effect of primary stroke center designation is undocumented, although the benefits seem self-evident. Nevertheless, a need exists to rigorously determine whether the JCAHO designation enhances the delivery of stroke care. Primary Stroke Center adoption is proceeding steadily, but slowly, with 43 states yet to formally endorse this organization of acute stroke services. There remains a need to develop research infrastructure within many Primary Stroke Centers to facilitate translational research. In SPOTRIAS centers, a requirement that the patient access core treat a minimum of 1 patient per month under 2 hours from stroke symptom onset may also enhance delivery, by incentivizing prompt care. The effect of this SPOTRIAS program requirement remains to be documented. The need for comprehensive stroke centers seems self-evident, but the attendant requirement for prompt transfer of patients from primary stroke centers, or even medic bypass of other medical centers, has social and economic implications in some communities. There remains a need for NINDS to assess the implications of comprehensive stroke center designation. There is not yet a formal certification process for Comprehensive Stroke Centers. Such a process may permit the delivery of advanced endovascular, neurocritical care, and imaging interventions to a greater proportion of the American populace.
D. Pediatric stroke: Data on safety and efficacy of lytics and other therapies in pediatric patients is needed.
E. Emergency Department Investigators and Protocols: First, there is a brief time-window of intervention associated with many therapies, and investigating them can be difficult. Addressing this will require a degree of innovation similar to that in the FAST-MAG trial, in which patients are being treated within 1-2 hours of symptom onset. Second, the time and financial resources required to develop the infrastructure necessary to conduct a multi-center trial for a specific acute intervention for stroke are significant. Experience in the pre-hospital and emergency department setting with acute stroke trial enrollment is not impressive, and the NETT Network is yet to be tested. Most completed trials have had time windows late in the evolution of acute stroke injury. Third, we have not stimulated much interest in the Emergency Medicine community in acute stroke research (with a few notable exceptions). Since the publication of the NINDS rt-PA stroke trial, little progress has been made, and we must determine why acute stroke does not seem to be a priority for the Emergency Medicine community.
F. Telestroke. Although telemedicine is used widely in acute stroke care, it's efficacy in stroke has still yet to be proven in any randomized clinical trial. The ultimate assessment of telemedicine's efficacy in stroke will include an increased number of patients receiving thrombolytic therapy and also an increased proportion of correct decisions to treat or not to treat when utilizing such a system. Telemedicine efficacy in stroke is under investigation in the NINDS funded STRokE DOC telemedicine clinical trial as part of the San Diego SPOTRIAS program.
Additional areas of future assessment and clarification may include establishing technical requirements, assessing cost, facilitating reimbursement, clarifying legal responsibilities, determining telemedicine's role in stroke center designation, assessing the use of telemedicine for clinical trial enrollments and improving stroke patient care throughout multiple locations within the healthcare system.
Expanding upon those technical and clinical requirements detailed above, ISDN bound vs. site- independent systems should also be examined critically. Lack of mobility may cause delay to patient treatment. Site independent systems that minimize delay to system access may be encouraged in the future. Systems currently range in price from $10,000 per bound workstation (not including a $3-12,000 per year cost of networking lines) to $50,000 per site independent system. Hardware and software costs will likely continue to decrease as technologies advance, though costs associated with practitioner consultations and other dedicated resources for management and support still need to be addressed. Reimbursement must be addressed and championed in order for telemedicine to secure a place in the future of stroke care. Similar to the newly established DRG for thrombolysis, care should be taken to ensure reimbursement for teleconsultations. To date, few economic assessments, other than for tele-radiology, have shown success in economic models of telemedicine. Documenting consultations, ensuring appropriate practitioner licensure, and obtaining hospital credentials should help to smooth issues of liability and legal responsibility for telemedicine. This would likely give teleconsultations legal standing similar to standard face to face consultations. A further issue of endorsement may be the Joint Commission on Accreditation of Hospital Organizations (JCAHO), which certifies primary stroke centers. Telemedicine, if effective, could be encouraged as a means to satisfy JCAHO requirements in order to maximize speed and efficiency of stroke patient evaluations in even more facilities. Telemedicine will undoubtedly be used for the purposes of enrolling research participants into clinical trials as well. One hurdle to this use is the general decreased experience or unfamiliarity with performing clinical research by practitioners in remote settings. NINDS should foster research to assess the reliability of telemedicine for clinical trial recruitment and enrollment. Finally, critically assessing the use of telemedicine in various stages and locations of the patient's healthcare (including the ED, inpatient, or even rehabilitation facility) should be addressed and encouraged as well.
G. Reimbursement. The increased reimbursement for acute stroke patients receiving thrombolytic agents, using the new DRG and new ICD-9 Procedure Code, represents a significant advance for stroke centers. Hospitals are now reimbursed for the greater costs associated with caring for these patients and are more likely to provide the resources necessary to establish stroke centers capable of delivering acute stroke care. This will hopefully increase the appropriate treatment of acute stroke patients with thrombolytic agents. However, significant problems remain. The DRG modifications do not address the issue of increased reimbursement for physicians who are required to respond to stroke emergently and spend considerable time with acute evaluation and treatment decisions. Stroke centers also require physician coverage 24/7/365. Additionally, many major stroke centers receive patients in whom IV tPA is initiated elsewhere in a "drip and ship" model. Because the IV tPA is administered at the originating hospital but the patient is admitted to the receiving hospital, DRG 559 cannot be utilized by the receiving hospital because no thrombolytic agent is given there. Thus the stroke center is not reimbursed for the added costs associated with caring for patients receiving the thrombolytic agent. This runs counter to the reasoning for the creation of the new DRG.
H. Diversity. Gender questions have emerged, as pooled TPA datasets suggest gender differences in IV lytic response. Further research into gender differences in response to thrombolytics is required to understand the mechanism of this interaction. Gender differences were also observed in neuroprotection studies, as with Tirilazad showing poorer outcomes in females. There have been too few African-American women in any acute stroke study. In Alzheimer disease, under-representation of minorities in trials was targeted by making funding of ADRCs contingent upon enrolling certain percentages of minorities. Also NCMHD is funding new P20 centers to enhance recruitment of under-represented minorities.
I. Stroke Mechanisms. Research is needed to (1) more rapidly and accurately identify stroke mechanism; (2) identify mechanism-directed therapies, with animal models for different stroke subtypes; and (3) determine whether or not such therapies are differentially effective for separate stroke subtypes. A single multimodal MRI or CT session, imaging the heart, vessels from the heart through intracranial circulation, and brain might prove to be useful in accomplishing the first aim. With regard to the second aim, most current animal models of stroke use the MCA occlusion model; animal models of other stroke subtypes are needed. Advances in serum diagnostics of acute stroke have occurred at only a slow pace and considerable further work is needed to clarify the role of serum biomarkers that may indicate the mechanism of the presenting stroke. Another need exists to determine whether any biomarker, serum or imaging, can differentiate stroke from stroke-mimcs. Considerable effort will be needed to determine whether imaging, with the emergence of multimodal CT and further refinement of multimodal MR, can help to select patients for treatment after the 3-hour.
J. Endpoints. Several new endpoint analytic approaches have advanced over the last 5 years, partly in response to the SPRG. A resulting emerging question is how best to select among competing available approaches to analyzing outcome. Therapeutic success has created new targets for further therapeutic development. Now that reperfusion can increasingly be achieved by pharmacologic or mechanical recanalization, reperfusion injury has become an important clinical entity. Similarly, hemorrhagic transformation, early recurrent ischemia, and late secondary, apoptotic elaboration of injury are important new therapeutic targets requiring endpoint elaboration.
K. Collateral Perfusion. Collateral enhancement is an additional strategy of acute ischemic stroke treatment that has progressed. NIH has funded studies of HHH. Collateral enhancement devices such as Coaxia's Neuroflo have also entered trials. An unresolved question remains, however: Is there really a window of opportunity for late collateral enhancement therapy? Larger, randomized placebo/sham-controlled trials of collateral enhancement interventions are needed to determine efficacy for improving perfusion and function in acute ischemic stroke. Case studies have indicated that patients with large vessel critical stenosis may have extensive brain tissue that is viable but receiving too little blood to function. Such patients seem to respond to such treatments up to a week or more post onset of ischemic symptoms. It is possible that the gradual increase in the degree of stenosis results in ischemic preconditioning that extends the viability of ischemic tissue. Therefore, the time window for effective use of these interventions needs to be determined.
L. Given the lack of appropriate controls in the MERCI trial, there is still considerable debate as to the safety and efficacy of mechanical thrombectomy with the Merci Retriever system for the treatment of acute stroke. The approval of the device, however, has made it extremely difficult to perform efficacy trials where patients may be randomized to a medical treatment only arm.
2c. What needs to be done to address these questions?
NIH needs to clarify current Waiver of Consent issues and achieve harmony among FDA, IRBs, and NIH guidelines. NIH needs to examine the feasibility of centralized national IRB approval for complex multi-center trials. Also, concordance of regulations for indirects and subcontracts is required.
The NINDS needs to continue to actively promote acute stroke care and research in the Emergency Medicine community through education, mentorship and financial support. Measures could be instituted at various points in the time-line (or pipeline) of the development of emergency department investigators. NINDS support of training in both the clinical care of acute stroke as well as research (in the form of training supplements) at a very early time-point in Emergency Medicine clinical training, i.e., residency training, would do a significant amount to increase awareness of the importance of acute stroke research and care in the emergency medicine community. Enhanced NINDS support of training in basic science and clinical research in acute stroke for early-career emergency medicine investigators would significantly aid in the maturation of a cohort of emergency department investigators. An investment in subsequent emergency medicine collaborations with neurological specialists would result in innovations in clinical trial design in acute stroke research, especially for therapies with brief or early time-windows, and allow an investigation of diagnosis and treatment strategies which could be applied very early on in stroke evolution, possibly in the field, by paramedics. It would be advantageous to develop a network of experienced "emergency department stroke centers of excellence" where numerous acute stroke trials could be conducted resulting in expedited patient enrollment and drug/device approval.
--Studies are needed to investigate under which conditions dichotomized analysis, global statistic, responder analysis, shift analysis, and other analytic techniques have differential advantages and disadvantages. Different treatment are likely to have different profiles of impact on outcome, as recanalization agents, cytoprotective agents, and collateral enhancement agents each exert their effects in markedly different ways. Analytic techniques should be selected to optimize detection of clinical relevant, agent-specific treatment effects.
--Imaging biomarkers have been described that correlate with all, and serum biomarkers have been described for several, of the pathophysiologic processes of reperfusion injury, hemorrhagic transformation, early recurrent ischemia, and late secondary, apoptotic elaboration of injury. Refinement of these and development of additional biomarkers of these processes for use in phase 2 trials is critical for the development of the next platform of therapeutics that will minimize acute ischemic brain injury.
Devices are often developed by physicians in collaboration with device companies. Physicians chose to collaborate with companies because they find it difficult to organize large clinical trials alone as they are not sufficiently familiar with the device field, device regulations or the Food and Drug Administration (FDA) regulations. In addition, many physicians often have consulting roles and are on scientific advisory boards of device companies. The collaboration for device development is therefore a natural extension of the already established relationship with the company.
With these kinds of collaborations however, physicians do not have the final decision regarding clinical trial design. Given the rapid and continued changes in technology, it would be impossible to require a clinical trial for each new iteration of a device. Before any given class of devices is adopted for routine use, however, it would seem appropriate that the safety and benefit of the devices for their intended use be proven in a randomized controlled trial. Unfortunately, once the devices are available, it is difficult to complete trials which randomize patients to a medical treatment arm. The difficulty in randomization stems largely from what may be regarded as innocent misperception of the patient or treating physician that use of the device is superior to medical therapy, despite the lack of evidence. Given that the efficacy is a critical concern to the clinical community, new devices should not be used prior to a demonstration of efficacy. These kinds of studies can be encouraged by NIH through seed grants to encourage such collaboration for developing such devices. Furthermore, we encourage companies to perform proper studies proving efficacy, NIH can help support funding to private companies that may not have the capital to perform large randomized trials. Finally, in order to complete trials comparing treatments where there is clinical equipoise, we must remove the barriers to randomization. While provider and patient education is paramount, another strategy is to remove the financial incentive for non-randomization. If CMS and private insurance companies would reimburse only those procedures and devices shown to improve outcome in prospective randomized controlled trials, the interest in completing those trials in a timely fashion would increase. Reimbursement for patients treated within a pivotal clinical trial would further increase the incentive for randomization.
2d. What new key research areas emerged since the first SPRG meeting in 2001?
See above.
BIOLOGY OF REPAIR
Co-Chairs: Michael Chopp, Larry B. Goldstein
Members: S. Thomas Carmichael, Steve Cramer, Bryan Kolb, Randolph Nudo, Jack Parent, Tim Schallert, Samuel Weiss
NINDS Liaison: Eugene Golvanov
SEMINAL SCIENTIFIC ADVANCES:
1) Basic studies in animal models of experimental stroke have established that focal ischemia induces alterations at the molecular and cellular levels in areas of brain adjacent and distant to the injury. These alterations are associated with neuronal migration to areas of injury as well as axonal and dendritic sprouting, the formation of novel projections, neurogenesis and angiogenesis within both the partially damaged and intact brain and spinal cord.
2) Improved behavioral recovery associated with structural changes in brain has been demonstrated after stroke in a variety of animal model systems (e.g. ischemic and hemorrhagic stroke) with a variety of approaches including cell-based (MSCs, cord blood, stem cells, neurospheres), pharmacological (cGMP, growth and neurotrophic factors, amphetamine, EPO/CEPO, statins), behavioral (enriched environment, voluntary exercise), electrical stimulation, and immune-based interventions.
3) Advances in imaging technology with potential application to the study of brain repair that can be applied in vitro, in tissues and in vivo have include the development of novel MRI sequences and optical imaging techniques (e.g., dual-photon, laser capture microscopy).
4) Recognition of the importance of the neurovascular unit has led to a paradigm shift from a neurocentric to a tissue and cell-cell coupling systems approach to understand brain tissue damage and recovery.
5) Functional sensorimotor and cognitive tests for rats, mice and other animal model systems have been developed to allow for better translational research.
6) Studies show that both aged and young animals can recover after stroke suggesting that brain repair treatments may have similar types of effects in old vs. young brain.
7) Human imaging studies using a variety of techniques (e.g. MRI, PET and TMS) have shown that functional recovery of motoric, sensory, language and attention functions in cortex ipsilateral to a stroke are closely correlated with successful neurological recovery, whereas activation of cortex contralateral to the stroke correlates with poor functional recovery, at least at some time points.
8) DNA-micro array techniques have become available and are being applied to studies of brain plasticity.
Key Unresolved Questions:
1) What are the key cellular and molecular events that mediate behavioral recovery post stroke?
2) Which therapeutic strategies stimulate recovery after stroke?
3) Does the human brain undergo similar restorative changes to that found in experimental animals?
New Key Research Areas That Have Emerged Since Sprg-1:
1) What are the relationships between cellular (e.g., axonal/dendritic sprouting, neurogenesis, angio-genesis, and glial and white matter changes) and molecular events following brain injury and which are causally related to behavioral recovery?
2) What key molecular events regulate post-stroke plasticity and recovery and what are their detailed temporal profiles? What are the interactions between neurogenesis and angiogenesis, and their impact on the brain microenvironment? Which genes and proteins regulate these processes?
3) Which therapeutic strategies most effectively stimulate and enhance recovery after stroke (e.g. cell, drug, environmental enrichment, or combination therapies)? What are the underlying mechanisms that promote recovery of function using cell-based and pharmacological restorative therapies? What are potential adverse effects of these therapies? What is the optimal timing of interventions based on temporal profiles from cell interaction and genomic and proteomic studies? How does the size and location (e.g. cortical, subcortical) of an infarct impact recovery of function and the response to restorative therapies? Can the brain be "primed" to enhance restorative therapy?
4) How does an animal's behavioral experience affect the processes underlying behavioral recovery?
5) Does the human brain undergo the same types of adaptive changes found in animal model systems? How does repair in animal model systems, especially rodents, relate to humans at multiple levels (gene, protein, cell system, and behavior).
6) Can neuroimaging be used to identify patients likely to benefit from specific interventions? How can MRI (e.g., tractography, fractional anisotropy, fMRI) or other techniques be used to identify changes in brain predictive of and related to recovery such as axonal sprouting, angiogenesis, and endogenous neurogenesis in the brains of experimental animals and humans after stroke? Can these techniques be used to monitor the response to therapy?
7) Better characterize the chronic phase of human and experimental stroke, including natural history, imaging, patterns and mechanisms of brain adaptation to stroke and strategies for long-term repair.
8) Support Phase I/II clinical trials to test neurorestorative therapeutic approaches for the treatment of stroke.
9) Evaluate tissue engineering approaches to treatment of post-ischemic brain, including use of scaffolds.
10) Determine genetic factors that affect recovery in stroke patients.
What Needs To Be Done?
1) Standardize experimental and clinical methodologies for neurorestorative research and accelerate their development.
2) Support translational research by fostering interactions between basic scientists, preclinical and clinical investigators involved in post stroke recovery research to better couple preclinical and clinical studies.
3) Support descriptive and collaborative research efforts in post stroke recovery.
4) Support the development of imaging (e.g. MRI) for assessing the processes underlying recovery from stroke .
5) Increase the number of Phase I/II clinical trials for recovery after stroke.
6) Promote the development of consortia for restorative clinical stroke trials.
7) Improve patient enrollment in clinical trials of stroke.
8) Develop a bank of human autopsy material to evaluate neurogenesis, angiogenesis and neuronal reorganization after stroke.
CLINICAL TRIALS
Co-Chairs: Joseph P. Broderick, Robert G. Hart, Karen C. Johnston
Members: Gabrielle DeVeber, Michael D. Hill, Rebecca Ichord, S. Claiborne Johnston, Paul Muizelaar, Arthur Pancioli, Peter A. G. Sandercock, Barbara C. Tilley
NINDS Liaison: Robin Conwit, John Lynch, Claudia S. Moy, Katherine Woodbury-Harris
Clinical trials in stroke are an essential component of the research mission of NINDS. The value of clinical trials in moving experimental therapies into clinical practice is indisputable (Lancet 2006). In 2001, the SPRG identified a number of goals, challenges, and barriers to continued progress in stroke clinical trials. Despite considerable progress since that time, many challenges and barriers remain and are the focus of this report.
Per the format requested by the SPRG leadership at the September 19-20 meeting, this report is organized into four topic areas:
1. Seminal scientific advances in stroke clinical trials
- Stroke is treatable beyond the three-hour window (but time is critical).
- Neuroprotection remains a viable strategy for acute stroke treatment.
- Treatment effects for secondary prevention may vary by ischemic stroke subtypes and baseline patient characteristics
- Trials have advanced knowledge regarding the optimal medical and surgical treatment for prevention (including antithrombotic agents, blood pressure control, lipid-lowering, aneurysm coiling etc.).