The current European Stroke Organisation expedited recommendation on tenecteplase (TNK) for acute ischemic stroke (AIS) advocates that TNK 0.25 mg/kg can be used alternatively to alteplase (tissue plasminogen activator [TPA]) for AIS of <4.5 hours duration, based on a meta-analytical approach establishing noninferiority. Since the publication of these guidelines, 4 additional randomized controlled clinical trials (RCTs) have provided further insight. We conducted an updated systematic review and meta-analysis including all available RCTs that investigated efficacy and safety of TNK 0.25 mg/kg compared with TPA for the treatment of AIS within 4.5 hours of onset. The primary outcome was defined as the excellent functional outcome at 3 months (modified Rankin Scale [mRS] score 0-1), whereas good functional outcome (mRS score 0-2), reduced disability at 3 months (≥1-point reduction across all mRS scores), symptomatic intracranial hemorrhage (sICH), and 3-month mortality were evaluated as secondary outcomes. Pooled estimates were calculated with random-effects model. A prespecified subgroup analysis was performed stratifying for TNK formulation, that is, original TNK vs biocopy: recombinant human TNK tissue-type plasminogen activator that is available in China and has a different production process. Eleven RCTs were included comprising a total of 3,788 patients treated with TNK vs 3,757 patients treated with TPA. TNK was associated with higher likelihood of excellent functional outcome (risk ratio [RR] 1.05, 95% CI 1.01-1.10; p = 0.012; I² = 0%; risk difference 2.95%; 95% CI 0.76%-5.14%; p = 0.008; I² = 0%) and reduced disability at 3 months (common odds ratio 1.10, 95% CI 1.01-1.19; p = 0.034; I² = 0%) compared with TPA while good functional outcome (RR 1.03, 95% CI 0.99-1.07; p = 0.142; I² = 28%) was similar between the groups. Regarding safety outcomes, similar rates of sICH (RR 1.12, 95% CI 0.83-1.53; p = 0.456; I² = 0%) and 3-month mortality (RR 0.97, 95% CI 0.82-1.15; p = 0.727; I² = 12%) were observed. When stratified for TNK regimen (original vs biocopy), statistical significance in achieving an excellent functional outcome at 3 months was retained for the original TNK (RR 1.05, 95% CI 1.00-1.10; p = 0.044; I² = 0%). The updated meta-analysis confirms similar safety between TNK 0.25 mg/kg and TPA, while showing that TNK is superior to TPA regarding excellent functional outcome and reduced disability at 3 months. These findings support transitioning to TNK in clinical practice.

Background: There are limited data regarding the prevalence of distinct clinical, neuroimaging and genetic markers among patients diagnosed with cerebral amyloid angiopathy–related inflammation (CAA-ri). We sought to determine the prevalence of clinical, radiological, genetic and cerebrospinal fluid biomarker findings in patients with CAA-ri. Methods: A systematic review and meta-analysis of published studies including patients with CAA-ri was conducted to determine the prevalence of clinical, neuroimaging, genetic and cerebrospinal fluid biomarker findings. Subgroup analyses were performed based on (1) prospective or retrospective study design and (2) CAA-ri diagnosis with or without available biopsy. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using Cochran-Q and I ² -statistics. Results: We identified 4 prospective and 17 retrospective cohort studies comprising 378 patients with CAA-ri (mean age, 71.5 years; women, 52%). The pooled prevalence rates were as follows: cognitive decline at presentation 70% ([95% CI, 54%–84%]; I ² =82%), focal neurological deficits 55% ([95% CI, 40%–70%]; I ² =82%), encephalopathy 54% ([95% CI, 39%–68%]; I ² =43%), seizures 37% ([95% CI, 27%–49%]; I ² =65%), headache 31% ([95% CI, 22%–42%]; I ² =58%), T2/fluid-attenuated inversion recovery-hyperintense white matter lesions 98% ([95% CI, 93%–100%]; I ² =44%), lobar cerebral microbleeds 96% ([95% CI, 92%–99%]; I ² =25%), gadolinium enhancing lesions 54% ([95% CI, 42%–66%]; I ² =62%), cortical superficial siderosis 51% ([95% CI, 34%–68%]; I ² =77%) and lobar macrohemorrhage 40% ([95% CI, 11%–73%]; I ² =88%). The prevalence rate of the ApoE (Apolipoprotein E) ε4/ε4 genotype was 34% ([95% CI, 17%–53%]; I ² =76%). Subgroup analyses demonstrated no differences in these prevalence rates based on study design and diagnostic strategy. Conclusions: Cognitive decline was the most common clinical feature. Hyperintense T2/fluid-attenuated inversion recovery white matter lesions and lobar cerebral microbleeds were by far the most prevalent neuroimaging findings. Thirty-four percent of patients with CAA-ri have homozygous ApoE ε4/ε4 genotype and scarce data exist regarding the cerebrospinal fluid biomarkers and its significance in these patients.

Background: High level evidence for direct oral anticoagulants (DOACs) in patients with cerebral venous thrombosis is lacking. We performed a systematic review and meta-analysis to assess the efficacy and safety of DOACs versus vitamin K antagonists in patients with cerebral venous thrombosis. Methods: This systematic review was registered in PROSPERO (CRD42021228800). We searched MEDLINE (via Ovid), EMBASE, CINAHL, and the Web of Science Core Collection between January 1, 2007 and Feb 22, 2022. Search terms included a combination of keywords and controlled vocabulary terms for cerebral venous thrombosis, vitamin K antagonists/warfarin, and DOACs. We included both randomized and nonrandomized studies that compared vitamin K antagonists and DOACs in 5 or more patients with cerebral venous thrombosis. Where studies were sufficiently similar, we performed meta-analyses for efficacy (recurrent venous thromboembolism and complete recanalization) and safety (major hemorrhage) outcomes, using relative risks (RRs). Results: Out of 10 665 records identified, we screened 254 as potentially eligible. Nineteen studies (16 observational studies [n=1735] and 3 randomized controlled trials [n=215]) met the inclusion criteria. All 3 randomized controlled trials had some concerns, and all 16 observational studies had at least moderate risk of bias. When compared with vitamin K antagonist treatment, DOAC had comparable risks of recurrent venous thromboembolism (relative risk [RR], 0.85 [95% CI, 0.52–1.37], I ² =0%), major hemorrhage (RR, 0.70 [95% CI, 0.40–1.21], I ² =0%), intracranial hemorrhage (RR, 0.58 [95% CI, 0.30–1.12]; I ² =0%), death (RR, 1.14 [95% CI, 0.54–2.43], I ² =1%), and complete venous recanalization (RR, 0.98 [95% CI, 0.87–1.11]; I ² =0%). Conclusions: This systematic review and meta-analysis suggest that in patients with cerebral venous thrombosis, DOACs, and warfarin may have comparable efficacy and safety. Given the limitations of the studies included (low number of randomized controlled trials, modest total sample size, rare outcome events), our findings should be interpreted with caution pending confirmation by ongoing randomized controlled trials and large, prospective, observational studies.

Background: Limited data exist regarding the prevalence of clinical and neuroimaging manifestations among patients diagnosed with cerebral amyloid angiopathy (CAA). We sought to determine the prevalence of clinical phenotypes and radiological markers in patients with CAA. Methods: Systematic review and meta-analysis of studies including patients with CAA was conducted to primarily assess the prevalence of clinical phenotypes and neuroimaging markers as available in the included studies. Sensitivity analyses were performed based on the (1) retrospective or prospective study design and (2) probable or unspecified CAA status. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using the Cochran Q and I ² statistics. Results: We identified 12 prospective and 34 retrospective studies including 7159 patients with CAA. The pooled prevalence rates were cerebral microbleeds (52% [95% CI, 43%–60%]; I ² =93%), cortical superficial siderosis (49% [95% CI, 38%–59%]; I ² =95%), dementia or mild cognitive impairment (50% [95% CI, 35%–65%]; I ² =97%), intracerebral hemorrhage (ICH; 44% [95% CI, 27%–61%]; I ² =98%), transient focal neurological episodes (48%; 10 studies [95% CI, 29%–67%]; I ² =97%), lacunar infarcts (30% [95% CI, 25%–36%]; I ² =78%), high grades of perivascular spaces located in centrum semiovale (56% [95% CI, 44%–67%]; I ² =88%) and basal ganglia (21% [95% CI, 2%–51%]; I ² =98%), and white matter hyperintensities with moderate or severe Fazekas score (53% [95% CI, 40%–65%]; I ² =91%). The only neuroimaging marker that was associated with higher odds of recurrent ICH was cortical superficial siderosis (odds ratio, 1.57 [95% CI, 1.01–2.46]; I ² =47%). Sensitivity analyses demonstrated a higher prevalence of ICH (53% versus 16%; P =0.03) and transient focal neurological episodes (57% versus 17%; P =0.03) among retrospective studies compared with prospective studies. No difference was documented between the prevalence rates based on the CAA status. Conclusions: Approximately one-half of hospital-based cohort of CAA patients was observed to have cerebral microbleeds, cortical superficial siderosis, mild cognitive impairment, dementia, ICH, or transient focal neurological episodes. Cortical superficial siderosis was the only neuroimaging marker that was associated with higher odds of ICH recurrence. Future population-based studies among well-defined CAA cohorts are warranted to corroborate our findings.

Background: Among the currently approved antiobesity medications, the glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) liraglutide and semaglutide, and the dual glucose-dependent-insulinotropic-polypeptide (GIP)/GLP-1 RA tirzepatide have been suggested to reduce cardiovascular-risk in overweight or obesity without diabetes. Objectives: The objective of this study was to evaluate the cardio- and neuroprotective potential of these novel agents in the nondiabetic overweight/obese adult population. Data sources and methods: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate the risk of major adverse cardiovascular events (MACE), all-cause and cardiovascular mortality in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). Secondary outcomes included the risk of myocardial infarction (MI) and stroke. Results: Sixteen RCTs (13 and 3 on GLP-1 RAs and tirzepatide, respectively) comprising 28,168 participants were included. GLP-1 or GIP/GLP-1 RAs reduced MACE (odds ratio (OR): 0.79; 95% confidence interval (CI): 0.71–0.89; p < 0.01; I² = 0) and all-cause mortality (OR: 0.80; 95% CI: 0.70–0.92; p < 0.01; I² = 0), while there was a trend toward lower cardiovascular-mortality (OR: 0.84; 95% CI: 0.71–1.01; p = 0.06; I² = 0%) compared to placebo. Additionally, GLP-1 or GIP/GLP-1 RAs reduced the odds of MI (OR: 0.72; 95% CI: 0.61–0.86; p < 0.01; I² = 0%) and nonfatal-MI (OR: 0.72; 95% CI: 0.61–0.85; p < 0.01; I² = 0%); while no associations between antiobesity treatment and fatal-MI, stroke, nonfatal, or fatal stroke were uncovered. Conclusion: GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and all-cause mortality in overweight or obese adults without diabetes. Additionally, GLP-1 RAs and GIP/GLP-1 RAs attenuate the risk of MI. Since data on stroke are still limited, future RCTs are warranted to evaluate the neuroprotective potential of these novel antiobesity agents. Trial registration: PROSPERO CRD42024515966.

Background: Despite successful recanalization following endovascular thrombectomy (EVT) for acute ischemic stroke (AIS) with large‐vessel occlusion (LVO), many patients fail to achieve excellent functional outcomes. Post‐EVT intra‐arterial thrombolysis (IAT) has emerged as a potential adjunctive strategy to improve microvascular reperfusion and clinical recovery.Methods: We conducted a systematic review and meta‐analysis of randomized‐controlled clinical trials (RCTs) comparing IAT plus best medical therapy (BMT) versus BMT alone in LVO‐AIS patients with successful recanalization post‐EVT. The primary efficacy outcome was 3‐month excellent functional outcome [modified Rankin Scale (mRS)‐score: 0–1]. Secondary efficacy outcomes included good functional outcome (mRS‐score: 0–2) and reduced disability (mRS‐score shift analysis) at 3 months. The primary safety outcome was symptomatic intracranial hemorrhage (sICH); secondary safety outcomes included any‐ICH and 3‐month all‐cause mortality. Subgroup and network meta‐analyses were performed evaluating the effects of different thrombolytic agents.Results: Seven RCTs were included, comprising 1083 patients treated with IAT and 1048 patients treated with BMT alone. IAT was associated with higher likelihood of excellent functional outcome (RR: 1.23; 95% CI: 1.11–1.36; I² = 0%) and reduced disability at 3 months (common‐OR: 1.10; 95% CI: 1.03–1.18; I² = 0%) compared with BMT alone. Similar rates of 3‐month good functional outcome, 3‐month mortality, sICH and any‐ICH were observed. Although no significant subgroup differences emerged, in the network meta‐analysis alteplase ranked highest in efficacy [surface under the cumulative rank curve (SUCRA): 90%], followed by tenecteplase (61%) and urokinase (40%) in achieving 3‐month excellent functional outcome.Conclusions: IAT improves excellent functional outcomes without compromising safety in LVO‐AIS patients with successful recanalization after EVT.Trial Registration: The prespecified protocol of the present systematic review and meta‐analysis has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (registration ID: CRD420251035903)