Liisa Tomppo

Introduction: Patients with minor ischaemic stroke (NIHSS ≤ 5) and intracranial occlusion or focal perfusion abnormality ≤ 12 h of onset did not benefit from intravenous tenecteplase compared to non-thrombolytic standard care (control) in the Tenecteplase vs Standard of Care for Minor Ischaemic Stroke with Proven Occlusion (TEMPO-2) trial. We tested whether tenecteplase was associated with better outcomes in subgroups defined by baseline vessel occlusion status. Patients and methods: In this secondary analysis of the randomised, controlled, blinded TEMPO-2 trial, patients were divided into 3 subgroups: complete occlusion (revised arterial occlusive lesion score 0), near occlusion (score 1) and no visible occlusion (focal perfusion abnormality present). The primary outcome was return to pre-stroke neurological functioning or better, assessed with 90-day mRS. Outcomes were analysed using a generalised linear model adjusted for age, sex, onset-to-randomisation time and baseline stroke severity. Results: Of 881 patients, complete occlusion was present in 218 in the control and 216 in the tenecteplase arm, near occlusion in 102 and 92 and no visible occlusion in 130 and 123, respectively. At baseline, there were longer treatment delays in the control arm with near occlusion, and older age, more hypertension and higher creatinine levels in the tenecteplase arm with complete occlusion. We found no difference in the primary outcome between tenecteplase and control in any subgroup (no visible occlusion: adjusted RR 1.03 [95% CI, 0.90–1.18]; near occlusion: adjusted RR 0.85 [95% CI, 0.71–1.01]; complete occlusion: adjusted RR 1.00 [95% CI, 0.89–1.12]). Discussion and conclusion: There was no difference in outcome between tenecteplase and standard care for patients with mild stroke based on their baseline vessel occlusion status. Trial registration: Clinicaltrials.gov: NCT02398656.

BACKGROUND: The incidence of cryptogenic ischemic stroke (CIS) in young adults is increasing, particularly among those without traditional vascular risk factors. Thrombophilia may contribute to CIS pathogenesis, yet guidelines differ on the relevance of screening. We investigated the sex-specific prevalence of routinely applied thrombophilia screening in young-onset CIS and its association with clinical characteristics and standard laboratory results. METHODS: We included young patients with CIS aged 18 to 49 years from the SECRETO study (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome). Routinely used thrombophilia panels obtained at admission and repeated testing within 1 year of stroke were analyzed. Ten thrombophilia markers were assessed and categorized according to the grade of deviation into lowest, low, and high thrombosis risks. Factors associated with any deviation in thrombophilia markers were investigated with multivariable logistic regression. RESULTS: Of 598 initially enrolled patients with CIS, 556 undergoing baseline thrombophilia testing were analyzed (median age, 41.0 [interquartile range, 34.1–45.8] years; male:female ratio 1.2:1). Of these, 120 (21.6%) and 36 (6.5%) were retested by 3 and 12 months, respectively. At baseline, any thrombophilia abnormality was observed in 206 patients (37.1%; men, 38.2%; women, 35.7%). High-risk thrombophilia was identified in 29 patients (5.2%) at baseline, in 13 retested patients (11.1%) at 3 months, and in 5 retested patients (13.9%) at 12 months. Overall, 45 patients (8.1%) had persistent thrombophilia abnormalities (men, 7.9%; women, 8.3%). Physical inactivity, a history of venous thromboembolism, low HDL (high-density lipoprotein)-cholesterol, and low hemoglobin were associated with any deviation in the thrombophilia markers. Anticoagulation was initiated in 50.0% of patients with abnormal baseline thrombophilia versus 35.7% without ( P =0.042) and in 26.9% versus 6.2% with and without persistent abnormalities ( P <0.001). CONCLUSIONS: Over a third of young adults with CIS had thrombophilia deviations at admission although high-risk thrombophilia results remained rare. Screening may be considered in young patients with CIS with a history of venous thromboembolism, physical inactivity, and low hemoglobin or HDL-cholesterol.

Direct oral anticoagulants (DOACs) are at least as effective as vitamin K antagonists (VKAs) in preventing ischemic stroke in patients with atrial fibrillation (AF) with lower rates of symptomatic ...

Familial aggregation of stroke is well-documented, yet few studies have examined associations between stroke subtypes—particularly early-onset cryptogenic ischaemic stroke (eCIS)—and broader family history (FH) of cardiovascular disease. Such associations may provide insights into underlying etiologic mechanisms. In this multicentre case–control study, we included eCIS patients aged 18–49 years and matched stroke-free controls. We analysed the association between FH of stroke, venous thromboembolism (VTE), coronary artery disease (CAD), aneurysms and eCIS using multivariable logistic regression, with a subgroup analysis stratifying patients by high-risk patent foramen ovale (HR-PFO). We enrolled 508 eCIS patients (182 [36%] with HR-PFO) and 520 controls. Compared with controls, patients more frequently reported FH of stroke among first-degree relatives (FDR) (20% vs. 14%, P = .01) and grandparents (47% vs. 39%, P = .01), FH of early-onset stroke among FDR (5% vs. 2%, P = .01) and FH of early-onset VTE among FDR (5% vs. 2%, P = .003). In adjusted analyses, eCIS was associated with FH of stroke among FDR (OR 1.50; 95% CI, 1.04–2.16) and grandparents (1.50; 1.12–1.99), with FH of early-onset stroke among FDR (2.36; 1.11–5.04); and with FH of early-onset VTE among FDR (3.45; 1.47–8.13). eCIS was also associated with FH of VTE among FDR (1.80, 1.09–2.98) in the presence of HR-PFO. FH of CAD or aneurysms was not associated with eCIS. FH of stroke and VTE, particularly early-onset events and in the presence of HR-PFO, are associated with eCIS. These findings support familial predisposition and highlight prothrombotic mechanisms in eCIS. www.clinicaltrials.gov/study/NCT01934725

BACKGROUND: It remains unclear whether outcomes of patients treated with endovascular thrombectomy with large-vessel occlusion and unwitnessed onset of stroke differ from those with witnessed onset in the extended time window. METHODS: We enrolled patients with anterior circulation large-vessel occlusion (internal carotid artery, M1, or M2 segment of the middle cerebral artery) undergoing endovascular thrombectomy within 6 to 24 hours from the time last seen well, from 2014 to 2022, at 66 sites in Europe, North America, and Asia. Patients with a prestroke modified Rankin Scale score of >3 or age P =0.022). Mortality was 21.6% among unwitnessed and 22.0% among witnessed ( P =0.847), and symptomatic intracranial hemorrhage rates were 6.6% and 5.8%, respectively ( P =0.623). The primary outcome (modified Rankin Scale shift) showed no difference comparing unwitnessed to witnessed patients (odds ratio, 1.35 [95% CI, 0.82–2.20]; P =0.235) in the inverse probability of treatment weighting. Unwitnessed patients were more likely to achieve functional independence or return of Rankin (1.53 [1.01–2.33]; P =0.045). Other secondary outcomes did not differ between the witnessed and unwitnessed patients. CONCLUSIONS: In the extended time window, unwitnessed patients with large-vessel occlusion undergoing endovascular thrombectomy have at least the same likelihood of favorable outcomes as witnessed patients. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04096248.

BACKGROUND: There is uncertainty about whether patients with M2 occlusion benefit from endovascular therapy (EVT) in the late (6–24-hour) time window. We evaluated the clinical outcomes of patients with M2 occlusion selected for EVT compared with those who received medical management (MM) in the late window. METHODS: This multinational cohort study was conducted at 66 sites across 10 countries (January 2014 to May 2022). We included consecutive patients with late-window stroke due to M2 occlusion, baseline National Institutes of Health Stroke Scale score of ≥5, and premorbid modified Rankin Scale score of ≤2 who received EVT or MM alone. The primary end point was 90-day ordinal shift in the modified Rankin Scale score. Safety end points were symptomatic intracranial hemorrhage and 90-day mortality. Differences in outcomes were determined using inverse probability of treatment weighting–adjusted logistic regression models. RESULTS: Among 5098 patients, 496 met inclusion criteria (median [interquartile range] age, 74 years [62–81 years]; baseline National Institutes of Health Stroke Scale score, 12 [8–17]), of whom 394 (79.4%) received EVT and 102 (20.6%) MM. In inverse probability of treatment weighting adjusted analyses, there was no favorable 90-day ordinal modified Rankin Scale shift (odds ratio, 1.39 [95% CI, 0.92–2.12]) and no difference of functional independence rates (modified Rankin Scale score of 0–2; odds ratio, 1.72 [95% CI, 0.93–3.15]) with EVT compared with MM. Moreover, symptomatic intracranial hemorrhage risk (odds ratio, 3.46 [95% CI, 0.50–23.92]) and 90-day mortality (odds ratio, 1.11 [95% CI, 0.66–1.87]) were not statistically different between treatment groups. CONCLUSIONS: In patients with M2 occlusion in the 6- to 24-hour time window, there was no difference in disability outcomes or symptomatic intracranial hemorrhage risk between patients treated with EVT compared with MM. Results of ongoing randomized trials will provide further insight. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04096248.

There is uncertainty about whether patients with an anterior circulation large vessel occlusion (LVO) and a low NIH Stroke Scale (NIHSS) score (≤5) benefit from endovascular therapy (EVT) in the late time window (6-24 hours). We compared the clinical outcomes of these patients receiving EVT with those receiving medical management (MM). The CT for Late Endovascular Reperfusion multinational cohort study was conducted at 66 sites across 10 countries from January 2014 to May 2022. This subanalysis included consecutive patients with late-window stroke due to an anterior circulation LVO, defined as occlusion of the internal carotid artery or proximal middle cerebral artery (M1/M2 segments), and a baseline NIHSS score ≤5 who received EVT or MM alone. The primary end point was a 90-day ordinal shift in the modified Rankin Scale (mRS) score. Secondary outcomes were 90-day excellent outcome (defined as mRS scores 0-1 or return to baseline mRS score in patients with a prestroke mRS score >1) and favorable outcome (defined as mRS scores 0-2 or return to baseline mRS score in patients with prestroke mRS score >2). Safety outcomes were symptomatic intracranial hemorrhage and 90-day mortality. We used ordinal and binary logistic regression models to test for outcome differences. Among 5,098 patients, 318 patients were included (median [interquartile range] age 67 [56-76] years; 149 [46.9%] were female; baseline NIHSS score was 4 [2-5]). A total of 202 patients (63.5%) received EVT and 116 MM (36.5%). There was no difference in favorable 90-day ordinal mRS score shift (adjusted common odds ratio [OR] 0.77, 95% CI 0.45-1.32), excellent outcome (adjusted OR 0.86, 95% CI 0.49-1.50), or favorable outcome (adjusted OR 0.72, 95% CI 0.35-1.50) in the EVT group compared with MM. Symptomatic intracranial hemorrhage risk (adjusted OR 3.40, 95% CI 0.84-13.73) and mortality at 90 days (adjusted OR 2.44, 95% CI 0.60-10.02) were not statistically different between treatment groups. In patients with an anterior LVO and low NIHSS score in the 6-24-hour time window, there was no statistical difference in disability outcomes or intracranial bleeding risk between patients treated with EVT compared with MM. The retrospective and observational design limits our findings. Ongoing randomized controlled trials will provide further insight. This study provides Class III evidence that in adult patients with anterior circulation LVO and low NIHSS score (≤5) presenting in the late time window (6-24 hours), EVT does not improve clinical outcome vs MM. This study was registered at clinicaltrials.gov under NCT04096248.

Introduction: The benefit of endovascular therapy (EVT) among stroke patients with large ischemic core (ASPECTS 0–5) in the extended time window outside of trial settings remains unclear. We analyzed the effect of EVT among these stroke patients in real-world settings. Patients and methods: The CT for Late Endovascular Reperfusion (CLEAR) study recruited patients from 66 centers in 10 countries between 01/2014 and 05/2022. The extended time-window was defined as 6–24 h from last-seen-well to treatment. The primary outcome was shift of the 3-month modified Rankin scale (mRS) score. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and mortality. Outcomes were analyzed with ordinal and logistic regressions. Results: Among 5098 screened patients, 2451 were included in the analysis (median age 73, 55% women). Of patients with ASPECTS 0–5 (n = 310), receiving EVT (n = 209/310) was associated with lower 3-month mRS when compared to medical management (median 4 IQR 3–6 vs 6 IQR 4–6; aOR 0.4, 95% CI 0.2–0.7). Patients undergoing EVT had higher sICH (11.2% vs 4.0%; aOR 4.1, 95% CI 1.2–18.8) and lower mortality (31.6% vs 58.4%, aOR 0.4; 95% CI 0.2–0.9) compared to medically managed patients. The relative benefit of EVT was comparable between patients with ASPECTS 0 and 5 and 6–10 in the extended time window (interaction aOR 0.9; 95% CI 0.5–1.7). Conclusion: In the extended time window, patients with ASPECTS 0–5 may have preserved relative treatment benefit of EVT compared to patients with ASPECTS 6–10. These findings are in line with recent trials showing benefit of EVT among real-world patients with large ischemic core in the extended time window. Trial registration number: clinicaltrials.gov; Unique identifier: NCT04096248

Background: With the expanding eligibility for endovascular therapy (EVT) of patients presenting in the late window (6–24 hours after last known well), we aimed to derive a score to predict favorable outcomes associated with EVT versus best medical management. Methods and Results: A multinational observational cohort of patients from the CLEAR (Computed Tomography for Late Endovascular Reperfusion) study with proximal intracranial occlusion (2014–2022) was queried (n=58 sites). Logistic regression analyses were used to derive a 9‐point score for predicting good functional outcome (modified Rankin Scale score 0–2 or return to premorbid modified Rankin Scale score) at 90 days, with sensitivity analyses for prespecified subgroups conducted using bootstrapped random forest regressions. Secondary outcomes included 90‐day functional independence (modified Rankin Scale score 0–2), poor outcome (modified Rankin Scale score 5–6), and 90‐day survival. The score was externally validated with a single‐center cohort (2014–2023). Of the 3231 included patients (n=2499 EVT), a 9‐point score included age, early computed tomography ischemic changes, and stroke severity, with higher points indicating a higher probability of a good functional outcome. The areas under the curve for the primary outcome among EVT and best medical management subgroups were 0.72 (95% CI, 0.70–0.74) and 0.87 (95% CI, 0.84–0.90), respectively, with similar performance in the external validation cohort (area under the curve, 0.71 [95% CI, 0.66–0.76]). There was a significant interaction between the score and EVT for good functional outcome, functional independence, and poor outcome (all P _interaction <0.001), with greater benefit favoring patients with lower and midrange scores. Conclusions: This score is a pragmatic tool that can estimate the probability of a good outcome with EVT in the late window. Registration: URL: https://www.Clinicaltrials.gov ; Unique identifier: NCT04096248.

BACKGROUND: Studies comparing bridging intravenous thrombolysis (IVT) with direct endovascular therapy (EVT) in patients with acute ischemic stroke who present late are limited. We aimed to compare the clinical outcomes and safety of bridging IVT in patients with acute ischemic stroke due to anterior circulation large vessel occlusion who underwent EVT 6 to 24 hours after time last known well. METHODS: We enrolled patients with anterior circulation large vessel occlusion stroke and a National Institutes of Health Stroke Scale score of ≥6 from 20 centers across 10 countries in the multicenter retrospective CLEAR study (CT for Late Endovascular Reperfusion) between January 2014 and May 2022. We used inverse probability of treatment weighting modeling adjusted for clinical and imaging confounders to compare functional outcomes, reperfusion success, symptomatic intracranial hemorrhage, and mortality between EVT patients with and without prior IVT. RESULTS: Of 5098 patients screened for eligibility, we included 2749 patients, of whom 549 received bridging IVT before EVT. The timing of IVT was not recorded. Witnessed stroke onset and transfer rates were higher in the bridging IVT group (25% versus 12% and 77% versus 55%, respectively, P value for both P 6 hours after last known well. CONCLUSIONS: In patients with an anterior circulation large vessel occlusion stroke who underwent EVT 6 to 24 hours from last known well, bridging IVT was not associated with a difference in outcomes compared with direct EVT. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04096248.