Utility-weighted Modified Rankin Scale Research Articles

Blood-based frailty index in patients with acute ischemic stroke undergoing endovascular treatment.

Frailty is a syndrome depicting vulnerability of multiple physiological systems to stressors. Frailty measures, such as Hospital Frailty Risk Score (HFRS), can be used to identify frailty and predict outcome more reliably. Our aim was to analyse a blood-based frailty index (FI-B) at admission for prediction outcome of patients with acute ischemic stroke (AIS) undergoing endovascular treatment (EVT). We conducted a retrospective study of consecutive AIS patients undergoing EVT in a single tertiary centre during a period of five years. A set of eighteen blood parameters at admission were collected and nine of these were utilized to calculate FI-B. We analysed the relationship between FI-B and HFRS. We examined the baseline characteristics of the study population based on FI-B-tertiles. Multivariable regression models were employed to ascertain the association between FI-B and in-hospital mortality, 3-month mortality and 3-month functional outcome. The final study population comprised 489 patients, with a median age of 75.6 years, 49.5% of patients were male. The FI-B exhibited a weak positive correlation with HFRS (rho=0.113, p=0.016). Patients in higher FI-B-tertiles were older and more frequently presented with pre-stroke functional dependence and comorbidities. Moreover, an increasing FI-B was independently associated with increased likelihood of in-hospital mortality (adjusted odds ratio [aOR]=1.29, 95% confidence interval [95%CI]=1.14-1.47), 3-month mortality (aOR=1.26, 95%CI=1.11-1.43), and of increasing 3-month functional disability measured by utility-weighted modified Rankin Scale (common aOR=0.84, 95%CI=0.76-0.93). A frailty index based on blood values at admission was able to identify frailty in AIS patients undergoing EVT and was an independent predictor of short- and medium-term outcome after stroke.

Statistical analysis plan for the Chinese Herbal medicine in Acute INtracerebral haemorrhage (CHAIN) trial.

The traditional Chinese medicine (TCM) herbal compound FYTF-919 (Zhong Feng Xing Nao prescription) may improve outcome from acute intracerebral hemorrhage (ICH) by reducing brain edema, hematoma absorption, and enhancement of the immune system. We outline the statistical analysis plan (SAP) for the Chinese Herbal medicine in Acute INtracerebral haemorrhage (CHAIN) study. CHAIN is a multicenter, prospective, randomized, double-blind, placebo-controlled trial being undertaken at 20-30 hospitals in China. After the completion of eligibility checks, patients are randomly allocated to FYTF-919 (100 mL per day, oral) or matching placebo over 28 days. A sample size of 1504 patients is estimated to provide 90% power (α 0.05) for a 0.06 absolute improvement in the primary outcome of utility-weighted modified Rankin scale scores at 90 days, analyzed by general linear regression. The statistical analysis plan was developed by the study statistician, principal investigators, international experts, and the study project manager. The plan provides details for analyzing baseline characteristics, patient management, and outcomes. It includes provisions for covariate adjustments, subgroup analysis, the handling missing data, and in the conduct of sensitivity analyzes. A predefined statistical analysis plan was established for CHAIN, facilitating transparent and verifiable analysis. The CHAIN statistical analysis plan was prospectively developed with a focus on maintaining high-quality standards of internal validity to minimise potential analysis biases. ClinicalTrials.gov (NCT05066620).

Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage

BackgroundTrials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known.MethodsIn this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients’ assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment.ResultsA total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and −0.013 (95% Bayesian credible interval, −0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration.ConclusionsAmong patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.)

Abstract HUP8: Mobile Stroke Unit Management Associated With Reduction In Racial Disparities In Stroke Treatment Metrics

Background: Racial and ethnic disparities in stroke exist across the continuum of care, including prehospital care. The impact of Mobile Stroke Units (MSUs) on racial disparities in thrombolytic treatment metrics is not reported. Methods: A pre-specified sub-study of ischemic stroke patients enrolled in BEST-MSU was conducted. MSU and standard management (SM) groups were divided into Non-Hispanic White (NHW), Non-Hispanic Black (NHB), and Hispanic (H) cohorts. Other racial groups were excluded (small n). Primary outcome was last seen normal to tPA time . Secondary outcomes included 90-day utility-weighted modified Rankin Scale (uw-mRS), functional independence (mRS 0-1), and mortality. Results: A total of 1420 patients were included: 557 NHW, 586 NHB, and 277 H. NHB and H groups were younger, had lower education, and higher proportions uninsured. In SM, NHB and H patients received slower care and less frequent tPA compared to NHW (Table 1). In contrast, MSU management reduced time to treatment (19 min NHW vs 46.5 min NHB vs 46 min H; p=<0.001) in NHB and H, and led to more frequent tPA (13% more NHW, 11% more NHB, 25% more H) in H. MSU management was associated with better uw-mRS across all groups (Figure 1). More functional independence was seen in NHW and NHB (adjusted OR NHW 1.79 [1.10-2.95] p=0.019; NHB 2.13 [1.38-3.33] p=0.0007). Mortality benefit was seen in H (p=0.03). Conclusion: MSUs overcome known disparities in thrombolytic utilization and treatment metrics in Non-Hispanic Black and Hispanic groups. Further studies are needed to evaluate care inequities that are overcome through integration of a MSU into the prehospital setting.

Abstract 88: Mobile Stroke Unit Management Associated With Reduction in Racial Disparities in Stroke Treatment Metrics

Background: Racial and ethnic disparities in stroke exist across the continuum of care, including prehospital care. The impact of Mobile Stroke Units (MSUs) on racial disparities in thrombolytic treatment metrics is not reported. Methods: A pre-specified sub-study of ischemic stroke patients enrolled in BEST-MSU was conducted. MSU and standard management (SM) groups were divided into Non-Hispanic White (NHW), Non-Hispanic Black (NHB), and Hispanic (H) cohorts. Other racial groups were excluded (small n). Primary outcome was last seen normal to tPA time[GJ1] . Secondary outcomes included 90-day utility-weighted modified Rankin Scale (uw-mRS), functional independence (mRS 0-1), and mortality. Results: A total of 1420 patients were included: 557 NHW, 586 NHB, and 277 H. NHB and H groups were younger, had lower education, and higher proportions uninsured. In SM, NHB and H patients received slower care and less frequent tPA compared to NHW (Table 1). In contrast, MSU management reduced time to treatment (19 min NHW vs 46.5 min NHB vs 46 min H; p=<0.001) in NHB and H, and led to more frequent tPA (13% more NHW, 11% more NHB, 25% more H) in H. MSU management was associated with better uw-mRS across all groups (Figure 1). More functional independence was seen in NHW and NHB (adjusted OR NHW 1.79 [1.10-2.95] p=0.019; NHB 2.13 [1.38-3.33] p=0.0007). Mortality benefit was seen in H (p=0.03). Conclusion: MSUs overcome known disparities in thrombolytic utilization and treatment metrics in Non-Hispanic Black and Hispanic groups. Further studies are needed to evaluate care inequities that are overcome through integration of a MSU into the prehospital setting.

Outcomes of patients with pre-existing disability managed by mobile stroke units: A sub-analysis of the BEST-MSU study.

Few data exist on acute stroke treatment in patients with pre-existing disability (PD) since they are usually excluded from clinical trials. A recent trial of mobile stroke units (MSUs) demonstrated faster treatment and improved outcomes, and included PD patients. To determine outcomes with tissue plasminogen activator (tPA), and benefit of MSU versus management by emergency medical services (EMS), for PD patients. Primary outcomes were utility-weighted modified Rankin Scale (uw-mRS). Linear and logistic regression models compared outcomes in patients with versus without PD, and PD patients treated by MSU versus standard management by EMS. Time metrics, safety, quality of life, and health-care utilization were compared. Of the 1047 tPA-eligible ischemic stroke patients, 254 were with PD (baseline mRS 2-5) and 793 were without PD (baseline mRS 0-1). Although PD patients had worse 90-day uw-mRS, higher mortality, more health-care utilization, and worse quality of life than non-disabled patients, 53% returned to at least their baseline mRS, those treated faster had better outcome, and there was no increased bleeding risk. Comparing PD patients treated by MSU versus EMS, 90-day uw-mRS was 0.42 versus 0.36 (p = 0.07) and 57% versus 46% returned to at least their baseline mRS. There was no interaction between disability status and MSU versus EMS group assignment (p = 0.67) for 90-day uw-mRS. PD did not prevent the benefit of faster treatment with tPA in the BEST-MSU study. Our data support inclusion of PD patients in the MSU management paradigm.

Abstract WP171: Impact Of Pre-stroke Sulfonylurea Use On Functional Outcomes In The SHINE Trial

Background: Pharmacological and clinical evidence suggest that sulfonylurea (SU) medications may improve acute ischemic stroke (AIS) outcomes. The SHINE trial studied intensive vs standard blood sugar management in patients presenting with AIS and hyperglycemia. We investigated whether pre-existing SU use impacted functional outcomes in SHINE. Methods: SHINE data collection forms were reviewed to identify AIS patients taking SUs at the time of study enrollment. Our primary outcome compared the adjusted 90-day utility weighted modified Rankin Scale (UW-mRS) score in the SU and non-SU cohorts. The UW-mRS score was adjusted for age, baseline NIHSS, baseline glucose, and reperfusion therapy. Pre-specified analyses of the 90-day UW-mRS scores assessed for heterogeneity of SU effect across the following subgroups: age, stroke severity, reperfusion therapy, type of SU, and SHINE study arm. Results: In total, 1066 SHINE subjects with a final diagnosis of AIS were included (SU=248 [23.3%], non-SU=818 [76.7%]). Baseline demographics were generally similar (Table 1). Calculated 90-day mean UW-mRS score were higher in the non-SU group compared to the SU group: mean 0.617 ± 0.012 versus mean 0.566 ± 0.022 (Diff 0.051, 95% CI 0.001-0.1) without heterogeneity of treatment effect (Figure 1). Conclusion: Contrary to our hypothesis and published literature, our retrospective analysis of the SHINE trial demonstrated better functional outcomes in the non-SU cohort. This may be due to selection bias with inadequate controlling for baseline risk factors present in the SU cohort. Definitive prospective studies are required.

Abstract 60: Patient Engagement With Stroke Nurse Navigator Reduces Readmissions

Objective: We aimed to evaluate whether the level of engagement with stroke nurse navigators affected readmission rates and outcomes in acute ischemic stroke (AIS). Engagement is defined as a phone or virtual encounter between the patient and the navigator. We further defined the level of engagement as: low engagement < 5 encounters or high engagement ≥ 5 encounters in 90 days. Methods: Multicenter retrospective analysis of AIS patients with admission from January 2021 to April 2022. Patients were excluded if: died during index hospitalization, discharged to hospice or had incomplete data. Our primary outcome was readmission within 90 days analyzed with a binomial logistic regression. Secondary outcomes were: attendance of neurology appointments, recurrent neurologic symptoms, both assessed with a binomial logistic regression, and functional outcome as defined by utility weighted modified Rankin Scale (UWmRS) at 90 days post discharge which we used a hierarchical multiple regression analysis. Sensitivity analysis examined outcomes in patients who were discharged to home. Results: Stroke nurse navigators enrolled 2,584 patients. 2,035 patients were analyzed. Of the 2,035 patients, 1195 (58.7%) were highly engaged and 840 (41.3%) were less engaged. Highly engaged patients were less likely to be readmitted within 90 days compared to less engaged patients (20.9% vs. 33.3%), adjusted odds ratio (aOR)= 0.57 [95%CI, 0.46 - 0.72], p< 0.001. Additionally highly engaged patients compared to less engaged patients were: more likely to attend neurology follow-up appointments (64.6% vs. 43.3%), aOR= 1.94 [95%CI 1.59 - 2.37], p<0.001; less likely to have a recurrent neurologic event (6.5% vs. 9.3%), aOR=0.56 [95%CI 0.39 - 0.81], p = 0.002 and had greater functional ability at 90 days (7.9±2.6 vs. 5.4±4.0), b=0.98 [95%CI, 0.71, 1.25], p<0.001. Sensitivity analyses suggested that trends found in primary and secondary analyses were similar when examining only patients discharged to home, all p<0.05. Conclusion: Patients with AIS actively engaged with a stroke nurse navigator were found to have better outcomes and less readmissions through 90-days of post-discharge care irrespective of discharge location.

Abstract WMP2: Acute Stroke Treatment In Patients With Pre-exiting Disability: A Secondary Analysis Of The BEST-MSU Trial

Background: Few data exists on acute stroke treatment in patients with pre-existing disability (PD) since they are usually excluded from clinical trials. Methods: A pre-specified subgroup analysis of tPA-eligible patients with PD enrolled in a prospective multicenter trial of Mobile Stroke Units (MSUs) vs standard management by emergency medical services (EMS). All patients had baseline mRS scores. Co-primary outcomes were mean utility-weighted modified Rankin Scale score (uw-mRS) and return to baseline mRS at 90 days. Linear and logistic regression models compared outcomes in patients with vs without PD, and patients with PD treated by MSU vs EMS. Time metrics, safety, quality of life, and health-care utilization were also compared. Results: Of 1047 patients, 254 had baseline mRS >= 2 (159 MSU, 95 EMS; 31% mRS 2, 52% mRS 3, 17% mRS 4). Compared to patients without disability, patients with PD were older, had higher NIHSS, more comorbidities, less often lived at home, were treated slower, and had less thrombectomy. Patients with PD had worse 90-day uw-mRS (0.39 vs 0.80), higher mortality, more health-care utilization and worse quality of life than patients without PD. However, rates of symptomatic intracranial hemorrhage and final diagnoses of stroke mimics were similar between groups, and 52% of patients with PD returned to their baseline mRS. Patients with PD treated within the first hour had better 90-day uw-mRS than those treated later (0.48 vs 0.36, p=0.01). Comparing patients with PD treated by MSU vs EMS, time from last-known-well to tPA bolus was shorter (82 vs 111 min), and 24% vs 0% were treated in the first hour. Among patients with PD, MSU patients had non-significantly better 90-day uw-mRS (0.41 vs 0.35, p=0.09) and higher rate of returning to baseline mRS (56% vs 44%, p=0.09) than EMS patients. There was no interaction between either time to treatment (p=0.24) or MSU vs EMS group assignment (p= 0.42), 90-day uw-mRS, and PD vs no disability status. Conclusion: Although outcomes after stroke are less favorable in patients with vs without PD, in a large, controlled trial, we found no interaction between baseline disability and the benefit of MSU treatment. Our data support the earliest treatment of acute stroke patients regardless of premorbid functional status.

Abstract 24: Mobile Stroke Units Associated With Favorable Clinical Outcome In Large Vessel Occlusion Stroke Patients: BEST-MSU Substudy

Introduction: Mobile Stroke Units (MSUs) improve clinical outcome in patients treated with tPA compared to standard management by Emergency Medical Services (EMS), but the impact of MSUs on outcomes in patients with large vessel occlusions (LVOs) having endovascular thrombectomy (EVT) has yet to be determined. Methods: A pre-specified substudy of tPA-eligible stroke patients with LVOs on CT and/or CTA who were enrolled in the Benefits of Stroke Treatment Using a Mobile Stroke Unit (BEST-MSU), a prospective multicenter controlled trial comparing MSU with standard EMS management, was conducted. The primary outcome was the score on the 90-day utility-weighted modified Rankin Scale (uw-mRS). Secondary outcomes were rate of early neurologic recovery (30% improvement in NIHSS score) at 24 hours and functional independence (mRS 0-1) at 90 days. Results: A total of 295 patients were included, 169 in the MSU group and 126 in the EMS group. Baseline characteristics were comparable between the groups, with the exception of baseline NIHSS (MSU median 19.0 [IQR 13.0, 23.0] vs EMS 16.0 [11.0, 20.0], p=0.003). 92% MSU vs 87% EMS LVO patients received tPA, and 78% vs 85% went on to have EVT. MSU LVO patients had faster tPA bolus from symptom onset (65.0 min [50.5, 92.0] vs 96.0 [79.3, 130.0], p<0.001), however the two groups had similar onset to groin puncture (169.0 min [133.8, 212.3] vs 162.0 [135.3, 207.0], p=0.77). The mean (±SD) score on the uw-mRS at 90 days was 0.64±0.39 in the MSU group and 0.50±0.40 in the EMS group (mean difference 0.16, 95% CI [0.07, 0.25] after adjustment for age, baseline NIHSS, premorbid functional status, prior stroke/TIA and site; p<0.001). Early neurologic recovery (68% vs 52%; adjusted OR 1.89 95% CI [1.14,3.17]) and functional independence (Figure 1, 42% vs 29%; 2.48 [1.38,4.55]) also favored the MSU group. Conclusions: In tPA-eligible LVO stroke patients, MSU management was associated with better clinical outcomes compared with standard EMS management.

Building a Mobile Stroke Unit Based on 5G Technology - A Study Protocol.

Background: In-time treatment of acute stroke is critical to saving people’s lives and improving the quality of post-stroke life. A mobile stroke unit (MSU) with fifth-generation (5G) mobile networks strengthens the interaction of patient information and healthcare resources, thereby reducing response times and improving thrombolysis results. However, clinical evidence of better outcomes compared to regular care is still lacking.Method and Design: In this randomized controlled trial, 484 patients with acute stroke are allocated into the MSU and regular care groups. We establish medical records for each patient and conduct a follow-up of 90 days. The primary outcomes are functional results as defined by utility-weighted modified Rankin Scale (uw-mRS) 90 days after the incidence occurred, whereas secondary outcomes include the alarm to CT scan completed time, the alarm to treatment decision time, the alarm to thrombolytic time, quality of life, and symptomatic intracranial hemorrhage combined with NIHSS score as well as cost-effectiveness.Discussion: This study establishes an innovative MSU (based on 5G) to manage acute stroke, comparing its clinical and economic outcomes to regular care and informing decision-makers of the effectiveness of the stroke emergency system.Clinical Trial Registration: [http://www.chictr.org.cn/showproj.aspx?proj=63874], identifier [ChiCTR2000039695].

Prospective, Multicenter, Controlled Trial of Mobile Stroke Units

BackgroundMobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied.MethodsIn an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients.ResultsWe enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval [CI], 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group.ConclusionsIn patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.)

Healthy Life-Year Costs of Treatment Speed From Arrival to Endovascular Thrombectomy in Patients With Ischemic Stroke

The benefits of endovascular thrombectomy (EVT) are time dependent. Prior studies may have underestimated the time-benefit association because time of onset is imprecisely known. To assess the lifetime outcomes associated with speed of endovascular thrombectomy in patients with acute ischemic stroke due to large-vessel occlusion (LVO). PubMed was searched for randomized clinical trials of stent retriever thrombectomy devices vs medical therapy in patients with anterior circulation LVO within 12 hours of last known well time, and for which a peer-reviewed, complete primary results article was published by August 1, 2020. All randomized clinical trials of stent retriever thrombectomy devices vs medical therapy in patients with anterior circulation LVO within 12 hours of last known well time were included. Patient-level data regarding presenting clinical and imaging features and functional outcomes were pooled from the 7 retrieved randomized clinical trials of stent retriever thrombectomy devices (entirely or predominantly) vs medical therapy. All 7 identified trials published in a peer-reviewed journal (by August 1, 2020) contributed data. Detailed time metrics were collected including last known well-to-door (LKWTD) time; last known well/onset-to-puncture (LKWTP) time; last known well-to-reperfusion (LKWR) time; door-to-puncture (DTP) time; and door-to-reperfusion (DTR) time. Change in healthy life-years measured as disability-adjusted life-years (DALYs). DALYs were calculated as the sum of years of life lost (YLL) owing to premature mortality and years of healthy life lost because of disability (YLD). Disability weights were assigned using the utility-weighted modified Rankin Scale. Age-specific life expectancies without stroke were calculated from 2017 US National Vital Statistics. Among the 781 EVT-treated patients, 406 (52.0%) were early-treated (LKWTP ≤4 hours) and 375 (48.0%) were late-treated (LKWTP >4-12 hours). In early-treated patients, LKWTD was 188 minutes (interquartile range, 151.3-214.8 minutes) and DTP 105 minutes (interquartile range, 76-135 minutes). Among the 298 of 380 (78.4%) patients with substantial reperfusion, median DTR time was 145.0 minutes (interquartile range, 111.5-185.5 minutes). Care process delays were associated with worse clinical outcomes in LKW-to-intervention intervals in early-treated patients and in door-to-intervention intervals in early-treated and late-treated patients, and not associated with LKWTD intervals, eg, in early-treated patients, for each 10-minute delay, healthy life-years lost were DTP 1.8 months vs LKWTD 0.0 months; P < .001. Considering granular time increments, the amount of healthy life-time lost associated with each 1 second of delay was DTP 2.2 hours and DTR 2.4 hours. In this study, care delays were associated with loss of healthy life-years in patients with acute ischemic stroke treated with EVT, particularly in the postarrival time period. The finding that every 1 second of delay was associated with loss of 2.2 hours of healthy life may encourage continuous quality improvement in door-to-treatment times.

Intra-Individual Variability of the Utility Weighted Modified Rankin Scale in the Initial Post-Stroke Period (1736)

Intra-Individual Variability of the Utility Weighted Modified Rankin Scale in the Initial Post-Stroke Period (1736)

Abstract 17: Time-Benefit Association is Magnified in Door-To-Puncture Window: Lose 1 Second, Lose 2.2 Hours of Healthy Life

Background: The benefits of endovascular thrombectomy (EVT) are time dependent. Prior studies may have underestimated the magnitude of the time-benefit relation because time of onset (last known well ”LKW”) is imprecisely known, and analyses including late-arriving patients have under-representation of “fast-progressors.” Methods: Patient level data were pooled by the HERMES Investigators from all 7 RCTs of stent retriever thrombectomy devices (entirely or predominantly) versus medical therapy. Analysis was confined to early-treated patients (LKW-to-puncture≤4h). Exposures: last known well-to-door (LKWTD) time; door-to-puncture (DTP) time; door-to-reperfusion (DTR) time. Outcomes: stroke-related quality of life at 3m (utility-weighted modified Rankin Scale); years of healthy life lost [disability-adjusted life years (DALYs)]. Results: Among the 781 EVT-treated patients, 406 (52.0%) were treated within 4h of LKW, with LKW-to-Door time median 188 minutes (IQR 151-215) and DTP time 105 minutes (IQR 76-135). Among the 295/372 (79.3%) with substantial reperfusion, DTR time was median 145 minutes (IQR 111-186). Care process delays were more strongly associated with worse clinical outcomes in the DTP and DTR epochs than the LKW-To-Door epoch (Table 1A), e.g., for each 10 minute delay, healthy life-years lost were: DTP 1.8 months vs LKW-to-Door 0.0 months, p &lt; 0.0001. Considering granular time increments, the amount of healthy life-years lost associated with each 1 second of delay was: DTP 2.2 hours, DTR 2.1 hours.(Table 1B) Conclusion: Post-arrival care delays are strongly associated with worse EVT patient outcomes in the early post-arrival time period. With every 1 second of delay in EVT delivery, patients lose 2.2 hours of healthy life-years. Continuous quality improvement to minimize delays in DTP and DTR for endovascular thrombectomy is warranted.

The Design of an Adaptive Clinical Trial to Evaluate the Efficacy of Extra-Corporeal Membrane Oxygenation for Out-of-Hospital Cardiac Arrest

BACKGROUNDExtracorporeal cardiopulmonary resuscitation (ECPR) is a promising therapy for out-of-hospital cardiac arrest (OHCA) that is refractory to standard therapy, but no multicenter randomized clinical trials have been conducted to establish its efficacy. We report the design and operating characteristics of a proposed randomized Bayesian adaptive “enrichment” clinical trial designed to determine whether ECPR is effective for refractory OHCA and, if effective, to define the interval after arrest during which patients derive benefit. METHODSThrough iterative trial simulation and trial design modification, we developed a Bayesian adaptive trial of ECPR for adults who experience non-traumatic out-of-hospital cardiac arrest. Our proposed trial design addresses the threats to trial success identified during the design process, which were (1) the uncertainty surrounding the cardiac arrest (CA)-to-ECPR interval within which clinical benefit might be preserved (2) the difference in prognosis between patients with an initial rhythm that is non-shockable vs. shockable. Trial subjects will be randomized 1:1 to receive either standard care or expedited transport to a hospital for potential ECPR. The CA-to-ECPR interval will be estimated in real time based on the sum of the estimated paramedic response time (911 call to scene arrival), paramedic scene time, and transport time to hospital. A Bayesian decreasing step function will be used to estimate the efficacy of the treatment with an outcome of the 90-day utility-weighted Modified Rankin Scale (uwmRS) for each rhythm subgroup and estimated CA-to-ECPR interval at pre-specified interims. The trial will adaptively lengthen the estimated CA-to-ECPR eligibility window if the treatment appears effective at the upper limit of initial eligibility window. If ECPR appears ineffective at longer estimated CA-to-ECPR intervals, the upper limit of the window for enrollment eligibility will be shortened. The analysis will be stratified by rhythm subgroup. RESULTSWith a maximum total sample size of 400, and a cap on the maximum sample size of 300 for the non-shockable rhythm subgroup, the trial design has power ranging from 91–100% to detect a benefit from ECPR for non-shockable rhythms under the various efficacy scenarios simulated and power ranging from 69–98% for shockable rhythms under the same scenarios. The trial design also has a high probability of correctly identifying the maximum CA-to-ECPR interval within which ECPR produces a clinically significant benefit of 0.2 on the uwMRS. If ECPR is equivalent to standard CA care, the type I error is 2.5% with a 99% probability of stopping enrollment early for futility in the non-shockable subgroup and a 97% probability of stopping enrollment early for futility in the shockable subgroup. CONCLUSIONThis proposed adaptive trial design helps to ensure the population of patients who are most likely to benefit from treatment—as defined both by rhythm subgroup and estimated CA-to-ECPR interval—is enrolled. The design promotes early termination of the trial if continuation is likely to be futile.

Abstract 269: The Design of an Adaptive Clinical Trial - The Extracorporeal Cardiopulmonary Resuscitation for Refractory Out of Hospital Cardiac Arrest (EROCA) Project

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA) is promising but unproven. We developed a concept for a randomized Bayesian adaptive clinical trial to define the interval after arrest during which patients derive benefit. Hypotheses: We hypothesized that the simulated design characteristics of the adaptive design would efficiently confirm or refute the existence of a therapeutic window for ECPR in a future trial. Methods: Through iterative simulation and design modification, we developed a Bayesian adaptive trial of ECPR for adults with OHCA. The goals of the trial design were to address the uncertainty surrounding the OHCA-to-ECPR interval within which clinical benefit might be preserved and the difference in prognosis between patients with non-shockable vs shockable rhythms. The treatment effect was defined as the mean 90-day utility-weighted Modified Rankin Scale (uwmRS) for each rhythm subgroup and estimated CA-to-ECPR interval. The trial adaptively lengthens or contracts the estimated CA-to-ECPR eligibility window depending on the probability of benefit from ECPR. We simulated trial performance under six potential ECPR efficacy scenarios. We compared the adaptive design to a fixed design. Results: The trial had 91-100% power to detect a benefit from ECPR for non-shockable rhythms and 69-98% power for shockable rhythms under the scenarios simulated (figure). The design had a high probability of identifying the maximum CA-to-ECPR interval within which ECPR produces a clinically significant benefit of 0.2 on the uwMRS. In null scenarios, the 97-99% of the simulated trials ended early declaring futility. Conclusions: The adaptive trial design helps to ensure the patient population most likely to benefit from treatment—as defined by rhythm subgroup and estimated CA-to-ECPR interval—are enrolled. The design also promotes early termination of the trial if continuation is likely to be futile.

Look closer: The multidimensional patterns of post-stroke burden behind the modified Rankin Scale.

The utility-weighted modified Rankin Scale, representing patient perspectives of quality of life, is a newly proposed measure to improve the interpretability of the modified Rankin Scale. Despite obvious advantages, such weighting imperfectly reflects the multidimensional patterns of post-stroke burden. To investigate multidimensional patterns of post-stroke burden formed by individual domains of Assessment of Quality of Life and Barthel Index for each modified Rankin Scale category. In the A Very Early Rehabilitation Trial (n = 2104), modified Rankin Scale scores and modified Rankin Scale-stratified Barthel Index scores of Self-care and Mobility, and Assessment of Quality of Life scores of Independent Living, Senses, Mental Health and Relationships were collected at three months. The multivariate relationship between individual Assessment of Quality of Life and Barthel Index domains, and modified Rankin Scale was investigated using random effects linear regression models with respective interaction terms. Of 2104 patients, simultaneously collected Assessment of Quality of Life, Barthel Index and modified Rankin Scale scores at three months were available in 1870 patients. While individual Assessment of Quality of Life and Barthel Index domain scores decreased significantly as modified Rankin Scale increased (p < 0.0001), the patterns of decrease differed by domains (p < 0.0001). Patients with modified Rankin Scale 0-1 had the largest post-stroke burden in the Mental Health and Relationship domains, while patients with modified Rankin Scale >3 showed the greatest burden in Independent Living, Mobility and Self-care domains. Across the modified Rankin Scale, individual domains are varyingly impacted demonstrating unique patterns of post-stroke burden, which facilitates appropriate assessment, articulation and interpretation of the modified Rankin Scale and utility-weighted modified Rankin Scale.

August 2020 Highlights.

August 2020 Highlights.

Utility-Weighted Modified Rankin Scale Scores for the Assessment of Stroke Outcome: Pooled Analysis of 20 000+ Patients.

Patient-centered care prioritizes patient beliefs and values towards wellbeing. We aimed to map functional status (modified Rankin Scale [mRS] scores) and health-related quality of life on the European Quality of Life 5-dimensional questionnaire (EQ-5D) to derive utility-weighted (UW) stroke outcome measures and test their statistical properties and construct validity. UW-mRS scores were derived using linear regression, with mRS as a discrete ordinal explanatory response variable in 8 large international acute stroke trials. Linear regression models were used to validate UW-mRS scores by assessing differences in mean UW-mRS scores between the treatment groups of each trial. To explore the variability in EQ-5D between individual mRS categories, we generated receiver operator characteristic curves for EQ-5D to differentiate between sequential mRS categories and misclassification matrix to classify individual patients into a matched mRS category based on the closest UW-mRS value to their observed individual EQ-5D value. Among 22 946 acute stroke patients, derived UW-mRS across mRS scores 0 to 6 were 0.96, 0.83, 0.72, 0.54, 0.22, -0.18, and 0, respectively. Both UW-mRS and ordinal mRS scores captured divergent treatment effects across all 8 acute stroke trials. The sample sizes required to detect the treatment effects using UW-mRS scores as a continuous variable were almost half that required in trials for a binary cut point on the mRS. Area under receiver operator characteristic curves based on EQ-5D utility values varied from 0.66 to 0.81. Misclassification matrix showed moderate agreement between actual and matched mRS scores (kappa, 0.68 [95% CI, 0.67-0.68]). Medical strategies that target avoiding dependency may provide maximum benefit in terms of poststroke health-related quality of life. Despite variable differences with mRS scores, the UW-mRS provides efficiency gains as a smaller sample size is required to detect a treatment effect in acute stroke trials through use of continuous scores. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00226096, NCT00716079, NCT01422616, NCT02162017, NCT00120003, NCT02123875. URL: http://ctri.nic.in; Unique identifier: CTRI/2013/04/003557. URL: https://www.isrctn.com; Unique identifier: ISRCTN89712435.