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Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.

Background Intracranial occlusions in embolic stroke of undetermined source are histopathologically similar to cardiac sources of embolism. Whether patients with embolic stroke of undetermined source and intracranial occlusion benefit from anticoagulation is unknown. Methods A multicenter retrospective cohort of adults with cryptogenic stroke was queried for patients with proximal or medium/distal vessel occlusion. The primary outcome was recurrent ischemic stroke, which was assessed in unadjusted and adjusted Cox proportional hazards models and repeated following 1:1 propensity score matching and biweight kernel density matching. Results Of the 2328 patients who were followed over a median of 1.31 years (interquartile range, 0.34–2.85), 999 (42.6%) had an intracranial occlusion. When compared with patients without an intracranial occlusion, those with an occlusion had fewer atherosclerotic vascular risk factors, more severe symptoms, and less severe cerebral microvascular disease. The rate of recurrent stroke was similar between patients with versus without an intracranial occlusion (6.8%/year [95% CI, 5.7–8.2] versus 7.0%/year [95% CI 6.0–8.1]; adjusted hazard ratio [HR], 1.09 [95% CI, 0.77–1.55]). There was no association between occlusion and recurrent stroke in the adjusted propensity score matching (HR, 1.01 [95% CI, 0.64–1.59]) or kernel density models (HR, 0.95 [95% CI, 0.62–1.45]). There was no interaction between occlusion and treatment with anticoagulation, sex, age, or high‐risk sources of embolism for the primary outcome in the unmatched and matched analyses. Conclusions Intracranial occlusion in patients with embolic stroke of undetermined source is not associated with a greater risk of recurrence when compared with patients without an intracranial occlusion. There was no difference in rate of recurrent stroke with anticoagulation when stratified by presence or absence of occlusion.

Background: Multiple randomized clinical trials failed to show benefit of anticoagulation over antiplatelets in the secondary prevention for embolic stroke of undetermined source (ESUS). However, the benefit of combination antithrombotic regimens remains unexplored in the same patient population. Methods: This is a subgroup analysis of a multicenter retrospective observational cohort of consecutive adult patients with ESUS (n=27 sites, 2015-2024). Comparisons were made between patients treated with single (SAPT) or dual antiplatelet therapy (DAPT), exclusive anticoagulation (AC) (direct oral anticoagulant, vitamin K antagonist, low molecular weight heparin) and combination anticoagulation and antiplatelet therapy initiated within the first 7 days of index stroke. The primary composite outcome of recurrent ischemic stroke, major bleeding, or death was assessed using unadjusted and adjusted Cox proportional hazards regression. Secondary outcomes were individual outcomes of recurrent ischemic stroke, major bleeding, or death. Results: Of the 2201 included patients, 1456 (66.1%) were on SAPT, 527 (23.9%) were on DAPT, 195 (8.8%) were on exclusive AC and 23 (1.0%) were on AC+AP (all of which were on DAPT). Patients treated with AC+AP were older (median 66 years [IQR 51-78]), more likely to have history of hypertension, stroke, hyperlipidemia, PFO and left atrial enlargement. Compared to SAPT, all treatment strategies were associated with similar risk of the primary outcomes in the unadjusted and adjusted cox regression. Similarly, there was no difference in individual outcomes including recurrent stroke, major bleeding and death in the adjusted cox regression. However, there was an increased risk of major bleeding with AC+AP in the unadjusted cox regression (HR 4.0, [95% CI 1.2-12.8], p=0.02) but not in the adjusted model when compared to SAPT. Also, DAPT was associated with lower risk of death than SAPT in the unadjusted model (HR 0.61 [95% CI 0.4-0.8],p=0.005) but not the adjusted model. Additionally, when adjusted by the HASBLED score, there was no difference in major bleeding when AC+AP was compared to SAPT. Conclusion: Over 90% of ESUS patients in this cohort were prescribed SAPT or DAPT. Antithrombotic therapy with DAPT, exclusive AC, or AC+AP was not associated with any lower risk of recurrent ischemic stroke, major bleeding and death compared with SAPT in an unselected cohort of ESUS patients.

Introduction: Four randomized clinical trials have not demonstrated the superiority of anticoagulation over antiplatelet therapy in the prevention of recurrent embolic stroke of undetermined source (ESUS). In this multicenter observational cohort study, we evaluated long-term outcomes associated with various antithrombotic strategies according to potential embolic sources. Methods: A multicenter retrospective observational cohort of consecutive adult patients with ESUS was queried (n=27 sites). Comparisons were made between patients treated with single or combination antiplatelet therapy versus anticoagulation (direct oral anticoagulant, vitamin K antagonist, low molecular weight heparin) with or without antiplatelet therapy initiated within 7 days of stroke. The primary composite outcome of recurrent stroke, major bleeding, or death was assessed using unadjusted and adjusted Cox proportional hazards regression, with clustering by site. Causal inference was assessed using inverse probability of treatment weighted regression adjustment (IPTWRA), accounting for propensity for antiplatelet treatment, with effect estimates summarized as the average treatment effect (ATE) over time (in days). Adjusted models accounted for age, stroke severity, vascular risk factors, and major categories of potential embolic sources. Results: Of the 2201 included patients (n=218 treated with anticoagulation) followed over a median of 564 days (interquartile range [IQR] 154-1124), the median age was 65y (IQR 54-74) and 49.8% were female. Patients treated with anticoagulation were older with more frequent previous stroke, concomitant left ventricular dysfunction, and more severe deficits. Over 4541 person-years of follow-up, the annualized incidence rate of the primary outcome was 14.6% (95% confidence interval [CI], 13.6%-15.8%). Compared to anticoagulation, antiplatelet(s) use was not associated with a lower risk of the primary outcome in the adjusted Cox model (HR 0.91, 95% CI, 0.64-1.29) or in the IPTWRA model (average treatment effect 0.14, 95% CI, -1376.6 to 1376.9). Major bleeding events trended toward significance in the adjusted Cox model (HR 0.51, 95% CI 0.25-1.04) but were no different with IPTWRA (ATE 58.9, 95% CI, -125.4 to 243.2). Conclusions: These results validate the observations of randomized trials indicating a lack of benefit of anticoagulation over antiplatelet therapy in ESUS. A more detailed analysis of heterogeneity of treatment effect is under way.

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.