Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry^1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis³, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach⁴, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry⁵. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA ₂ DS ₂ -VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0–1.3] for each point increase; P =0.05) and hypertension (OR, 2.3 [95% CI, 1.0–5.1]; P =0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0–1.2] for each year increase; P =0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4–14.2]; P =0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4–5.5]; P =0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8–1.7]). Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

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: 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 <0.0001), and time intervals between stroke onset and treatment were shorter (time last known well—start of EVT median 560 minutes [interquartile range, 432–791] versus 724 minutes [interquartile range, 544–912]; 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.

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.

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.