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

Safety and feasibility of NeuroFlo use in eight- to 24-hour ischemic stroke patients.

BACKGROUND: Acute treatment of ischemic stroke patients presenting more than eight-hours after symptom onset remains limited and largely unproven. Partial aortic occlusion using the NeuroFlo catheter can augment cerebral perfusion in animals. We investigated the safety and feasibility of employing this novel catheter to treat ischemic stroke patients eight-hours to 24 h following symptom onset. METHODS: A multicenter, single-arm trial enrolled ischemic stroke patients at nine international academic medical centers. Eligibility included age 18-85 years old, National Institutes of Health stroke scale (NIHSS) score between four and 20, within eight-hours to 24 h after symptom onset, and perfusion-diffusion mismatch confirmed by magnetic resonance imaging. The primary outcome was all adverse events occurring from baseline to 30 days posttreatment. Secondary outcomes included stroke severity on neurological indices through 90 days. This study is registered with ClinicalTrials.gov, number NCT00436592. RESULTS: A total of 26 patients were enrolled. Of these, 25 received treatment (one excluded due to aortic morphology); five (20%) died. Favorable neurological outcome at 90 days (modified Rankin score 0-2 vs. 3-6) was associated with lower baseline NIHSS (P < 0·001) and with longer duration from symptom discovery to treatment. There were no symptomatic intracranial hemorrhages or parenchymal hematomas. Asymptomatic intracranial hemorrhage was visible on computed tomography in 32% and only on microbleed in another 20%. CONCLUSIONS: Partial aortic occlusion using the NeuroFlo catheter, a novel collateral therapeutic strategy, appears safe and feasible in stroke patients eight-hours to 24 h after symptom onset

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

Non-vitamin K oral anticoagulants associated bleeding and its antidotes

Oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) accounts for nearly 20% of all ICH. The number of patients with an indication for oral anticoagulant therapy (OAT) increases with increasing age. OAT became less complicate with the introduction of non-vitamin K oral anticoagulants (NOAC) OAT because of easier handling, favorable risk-benefit profile, reduced rates of ICH compared to vitamin K antagonists and no need for routine coagulation testing. Consequently, despite a better safety profile of NOAC the number of patients with OAC-ICH will increase. The mortality and complication rates of OAC-ICH are high and therefore they are the most feared complication of OAT. Immediate normalization of coagulation is the main goal and therefore knowledge of pharmacodynamics and coagulation status is essential. Laboratory measurements of anticoagulant activity in NOAC patients is challenging as specific tests are not widely available. More accessible tests such as the prothrombin time and activated partial thromboplastin time have important limitations. In dabigatran-associated ICH 5 g Idarucizumab should be administered. In rivaroxaban and apixaban-associated ICHs administration of andexanet alpha should be considered. Prothrombin complex concentrate may be considered if andexanet alpha is not available or in case of an ICH associated with edoxaban. © 2018 Korean Stroke Society

Patent foramen ovale: Story closed?

The optimal treatment strategy for secondary prevention in patients with cryptogenic stroke and patent foramen ovale (PFO) has been a matter of controversy for decades. After three randomized trials failed to show a benefit of closure with an excess of complications in the interventional arm, two large recent trials suggest a benefit with regard of preventing further ischemic strokes. With this discrepancy in results it is important to discuss recent trials in detail and evolve an informed clinical approach for daily practice. © 2019 Korean Stroke Society

Percutaneous left atrial appendage occlusion for the prevention of stroke in patients with atrial fibrillation: Review and critical appraisal

The authors review the current status of percutaneous left atrial appendage (LAA) occlusion therapy in patients with atrial fibrillation with the goal to prevent ischemic stroke and systemic embolism and to reduce oral anticoagulation associated bleeding. While we cover the historical and also surgical background, and all tested devices, the main focus rests on the single currently U.S. Food and Drug Administration (FDA) approved LAA occluder, the WATCHMAN device, and its approval process. The authors also give a critical appraisal beyond the review of mere facts, trying to put the current data into perspective. © 2018 Korean Stroke Society

Reduced Mortality and Severe Disability Rates in the SENTIS Trial

BACKGROUND AND PURPOSE: 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. MATERIALS AND METHODS: The Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke trial was a multicenter, randomized, controlled trial that evaluated the safety and effectiveness of the NeuroFlo catheter in patients with stroke. The current analysis was performed on the as-treated population. All-cause and stroke-related mortality rates at 90 days were compared between groups, and logistic regression models were fit to obtain ORs and 95% CIs for the treated versus not-treated groups. We categorized death-associated serious adverse events as neurologic versus non-neurologic events and performed multiple logistic regression analyses. We analyzed severe disability and mortality by outcomes of the mRS. Patient allocation was gathered by use of a poststudy survey. RESULTS: All-cause mortality trended in favor of treated patients (11.5% versus 16.1%; P = .079) and stroke-related mortality was significantly reduced in treated patients (7.5% versus 14.2%; P = .009). Logistic regression analysis for freedom from stroke-related mortality favored treatment (OR, 2.41; 95% CI, 1.22, 4.77; P = .012). Treated patients had numerically fewer neurologic causes of stroke-related deaths (52.9% versus 73.0%; P = .214). Among the 90-day survivors, nominally fewer treated patients were severely disabled (mRS 5) (5.6% versus 7.5%; OR, 1.72; 95% CI, 0.72, 4.14; P = .223). Differences in allocation of care did not account for the reduced mortality rates. CONCLUSIONS: There were consistent reductions in all-cause and stroke-related mortality in the NeuroFlo-treated patients. This reduction in mortality did not result in an increase in severe disability

Antiplatelet pretreatment and outcomes in intravenous thrombolysis for stroke: a systematic review and meta-analysis

Since there are contradictory data regarding the association of antiplatelet pretreatment (AP) with safety and efficacy outcomes of intravenous thrombolysis (IVT) for acute ischemic stroke (AIS), we conducted a systematic review and meta-analysis of available randomized-controlled clinical trials (RCTs) to investigate the association of AP with outcomes of AIS patients treated with intravenous alteplase. The outcome events of interest included symptomatic intracranial hemorrhage (sICH), fatal ICH, complete recanalization (CR), 3-month favorable functional outcome (FFO, mRS score 0–1), 3-month functional independence (FI, mRS score 0–2), and mortality. The corresponding odds ratios (ORs) were calculated for all the outcome events using random-effects model. The adjusted age and admission NIHSS OR (ORadjusted) were also estimated for all available outcomes. We included 7 RCTs (4376 patients, 33.7% with AP). In unadjusted analyses, AP was associated with higher likelihood of sICH (OR = 1.89, 95% CI 1.40–2.56), death (OR = 1.59, 95% CI 1.24–2.03), and lower likelihood of 3-month FI (OR = 0.69, 95% CI 0.56–0.85). No association was detected between AP and fatal ICH (OR = 1.53, 95% CI 0.75–3.15), 3-month FFO (OR = 0.79, 95% CI 0.58–1.07), and CR (OR = 0.64, 95% CI 0.04–11.66). After adjustment for age and admission stroke severity, AP was not related to sICH (ORadjusted = 1.67, 95% CI 0.75–3.72), 3-month FI (ORadjusted = 0.88, 95% CI 0.54–1.42), or death (ORadjusted = 1.01, 95% CI 0.55–1.86) in adjusted analyses. In conclusion, after adjusting for confounders, AP was not associated with a higher risk of sICH and worse 3-month functional outcome in AIS treated with intravenous alteplase. Antiplatelet intake prior to tPA-bolus should not be used as a reason to withhold or lower alteplase dose in AIS patients treated with IVT. © 2017, Springer-Verlag Berlin Heidelberg

Endovascular thrombectomy with or without systemic thrombolysis?

Objectives: Current recommendations advocate that pretreatment with intravenous thrombolysis (IVT) should first be offered to all eligible patients with emergent large vessel occlusion (ELVO) before an endovascular thrombectomy (ET) procedure. However, there are observational data that question the safety and efficacy of IVT pretreatment in patients with ELVO. Methods: We performed a meta-analysis of the included subgroups from ET randomized controlled trials (RCTs) to evaluate the comparative efficacy between direct ET without IVT pretreatment and bridging therapy (IVT and ET) in patients with ELVO. Results: We included a total of seven RCTs, including 1764 patients with ELVO (52.8% men). Patients receiving bridging therapy (IVT followed by ET) had lower rates (p = 0.041) of 90-day death/severe dependency (modified Rankin Scale-score of 5-6; 19.0%, 95% CI: 14.1-25.1%) compared with patients receiving only ET (31.0%, 95% CI: 21.2-42.9%). Moreover, patients receiving IVT and ET had a nonsignificant (p = 0.389) trend towards higher 90-day functional independence rates (51.4%, 95% CI: 42.5-60.1%) compared with patients undergoing only ET (41.7%, 95% CI: 24.1-61.7%). Finally, shift-analysis uncovered a nonsignificant trend towards functional improvement at 90 days for bridging therapy over ET (cOR = 1.28, 95% CI: 0.91-1.89; p = 0.155). It should be noted that patients included in the present meta-analysis were not randomized to receive IVT, and thus the two groups (bridging therapy versus ET monotherapy) may differ in terms of baseline characteristics and, in particular, in terms of onset to groin puncture time and thus the risk of confounding bias cannot be ruled out. Conclusion: Despite the limitations and the risk of confounding bias, our findings contradict the recent notion regarding potential equality between ET and bridging therapy in ELVO patients and suggest that IVT and ET are complementary therapies that should be pursued in a parallel and noncompeting fashion. © 2017 SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses