BACKGROUND:Patients with extensive ischaemic change are often excluded from endovascular thrombectomy. We aimed to synthesise the evidence from recent trials in these patients by performing a systematic review and individual patient data meta-analysis to estimate treatment benefit, including within clinical and imaging subgroups. METHODS:In this systematic review and meta-analysis, we searched PubMed and Embase for randomised trials published between March 1, 2018, and March 1, 2025, that evaluated efficacy and safety of endovascular thrombectomy compared with medical management in patients with large-core ischaemic stroke (based on an Alberta Stroke Program Early CT Score [ASPECTS] of ≤5 or estimated ischaemic core ≥50 mL) presenting within 24 h of onset. Individual patient-level data from all eligible trials were obtained. A central imaging core laboratory readjudicated ASPECTS and reanalysed ischaemic core volume. A two-stage meta-analysis with random-effects model was used to evaluate the distribution of 90-day modified Rankin Scale (mRS) scores (the primary outcome) using adjusted pooled generalised odds ratios (aGenORs). Missing data were handled by multiple imputation. Safety outcomes were all-cause mortality within 90-day follow-up and neurological worsening within 24-48 h of randomisation, reported as adjusted pooled relative risk (aRR); and symptomatic intracerebral haemorrhage within 36 h of randomisation (reported as risk difference). Subgroup analyses based on clinical and imaging characteristics were done, including subgroups defined by ischaemic core volume, ASPECTS, and time window from onset to randomisation. The meta-analysis was registered with PROSPERO (CRD420251058584). FINDINGS:We included 1886 patients (944 assigned to endovascular thrombectomy and 942 assigned to medical management) from six trials. Baseline characteristics were similar between treatment groups. At day 90, the distribution of mRS scores was improved in patients in the endovascular thrombectomy group (median score 4 [IQR 3-6]; n=940) versus those in the medical management group (5 [4-6]; n=931; aGenOR 1·63 [95% CI 1·42-1·88], p<0·0001). The endovascular thrombectomy group also had reduced mortality (292 [31·1%]) compared with the medical management group (347 [37·3%]; aRR 0·82 [95% CI 0·70-0·97], p=0·022). No significant differences were observed in symptomatic intracranial haemorrhage (ten [1·1%] of 944 vs nine [1·0%] of 942 patients; pooled unadjusted risk difference -0·17 percentage points [95% CI -1·01 to 0·67], p=0·69) or neurological worsening (197 [22·0%] of 896 patients vs 161 [17·9%] of 899; aRR 1·19 [0·87-1·62], p=0·27). Improved functional outcomes with endovascular thrombectomy were consistent across clinical and imaging subgroups, except for those with an estimated ischaemic core volume of 150 mL or greater, in whom point estimates favoured endovascular thrombectomy, particularly in the early time window (0-6 h), but wide 95% CIs limited interpretation. INTERPRETATION:Endovascular thrombectomy was associated with improved functional outcomes and reduced mortality versus medical management in patients with large-core ischaemic stroke presenting within 24 h of onset. With the exception of very extensive ischaemic changes (core volume ≥150 mL) presenting beyond 6 h, where evidence remains limited, benefit was sustained across ASPECTS and ischaemic core strata for patients presenting up to 24 h after onset. FUNDING:None.
BACKGROUND:The efficacy and safety of early direct oral anticoagulant (DOAC) (re)initiation in patients with non-valvular atrial fibrillation (NVAF) after acute onset of intracranial hemorrhage (ICH) are unknown. This study evaluated ischemic and hemorrhagic risks following early DOAC (re)initiation after ICH in patients with NVAF. METHODS AND RESULTS:SAFE-ICH is a multicenter prospective observational single-arm registry study at 32 Japanese hospitals. Eligible patients had NVAF, were aged ≥20 years, and (re)initiated DOAC ≤14 days following symptomatic ICH. Among 240 patients who (re)initiated DOAC (61.3% male; mean [±SD] age 79.4±9.3 years), intraparenchymal hemorrhage predominated (84.6%), followed by subdural (12.9%), intraventricular (1.7%), and epidural (0.8%) hemorrhage. The median (interquartile range) baseline National Institutes of Health Stroke Scale score was 10 (3-16) and time to DOAC (re)initiation was 7 days (5-10 days). Edoxaban, apixaban, and rivaroxaban were used in 55.0%, 35.8%, and 9.2% of patients, respectively. The primary endpoint (composite of symptomatic ICH, any stroke, or death ≤30 days following DOAC [re]initiation) occurred in 12 (5.0%) patients. There were 4 recurrent ICH events (1.7%; all recurrent subdural hemorrhages). Five (2.1%) patients died of non-vascular causes. CONCLUSIONS:In Japanese patients with NVAF, early DOAC (re)initiation ≤14 days after ICH appears to have an acceptable risk for ischemic and hemorrhagic events, particularly in patients with intraparenchymal hemorrhage. In patients with subdural hematoma, early DOAC (re)initiation requires vigilant monitoring.
Approved treatment options for children and adolescents with ulcerative colitis (UC) are limited.1 The KEPLER phase 3 trial evaluated the efficacy, immunogenicity, pharmacokinetics (PK) and safety of vedolizumab (VDZ), an anti-α4β7 integrin biologic, administered as intravenous (IV) induction and maintenance therapy in children and adolescents with moderately to severely active UC. This phase 3, single arm trial (NCT04779307) enrolled patients with moderate-to-severe UC (modified Mayo score of 5-9 with endoscopic subscore ≥2) aged 2-17 years and weighing ≥10kg with prior failure of conventional therapy such as steroids, immunomodulators, and/or tumour necrosis factor (TNF) antagonists. VDZ IV was administered during a 14-week, open-label induction period followed by a 40-week, randomised, double-blind maintenance period evaluating low- (LD) or high-dose (HD) VDZ (1:1) by body weight (10-15kg [100 vs 150mg]; >15-<30kg [100 vs 200mg]; ≥30kg [150 vs 300mg]) given every 8 weeks. The primary endpoint was clinical remission by modified Mayo score at Week 54 in the intention-to-treat maintenance population. Secondary endpoints included clinical remission at Week 14, sustained clinical remission (at Weeks 14 and 54), corticosteroid-free clinical remission at Week 54, immunogenicity, PK, and safety. The trial enrolled 121 patients (10-15kg, n = 3; >15-<30kg, n = 27; ≥30kg, n = 91), of whom 120 were dosed; 93 were subsequently randomised into LD (n = 47) or HD n = 46) groups for maintenance therapy (Table 1). Forty-four of 93 (47.3%) patients achieved the primary endpoint of clinical remission at Week 54, with similar proportions in LD and HD groups (Fig. 1A). Clinical remission rates at Week 54 for patients categorised by weight, age, anti-TNF exposure, and baseline corticosteroid use are shown in Fig. 1B-E. Forty-two of 121 (34.7%) patients achieved clinical remission at Week 14. At Week 54, 27/93 (29.0%) patients achieved sustained clinical remission. Anti-VDZ antibodies occurred in 7/120 (5.8%) VDZ-exposed patients, including neutralizing antibodies in 4 (3.3%); similar VDZ serum trough levels were observed across weight groups. In the safety population, 103/120 (85.8%) patients had treatment emergent adverse events (TEAEs), including 15/120 (12.5%) related to VDZ. Twenty-five of 468 (5.3%) TEAEs were serious. Five (4.2%) patients had serious VDZ-related TEAEs. Seven (5.8%) patients had TEAEs leading to VDZ discontinuation (most common: UC worsening, n = 3; infection, n = 3). LD and HD VDZ IV were effective for children and adolescents with UC, including those with prior anti-TNF or corticosteroid failure. Similar rates were observed in adult patients with UC.2 VDZ was well tolerated, with no new safety signals identified. References: 1.Vuijk SA et al. J Crohns Colitis. 2024;18(Supplement_2):ii31-ii45. 2.Feagan BG et al. N Engl J Med. 2013;369(8):699-710. Conflict of interest: Turner, Dan: DT has received consultation fees, research grants, royalties or honorarium from Janssen, Pfizer, Shaare Zedek Medical Center, Hospital for Sick Children, Ferring, AbbVie, Takeda, Prometheus Biosciences, Eli Lilly, Sorriso Pharmaceuticals, Boehringer Ingelheim, Galapagos, BMS, Alfasigma and Merck. Kierkuś, Jarosław: JK has received grant or other support from Abbvie, Nestle, and Nutricia. Korczowski, Bartosz: BK has received grant support from Johnson & Johnson and Takeda. Strisciuglio, Caterina: CS has received consultation fees from Aboca and Sonofi. CS has acted as a Principle Investigator for Astrazeneca, Novalac, and Takeda. Chen, Jie: No conflict of interest Takaki, Yugo: No conflict of interest Szakos, Erzsébet: ES has acted as a Principle Investigator for Abbvie, Janssen, Pfizer, and Takeda. Arumugam, Ramalingam: No conflict of interest Rizvi, Anita: Employee of the study sponsor, Takeda, and holds Takeda stock or stock options. Yoon, MinJung: Employee of the study sponsor, Takeda, and holds Takeda stock or stock options. Campagne, Olivia: Employee of the study sponsor, Takeda, and holds Takeda stock or stock options. Angellotti, Edith: Employee of the study sponsor, Takeda, and holds Takeda stock or stock options. Candela, Ninfa: Employee of the study sponsor, Takeda, and holds Takeda stock or stock options. Velazco, Nerissa: I am a full-time employee of Takeda Pharmaceutical Company Limited. I have no additional financial interests, advisory roles, or external relationships that would influence my objectivity in relation to this work beyond my employment with Takeda.
The C-reactive protein/albumin ratio (CAR), an inflammatory marker, is a useful biomarker for pancreatic cancer. Although disease status is not constant, many inflammatory markers are only classified at the start of treatment. Therefore, biomarker analysis that considers the changes in inflammatory markers during treatment is desirable. We aimed to investigate whether time-dependent changes in the CAR during nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) administration can predict the prognosis of patients with unresectable or recurrent pancreatic cancer (urPC). CAR was measured in 150 participants of the NAPOLEON-2 study, an observational study involving patients with pancreatic cancer receiving NFF, and the patients were stratified by CAR. The CAR at NFF initiation was defined as CAR(1), while the minimum CAR before/throughout NFF administration was defined as CAR(min). Overall survival (OS) of patients in all groups was analyzed. Significant differences in OS between the CAR(1) < 0.54 and ≥ 0.54 groups and between the CAR(min) < 0.54 and ≥ 0.54 groups were observed. The OS was significantly better in the group with CAR(min)/CAR(1) < 0.5 than in the group with CAR(min)/CAR(1) ≥ 0.5. Dynamic changes in CAR were a clinically significant biomarker that considers not only the disease status at the start of treatment but also the response to treatment. CAR monitoring would help understand the disease status and thereby aid patients and physicians alike.
