Statistical analysis of the primary outcome in acute stroke trials

Common outcome scales in acute stroke trials are ordered categorical or pseudocontinuous in structure but most have been analyzed as binary measures. The use of fixed dichotomous analysis of ordered categorical outcomes after stroke (such as the modified Rankin Scale) is rarely the most statistically efficient approach and usually requires a larger sample size to demonstrate efficacy than other approaches. Preferred statistical approaches include sliding dichotomous, ordinal, or continuous analyses. Because there is no best approach that will work for all acute stroke trials, it is vital that studies are designed with a full understanding of the type of patients to be enrolled (in particular their case mix, which will be critically dependent on their age and severity), the potential mechanism by which the intervention works (ie, will it tend to move all patients somewhat, or some patients a lot, and is a common hazard present), a realistic assessment of the likely effect size, and therefore the necessary sample size, and an understanding of what the intervention will cost if implemented in clinical practice. If these approaches are followed, then the risk of missing useful treatment effects for acute stroke will diminish

Results of the MRI substudy of the intravenous magnesium efficacy in stroke trial

<p><b>Background and Purpose:</b>Although magnesium is neuroprotective in animal stroke models, no clinical benefit was confirmed in the Intravenous Magnesium Efficacy in Stroke (IMAGES) trial of acute stroke patients. The Magnetic Resonance in IMAGES (MR IMAGES) substudy investigated the effects of magnesium on the imaging surrogate outcome of infarct growth.</p> <p><b>Methods:</b> IMAGES trial patients in participating centers were randomized to receive either intravenous magnesium or placebo within 12 hours of stroke onset. Infarct growth was defined as volume difference between baseline diffusion-weighted imaging and day 90 fluid-attenuated inversion recovery image lesions. Patients who died were imputed the largest infarct growth observed.</p> <p><b>Results:</b> Among the 90 patients included in the primary analysis, there was no difference in infarct growth (median absolute growth, P=0.639; median percentage growth, P=0.616; proportion with any growth, P=0.212) between the 46 treated with magnesium and 44 with placebo. Infarct growth correlated with NIHSS score change from baseline to day 90. There was a trend showing baseline serum glucose correlated with infarct growth with magnesium treatment, but not in the placebo group. The mismatch frequency was reduced from 73% to 47% by increasing the mismatch threshold from >20% to >100% of core volume.</p> <p><b>Conclusions:</b> Infarct growth, confirmed here as a surrogate for clinical progression, was similar between magnesium and placebo treatment, paralleling the main IMAGES trial clinical outcomes. Glucose was a covariate for infarct growth with magnesium treatment. A more stringent mismatch threshold to define penumbra more appropriately would have excluded half of the patients in this 12-hour time window stroke study.</p&gt

Reduced Mortality and Severe Disability Rates in the SENTIS Trial

The Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke trial showed a trend for reduced all-cause mortality and positive secondary safety end point outcomes. We present further analyses of the mortality and severe disability data from the Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke trial

Automated final lesion segmentation in posterior circulation acute ischemic stroke using deep learning

Final lesion volume (FLV) is a surrogate outcome measure in anterior circulation stroke (ACS). In posterior circulation stroke (PCS), this relation is plausibly understudied due to a lack of methods that automatically quantify FLV. The applicability of deep learning approaches to PCS is limited due to its lower incidence compared to ACS. We evaluated strategies to develop a convolutional neural network (CNN) for PCS lesion segmentation by using image data from both ACS and PCS patients. We included follow-up non-contrast computed tomography scans of 1018 patients with ACS and 107 patients with PCS. To assess whether an ACS lesion segmentation generalizes to PCS, a CNN was trained on ACS data (ACS-CNN). Second, to evaluate the performance of only including PCS patients, a CNN was trained on PCS data. Third, to evaluate the performance when combining the datasets, a CNN was trained on both datasets. Finally, to evaluate the performance of transfer learning, the ACS-CNN was fine-tuned using PCS patients. The transfer learning strategy outperformed the other strategies in volume agreement with an intra-class correlation of 0.88 (95% CI: 0.83–0.92) vs. 0.55 to 0.83 and a lesion detection rate of 87% vs. 41–77 for the other strategies. Hence, transfer learning improved the FLV quantification and detection rate of PCS lesions compared to the other strategies

Healthy life-year costs of treatment speed from arrival to endovascular thrombectomy in patients with ischemic stroke: a meta-analysis of individual patient data from 7 randomized clinical trials

This meta-analysis evaluates outcomes along the full health-related quality-of-life range associated with time to endovascular thrombectomy in patients with ischemic stroke.Question What are the lifetime consequences associated with care process delays in patients with ischemic stroke who are treated with endovascular thrombectomy? Findings In this meta-analysis of pooled individual patient data from 406 adults in 7 randomized trials, delays in delivering endovascular thrombectomy were associated with marked reductions in healthy life-years after treatment. In the time interval from hospital arrival to endovascular procedure start, every 1 second of delay was associated with loss of 2.2 hours of healthy life. Meaning In this study, care delays in delivering endovascular thrombectomy to ischemic stroke patients were associated with substantial losses of healthy life-years; health care organization and workflow optimization should be a priority to facilitate faster reperfusion for acute stroke patients.Importance 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. Objective To assess the lifetime outcomes associated with speed of endovascular thrombectomy in patients with acute ischemic stroke due to large-vessel occlusion (LVO). Data Sources 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. Study Selection 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. Data Extraction/Synthesis 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. Main Outcomes and Measures 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. Results Among the 781 EVT-treated patients, 406 (52.0%) were early-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. Conclusions and Relevance 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.Paroxysmal Cerebral Disorder

Public Health and Cost Benefits of Successful Reperfusion After Thrombectomy for Stroke

Background and Purpose- The benefit that endovascular thrombectomy offers to patients with stroke with large vessel occlusions depends strongly on reperfusion grade as defined by the expanded Thrombolysis in Cerebral Infarction (eTICI) scale. Our aim was to determine the lifetime health and cost consequences of the quality of reperfusion for patients, healthcare systems, and society. Methods- A Markov model estimated lifetime quality-adjusted life years (QALY) and lifetime costs of endovascular thrombectomy-treated patients with stroke based on eTICI grades. The analysis was performed over a lifetime horizon in a United States setting, adopting healthcare and societal perspectives. The reference case analysis was conducted for stroke at 65 years of age. National health and cost consequences of improved eTICI 2c/3 reperfusion rates were estimated. Input parameters were based on best available evidence. Results- Lifetime QALYs increased for every grade of improved reperfusion (median QALYs for eTICI 0/1: 2.62; eTICI 2a: 3.46; eTICI 2b: 5.42; eTICI 2c: 5.99; eTICI 3: 6.73). Achieving eTICI 3 over eTICI 2b reperfusion resulted on average in 1.31 incremental QALYs as well as healthcare and societal cost savings of $10 327 and$20 224 per patient. A 10% increase in the eTICI 2c/3 reperfusion rate of all annually endovascular thrombectomy-treated patients with stroke in the United States is estimated to yield additional 3656 QALYs and save $21.0 million and$36.8 million for the healthcare system and society, respectively. Conclusions- Improved reperfusion grants patients with stroke additional QALYs and leads to long-term cost savings. Procedural strategies to achieve complete reperfusion should be assessed for safety and feasibility, even when initial reperfusion seems to be adequate

Effect of atrial fibrillation on endovascular thrombectomy for acute ischemic stroke. A meta-analysis of individual patient data from six randomised trials: Results from the HERMES collaboration

Background: Atrial fibrillation is an important risk factor for ischemic stroke, and is associated with an increased risk of poor outcome after ischemic stroke. Endovascular thrombectomy is safe and effective in acute ischemic stroke patients with large vessel occlusion of the anterior circulation. This meta-analysis aims to investigate whether there is an interaction between atrial fibrillation and treatment effect of endovascular thrombectomy, and secondarily whether atrial fibrillation is associated with worse outcome in patients with ischemic stroke due to large vessel occlusion. Methods: Individual patient data were from six of the recent randomised clinical trials (MR CLEAN, EXTEND-IA, REVASCAT, SWIFT PRIME, ESCAPE, PISTE) in which endovascular thrombectomy plus standard care was compared to standard care alone. Primary outcome measure was the shift on the modified Rankin scale (mRS) at 90 days. Secondary outcomes were functional independence (mRS 0–2) at 90 days, National Institutes of Health Stroke Scale score at 24 h, symptomatic intracranial hemorrhage and mortality at 90 days. The primary effect parameter was the adjusted common odds ratio, estimated with ordinal logistic regression (shift analysis); treatment effect modification of atrial fibrillation was assessed with a multiplicative interaction term. Results: Among 1351 patients, 447 p

Automatic segmentation of cerebral infarcts in follow-up computed tomography images with convolutional neural networks

Background and purpose: Infarct volume is a valuable outcome measure in treatment trials of acute ischemic stroke and is strongly associated with functional outcome. Its manual volumetric assessment is, however, too demanding to be implemented in clinical practice. Objective: To assess the value of convolutional neural networks (CNNs) in the automatic segmentation of infarct volume in follow-up CT images in a large population of patients with acute ischemic stroke. Materials and methods: We included CT images of 1026 patients from a large pooling of patients with acute ischemic stroke. A reference standard for the infarct segmentation was generated by manual delineation. We introduce three CNN models for the segmentati