Home Blood Pressure Telemonitoring and Nurse Case Management in Black and Hispanic Patients With Stroke: A Randomized Clinical Trial.

Importance: Black and Hispanic patients have high rates of recurrent stroke and uncontrolled hypertension in the US. The effectiveness of home blood pressure telemonitoring (HBPTM) and telephonic nurse case management (NCM) among low-income Black and Hispanic patients with stroke is unknown. Objective: To determine whether NCM plus HBPTM results in greater systolic blood pressure (SBP) reduction at 12 months and lower rate of stroke recurrence at 24 months than HBPTM alone among Black and Hispanic stroke survivors with uncontrolled hypertension. Design, Setting, and Participants: Practice-based, multicenter, randomized clinical trial in 8 stroke centers and ambulatory practices in New York City. Black and Hispanic study participants were enrolled between April 18, 2014, and December 19, 2017, with a final follow-up visit on December 31, 2019. Interventions: Participants were randomly assigned to receive either HBPTM alone (12 home BP measurements/week for 12 months, with results transmitted to a clinician; n = 226) or NCM plus HBPTM (20 counseling calls over 12 months; n = 224). Main Outcomes and Measures: Primary outcomes were change in SBP at 12 months and rate of recurrent stroke at 24 months. Final statistical analyses were completed March 14, 2024. Results: Among 450 participants who were enrolled and randomized (mean [SD] age, 61.7 [11.0] years; 51% were Black [n = 231]; 44% were women [n = 200]; 31% had ≥3 comorbid conditions [n = 137]; 72% had household income <$25 000/y [n = 234/324]), 358 (80%) completed the trial. Those in the NCM plus HBPTM group had a significantly greater SBP reduction than those in the HBPTM alone group at 12 months (-15.1 mm Hg [95% CI, -17.2 to -13.0] vs -5.8 mm Hg [95% CI, -7.9 to -3.7], respectively; P < .001). The between-group difference in SBP reduction at 12 months, adjusted for primary care physician clustering, was -8.1 mm Hg (95% CI, -11.2 to -5.0; P < .001) at 12 months. The rate of recurrent stroke was similar between both groups at 24 months (4.0% in the NCM plus HBPTM group vs 4.0% in the HBPTM alone group, P > .99). Conclusions and Relevance: Among predominantly low-income Black and Hispanic stroke survivors with uncontrolled hypertension, addition of NCM to HBPTM led to greater SBP reduction than HBPTM alone. Additional studies are needed to understand the long-term clinical outcomes, cost-effectiveness, and generalizability of NCM-enhanced telehealth programs among low-income Black and Hispanic stroke survivors with significant comorbidity. Trial Registration: Clinical Trials.gov Identifier: NCT02011685.

Racial/Ethnic Disparities in Atrial Fibrillation Treatment and Outcomes among Dialysis Patients in the United States.

BACKGROUND: Because stroke prevention is a major goal in the management of ESKD hemodialysis patients with atrial fibrillation, investigating racial/ethnic disparities in stroke among such patients is important to those who could benefit from strategies to maximize preventive measures. METHODS: We used the United States Renal Data System to identify ESKD patients who initiated hemodialysis from 2006 to 2013 and then identified those with a subsequent atrial fibrillation diagnosis and Medicare Part A/B/D. Patients were followed for 1 year for all-cause stroke, mortality, prescription medications, and cardiovascular disease procedures. The survival mediational g-formula quantified the percentage of excess strokes attributable to lower use of atrial fibrillation treatments by race/ethnicity. RESULTS: The study included 56,587 ESKD hemodialysis patients with atrial fibrillation. Black, white, Hispanic, and Asian patients accounted for 19%, 69%, 8%, and 3% of the population, respectively. Compared with white patients, black, Hispanic, or Asian patients were more likely to experience stroke (13%, 15%, and 16%, respectively) but less likely to fill a warfarin prescription (10%, 17%, and 28%, respectively). Warfarin prescription was associated with decreased stroke rates. Analyses suggested that equalizing the warfarin distribution to that in the white population would prevent 7%, 10%, and 12% of excess strokes among black, Hispanic, and Asian patients, respectively. We found no racial/ethnic disparities in all-cause mortality or use of cardiovascular disease procedures. CONCLUSIONS: Racial/ethnic disparities in all-cause stroke among hemodialysis patients with atrial fibrillation are partially mediated by lower use of anticoagulants among black, Hispanic, and Asian patients. The reasons for these disparities are unknown, but strategies to maximize stroke prevention in minority hemodialysis populations should be further investigated.

Concomitant Use of Gabapentinoids with Opioids Is Associated with Increased Mortality and Morbidity among Dialysis Patients.

BACKGROUND: The opioid epidemic is a public health emergency and appropriate medication prescription for pain remains challenging. Physicians have increasingly prescribed gabapentinoids for pain despite limited evidence supporting their use. We determined the prevalence of concomitant gabapentinoid and opioid prescriptions and evaluated their associations with outcomes among dialysis patients. METHODS: We used the United States Renal Data System to identify patients treated with dialysis with Part A, B, and D coverage for all of 2010. Patients were grouped into 4 categories of drugs exposure status in 2010: (1) no prescriptions of either an opioid or gabapentinoid, (2) ≥1 prescription of an opioid and no prescriptions of gabapentinoids, (3) no prescriptions of an opioid and ≥1 prescription of gabapenbtinoids, (4) ≥1 prescription of both an opioid and gabapentinoid. Outcomes included 2-year all-cause death, dialysis discontinuation, and hospitalizations assessed in 2011 and 2012. RESULTS: The study population included 153,758 dialysis patients. Concomitant prescription of an opioid and gabapentin (15%) was more common than concomitant prescription of an opioid and pregabalin (4%). In adjusted analyses, concomitant prescription of an opioid and gabapentin compared to no prescription of either was associated with increased risk of death (hazard ratio [HR] 1.16, 95% CI 1.12-1.19), dialysis discontinuation (HR 1.14, 95% CI 1.03-1.27), and hospitalization (HR 1.33, 95% CI 1.31-1.36). Concomitant prescription of an opioid and pregabalin compared to no prescription of either was associated with increased mortality (HR 1.22, 95% CI 1.16-1.28) and hospitalization (HR 1.37, 95% CI 1.33-1.41), but not dialysis discontinuation (HR 1.13, 95% CI 0.95-1.35). Prescription of opioids and gabepentinoids compared to only being prescribed opioids was associated with higher risk of hospitalizations, but not mortality, or dialysis discontinuation. CONCLUSIONS: Concomitant prescription of opioids and gabapentinoids among US dialysis patients is common, and both drugs have independent effects on outcomes. Future research should prospectively investigate the potential harms of such drugs and identify safer alternatives for treatment of pain in end-stage renal disease patients.

Epilepsy and antiseizure medications increase all-cause mortality in dialysis patients in the United States.

Seizures have been associated with uremia, but there are few data regarding the prevalence, treatment, and outcomes of patients with end-stage renal disease (ESRD) with epilepsy compared to those with ESRD without epilepsy. Here we conducted a retrospective cohort study using the United States Renal Data System to assess mortality and antiseizure medication prescriptions among patients with ESRD with and without a diagnosis of epilepsy. A modified Poisson regression with a robust variance was used to estimate the association between epilepsy status and mortality, and evaluate effect modification by neurology consultation. Additionally antiseizure medications were assessed in relation to mortality among those with epilepsy. Of 148,294 patients with ESRD in the cohort, 13,094 (8.8%) met a claims-based definition for epilepsy. Among those with epilepsy, 80.9% filled an anticonvulsant or hydantoin prescription in 2013-2014, compared to 33.3% without epilepsy. After adjustment for confounders, the mortality risk among those with epilepsy was 1.11 (95% confidence interval: 1.07, 1.14) times higher than those without. An epilepsy diagnosis was associated with a 15% increase in mortality risk among patients who did not have a neurology consultation (relative risk: 1.15 [95% confidence interval: 1.10, 1.20]), but this risk was attenuated among patients with a neurology consultation (1.07 [1.03, 1.11]). Prescription of gabapentin to patients with an epilepsy diagnosis compared to other antiseizure medications was associated with increased mortality (1.08 [1.01, 1.15]). Thus, patients with ESRD treated with dialysis have a high prevalence of epilepsy, which was associated with increased mortality risk compared to those without epilepsy. Hence, appropriate multidisciplinary care, treatment, and medication selection may reduce mortality among dialysis patients with epilepsy.

Defining Optimal Brain Health in Adults: A Presidential Advisory From the American Heart Association/American Stroke Association.

Cognitive function is an important component of aging and predicts quality of life, functional independence, and risk of institutionalization. Advances in our understanding of the role of cardiovascular risks have shown them to be closely associated with cognitive impairment and dementia. Because many cardiovascular risks are modifiable, it may be possible to maintain brain health and to prevent dementia in later life. The purpose of this American Heart Association (AHA)/American Stroke Association presidential advisory is to provide an initial definition of optimal brain health in adults and guidance on how to maintain brain health. We identify metrics to define optimal brain health in adults based on inclusion of factors that could be measured, monitored, and modified. From these practical considerations, we identified 7 metrics to define optimal brain health in adults that originated from AHA's Life's Simple 7: 4 ideal health behaviors (nonsmoking, physical activity at goal levels, healthy diet consistent with current guideline levels, and body mass index <25 kg/m2) and 3 ideal health factors (untreated blood pressure <120/<80 mm Hg, untreated total cholesterol <200 mg/dL, and fasting blood glucose <100 mg/dL). In addition, in relation to maintenance of cognitive health, we recommend following previously published guidance from the AHA/American Stroke Association, Institute of Medicine, and Alzheimer's Association that incorporates control of cardiovascular risks and suggest social engagement and other related strategies. We define optimal brain health but recognize that the truly ideal circumstance may be uncommon because there is a continuum of brain health as demonstrated by AHA's Life's Simple 7. Therefore, there is opportunity to improve brain health through primordial prevention and other interventions. Furthermore, although cardiovascular risks align well with brain health, we acknowledge that other factors differing from those related to cardiovascular health may drive cognitive health. Defining optimal brain health in adults and its maintenance is consistent with the AHA's Strategic Impact Goal to improve cardiovascular health of all Americans by 20% and to reduce deaths resulting from cardiovascular disease and stroke by 20% by the year 2020. This work in defining optimal brain health in adults serves to provide the AHA/American Stroke Association with a foundation for a new strategic direction going forward in cardiovascular health promotion and disease prevention.

Disparities and Trends in Door-to-Needle Time: The FL-PR CReSD Study (Florida-Puerto Rico Collaboration to Reduce Stroke Disparities).

BACKGROUND AND PURPOSE: In the United States, about half of acute ischemic stroke patients treated with tPA (tissue-type plasminogen activator) receive treatment within 60 minutes of hospital arrival. We aimed to determine the proportion of patients receiving tPA within 60 minutes (door-to-needle time [DTNT] ≤60) and 45 minutes (DTNT ≤45) of hospital arrival by race/ethnicity and sex and to identify temporal trends in DTNT ≤60 and DTNT ≤45. METHODS: Among 65 654 acute ischemic stroke admissions in the National Institute of Neurological Disorders and Stroke-funded FL-PR CReSD study (Florida-Puerto Rico Collaboration to Reduce Stroke Disparities) from 2010 to 2015, we included 6181 intravenous tPA-treated cases (9.4%). Generalized estimating equations were used to determine predictors of DTNT ≤60 and DTNT ≤45. RESULTS: DTNT ≤60 was achieved in 42% and DTNT ≤45 in 18% of cases. After adjustment, women less likely received DTNT ≤60 (odds ratio, 0.81; 95% confidence interval, 0.72-0.92) and DTNT ≤45 (odds ratio, 0.73; 95% confidence interval, 0.57-0.93). Compared with Whites, Blacks less likely had DTNT ≤45 during off hours (odds ratio, 0.68; 95% confidence interval, 0.47-0.98). Achievement of DTNT ≤60 and DTNT ≤45 was highest in South Florida (50%, 23%) and lowest in West Central Florida (28%, 11%). CONCLUSIONS: In the FL-PR CReSD, achievement of DTNT ≤60 and DTNT ≤45 remains low. Compared with Whites, Blacks less likely receive tPA treatment within 45 minutes during off hours. Treatment within 60 and 45 minutes is lower in women compared with men and lowest in West Central Florida compared with other Florida regions and Puerto Rico. Further research is needed to identify reasons for delayed thrombolytic treatment in women and Blacks and factors contributing to regional disparities in DTNT.

Stroke Hospital Characteristics in the Florida-Puerto Rico Collaboration to Reduce Stroke Disparities Study.

OBJECTIVES: Although disparities in stroke care and outcomes have been well documented nationally, state-based registries to monitor acute stroke care in Florida (FL) and Puerto Rico (PR) have not been established. The FL-PR Collaboration to Reduce Stroke Disparities (CReSD) was developed to evaluate race-ethnicity and regional disparities in stroke care performance. The objective of this study was to assess and compare hospital characteristics within a large quality improvement registry to identify characteristics associated with better outcomes for acute ischemic stroke care. METHODS: Trained personnel from 78 FL-PR CReSD hospitals (69 FL, 9 PR) completed a 50-item survey assessing institutional characteristics across seven domains: acute stroke care resource availability, emergency medical services integration, stroke center certification, data collection and use, quality improvement processes, FL-PR CReSD recruitment incentives, and hospital infrastructure. RESULTS: The rate of survey completion was 100%. Differences were observed both within FL and between FL and PR. Years participating in Get With The Guidelines-Stroke (8.9 ± 2.6 years FL vs 4.8 ± 2.4 years PR, P < 0.0001) and proportion of hospitals with any stroke center certification (94.2% FL vs 11.1% PR, P < 0.0001) showed the largest variations. Smaller hospital size, fewer years in Get With The Guidelines-Stroke, and lack of stroke center designation and acute stroke care practice implementation may contribute to poorer outcomes. CONCLUSIONS: Results from our survey indicated variability in hospital- and system-level characteristics in stroke care across hospitals in Florida and Puerto Rico. Identification of these variations, which may explain potential disparities, can help clinicians understand gaps in stroke care and outcomes and targeted interventions to reduce identified disparities can be implemented.

Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection.

BACKGROUND AND PURPOSE: The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial. METHODS: The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria. RESULTS: Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment. CONCLUSIONS: It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714.

Sex Disparities in Ischemic Stroke Care: FL-PR CReSD Study (Florida-Puerto Rico Collaboration to Reduce Stroke Disparities).

BACKGROUND AND PURPOSE: Sex-specific disparities in stroke care including thrombolytic therapy and early hospital admission are reported. In a large registry of Florida and Puerto Rico hospitals participating in the Get With The Guidelines-Stroke program, we sought to determine sex-specific differences in ischemic stroke performance metrics and overall thrombolytic treatment. METHODS: Around 51 317 (49% women) patients were included from 73 sites from 2010 to 2014. Multivariable logistic regression with generalized estimating equations evaluated sex-specific differences in the prespecified Get With The Guidelines-Stroke metrics for defect-free care in ischemic stroke, adjusting for age, race-ethnicity, insurance status, hospital characteristics, individual risk factors, and the presenting stroke severity. RESULTS: As compared with men, women were older (73±15 versus 69±14 years; P<0.0001), more hypertensive (67% versus 63%, P<0.0001), and had more atrial fibrillation (19% versus 16%; P<0.0001). Defect-free care was slightly lower in women than in men (odds ratio, 0.96; 95% confidence interval, 0.93-1.00). Temporal trends in defect-free care improved substantially and similarly for men and women, with a 29% absolute improvement in women (P<0.0001) and 28% in men (P<0.0001), with P value of 0.13 for time-by-sex interaction. Women were less likely to receive thrombolysis (odds ratio, 0.92; 95% confidence interval, 0.86-0.99; P=0.02) and less likely to have a door-to-needle time <1 hour (odds ratio, 0.83; 95% confidence interval, 0.71-0.97; P=0.02) as compared with men. CONCLUSIONS: Women received comparable stroke care to men in this registry as measured by prespecified Get With The Guidelines metrics. However, women less likely received thrombolysis and had door-to-needle time <1 hour, an observation that calls for the implementation of interventions to reduce sex disparity in these measures.

The Science of Vascular Contributions to Cognitive Impairment and Dementia (VCID): A Framework for Advancing Research Priorities in the Cerebrovascular Biology of Cognitive Decline.

The World Health Organization reports that 47.5 million people are affected by dementia worldwide. With aging populations and 7.7 million new cases each year, the burden of illness due to dementia approaches crisis proportions. Despite significant advances in our understanding of the biology of Alzheimer's disease (AD), the leading dementia diagnosis, the actual causes of dementia in affected individuals are unknown except for rare fully penetrant genetic forms. Evidence from epidemiology and pathology studies indicates that damage to the vascular system is associated with an increased risk of many types of dementia. Both Alzheimer's pathology and cerebrovascular disease increase with age. How AD affects small blood vessel function and how vascular dysfunction contributes to the molecular pathology of Alzheimer's are areas of intense research. The science of vascular contributions to cognitive impairment and dementia (VCID) integrates diverse aspects of biology and incorporates the roles of multiple cell types that support the function of neural tissue. Because of the proven ability to prevent and treat cardiovascular disease and hypertension with population benefits for heart and stroke outcomes, it is proposed that understanding and targeting the biological mechanisms of VCID can have a similarly positive impact on public health.

Examining Barriers and Practices to Recruitment and Retention in Stroke Clinical Trials.

BACKGROUND AND PURPOSE: The National Institutes of Health policy calls for the inclusion of under-represented groups, such as women and minorities, in clinical research. Poor minority recruitment and retention in stroke clinical trials remain a significant challenge limiting safety and efficacy in a general population. Previous research examines participant barriers to clinical trial involvement, but little is known about the investigator perspective. This study addresses this gap and examines researcher-reported barriers and best practices of minority involvement in stroke clinical trials. METHODS: Quantitative and qualitative methods, including surveys, focus groups, and key informant interviews were used. RESULTS: In a survey of 93 prominent stroke researchers, 43 (51.2%; 70% response rate) respondents reported proactively setting recruitment goals for minority inclusion, 29 respondents (36.3%) reported requiring cultural competency staff training, and 44 respondents (51.2%) reported using community consultation about trial design. Focus groups and key informant interviews highlighted structural and institutional challenges to recruitment of minorities, including mistrust of the research/medical enterprise, poor communication, and lack of understanding of clinical trials. Researcher-identified best practices included using standardized project management procedures and protocols (eg, realistic budgeting to support challenges in recruitment, such as travel/parking reimbursement for participants), research staff cultural competency and communication training, and developing and fostering community partnerships that guide the research process. CONCLUSIONS: This study's formative evaluation contributes a new dimension to the literature as it highlights researcher-reported barriers and best practices for enhancing participation of minority populations into stroke clinical trials.

Prophylactic Antiepileptic Drug Use and Outcome in the Ethnic/Racial Variations of Intracerebral Hemorrhage Study.

BACKGROUND AND PURPOSE: The role of antiepileptic drug (AED) prophylaxis after intracerebral hemorrhage (ICH) remains unclear. This analysis describes prevalence of prophylactic AED use, as directed by treating clinicians, in a prospective ICH cohort and tests the hypothesis that it is associated with poor outcome. METHODS: Analysis included 744 patients with ICH enrolled in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study before November 2012. Baseline clinical characteristics and AED use were recorded in standardized fashion. ICH location and volume were recorded from baseline neuroimaging. We analyzed differences in patient characteristics by AED prophylaxis, and we used logistic regression to test whether AED prophylaxis was associated with poor outcome. The primary outcome was 3-month modified Rankin Scale score, with 4 to 6 considered poor outcome. RESULTS: AEDs were used for prophylaxis in 289 (39%) of the 744 subjects; of these, levetiracetam was used in 89%. Patients with lobar ICH, craniotomy, or larger hematomas were more likely to receive prophlyaxis. Although prophylactic AED use was associated with poor outcome in an unadjusted model (odds ratio, 1.40; 95% confidence interval, 1.04-1.88; P=0.03), this association was no longer significant after adjusting for clinical and demographic characteristics (odds ratio, 1.11; 95% confidence interval, 0.74-1.65; P=0.62). CONCLUSIONS: We found no evidence that AED use (predominantly levetiracetam) is independently associated with poor outcome. A prospective study is required to assess for a more modest effect of AED use on outcome after ICH.

From Data to Action: Neuroepidemiology Informs Implementation Research for Global Stroke Prevention and Treatment.

As a scientific field of study, neuroepidemiology encompasses more than just the descriptive study of the frequency, distribution, determinants and outcomes of neurologic diseases in populations. It also includes experimental aspects that span the full spectrum of clinical and population science research. As such, neuroepidemiology has a strong potential to inform implementation research for global stroke prevention and treatment. This review begins with an overview of the progress that has been made in descriptive and experimental neuroepidemiology over the past quarter century with emphasis on standards for evidence generation, critical appraisal of that evidence and impact on clinical and public health practice at the national, regional and global levels. Specific advances made in high-income countries as well as in low- and middle-income countries are presented. Gaps in implementation as well as evidence gaps in stroke research, stroke burden, clinical outcomes and disparities between developed and developing countries are then described. The continuing need for high quality neuroepidemiologic data in low- and middle-income countries is highlighted. Additionally, persisting disparities in stroke burden and care by sex, race, ethnicity, income and socioeconomic status are discussed. The crucial role that national stroke registries have played in neuroepidemiologic research is also addressed. Opportunities presented by new directions in comparative effectiveness and implementation research are discussed as avenues for turning neuroepidemiological insights into action to maximize health impact and to guide further biomedical research on neurological diseases.

Selecting trial centers using a standardized, automated site assessment survey instrument (SASI).

BACKGROUND: To improve the site selection process for clinical trials, we expanded a site survey to include standardized assessments of site commitment time, team experience, feasibility of tight timelines, and local medical community equipoise as factors that might better predict performance. We also collected contact information about institutional research services ahead of site onboarding. AIM: As a first step, we wanted to confirm that an expanded survey could be feasible and generalizable-that asking site teams for more details upfront was acceptable and that the survey could be completed in a reasonable amount of time, despite the assessment length. METHODS: A standardized, two-part Site Assessment Survey Instrument (SASI), examining qualitative components and with multiple contact list sections, was developed using a publicly accessible dashboard and later transferred to a REDCap platform. After multiple rounds of internal testing, the SASI was deployed 11 times for multicenter trials. Follow-up questionnaires were sent to site teams to confirm that an expanded survey instrument is acceptable to the research community and could be completed during a brief work shift. RESULTS: Respondents thought the SASI collected useful and relevant information about their sites (100%). Sites were "comfortable" (90%) supplying detailed information early in the site selection process and 57% completed the SASI in one to two hours. CONCLUSIONS: Coordinating centers and sites found the SASI tool to be acceptable and helpful when collecting data in consideration of multicenter trial site selection.

The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study protocol.

BACKGROUND AND PURPOSE: Epidemiological studies of intracerebral hemorrhage (ICH) have consistently demonstrated variation in incidence, location, age at presentation, and outcomes among non-Hispanic white, black, and Hispanic populations. We report here the design and methods for this large, prospective, multi-center case-control study of ICH. METHODS: The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a multi-center, prospective case-control study of ICH. Cases are identified by hot-pursuit and enrolled using standard phenotype and risk factor information and include neuroimaging and blood sample collection. Controls are centrally identified by random digit dialing to match cases by age (±5 years), race, ethnicity, sex, and metropolitan region. RESULTS: As of March 22, 2013, 1655 cases of ICH had been recruited into the study, which is 101.5% of the target for that date, and 851 controls had been recruited, which is 67.2% of the target for that date (1267 controls) for a total of 2506 subjects, which is 86.5% of the target for that date (2897 subjects). Of the 1655 cases enrolled, 1640 cases had the case interview entered into the database, of which 628 (38%) were non-Hispanic black, 458 (28%) were non-Hispanic white, and 554 (34%) were Hispanic. Of the 1197 cases with imaging submitted, 876 (73.2%) had a 24 hour follow-up CT available. In addition to CT imaging, 607 cases have had MRI evaluation. CONCLUSIONS: The ERICH study is a large, case-control study of ICH with particular emphasis on recruitment of minority populations for the identification of genetic and epidemiological risk factors for ICH and outcomes after ICH.

Comparative effectiveness and implementation research: directions for neurology.

There is an enormous unmet need for knowledge about how new insights from discovery and translational research can yield measurable, population-level improvements in health and reduction in mortality among those having or at risk for neurological disease. Once several, well-conducted randomized controlled trials establish the efficacy of a given therapy, implementation research can generate new knowledge about barriers to uptake of the therapy into widespread clinical care, and what strategies are effective in overcoming those barriers and in addressing health disparities. Comparative effectiveness research aims to elucidate the relative value (including clinical benefit, clinical harms, and/or costs) of alternative efficacious management approaches to a neurological disorder, generally through direct comparisons, and may include comparisons of methodologies for implementation. Congress has recently appropriated resources and established an institute to prioritize funding for such research. Neurologists and neuroscientists should understand the scope and objectives of comparative effectiveness and implementation research, their range of methodological approaches (formal literature syntheses, randomized trials, observational studies, modeling), and existing research resources (centers for literature synthesis, registries, practice networks) relevant to research for neurological conditions, to close the well-documented evidence-to-practice gap. Future directions include building this research resource capacity, producing scientists trained to conduct rigorous comparative effectiveness and implementation research, and embracing innovative strategies to set research priorities in these areas.

Approaches for enhancing the informativeness and quality of clinical trials: Innovations and principles for implementing multicenter trials from the Trial Innovation Network.

One challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities. This communication draws on the experience of the National Center for Advancing Translational Science (NCATS) Trial Innovation Network (TIN) to develop approaches for enhancing the informativeness of clinical trials. We distilled this information into three principles: (1) assemble a diverse team, (2) leverage existing processes and systems, and (3) carefully consider budgets and contracts. The TIN, comprised of NCATS, three Trial Innovation Centers, a Recruitment Innovation Center, and 60+ CTSA Program hubs, provides resources to investigators who are proposing multicenter collaborations. In addition to sharing principles that support the informativeness of clinical trials, we highlight TIN-developed resources relevant for multicenter trial initiation and conduct.

Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned.

New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or "hybrid" trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.

A causal roadmap for generating high-quality real-world evidence.

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.