Secondary Stroke Prevention Trials Research Articles

Are we ready to cure post-stroke cognitive impairment? Many key prerequisites can be achieved quickly and easily.

Post-stroke (PS) cognitive impairment (CI) is frequent and its devastating functional and vital consequences are well known. Despite recent guidelines, they are still largely neglected. A large number of recent studies have re-examined the epidemiology, diagnosis, imaging determinants and management of PSCI. The aim of this update is to determine whether these new data answer the questions that are essential to reducing PSCI, the unmet needs, and steps still to be taken. Literature review of stroke unit-era studies examining key steps in the management of PSCI: epidemiology and risk factors, diagnosis (cognitive profile and assessments), imaging determinants (quantitative measures, voxelwise localization, the disconnectome and associated Alzheimer's disease [AD]) and treatment (secondary prevention, symptomatic drugs, rehabilitation and noninvasive brain stimulation) of PSCI. (1) the prevalence of PSCI of approximately 50% is probably underestimated; (2) the sensitivity of screening tests should be improved to detect mild PSCI; (3) comprehensive assessment is now well-defined and should include apathy; (4) easily available factors can identify patients at high risk of PSCI; (5) key imaging determinants are the location and volume of the lesion and the resulting disconnection, associated AD and brain atrophy; WMH, ePVS, microhemorrhages, hemosiderosis, and cortical microinfarcts may contribute to cognitive impairment but are more likely to be markers of brain vulnerability or associated AD that reduce PS recovery; (6) remote and online assessment is a promising approach for selected patients; (7) secondary stroke prevention has not been proven to prevent PSCI; (8) symptomatic drugs are ineffective in treating PSCI and apathy; (9) in addition to cognitive rehabilitation, the benefits of training platforms and computerized training are yet to be documented; (10) the results and the magnitude of improvement of noninvasive brain stimulation, while very promising, need to be substantiated by large, high-quality, sham-controlled RCTs. These major advances pave the way for the reduction of PSCI. They include (1) the development of more sensitive screening tests applicable to all patients and (2) online remote assessment; crossvalidation of (3) clinical and (4) imaging factors to (5) identify patients at risk, as well as (6) factors that prompt a search for associated AD; (7) the inclusion of cognitive outcome as a secondary endpoint in acute and secondary stroke prevention trials; and (8) the validation of the benefit of noninvasive brain stimulation through high-quality, randomized, sham-controlled trials. Many of these objectives can be rapidly and easily attained.

Abstract 132: Disability and Enrollment in Secondary Stroke Prevention Trials: Evidence for a New Paradigm of Inclusion

Background: Ischemic stroke secondary prevention trials have disproportionately enrolled participants with mild or no disability. The impact of this skew on trial event rates is unclear. Methods: We included participants with ischemic stroke in two secondary stroke prevention trials, PRoFESS and IRIS. The exposure was functional status at entry, defined as modified Rankin Scale (mRS) 0 vs. 1-2 vs. >2. The primary outcome was recurrent stroke (ischemic or hemorrhagic). The secondary outcome was a composite of major adverse cardiovascular events (MACE=stroke, myocardial infarction, heart failure, and vascular death). Results: The cohorts had 20,384 participants from PRoFESS and 3,374 from IRIS. The mean duration of follow-up was 2.4 years in PRoFESS and 3.8 years in IRIS. The rate of recurrent stroke in the mRS categories (0 vs. 1-2 vs. >2) was 7.2%, 8.7%, and 10.6% in PRoFESS and 6.2%, 9.1%, and 11.9% in IRIS (both p≤0.001). The rate of MACE in the mRS categories was 10.1%, 12.2%, and 17.3% in PRoFESS (p<0.001) and 10.6%, 13.3%, and 15.3% in IRIS (p=0.030). In both trials we saw consistent increases in the hazard ratio for recurrent stroke (Table 1) and MACE (Table 2) across mRS categories, after adjusting for potential confounders. There was no evidence that treatment effects differed across mRS categories (mRS by treatment interaction p>0.4). Conclusion: Secondary stroke prevention trial participants with higher levels of baseline disability have increased rates of recurrent stroke and MACE. By enrolling participants across the full range of disability, stroke trials would observe more recurrent stroke events, enhance statistical power, and improve generalizability of results.

Assessment of Process Evaluations of Complex Stroke Rehabilitation and Secondary Stroke Prevention Trials—A Scoping Review

Background Complexity of interventions and lack of methodological clarity makes process evaluations (PEs) challenging. Assessment of PEs conducted for complex stroke rehabilitation and nonpharmacologic secondary stroke prevention interventions is lacking with only one study conducted for the latter. To address this gap, we conducted a scoping review. Methods Development and reporting of review follows Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for Scoping Reviews. Research questions were identified and search phrases developed according to keywords on 3 electronic databases: PubMed, Web of Science, and Cochrane Library. All titles and available abstracts were independently reviewed by 2 authors and disagreements settled by other authors. Inclusion criteria centered on complex secondary stroke nonpharmacologic prevention or a rehabilitation trial. Results Selected studies (n = 11) were derived from (n = 24) articles reporting on PE of main trial (n = 10). Studies are from 2015 onward with 9 studies for stroke rehabilitation and 1 from secondary stroke prevention, out of these 7 are randomized clinical trials. Medical Research Council’s framework was most widely used with common data collection method being interviews, surveys and log records. More than half of the studies are mobile health based which reveals future for stroke rehabilitation and stroke prevention interventions. We identified 3 themes on qualitative analysis of articles. Conclusion Paucity of relevant research studies indicates that more research should be carried out for PEs in stroke rehabilitation and prevention. Researchers in future may find guidance from this review where we support clarity on framework and its elements that helped to evaluate methodology.

Abstract WP47: Telemedicine And Remote Research Practice Use In Clinical Trials Among StrokeNet Sites

Background: A hybrid of remote and in-person conduct of research may improve recruitment and retention rates in clinical trials. However, little is known about the current state of remote research practices (RRPs) in stroke trials. Our objective was to characterize the use of telemedicine and RRPs among sites, including Regional Coordinating Centers (RCCs), within NIH StrokeNet. Methods: All NIH StrokeNet clinical sites were sent a standardized questionnaire surveying their voluntary adoption of telemedicine and RRPs in stroke clinical trial recruitment both locally and remotely at affiliated stroke hospitals. The survey was distributed to attendees of the spring StrokeNet conference. The survey results are described using descriptive statistics. Results: Overall, 39 StrokeNet sites (16 RCCs [64.0%]) responded to the survey between April 2022 and July 2022. Thirty-one sites (79.5%) used telemedicine in clinical trials in the following settings: outpatient (66.7%), Emergency Department (46.2%), and inpatient (41.0%). Telemedicine was most commonly utilized for follow-up assessment (51.3%), trial screening (43.6%), obtaining informed consent (43.6%), and guiding the study intervention (33.3%). Reported rates of electronic informed consent use was as follows: 30 sites (76.9%) for acute stroke trials, 22 (56.4%) for secondary stroke prevention trials, and 15 (38.4%) for stroke recovery trials. Only 9 sites (23.1%) reported remotely enrolling patients at affiliated telestroke hospitals and 8 sites (20.5%) initiated study interventions remotely. Conclusions: Telemedicine and e-consent were used at many responding StrokeNet clinical trial sites. Future research is needed to understand the added value of telemedicine and RRPs in clinical research, barriers to adoption, and ideal future state.

Impact of Model Choice When Studying the Relationship Between Blood Pressure Variability and Risk of Stroke Recurrence.

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Cilostazol for Secondary Stroke Prevention: History, Evidence, Limitations, and Possibilities.

Cilostazol is a PDE3 (phosphodiesterase III) inhibitor with a long track record of safety that is Food and Drug Administration and European Medicines Agency approved for the treatment of claudication in patients with peripheral arterial disease. In addition, cilostazol has been approved for secondary stroke prevention in several Asian countries based on trials that have demonstrated a reduction in stroke recurrence among patients with noncardioembolic stroke. The onset of benefit appears after 60 to 90 days of treatment, which is consistent with cilostazol's pleiotropic effects on platelet aggregation, vascular remodeling, blood flow, and plasma lipids. Cilostazol appears safe and does not increase the risk of major bleeding when given alone or in combination with aspirin or clopidogrel. Adverse effects such as headache, gastrointestinal symptoms, and palpitations, however, contributed to a 6% increase in drug discontinuation among patients randomized to cilostazol in a large secondary stroke prevention trial (CSPS.com [Cilostazol Stroke Prevention Study for Antiplatelet Combination]). Due to limitations of prior trials, such as open-label design, premature trial termination, large loss to follow-up, lack of functional or cognitive outcome data, and exclusive enrollment in Asia, the existing trials have not led to a change in clinical practice or guidelines in Western countries. These limitations could be addressed by a double-blind placebo-controlled randomized trial conducted in a broader population. If positive, it would increase the evidence in support of long-term treatment with cilostazol for secondary prevention in the millions of patients worldwide who have experienced a noncardioembolic ischemic stroke.

Increased prevalence of Stroke Recurrence and Stroke Related Mortality in Children with Sickle Cell Disease in Nigeria: evidence for a Secondary Stroke Prevention Trial.

Introduction- Nigeria has the highest burden of sickle cell anemia (SCA) in the world accounting for 50% of the 300,000 SCA births globally. In a recent survey conducted locally in Nigeria, Kano state was shown to have the highest number of children with SCA in Nigeria, with Kano metropolitan city alone having over 15,000 children with SCA. Stroke is one of the most devastating yet preventable complications in children with SCA. Without transcranial Doppler (TCD) screening and treatment, approximately 7 to 10% of the children with SCA will develop strokes. Among untreated children with strokes, there is at least a 50% recurrence rate after 2 years. Due to the high rate of stroke recurrence and the absence of regular blood transfusion therapy as a viable option due to availability, poor parental acceptance of blood transfusion, and cost, hydroxyurea therapy is the only viable option for the majority of children. However, the benefit and risks of hydroxyurea for secondary stroke prevention is poorly defined in Nigeria.Methodology- In preparation for a phase III trial of hydroxyurea for secondary stroke prevention in children with SCA in sub-Saharan Africa, we initiated a standard care protocol in 2014 to manage children with strokes at Aminu Kano Teaching Hospital Kano, Nigeria, to determine the prevalence of stroke among children with SCA between Jan 2014 to May 2017. Ethical approval to conduct the study was received from the ethics committee of Aminu Kano Teaching hospital in Kano, Nigeria.Result-We identified 29 children with SCA who had an initial stroke within the study period, with 7 children having >1 stroke, and a mortality rate of 6.9% (2/29). Death was unrelated to any toxicity associated with hydroxyurea. None of the children treated with hydroxyurea, had therapy held because of myelosuppression or anemia. The rate of initial stroke in the pediatric clinic population of approximately 500 children (age birth through 12 years) over a three-year period was 1.97 per 100 patient-years. The median age for the first stroke was 5.6 years (range 1.1 to 14.2 years). Children with initial strokes were followed for a total of 38.8 years and had a rate of recurrence of 18.1 events per 100 patient-years, (figure 1) significantly below the expected rate of 29 events per 100 patient years if no treatment was offered, but a significantly higher incidence rate compared to regular blood transfusion of 1.9 events per patient year. Of the patients with an initial stroke, 65.5% received an exchange transfusion and 92.6% were either already on hydroxyurea (n=1) or started on fixed dose hydroxyurea (n=24), 20 mg/kg/day, within 2 months of the stroke, as part of standard care. The median modified Rankin was 1 with a range from 0 to 6, on the gross motor function classification system score. 10 children (40.0%) had normal function and 6 (24.0%) had level III or higher. Both measurements were completed at a median of 1.6 years (IQR 1.9 years) after the initial stroke. (Table I)Conclusion-Our results provide strong evidence for the high prevalence of stroke and death following a stroke in children with SCA in Nigeria. Optimal hydroxyurea dose for secondary stroke prevention is unknown in low-resource setting. Given the prevalence of strokes in unscreened and untreated children with SCA, primary and secondary stroke prevention program are a public urgency in children with SCA living in Nigeria. We are currently conducting a randomized controlled trial for secondary prevention of strokes comparing fixed dose of 20 mg/kg/day vs 10 mg/kg/day (NCT NCT01801423). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cross-sectional study on patients' understanding and views of the informed consent procedure of a secondary stroke prevention trial.

Improving understanding of study contents and procedures might enhance recruitment into studies and retention during follow-up. However, data in stroke patients on understanding of the informed consent (IC) procedure are sparse. We conducted a cross-sectional study among ischemic stroke patients taking part in the IC procedure of an ongoing cluster-randomized secondary prevention trial. All aspects of the IC procedure were assessed in an interview using a standardized 20-item questionnaire. Responses were collected within 72h after the IC procedure and analyzed quantitatively and qualitatively. Participants were also asked their main reasons for participation. A total of 146 stroke patients (65±12years old, 38% female) were enrolled. On average, patients recalled 66.4% (95% confidence interval = 65.2%-67.5%) of the content of the IC procedure. Most patients understood that participation was voluntary (99.3%) and that they had the right to withdraw consent (97.1%); 79.1% of the patients recalled the study duration and 56.1% the goal. Only 40.3% could clearly state a benefit of participation, and 28.8% knew their group allocation. Younger age, higher graduation, and allocation to the intervention group were associated with better understanding. Of all patients, 53% exclusively stated a personal and 22% an altruistic reason for participation. Whereas understanding of patient rights was high, many patients were unable to recall other important aspects of study content and procedures. Increased attention to older and less educated patients may help to enhance understanding in this patient population. Actual recruitment and retention benefit of an improved IC procedure remains to be tested in a randomized trial.

Impact of model choice when studying the relationship between blood pressure variability and risk of stroke

Long-term blood pressure variability (BPV), an increasingly recognized vascular risk factor, is challenging to define and to analyze. In order to take into account two major methodological issues - conditioning on the future and uncertainty around BPV value - we compared different models on the risk of stroke in a large dataset. We used data from the PROGRESS trial, a secondary stroke prevention trial which included 6105 subjects followed-up during four years. The median number of BP measurements was 12 and 727 strokes occurred. We compared a naive Cox model including BPV as a fixed covariate calculated on the entire follow-up, to other models aimed at avoiding conditioning on the future and taking into account uncertainty around BPV value. We found that BPV was associated with an increased risk of stroke when using a naive Cox Model (HR = 1.19, 95% CI: 1.10–1.30) but not when using other models dealing more appropriately with the issue of conditioning on the future. These results illustrate that the methods used to estimate the association between BPV and stroke may affect the estimates and that more appropriate models tend to reduce this association. Figure: http://extranet.insight-outside.fr/upload/compte1352/Base/inscriptions_projets/image/99861-image.pdf

IMPACT OF MODEL CHOICE WHEN STUDYING THE RELATIONSHIP BETWEEN BLOOD PRESSURE VARIABILITY AND RISK OF STROKE

Objective: Long-term blood pressure variability (BPV), an increasingly recognized vascular risk factor, is challenging to define and to analyze. In order to take into account two major methodological issues - conditioning on the future and uncertainty around BPV value - we compared different models on the risk of stroke in a large dataset Design and method: We used data from the PROGRESS trial, a secondary stroke prevention trial which included 6105 subjects followed-up during 4 years. The median number of BP measurements was 12 and 727 strokes occurred. We compared a naive Cox model including BPV as a fixed covariate calculated on the entire follow-up, to other models aimed at avoiding conditioning on the future and taking into account uncertainty around BPV value. Results: We found that BPV was associated with an increased risk of stroke when using a naive Cox Model (HR = 1.19, 95% CI: 1.10 – 1.30) but not when using other models dealing more appropriately with the issue of conditioning on the future. Conclusions: These results illustrate that the methods used to estimate the association between BPV and stroke may affect the estimates and that more appropriate models tend to reduce this association.

Abstract WMP95: Sociodemographic Factors Associated With Retention of Minorities: Findings From the Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities (SUCCEED) Trial

Background: Minority and socioeconomically disadvantaged individuals are underrepresented in secondary stroke prevention trials. Little is known about factors associated with study retention in these populations. Objective: To evaluate the impact of sociodemographic characteristics on retention in the Secondary stroke prevention by Uniting Community and Chronic care model teams Early to End Disparities (SUCCEED) trial. Methods: 487 participants ≥40 years with stroke/TIA were recruited from 4 safety-net hospitals and 1 stroke center serving low income zip codes. Strategies for boosting retention included: having bilingual research assistants from similar cultures establish rapport and follow participants; culturally and linguistically tailoring materials; arranging visits around participants’ schedules; offering transportation, and conducting assessments in the home and community. We compared sociodemographic characteristics among those retained at 12 months (n=412) vs. those not retained (n=75) using t-test, Chi Square, and Fisher exact tests. Independent factors associated with retention were determined using logistic regression. Results: Average age was 57 years, 18% were black, 71% were Hispanic, 58% were Spanish-speaking, and 72% were born outside the US. 12-month retention was 85%. On bivariate analysis, factors associated with retention were: Spanish-speaking, Hispanic ethnicity, younger age, born outside the US, and married status (all p<0.05). After multivariate analysis, study site, younger age (<64 vs ≥65 years OR 2.2, 95% CI 1.1,4.4), married status (OR 2.0, 1.0,4.2), government insurance (vs uninsured OR 25.1, 1.2,5.1), private insurance (vs uninsured, OR 4.6, 1.3,16.4), and inability to afford medical care (OR 2.9, 1.3,6.7) were associated with retention. Discussion: In this secondary prevention trial of stroke survivors from predominantly minority backgrounds, younger age, marriage, and insurance were associated with retention, suggesting that addressing barriers in the elderly, and those without insurance or spousal support may be beneficial. Financial constraints were associated with retention suggesting that study participation appealed to more socioeconomically vulnerable individuals.

Abstract WP356: Recruitment and Retention of Minorities in a Safety-Net Setting: Lessons From the S econdary Stroke Prevention by U niting C ommunity and C hronic Care Model Teams E arly to E nd D isparities (SUCCEED) Trial

Background: Minority, disadvantaged populations are often underrepresented in secondary stroke prevention trials despite known disparities in risk factor control. When they do enroll, retention is poor due to competing needs, transiency, unstable housing, transportation barriers, and inconsistent telephone access. Methods: We recruited 487 English- or Spanish-speaking adults (age >40 yrs) with a recent TIA or ischemic/hemorrhagic stroke, and systolic BP ≥130 mm Hg or diagnosed hypertension and SBP≥120mm Hg, from 4 Los Angeles County-Department of Health Services hospitals and 1 stroke center serving low income zip codes. We used recruitment and retention strategies from a prior trial; leadership and staff met regularly to track progress and design and implement new strategies. Meeting notes were reviewed to compile approaches . Results: Average age was 57.1 years; race/ethnicity was 71.4% Hispanic, 17.6% black, 6.4% Asian; 72.5% were born outside the US; 62.6% had not graduated high school; 40% rarely spoke English at home. Follow-up data collection was 440/487 (90%) at 3 months, 382/487 (78%) at 8 months, and 394/475 (83%) of eligibles at 12 months. Prior recruitment strategies used were bilingual research assistants (RAs) from similar cultural backgrounds, inpatient clinical team introduction of potential enrollees to RAs, embedding RAs on the inpatient unit, piloting and tailoring recruitment scripts prior to study initiation, and allowing potential participants to discuss the study with others prior to enrollment. Prior retention strategies used were obtaining ≥3 contact numbers at enrollment and reviewing medical records for upcoming appointments. New retention strategies developed and applied were offering in-home assessments, providing transportation, offering weekend/evening visits, using phone, mail, and registered mail to contact participants, routinely using the same RA for a given participant, and reminding patients of prior interactions with RAs/visits. Conclusion: To maximize retention and recruitment, the combined approach of beginning with a broad set of previously effective strategies, and tracking and developing new ones over the course of the trial was effective. Trial Registry Trial Number: NCT01763203

Abstract TMP114: Exploring the Role of Cognitive Function in Secondary Stroke Prevention: Evidence from the Discharge Educational Strategies for Reduction of Vascular Events (DESERVE) Study

Studies suggest that cognitive impairment is common, even following mild stroke. Yet, secondary prevention strategies typically do not take into account patients’ cognitive functioning. Data from DESERVE, a secondary stroke prevention trial, were used to investigate relationships between cognition 6 months post-stroke and changes in medication adherence (MA) and total cholesterol (TC) between baseline and 12-month follow-up among mild/moderate stroke and TIA patients. Patients with any documented history of cognitive impairment and those unable to provide informed consent were excluded from the study. At six months, cognition was measured using three cognitively focused variables from the Stroke Impact Scale: Concentration, Remember Things Told to You (‘Memory’) and Orientation in Time. Items were scored from 1 to 5, with 1-3 = severe impairment, 4 = mild impairment, and 5 = no impairment. MA was measured using the 8-item Morisky Medication Adherence Scale. ANCOVA models were used to analyze associations between cognition and changes in MA and TC, and association between MA and TC, adjusting for key socio-demographic and clinical characteristics and intervention status. The analytic sample (n=396) was 48% male, 27% white, 32% black, 35% Hispanic, with mean age 64. Impairment in Memory was 13.4% severe, 13.6% mild, 44.7% none. In fully adjusted models, patients who were severely impaired in Memory, showed less improvement in MA compared to mild and no impairment: 0.3 vs. 0.2 vs 1.3 points (p<0.001, n=275), respectively. There was a U-shape trend relationship between cognitive status and cholesterol change, with no impairment performing best, mild performing worst, and moderate in between (decreases of 27.6 vs 13.1 vs 30.7 mg/dl; p=0.104, n=278 in Memory). The other cognitive domains showed similar relationships in both MA and TC. Cognition was thus related to MA, and MA in turn directly related to TC (b=-7.5, p<0.001, n=223). This is one of the first studies to identify post-stroke cognitive impairment as a potential barrier to effective secondary stroke prevention.

Abstract 37: Secondary Stroke Prevention With Aspirin and Clopidogrel in CYP2C19 *17 Carriers Increases Risk of Major Non-CNS Bleeding

Combination aspirin and clopidogrel reduces risk of recurrent ischemic stroke, but was also associated with risk of non-central nervous system (CNS) major bleeding in the Platelet-Oriented Inhibition in New TIA or minor stroke clinical trial. The loss-of-function CYP2C19*2 allele potentially reduces clopidogrel efficacy, while the gain-of-function CYP2C19*17 allele may increase bleeding risk. The clinical application of these alleles is unclear. SNP genotyping of CYP2C19*2 and CYP2C19*17 are available in the Secondary Prevention of Small Subcortical Strokes clinical trial, a 2x2 factorial study in patients with lacunar infarcts where one arm tested the efficacy of secondary stroke prevention with aspirin plus clopidogrel versus aspirin alone. We hypothesized that patients carrying CYP2C19*2 would have more clopidogrel failure events (defined as a composite of ischemic stroke, transient ischemic attack, and cognitive decline), while patients carrying at least one CYP2C19*17 allele, would have more major bleeding, including sub-analysis of CNS and non-CNS major bleeding. The associations of CYP2C19*2 with treatment failure and CYP2C19*17 with major bleeding were assessed through logistic regression, adjusting for age, gender, race, and excluding CYP2C19*2/*17 carriers. The mean age of the cohort (n=522) was 62 (62% male). There were no significant differences in treatment failure events between *2 carriers and *2 non-carriers (Odds ratio (OR) [95% confidence interval (CI)] = 1.60 [0.66-3.87], p-value=0.29), adjusting for *17. Patients with a *17 allele had a significantly higher odds of a non-CNS hemorrhage (OR [95% CI] =2.50 [1.03-6.09], p-value=0.043), and a trend for significance after adjusting for *2, p-value=0.06. Only two CNS hemorrhages occurred in the total cohort; both occurred in normal CYP2C19 metabolizers. Although limited by sample size, the study suggests that CYP2C19 carrier status may contribute to non-CNS major bleeding risks seen in dual antiplatelet therapy secondary stroke prevention trials. Further studies are needed to confirm whether the presence of CYP2C19*17 or absence of *2 increases the risk of bleeding complications, which could have implications for treatment decisions in a precision medicine approach.

Stroke Recurrence in Nigerian Children With Sickle Cell Disease: Evidence for a Secondary Stroke Prevention Trial

BackgroundTo improve the quality of care for children with sickle cell anemia in Kano, Nigeria, we initiated a standard care protocol in 2014 to manage children with strokes at Aminu Kano Teaching Hospital. MethodsThe standard care protocol requires that children with acute strokes be treated with hydroxyurea at a fixed dose of 20 mg/kg/day within two months of the stroke. ResultsTwenty-nine children with sickle cell anemia and initial stroke were identified based on clinical World Health Organization criteria from 2014 to 2017. Follow-up was a median of 1.04 years (interquartile range 0.43 to 1.83 years) to either July 2017 or a second stroke, corresponding to an initial stroke incidence rate of 0.88 per 100 patient-years. Eight children had a recurrent stroke, six of whom were prescribed hydroxyurea 20 mg/kg/day by two months after initial stroke. Two children died. Six of the recurrent strokes occurred within six months of the initial stroke, two before hydroxyurea prescription. The stroke recurrence rate was 17.4 events per 100 patient-years. Adherence was approximately 60%, partly because families had to pay for hydroxyurea. Stroke incidence is probably underestimated because despite formal training for stroke detection during the quality improvement period, no participant had assessment using a standardized pediatric stroke scale and neuroimaging was not available. ConclusionsIn children with sickle cell anemia, a high rate of initial and recurrent strokes exists in a low-resource setting. Ongoing needs include training to detect strokes with an objective stroke assessment and government-supported free access to hydroxyurea for stroke prevention.

Secondary Stroke Prevention in Cryptogenic Stroke and Embolic Stroke of Undetermined Source (ESUS).

The purpose of the study was to review the literature on cryptogenic stroke and embolic stroke of undetermined stroke (ESUS). Cryptogenic stroke according to TOAST criteria is a stroke which is not due to cardiogenic embolism, small vessel disease with lacunes or large vessel disease of brain supplying arteries. In the context of secondary stroke prevention studies, cryptogenic stroke is not operationally defined. The new concept of "embolic stroke of undetermined source" (ESUS) provides an operational definition. ESUS is diagnosed as a non-lacunar stroke on cerebral imaging and exclusion of large vessel atherosclerosis by CTA, MRA or ultrasound. Cardiogenic embolism is made less likely by ECG monitoring and echocardiography. At present, aspirin is used for secondary stroke prevention in patients with cryptogenic stroke. Based on the construct that ESUS might be caused by undetected atrial fibrillation or other embolic mechanisms, ongoing randomised secondary stroke prevention trials are comparing non-vitamin K oral anticoagulants (NOACs) with aspirin.

Abstract WMP58: Blacks Have Higher Risk of 1-Year Recurrent Ischemic Stroke: An Analysis of White and Black Medicare Beneficiaries 1999-2013

Introduction: Blacks have a higher incidence of stroke compared with whites. Most stroke survivors in the United States are 65 years and older but few data are available on racial differences in recurrent stroke risk in this age group. Methods: We conducted a retrospective cohort of Medicare beneficiaries in the 5% sample from 1999-2013 to compare 1-year recurrent stroke risk in older black and white Americans following hospitalization for ischemic stroke. We studied beneficiaries with Medicare fee-for-service coverage for 182 days before the index stroke hospitalization with no claims for stroke-related events. Patients were divided into two age groups (66-74, 75 years and above) and stratified into 3 calendar periods (1999-2001, 2002-2006, 2007-2013) allowing for implementation of secondary stroke prevention trial findings (PROGRESS, 2001; SPARCL, 2006). Hazard ratios for recurrent ischemic stroke comparing blacks to whites were calculated with adjustment for demographics, risk factors, and the competing risk of death. Results: Of 128,789 ischemic stroke patients (mean age 80 years [SD 8], 11.1% black, 60.4% male), 7.8% of whites and 11.0% of blacks had a recurrent ischemic stroke overall (Table 1). For each time period, blacks had a higher risk of recurrent stroke compared with whites (Figure 1). This disparity increased over time among patients age 66-74 years (p=0.038) but no trend was present for those 75 years and above (p=0.301). Conclusion: The risk of stroke recurrence among older Americans hospitalized for ischemic stroke is higher for blacks than whites, regardless of age group.

Abstract 2: Tolerability and Medication Requirements of Aggressive Medical Management in SAMMPRIS

Introduction: SAMMPRIS was the first secondary stroke prevention trial to employ multi-modal protocol-driven aggressive medical management (AMM). Achievement of target SBP, LDL and physical activity were predictors of lower vascular event rates. We sought to determine the tolerability and medication requirements related to AMM. Methods: Medications and adverse events (AEs) in all 451 SAMMPRIS patients were recorded by sites at baseline, 30 days, 4 monthly visits, and closeout. Start and stop dates were recorded for each medication and AE, with AEs classified by the site as possibly, probably, definitely, or unrelated to risk factor treatment. AEs were adjudicated centrally by consensus of 3 neurologists after the trial ended. Standard descriptive statistics were used. Results: As Table 1 shows, most subjects were on statins and BP medications at baseline. The use of rosuvastatin, which was donated for the trial, increased during follow-up. ACE inhibitors were the most commonly used BP medication. AEs related to BP medications (e.g. standing BP drop > 15mm Hg or postural hypotension) occurred in 240 (53.2%) patients at any point in the trial (including baseline), of which 123 (27.3%) were symptomatic. Syncope occurred in 11 patients, with 3 considered probably or definitely related to study treatment. AEs related to lipid lowering medications occurred in 18.8% patients, 16.6% of which were myopathy symptoms and 1.3% were AST/ALT > 3 times normal, and there were no reported cases of rhabdomyolysis. AEs related to other risk factor treatments occurred in 17.5% patients (e.g. hypoglycemia secondary to glipizide). Conclusion: In the SAMMPRIS trial, AMM required the use of multiple risk factor medications and was well tolerated by most patients, with AE rates similar to SPS3 and SPARCL.

Inflammatory Biomarkers in Childhood Arterial Ischemic Stroke

Among children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS. In an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-α. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS. Median age at index stroke was 8.2 years (interquartile range, 3.6-14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3-10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies. Among children with AIS, specific inflammatory biomarkers correlate with cause and-in the arteriopathy group-risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials.

Vorapaxar monotherapy for secondary stroke prevention: A call for randomized trial.

Vorapaxar, a novel platelet thrombin protease-activated receptor 1 blocker, is currently approved for post-myocardial infarction and peripheral artery disease indications on top of clopidogrel or/and aspirin. We sought to summarize the conflicting stroke data after vorapaxar for justifying a secondary stroke prevention trial. Analyses of the stroke data after vorapaxar yielded from thrombin-receptor antagonist vorapaxar in acute coronary syndromes (TRACER) and TRA2P clinical trials, and affiliated Food and Drug Administration (FDA) reviews. The stroke data are mixed, with catastrophic 2.5 excess of intracranial bleeding risks (HR = 2.52; 95% CI = 1.46-4.36, p < 0.0001); trend to worsened second stroke rates (13.0% vs. 11.7%; HR = 1.03; 95% CI = 0.85-1.25, p = NS), but a hint towards less primary ischemic strokes in vorapaxar indicated population (HR = 0.57; 95% CI = 0.43 to 0.75; p < 0.001). These conflicting data are not solely attributed to vorapaxar, but rather reflect unreasonably aggressive triple antiplatelet strategies utilized frequently in TRA2P and dominant in TRACER. Overall, the FDA-confirmed evidence advocates future vorapaxar secondary stroke prevention trial due to being first-in-class agent, unique pharmakynetics, and exhibiting very mild "comfort zone" antiplatelet profile. The three arm trial testing head-to-head monotherapy with vorapaxar (Zontivity®), versus clopidogrel (Plavix®), and versus extended-released dipyridamole with very low dose aspirin (Aggrenox®) is warranted. Vorapaxar may be superior to currently recommended antiplatelet strategies and should be tested as a monotherapy in a randomized outcome-driven secondary stroke prevention trial.