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BACKGROUND: Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. METHODS: We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. RESULTS: Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21–1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97–1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10–0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83–1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04–0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15–0.73]). CONCLUSIONS: After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06398366.

Background: Although the embolic stroke of undetermined source (ESUS) construct was proposed as a unifying concept for embolic-appearing strokes without an identified cause, it includes patients with diverse and often unrecognized underlying mechanisms. This study investigates the differential rate of recurrent stroke according to the completeness of neurodiagnostic testing in a diverse multicenter cohort. Methods: This was a retrospective analysis of a multicenter observational cohort study (n=27 sites). Patients with ESUS were categorized into three groups: (1) established mechanism after further work up (ESUS-E), (2) patients who underwent a comprehensive diagnostic workup without an identified etiology (ESUS 2.0), and (3) no advanced workup (ESUS-NAW). The primary outcome of recurrent ischemic stroke was assessed by comparing ESUS 2.0 to both ESUS-E and ESUS-NAW groups using adjusted Cox proportional hazards models. Results: Of the 2,281 patients included, 694 (30%) were classified as ESUS-E, 344 (15%) as ESUS 2.0, and 1,443 (55%) as ESUS-NAW. The ESUS 2.0 group had a significantly lower annualized recurrence rate (1.98 per 100 person-years) compared to both the ESUS-NAW group (7.7 per 100 person-years; aHR 0.27, 95% CI: 0.11–0.62; p=0.002) and the ESUS-E group (6.10 per 100 person-years; aHR = 0.35; 95% CI 0.15–0.85, p=0.020). Within the ESUS-E group, cancer (aHR 5.33; 95% CI: 2.09–13.63; p < 0.001) and non-stenosing atherosclerotic disease or arch atheroma (aHR 3.40; 95% CI: 1.18–9.83; p = 0.023) were associated with significantly increased risk of recurrence when compared to ESUS 2.0. Conclusion: These findings demonstrate a lower risk of recurrent stroke in patients classified as ESUS 2.0, diverging from the 5–6% annual recurrence rates observed in prior ESUS trials. These findings suggest that patients who receive comprehensive diagnostic evaluation without identification of a specific etiology have a lower risk of recurrent stroke, an important consideration for the design of future ESUS studies.

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.

Background: Left ventricular (LV) injury is a cardioembolic etiology of ischemic stroke. We aimed to 1) evaluate recurrent stroke risk among patients with cryptogenic stroke and LV injury, and 2) determine if there is a treatment effect with anticoagulation in this population. Methods: We analyzed the multicenter, retrospective Cardiac Abnormalities in Stroke Prevention and Recurrence cohort of patients with cryptogenic ischemic stroke. The exposure was LV injury defined by 1) LV ejection fraction (EF) 20-40% and/or 2) LV wall motion abnormality (hypokinesis or akinesis). The primary composite outcome included recurrent stroke, major bleeding, or death. Cox proportional hazard models were built and sequentially adjusted for 1) age and sex (Model 1), and 2) age, sex, race, ethnicity, anti-thrombotic use, and vascular risk factors (Model 2). We then assessed if there was heterogeneity in treatment effect by LV injury status with an interaction term of LV injury and oral anticoagulation use in Model 2. Results: Of 2,641 patients in CASPR, the analytic cohort included 2,191 patients with complete exposure and outcome data (median age 65 years, 49.8% female, median follow-up 1.55 years). There were 113 (5.2%) patients with LV injury (median LVEF 30%, interquartile range 25-34%). There were 559 incident events (321 recurrent strokes [288 ischemic], 71 major hemorrhages, 250 deaths). Among patients with LV injury, 15.9% were prescribed an anticoagulant within 7 days of index stroke (vs 9.6% without LV injury, p=0.03). The unadjusted risk of the primary outcome was non-significantly higher among patients with LV injury vs without (HR 1.40; 95% confidence interval [CI], 0.98-2.00), but became significant in Model 1 (HR 1.50; 95% CI, 1.21-1.85) and in Model 2 (HR 1.35, 95% CI, 1.11-1.64). In the LV injury subgroup, anticoagulation vs antiplatelet therapy was associated with a significant reduction in the primary outcome (HR 0.63, 95% CI, 0.43-0.94). In patients without LV injury, anticoagulation was associated with a higher risk of the composite outcome (HR 4.35, 95% CI, 1.69-11.16, p[interaction]=0.002). Conclusion: In this observational study, there was an increased risk of the primary outcome which included recurrent stroke among patients with cryptogenic stroke and LV injury. Anticoagulation use in LV injury is associated with a significant reduction in the risk of the primary outcome. These findings warrant confirmation in a dedicated randomized controlled trial.

Introduction: Malignancy represents an important subgroup of embolic stroke of undetermined source (ESUS). We aim to compare infarct features, potential embolic sources, and long-term outcomes in ESUS patients with and without malignancy. Methods: In this pre-specified secondary analysis of the Cardiac Abnormalities in Stroke Prevention and Recurrence (CASPR) retrospective cohort study, active cancers were identified by site investigators and adjudicated as malignant if they were non-squamous or non-basal cell skin cancers. We compared the prevalence of various potential embolic sources (e.g., patent foramen ovale, left ventricular dysfunction, post-stroke atrial fibrillation) among patients with and without malignancy. The risk of recurrent stroke, major bleeding, or death was evaluated using adjusted Cox proportional hazards models, accounting for age, sex, vascular risk factors, competing potential embolic sources, and initial treatment with anticoagulation versus non-anticoagulant (e.g., antiplatelet) regimen. Results: Of the 2201 patients followed over a median of 564 days, 236 (10.7%) were diagnosed with cancer at the time of stroke. Patients with malignancy were older, more frequently hypertensive and did not differ with regards to prevalence of specific infarct patterns or potential cardiac embolic sources. No difference was observed in the composite outcome of recurrent stroke, major bleeding, or death (adjusted HR 1.02, 95% CI, 0.71-1.46). Age (adjusted HR per year 1.02, 95% CI, 1.01-1.03), baseline stroke severity (adjusted HR 1.03 per NIHSS point, 95% CI, 1.01-1.05), prior stroke (adjusted HR 1.68, 95% CI, 1.38-2.05), and multi-territorial infarct pattern (adjusted HR 1.67, 95% CI, 1.33-2.08) were significantly associated with this composite outcome, but anticoagulation was not. There was a nominally lower rate of major bleeding with malignancy (adjusted HR 0.45, 95% CI, 0.19-1.04), a significantly higher rate of death (adjusted HR 1.58, 95% CI, 1.09-2.30), but no significant difference in recurrent ischemic stroke (p=0.31). Conclusions: Patients with malignancy and ESUS had higher mortality but did not differ in recurrent stroke risk or major bleeding when compared to patients without malignancy. Anticoagulation was not independently associated with better outcomes. Further analysis of infarct topology and risk factors may better identify patients for whom anticoagulation may benefit.

ABSTRACTLarge‐scale studies have not addressed the knowledge level of US resident physicians regarding osteoporosis management. We gauged the knowledge level of family medicine, internal medicine, and obstetrics and gynecology resident physicians regarding osteoporosis management. In 2019, we sent an anonymous survey via e‐mail to all program directors of Accreditation Council for Graduate Medical Education–accredited residency programs in family medicine, internal medicine, and obstetrics and gynecology for distribution to resident physicians. Knowledge items assessed osteoporosis screening, diagnosis, and treatment. We received responses from 182 family medicine, 275 internal medicine, and 122 obstetrics and gynecology programs. Of 582 resident physician respondents, 31% were family medicine residents, 47% were internal medicine residents, and 21% were obstetrics and gynecology residents. Although 77% of respondents correctly selected the T‐score threshold for the diagnosis of osteoporosis among persons aged 50 years and older (−2.5), only 20% of respondents correctly identified minimal‐trauma hip fracture as being diagnostic of osteoporosis. One‐third of respondents correctly identified which medications were demonstrated in clinical trials to decrease hip fracture risk. Fifteen percent of respondents correctly identified that denosumab and alendronate are associated with osteonecrosis of the jaw; and 40% of respondents correctly identified that decline in bone density is more rapid after discontinuation of denosumab than after discontinuation of bisphosphonates. Less than half of resident physicians knew that bisphosphonate‐associated atypical femoral fractures are duration‐dependent. One‐quarter of respondents felt not at all prepared to manage osteoporosis. In this nationwide survey of resident physicians, knowledge regarding osteoporosis diagnosis and treatment was poor, with a striking lack of knowledge regarding the two most serious adverse effects of osteoporosis pharmacotherapy (osteonecrosis of the jaw and atypical femoral fractures). The undertreatment of osteoporosis is unlikely to improve without increased education of resident physicians. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.