Unmet Needs and Challenges in Clinical Research of Intracerebral Hemorrhage
Over 2.3 million people suffer hemorrhagic forms of stroke (intracerebral hemorrhage [ICH] and subarachnoid hemorrhage) worldwide every year; two-thirds survive with permanent disabilities.1 Unlike its ischemic counterpart, the incidence and morbidity of hemorrhagic stroke have not declined over recent decades, and rates are substantially rising in Asia, and low- and middle-income countries.1 There is considerable need for effective therapies to improve outcomes from hemorrhagic stroke, in particular for its most common subtype, ICH.
The first HEADS (Hemorrhagic Stroke Academia Industry) roundtable was convened in Baltimore, Maryland in May 2017. This collaborative one-and-a-half day meeting comprised leaders from academia, device, and pharmaceutical companies, the National Institute of Neurological Disorders and Stroke, and the Center for Drug Evaluation and Research Division of Neurology Products and the Center for Devices and Radiological Health Division of Neurological and Physical Medicine Devices of the US Food and Drug Administration, and the Center for Medicare and Medical Services. The meeting was modeled after the STAIR (Stroke Therapy Academic Industry Roundtable),2 and focused on ICH. Day 1 consisted of 4 sessions covering the following topics (1) translational challenges and therapeutic targets; (2) clinical trials—past and the future; (3) pharmaceuticals and devices in the pipeline; and (4) navigating the Food and Drug Administration, Center for Medicare and Medical Services, and National Institutes of Health regulations. Each session included a series of talks by experts in these areas, and a list of relevant challenges was formulated at the end of each session following an open group discussion. On day 2, participants were divided into 2 working subgroups, basic and clinical research. Each group was provided with a summary of emerging challenges from day-1 sessions and was tasked to define unmet needs and to develop recommendations and benchmark standards to improve the process of research and development to refine future therapies designed to treat ICH. The Chairs of the working groups facilitated the discussion and provided a summary of the recommendations from each group to all participants for further feedback. The manuscripts detailing these recommendations were drafted by the Chairs of the working groups and of the meeting then circulated to all participants for their input/feedback before final submission. Herein, the recommendations for clinical research are presented. Recommendations for basic and translational research and the criteria that must be met before deciding whether to take an experimental agent/procedure forward to clinical trial in ICH are discussed in a companion article.
Clinical Research Goals in ICH
Clinical research in ICH is focused on 5 broad goals (Table 1).
Cessation of Bleeding
Potential treatments to be further evaluated for cessation or control of bleeding during the hyperacute phase include the use of clotting factors to promote hemostasis, targeted treatment to reverse anticoagulation-associated ICH, and consistent approaches to blood pressure (BP) control in the setting where ICH is first diagnosed.
Minimizing Mass Effect and Ameliorating the Toxic Effects of Blood
Potential approaches include surgical aspiration of the clot with or without local thrombolysis, and the use of drugs to accelerate the removal of the toxic hemoglobin degradation products and iron or drugs that can impact other noniron mediators of secondary brain injury.3
Treatment of the Global and Secondary Effects of ICH
Potential approaches include the use of osmotherapy, specific drugs targeting the pathophysiological pathway of edema formation, nonpharmacological strategies such as temperature regulation, or surgical treatments such as craniectomy or placement of an external ventricular drain in cases of developing hydrocephalus.
Currently available therapies for enhancing recovery after ICH are derived from ischemic stroke and traumatic brain injury. There are no specific treatments or therapies for ICH patients.
Mitigating Conditions That Predispose to ICH and Its Recurrence
Prevention of ICH would have the greatest impact on its burden. This can be achieved by improved monitoring and treatment of hypertension and easy-to-comply-with antihypertensive regimens; the use of imaging and genetic biomarkers to identify those at high risk for ICH; and better delineation of the competing risks between prevention of ICH and cerebral and cardiovascular ischemia in patients requiring anticoagulation or statin therapy. There is also a need for better clarification of the pathological features, natural history, risk factors, and biomarkers (multiomics) of cerebrovascular pathologies predisposing to hemorrhage in young and old patients.
Current Landscape of ICH Clinical Research
Improved understanding of the mechanisms underlying primary and secondary injury after ICH has fueled clinical research in the field in recent years. Several important and landmark randomized controlled trials have been completed, few are ongoing, and many more are being planned. Table 2 lists some of these trials. The vast majority of clinical trials in ICH have targeted the primary injury, in particular limiting hematoma burden or growth. Two large randomized phase-3 trials (INTERACT2 [The Second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial] and ATACH2 [The Antihypertensive Treatment of Acute Cerebral Hemorrhage II Trial]) evaluated the efficacy of intensive BP lowering for improving functional outcome through reducing hematoma growth.4,5 Smaller randomized trials also evaluated the role of platelet transfusion, prothrombin complex concentrate, and the hemostatic agent recombinant factor VIIa in more selected groups of ICH patients.6,7,9 Reversal of coagulopathy because of direct oral anticoagulants is being investigated in the ANNEXA-4 trial (Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding Trial; URL: http://www.clinicaltrials.gov. Unique identifier: NCT02329327) and the antifibrinolytic agent, tranexamic acid, is being tested in the TICH-2 trial (Tranexamic Acid for Intracerebral Haemorrhage 2 Trial).10 STICH/STICH-II (Early Surgery Versus Initial Conservative Treatment in Patients With Spontaneous Supratentorial Lobar Intracerebral Haematomas Trial) and ICES (The Intraoperative Stereotactic CT-Guided Endoscopic Surgery Trial) tested surgical and stereotactic-guided endoscopic evacuation of ICH.11,12,14 The use of local thrombolysis to enhance the clearance of intraventricular hemorrhage was tested in CLEAR-III (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III Trial)13 and is currently under investigation in parenchymal ICH in MISTIE-III (Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III Trial; URL: http://www.clinicaltrials.gov. Unique identifier: NCT01827046). Another randomized trial (ENRICH, Early Minimally-Invasive Removal of Intracerebral Hemorrhage Trial; URL: http://www.clinicaltrials.gov. Unique identifier: NCT02880878) is testing the use of minimally invasive surgical aspiration of ICH. Few trials have targeted the secondary injury in ICH based on preclinical data, and even fewer secondary prevention trials are underway. A phase-2 trial investigating the use of the iron chelator, deferoxamine, in ICH is nearing completion (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02175225). Clearly, more needs to be done. The results and lessons learned from these trials are vital to improve the conduct and design of future clinical trials to find new and effective therapies for ICH patients.
Unmet Needs and Challenges
Cumulative experiences from previous and ongoing trials in ICH highlight several challenges, knowledge gaps, and needs that should be addressed. These include: difficulties with recruitment because of restrictions on eligibility criteria and competing trials; increased realization of the importance of time in ICH and the need for early intervention within 2 to 3 hours of symptom onset; the influence of variability in protocols for management of ICH on outcome; the optimal strategy and timing for outcome assessment; and barriers to extend research activities and procedures from the hospital to the rehabilitation setting.
The STAIR meetings have made important recommendations for ways to optimize and standardize the translation of preclinical work and conduct of clinical research in ischemic stroke.2 These recommendations were vital in improving the design, execution, and successes of endovascular stroke trials. The HEADS participants discussed these issues with relevance to ICH and reinforced the need to practice scientific rigor in the conduct and reporting of clinical studies. Many of the STAIR criteria for ischemic stroke are applicable to hemorrhagic stroke. The HEADS discussions particularly focused on identifying specific needs in the ICH field and used STAIR’s established methodology2 (Table 3).
Clinical Trials Design
Despite repeated calls to encourage the development and use of new and more efficient trial designs, including adaptive enrichment designs, these opportunities remain underutilized. Adaptive enrichment designs involve preplanned rules for modifying enrollment criteria based on accrued data in an ongoing trial. These designs have potential to more efficiently determine which subpopulations benefit in ICH, compared with standard designs.15 They are particularly appealing for phase II studies. However, the performance of such designs should be carefully evaluated before a trial is conducted, because adaptive designs are not guaranteed to have smaller sample size or be better than standard designs.
Because of the complexity of the mechanisms of brain injury after ICH, multitarget drugs and multimodality therapies are likely to have the greatest potential to improve ICH outcomes. Aside from adding a new therapy onto an already approved therapy, a factorial design is an option for a combination therapy trial. However, the logistical challenges in implementation and conduct of combination trials are discouraging. The use of adaptive enrichment designs, in which harm or poor response is identified early, could be helpful. Also, SMART (Sequential, Multiple Assignment, Randomized Trial) designs,16 where a participant who fails on initial treatment is randomized to another, could be advantageous. It is important to acknowledge that adaptive design trials have inherent logistical difficulties related to pretrial planning, funding, resources, and administrative issues, which limit their application.
Several drugs targeting the secondary injury of ICH are in various stages of development. Phase III trials of these therapies should not be conducted without adequate pharmacokinetic data from human studies, including effective plasma levels, therapeutic time window, dose–response relationships, and determination of the minimal dose that achieves the maximal effect of the drug. It is also important to demonstrate that adequate drug concentrations can be achieved in the target tissue. Intravenous administration represents the most commonly used route of drug delivery. Other routes of administration, such as intranasal or local delivery, might result in higher concentrations in the target tissue and minimize the risks of systemic toxicities. The use of radiolabeled drugs and positron-emission computed tomography, microdialysis, or clot aspirates, when minimally invasive clot removal is contemplated, could be of value. Various routes of administration of a specific drug should be examined in Phase II investigations before embarking on Phase III trials.
The primary injury after ICH is time-sensitive. Substantial hematoma expansion, a major predictor of early mortality and morbidity, often occurs within the first 3 to 4 hours after ICH onset.17 There are several reasons to account for the failure of previous studies that have aimed at arresting hematoma expansion in improving overall outcome. The most important being attributed to delayed initiation of treatment. There is increasing recognition that ICH, like its ischemic counterpart, is a medical emergency; and intuition that treatments aiming to reduce BP, reverse coagulopathy, or stop the bleeding should be initiated as early as possible after ICH onset, ideally within the first hours or in the prehospital setting—just like r-tPA (recombinant tissue-type plasminogen activator) for acute ischemic stroke (AIS). Early hematoma stabilization may also allow earlier initiation of clot evacuation. Increased availability of mobile stroke units could facilitate small proof-of-concept studies. However, there is a need to highlight that urgency in diagnosing and triaging ICH is essential, and to develop reliable methods or improve on existing attempts to use portable technology to diagnose ICH in the field.18
Time-to-enrollment in ICH studies involving time-sensitive interventions can be significantly shortened by implementing a waiver of documentation of informed consent or exception from informed consent. ICH studies in the prehospital setting, in particular, are well-suited for this approach. This requires increased efforts for community and Institutional Review Boards education about ICH, its pathophysiology, and available treatment options.
A challenge in designing ICH trials is determining the smallest clinically-meaningful effect size that would have an impact on clinical practice. Most recent trials (ATACH-2; iDEF; MISTIE-3) used an absolute effect size of 10% to 12% on dichotomized modified Rankin Scale (mRS). A more realistic absolute effect size for an acute intervention in ICH, given previous experience, should be 3% to 10% (average 5%). However, a smaller effect size would require substantial larger sample size, which can be prohibitive unless larger trials are undertaken. Prespecification of effect size for a particular intervention should take into account the cost of the proposed intervention. A small effect size might be worthwhile for treatments that are relatively low-cost, safe, and simple. On the other hand, a small effect size may not be justifiable for costly, risky, and complicated treatments.
Increased accessibility to data from federally-funded trials and collective data sets of previous ICH trials, such as National Institute of Neurological Disorders and Stroke funded ICH trials or the Virtual International Stroke Trials Archive would be helpful to closely examine the control (placebo-treated) distribution.19
Recruitment into ICH randomized trials is challenging. In the United States, a large number of ICH patients are often transferred from smaller hospitals to regional tertiary centers, and most are sedated and intubated before transport or en route. As a result, the process of obtaining informed consent is often difficult or delayed while awaiting legally authorized representatives. The low screening-to-enrollment ratio in recent ICH trials is also problematic. Only 5% of screened ICH patients are enrolled in an interventional (medical or surgical) study, largely because of the restrictive list of exclusion criteria. In addition, the relatively small pool of ICH patients (which comprise only 10% to 15% of stroke patients) increases the likelihood of their consideration for >1 ongoing trial. This particularly adversely impacts recruitment into medical versus competing surgical ICH trials, where the latter are often perceived to provide a more definitive treatment when the patient is at high risk for rapid deterioration and death.
Co-enrollment or sequential enrollment, whenever applicable, into ICH trials could address some of these issues. Co-enrollment into diagnostic and interventional studies or into acute and secondary prevention (eg, long-term BP control) studies and sequential enrollment into acute and recovery studies provide opportunities to examine the feasibility of these strategies and their potential to boost recruitment into various ICH trials. It is becoming increasingly apparent that many centers are needed to recruit a given number of patients with ICH. Based on recruitment data from MISTIE-3 and iDEF trials, the average enrollment rates are 3 patients per active site per year in iDEF and 1.3 in MISTIE-3. Accordingly, it is estimated that ≈150 to 175 active sites are needed for ≥4 years to recruit 1000 subjects. This highlights the need for global collaboration to complete enrollment in ICH trials. However, involvement of multinational sites has particular challenges that include coordinated administration of the trial activities across different systems of care; processes of human subject protection; careful navigation of cultural differences and attitudes toward participation in clinical trials and goals of care; distribution of drug or devices; site monitoring; and the implementation and enforcement of standardized acute and postacute care protocols.
Stratification of Disease Severity
Because ICH volume is a major predictor of outcome, patients with large hemorrhages are often excluded from ICH trials to eliminate the noise from the projected poor outcome. Furthermore, randomization into different treatment arms in ICH trials is often based on ICH volume at presentation. However, ICH volume is not the only determinant of outcome. Additionally, ICH is a dynamic process because of the ongoing and variable nature of hematoma expansion, edema formation/growth, and their consequences. These variables can impact final outcomes. As a result, balancing disease severity between treatment groups in randomized trials may be difficult to achieve.
To address these concerns, the stability of ICH volume on serial imaging has been used as an entry criterion for several trials.13,14 However, this approach results in delayed randomization and intervention for several hours-to-days, which could adversely impact the effectiveness of acute study intervention. Time-to-stability requires further investigation to better balance the need for reducing exposure to toxic blood products in surgical intervention trials. The use of alternative covariate-adjusted randomization schema including baseline ICH score (which incorporates many baseline variables known to affect the outcome)20 in combination with other measures of disease severity such as National Institutes of Health Stroke Scale score and Charlson Comorbidity Index should be considered. Although important, stratification based on the anatomic location of ICH (lobar versus deep) is often overlooked. Deep hemorrhages, particularly those involving the thalamus, are more likely to lead to intraventricular hemorrhage, ventricular compression, hydrocephalus, brain stem compression, and fatal consequences.
Standardization of Postenrollment Management/Interventions
The medical and surgical management of ICH during the hospital phase and the type and extent of therapy during rehabilitation vary widely among institutions. This variability in practice can impact the outcome of ICH patients. Few ICH trials enforce a standardized management approach, or control for important confounding variables, which can complicate the interpretation of the trial results. More needs to be done to streamline and minimize variability in practice, and these confounding variables must be collected, as part of the trial protocol, to examine their influence in secondary analyses. There is also a need to implement a protocolled and uniform approach to withdrawal-of-care among participants in ICH trials to minimize resulting noise.
Although there are many validated and reliable measures to assess functional outcomes, these were mostly developed in ischemic stroke patients. Like ischemic stroke, studies in ICH patients continue to struggle with the optimal outcome assessment method and its timing. Most studies use mRS (dichotomized as a score of 0–2 or 0–3 to define good outcome and 3–6 or 4–6 for the poor outcome) as the primary measure of functional outcome, and ordinal ranking score or shift analysis as a secondary measure. However, there are concerns that dichotomized mRS may be suitable only when a large difference in outcome between the treatment groups is anticipated. It has been argued that using the ordinal ranking provides more power when a change occurs across the entire distribution; however, this poses analytic challenges, such as proportionality of the odds. There are also concerns that scales like mRS, while practical, do not fully reflect the complexity in circuit biology and panoply of impairments in ICH.19
Although assessment of mortality is important, its use as a primary end point is questionable. Modality- and impairment-specific outcome measures taking into account baseline severity, ICH-specific patient-centered outcomes, utility-weighted mRS,21 patient-reported outcome measures, and the use of repeated measures analyses of outcomes require further development and evaluation in ICH populations. Additionally, there is a need for thorough assessment of the downstream consequences of outcomes such as nursing home placement or dependency versus return to own home, and postdischarge caregiver burden.
Cognitive impairment is common after ICH, even among patients with seemingly good mRS scores. One-fifth of ICH survivors develop dementia within 6 months of ICH onset, and an additional fifth develops later dementia.22,23 Yet, assessment for cognitive dysfunction as an end point is rarely done in ICH trials. This may be complicated in part by the fact that many ICH patients may have a preexisting cognitive impairment. Furthermore, the severity of the disease may make thorough assessments challenging. Ideally, cognitive testing should be short and include tests without major ceiling or floor effects. Testing should also target processing speed and executive function because these domains are likely most affected after ICH. Technology-assisted testing could improve speed and ease of cognitive testing at multiple time points. Studies are needed to assess the feasibility of cognitive testing in ICH trials.
The optimal timing for outcome assessment after ICH is also uncertain. The natural history of recovery after ICH, its plateau, and whether it varies by ICH location are poorly studied. There are some indications that recovery is protracted after ICH, and that long-term assessment of outcome beyond 90 days and up to 180 days or longer is required to capture the full extent of functional recovery,24 and durability and cost-effectiveness of the intervention. This poses financial and logistical challenges related to the costs of running longer trials and subject retention.
Surrogate markers of efficacy such as, residual volume of ICH/intraventricular hemorrhage or percent change from baseline volume after an intervention have been successfully utilized in studies aiming at clot evacuation.13 There is growing interest to use perihematoma edema as a surrogate marker to assess the efficacy of interventions targeting the secondary injury after ICH in proof-of-concept studies. However, there are several challenges and concerns related to the appropriate timing and frequency of these assessments, the imaging modality used (computed tomographic scan versus magnetic resonance imaging), the influence of various management decisions on fluid volume status and use of diuretics or osmotherapy on these measurements, and the debatable relationship between perihematoma edema and functional outcome.25
Government and Industry
Regulators are responsive to medical needs and public health imperatives, and regulatory pathways provide effective means to expedite products to patients. More can be done to use and further develop expedited and adaptive regulatory pathways within the existing regulatory framework to allow patients to have early access to new treatments. These pathways should be based on 3 principles (1) iterative development, beginning with a restricted patient population then expanding to wider patient populations; (2) gathering evidence through real-life use to support clinical trial data collected in an investigational study; and (3) early involvement of multiple stakeholders, including patients, providers, industry, academia, regulators, and payers on a medicine’s development. The development and refinement of such pathways requires ongoing dialogue and collaboration between the regulatory bodies, such as the Food and Drug Administration, Center for Medicare and Medical Services, patient groups, and leaders from industry and academia.
There is a need to develop academic/clinical strategic cooperative pathways for the lifecycle of devices used in ICH (research—device approval). There is also a need to work closely with regulators to set practical criteria for conducting pilot multimodality and drug combination trials.
There is a regulator-payer evidence gap. It is important that trialists/sponsors work with the Food and Drug Administration and Center for Medicare and Medical Services to bridge the gap between evidence that is generated through trials performed primarily to obtain the evidence of safety and effectiveness needed for regulation, and the evidence to support the reasonable and necessary characteristics of a device or treatment needed for reimbursement in practice. Similarly, recognition of the different evidence requirements of and engagement with regulatory authorities and payers by researchers earlier in the development process could better inform study design to meet these requirements and address gaps between marketing approval and reimbursement. Payers play an important role to influence reimbursement, promote participation in trials, and advance knowledge in the field. For example, reimbursement for the use of devices not specifically approved for ICH in ICH practice should only be considered if data collection on the use of these devices occurs within the context of an approved clinical trial.26 Ideally, tissue collection should be tied to reimbursement.
The challenging nature of recruitment in ICH trials underscores the importance of global partnership and collaboration, and involvement of multinational sites to complete large trials. Several trials addressing similar questions or interventions have been conducted in various regions by different investigators in recent years. These trials were either too small to provide definite conclusions, or varied in design and cumulatively resulted in inconsistent conclusions. An international ICH consortium could offer an advantage by allowing for the joint development of unified designs and protocols to eliminate redundant trials and streamline future ICH research. There are several important challenges that need to be addressed, such as the conflicting prestige of the lead investigators and the complexity of merging funds and administrative responsibilities. The role of the funding source(s) has important implications. National funding sources from participating regions need to find innovative and flexible ways to overcome bureaucracy to share resources and form a merger to facilitate peer review and combined funding of high-impact trials.
The HEADS participants made the following recommendations to address the aforementioned gaps and challenges and to improve clinical research in ICH (Table 4).
Like acute ischemic stroke, time is of the essence in the effective management of ICH. Prehospital/inhospital ICH systems of care must have the same time demands as ischemic stroke.
An advocacy campaign targeting emergency response personnel and emergency department physicians to emphasize the importance of urgency in triaging and treating ICH patients; and quick transfer to comprehensive stroke centers (if warranted) is needed. Additionally, professional organizations, such as the American Heart Association/American Stroke Association, should develop a set of metrics and time-targets for ICH evaluation akin to the Get With The Guidelines targets for evaluating acute ischemic stroke.
Strategies directed at hematoma growth may have different acute time frames than those directed at inflammation and clot removal.
Research Priorities and Trial Design
More research is needed to develop innovative methods to diagnose ICH in the field, and control BP, reverse coagulopathy, and conduct effectiveness studies of hemostatic therapies trials in the prehospital setting.
Future trials in ICH must be more effective and efficient. Adaptive designs may offer benefits, particularly in phase II trials.
Phase II trials must assess the optimal dose, therapeutic time window, duration, and route of administration of experimental agents.
Trials exploring drug or multimodal combination therapy, and interventions to aid recovery, such as brain stimulation and restorative therapy, are needed.
Recruitment in ICH Trials
The feasibility of waiver of consent, community consent, or the use of technology such as telemedicine or smartphone video calling services to facilitate timely consent should be examined in future trials, particularly in the prehospital setting.
Collaborative efforts between the investigators, biostatisticians, funding, and regulatory agencies are needed to address some of the challenges limiting the use of adaptive and treatment-combination trials and to facilitate the best design tailored to the research question.
Increased cross-specialty collaboration and coordination between neurosurgeons, neurologists, intensivists, and emergency physicians at a given site is essential to balance recruitment into ICH trials and to assure fair randomization of patients into competing trials to minimize selection bias.
Innovations should not be limited to trials design, but should also extend to trials’ execution. Co-enrollment and sequential enrollment in ICH trials require further study and exploration.
Trial Conduct and Outcome Assessments
There is a need to develop specific ICH patient-centered outcome measures, and efficacy trials must assess functional outcomes up to 180 days or longer to capture the full extent of functional recovery. Additionally, cognitive assessments must be included as end points in all ICH trials.
The ability to conduct research activities at rehabilitation institutions must be improved to facilitate the transition of research activities to match the continuum of care from hospital-to-rehabilitation. The use of technology to facilitate and centralize follow-up assessments is encouraged.
Global and Multiorganizational Collaboration
ICH is a global disease and global collaboration is essential to facilitate timely completion of large ICH trials and ensure real-world applicability.
Research priorities must be aligned to avoid duplicate studies and expenses. We call on leaders of various ICH regional professional groups, such as HEADS, CoHESIVE (Canadian Hemorrhagic Stroke Trials Initiative), and EURONICH (European Research Network on Intracerebral Haemorrhage), to form a multidisciplinary international consortium of ICH collaborators to jointly develop and execute hemorrhagic stroke trials.
Funding agencies from various countries also need to work collaboratively to develop flexible pathways to facilitate multinational peer review and funding of high-impact trials.
Regulatory agencies, reimbursement organizations, academicians, and pharmaceutical and device companies need to work collaboratively to develop clear guidelines to allow the use of marketed devices for ICH in practice.
Efforts to develop effective treatments for ICH require adapting and improving the clinical trial design and protocol execution, global collaboration and partnership, and ongoing dialogue and cooperation between patients, providers, government regulatory, funding, and reimbursement bodies, industry, and academia. Research questions must be prioritized, protocols must be unified, and novel and more efficient trial designs are needed. We are hopeful that emerging recommendations from HEADS, which integrated thought-provoking and free debate between various stakeholders, will serve as benchmarks and standards for preclinical and human research in hemorrhagic stroke to accelerate the development of effective therapies for this devastating condition. Future HEADS meetings will extend focus to include subarachnoid hemorrhage, and treatment of cerebral aneurysms and vascular malformations.
HEADS Roundtable Participants
Chairs: Magdy Selim; Daniel Hanley.
Clinical: Joseph Broderick (Chair), Joshua N. Goldstein, Barbara A. Gregson, Guido Falcione, Nicole R. Gonzales, Edip Gurol, Jocelyn Kersten, Henry Lewkowicz, A. David Mendelow, Susanne Muehlschlegel, Richey Neuman, Yuko Palesch, Michael Rosenblum, Kevin N. Sheth, Vineeta Singh, Wendy Ziai.
Basic: Richard F. Keep (Chair), Jaroslaw Aronowski, Curtis Genstler, Michael L. James, Rajiv Ratan, Lauren Sansing, Anna Youd, Guohua Xi, Marietta Zille.
Other Participants and Contributors: Craig Anderson, Issam Awad, Eric Bastings, Martin Bednar, Alexander L. Coon, Rebecca Gottesman, Bryan Katz, Saima Khan, James Koenig, Walter Koroshetz, Shari Ling, Christopher Loftus, John Lockhardt, Thomas Louis, John Marler, Claudia Moy, Carlos Peña, Charles Pollack, Laurel Omert, Monica Shah, Ashkan Shoamanesh, Michael Singer, Thorsten Steiner, Michel Torbey, Mike Tymianski, Ajay Wakhloo, Paul Vespa, Mario Zuccarello, Xiaolin Zheng.
We thank Mani Bèrète Keita, Jamie Braun, Casey Norton, Claire Ruberman, the staff at Brain Injury Outcomes at Johns Hopkins, and Kenes Group for their help in organizing the HEADS (Hemorrhagic Stroke Academia Industry) meeting.
Sources of Funding
Dr Selim receives grant support from the National Institute of Neurological Disorders and Stroke (U01NS 074425) and American Heart Association (15CSA24540001).
- Received September 25, 2017.
- Revision received February 12, 2018.
- Accepted February 23, 2018.
- © 2018 American Heart Association, Inc.
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