A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Non-HLA Matched, Unrelated Donor, Cord Blood Infusion for Ischemic Stroke.

Stroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center. Study product was infused 3-10 days following index stroke. The primary endpoint was change in modified Rankin Scale (mRS) from baseline to day 90. Key secondary outcomes included functional independence, NIHSS, the Barthel Index, and assessment of adverse events. The trial was terminated early due to slow accrual and logistical concerns associated with the COVID-19 pandemic, and a total of 73 of a planned 100 participants were included in primary analyses. The median (range) of the change in mRS was 1 point (-2, 3) in UCB and 1 point (-1,4) in Placebo (P = 0.72). A shift analysis comparing the mRS at day 90 utilizing proportional odds modeling showed a common odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline NIHSS and randomization strata. The distribution of adverse events was similar between arms. Although this study did not suggest any safety concerns related to UCB in ischemic stroke, we did not show a clinical benefit in the reduced sample size evaluated.

Baseline ASPECTS and hypoperfusion intensity ratio influence the impact of first pass reperfusion on functional outcomes.

BACKGROUND: First pass reperfusion (FPR) has been established as a key performance metric in mechanical thrombectomy (MT). The impact of FPR may be more relevant in fast progressors. We aim to study the impact of baseline Alberta Stroke Program Early CT Score (ASPECTS) on non-contrast CT and hypoperfusion intensity ratio (HIR) on CT perfusion on clinical outcomes after FPR. METHODS: A prospective MT database was reviewed for patients with isolated occlusion of the intracranial internal carotid artery and/or middle cerebral artery M1 segment who underwent MT with complete reperfusion (modified Thrombolyis in Cerebral Infarction score 2c-3) from January 2012 to May 2019. The overall population was divided into ASPECTS >7 versus ≤7 and the subgroup of patients with baseline CT perfusion was divided into HIR <0.3 versus ≥0.3. Univariable and multivariable analyses were performed to establish the predictors of 90-day functional independence (modified Rankin Scale (mRS) ≤2) in each subgroup. RESULTS: A total of 436 patients were included in the analyses. FPR was achieved in 254 (58.3%) patients. ASPECTS modified the effect of FPR on clinical outcomes, with FPR predicting good outcomes in patients with ASPECTS ≤7 (46% vs 29%, adjusted OR 3.748; 95% CI 1.590 to 8.838, p=0.003) while no significant effect was detected in those with ASPECTS >7 (62.3% vs 53.1%, adjusted OR 1.372; 95% CI 0.798 to 2.358, p=0.25). Similarly, FPR predicted good outcomes in patients with HIR ≥0.3 (54.8% vs 41.9%, adjusted OR 2.204; 95% CI 1.148 to 4.233, p=0.01) but not in those with HIR <0.3 (62.9% vs 52.8%, adjusted OR 1.524; 95% CI 0.592 to 3.920, p=0.38). CONCLUSIONS: The impact of FPR on functional outcomes is highly dependent on baseline imaging characteristics, with a more prominent influence in patients presenting with lower ASPECTS and/or higher HIR.

Disposition to home or acute rehabilitation is associated with a favorable clinical outcome in the SENTIS trial.

OBJECTIVE: To explore the impact of stroke severity and discharge disposition on 90-day outcomes in US patients enrolled in the SENTIS trial. METHODS: SENTIS is a previously published prospective randomized controlled trial. We analyzed the demographic information, National Institutes of Health Stroke Scores (NIHSS) on day 4, discharge disposition and 90-day modified Rankin Score (mRS). Univariate models were constructed to determine the impact of discharge disposition on 90-day outcomes as well as the association of the day 4 NIHSS with outcomes. RESULTS: A total of 292 patients with a mean age of 65 ± 14 years were analyzed. Discharge disposition was distributed as follows: 153 (52.1%) to an inpatient rehabilitation facility (IRF), 111 (38.0%) to home and 28 (9.6%) to a skilled nursing facility (SNF). Only 2 out of 28 patients (7.1%) discharged to a SNF achieved a 90-day mRS ≤ 2 compared with 60/153 (39.2%) in the IRF group (OR 8.39 (95% CI 1.92 to 36.64), p = 0.0047). This association persisted after adjusting for age and admission NIHSS. Only 3 of 50 patients (6%) with a NIHSS of ≥ 14 at day 4 achieved a mRS 0-2 at day 90. CONCLUSIONS: This analysis shows that discharge to an IRF is associated with better neurological outcomes than discharge to a SNF. Additionally, patients with a NIHSS of ≥ 14 at day 4 are unlikely to achieve independent function.

ASPECTS decay during inter-facility transfer predicts patient outcomes in endovascular reperfusion for ischemic stroke: a unique assessment of dynamic physiologic change over time.

BACKGROUND: Pretreatment Alberta Stroke Program Early CT Scores (ASPECTS) is associated with clinical outcomes. The rate of decline between subsequent images, however, may be more predictive of outcomes as it integrates time and physiology. METHODS: A cohort of patients transferred from six primary stroke centers and treated with intra-arterial therapy (IAT) was retrospectively studied. Absolute ASPECTS decay was defined as ((ASPECTS First CT-ASPECTS Second CT)/hours elapsed between images). A logistic regression model was performed to determine if the rate of ASPECTS decay predicted good outcomes at 90 days (modified Rankin Scale score of 0-2). RESULTS: 106 patients with a mean age of 66±14 years and a median National Institutes of Health Stroke Scale score of 19 (IQR 15-23) were analyzed. Median time between initial CT at the outside hospital to repeat CT at our facility was 2.7 h (IQR 2.0-3.6). Patients with good outcomes had lower rates of absolute ASPECTS decay compared with those who did not (0.14±0.23 score/h vs 0.49±0.39 score/h; p<0.001). In multivariable modeling, the absolute rate of ASPECTS decay (OR 0.043; 95% CI 0.004 to 0.471; p=0.01) was a stronger predictor of good patient outcome than static pretreatment ASPECTS obtained before IAT (OR 0.64; 95% CI 0.38 to 1.04; p=0.075). In practical terms, every 1 unit increase in ASPECTS decline per hour correlates with a 23-fold lower probability of a good outcome. CONCLUSIONS: Patients with faster rates of ASPECTS decay during inter-facility transfers are associated with worse clinical outcomes. This value may reflect the rate of physiological infarct expansion and thus serve as a tool in patient selection for IAT.

Discharge disposition to skilled nursing facility after endovascular reperfusion therapy predicts a poor prognosis.

OBJECTIVE: We explore the impact of discharge disposition (independent rehabilitation facility (IRF) vs skilled nursing facility (SNF)) on 90 day outcomes in persons with stroke who received acute endovascular treatment. METHODS: Using a database from a single primary care stroke center, discharge disposition, National Institutes of Health Stroke Scale (NIHSS), Totaled Health Risks in Vascular Events (THRIVE), Houston Intra-Arterial Therapy 2 (HIAT-2), and Acute Physiology and Chronic Health Evaluation (APACHE II) scores, and successful reperfusion were obtained. Univariate analysis was performed to assess predictors of good clinical outcome, as defined by 90 day modified Rankin Scale (mRS) scores ≤2. A binary logistic regression model was used to determine the impact of placement to an IRF versus an SNF on clinical outcomes. RESULTS: 147 subjects were included in the analysis with a mean age of 63±14 years and median NIHSS of 18 (IQR 14-21). Final infarct volumes, and modified APACHE II, THRIVE, and HIAT-2 scores were similar between those discharged to an IRF and those discharged to an SNF.However, their 90 day outcomes were significantly different, with far fewer patients at SNFs achieving good clinical outcomes (25% vs 46%; p=0.023). Disposition to SNF was significantly associated with a lower probability of achieving an mRS score of 0-2 at 90 days (OR = 0.337 (95% CI 0.12 to 0.94); p<0.04). CONCLUSIONS: Subjects discharged to SNFs and IRFs after thrombectomy have similar medical and neurological severity at admission and similar final infarct volumes at discharge. Despite these similarities, patients discharged to an SNF had a significantly lower probability of achieving a good neurological outcome. These results have implications for future acute stroke trial design.

Endovascular Reperfusion and Cooling in Cerebral Acute Ischemia (ReCCLAIM I).

BACKGROUND: The efficacy of hypothermia as a neuroprotectant has yet to be demonstrated in acute ischemic stroke. We conducted a phase I pilot study to assess the feasibility and safety of performing intravascular hypothermia after definitive intra-arterial reperfusion therapy (IAT). METHODS: ReCCLAIM (Reperfusion and Cooling in Cerebral Acute Ischemia) is a prospective single-arm open-label clinical trial conducted between May and August 2012 at Grady Memorial Hospital. Twenty patients with Alberta Stroke Program Early CT Score (ASPECTS) 5-7 and NIH Stroke Scale (NIHSS) score > 13 were enrolled and treated with intravascular cooling immediately after IAT. The incidence of pneumonia, deep vein thrombosis, cardiac arrhythmias and postoperative hemorrhages was documented for the entire length of stay. Secondary outcomes included blood-brain barrier (BBB) breakdown on gadolinium-enhanced MRIs and 90-day modified Rankin scores (mRS). RESULTS: The mean age, median NIHSS score and median final infarct volume were 59.7 ± 14.6 years, 19 (IQR16-22) and 78 cm(3) (IQR 16-107), respectively. The average time to the target temperature (33 °C) was 64 ± 50 min. Intracranial hemorrhages were found in three patients, of which one was symptomatic. Evidence of BBB breakdown was observed on 3 of 14 MRIs (21%). Six patients died due to withdrawal of care, whereas six patients (30%) achieved mRS of 0-2 at 90 days. In a binary logistical regression model comparing ReCCLAIM patients with 68 historical controls at our institution, hypothermia was protective against intracerebral hemorrhages (OR 0.09, 95% CI 0.02 to 0.56; p<0.01). CONCLUSIONS: Hypothermia can be safely performed after definitive IAT in patients with large pretreatment core infarcts. A phase II study randomizing patients to hypothermia or normothermia is needed to properly assess the efficacy of hypothermia as a neuroprotectant for reperfusion injury. TRIAL REGISTRATION NUMBER: NCT01585597.

Higher volume endovascular stroke centers have faster times to treatment, higher reperfusion rates and higher rates of good clinical outcomes.

BACKGROUND AND PURPOSE: Technological advances have helped to improve the efficiency of treating patients with large vessel occlusion in acute ischemic stroke. Unfortunately, the sequence of events prior to reperfusion may lead to significant treatment delays. This study sought to determine if high-volume (HV) centers were efficient at delivery of endovascular treatment approaches. METHODS: A retrospective review was performed of nine centers to assess a series of time points from obtaining a CT scan to the end of the endovascular procedure. Demographic, radiographic and angiographic variables were assessed by multivariate analysis to determine if HV centers were more efficient at delivery of care. RESULTS: A total of 442 consecutive patients of mean age 66 ± 14 years and median NIH Stroke Scale score of 18 were studied. HV centers were more likely to treat patients after intravenous administration of tissue plasminogen activator and those transferred from outside hospitals. After adjusting for appropriate variables, HV centers had significantly lower times from CT acquisition to groin puncture (OR 0.991, 95% CI 0.989 to 0.997, p=0.001) and total procedure times (OR 0.991, 95% CI 0.986 to 0.996, p=0.001). Additionally, patients treated at HV centers were more likely to have a good clinical outcome (OR 1.86, 95% CI 1.11 to 3.10, p<0.018) and successful reperfusion (OR 1.82, 95% CI 1.16 to 2.86, p<0.008). CONCLUSIONS: Significant delays occur in treating patients with endovascular therapy in acute ischemic stroke, offering opportunities for improvements in systems of care. Ongoing prospective clinical trials can help to assess if HV centers are achieving better clinical outcomes and higher reperfusion rates.