Testing early haemostatic therapy for acute intracerebral haemorrhage.

# Testing early haemostatic therapy for acute intracerebral haemorrhage *The Lancet 2026* Comment analyses of all primary and secondary clinical endpoints. GTs has received unrestricted research or education grants (paid to institution) Third, the tenecteplase administered in the trial was a from Novartis, Genesis Pharma, Teva, Shore, Merck, Abbott, Allergan, Boehringer Ingelheim, Medtronic, Amicus, AbbVie, Ipsen, Bayer, Roche, Novalis, Bristol Myers biosimilar formulation that does not have marketing Squibb, Rare Disease Greece, Attica Rehab, and CSL Behring; received payment or authorisation in Europe, North America, and Australia. honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, Sanofi, Biogen, Genesis Pharma, Teva, Shire, Fourth, differences in underlying stroke risk factors and Merck, Bayer, Daichii-Sankyo, Allergan, Specifar, Boehringer Ingelheim, Medtronic, aetiologies across different ethnicities might limit the CSL Behring, Abbott, Taekda, AbbVie, Ipsen, ITF, Shionogi, Novasignal, Bristol Myers Squibb, AstraZeneca, Medison, Biomarin, Chiesi, UCB, Viatris, and Sandoz; generalisability of the study findings outside China. Fifth, and participated on data safety monitoring boards for DISTAL (NCT05029414), there was substantial variation in the recruitment rates ZODIAC (NCT03728738), and ADAPT II (NCT02281838). LP has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or across different centres, with 34 sites being unable to educational events from AstraZeneca, Biomarin, Boehringer Ingelheim, and Sanofi; recruit any patient and 14 sites enrolling a single patient, and support for attending meetings or travel from the European Stroke Organisation (Emerging Leader Programme). GTu has received consulting fees in contrast to a sole centre that enrolled 91 patients with from Neurologica, served on an advisory board for IA-Stroke, and received lecture basilar artery occlusion over 18 months. This variation fees from Guerbet France. might raise concerns regarding disparities in recruitment, *Georgios Tsivgoulis, Lina Palaiodimou, Guillaume Turc performance, and patient representativeness across tsivgoulisgiorg@yahoo.gr the different participating centres. Finally, TRACE-5 was Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, “Attikon” University Hospital, Athens 12462, Greece not powered to demonstrate a significant benefit in the (GTs, LP); Department of Neurology, GHU Paris Psychiatrie et Neurosciences, subgroup of patients who were intended for endovascular Paris, France (GTu); Institute of Psychiatry and Neuroscience of Paris, Université Paris Cité, INSERM U1266, Paris, France (GTu) thrombectomy. However, there was no evidence of a 1 Strbian D, Tsivgoulis G, Ospel J, et al. European Stroke Organisation and differential treatment effect. The ongoing POST-ETERNAL European Society for Minimally Invasive Neurological Therapy guideline on acute management of basilar artery occlusion. Eur Stroke J 2024; 9: 835–84. trial (NCT05105633) and the planned individual patient 2 Berge E, Whiteley W, Audebert H, et al. European Stroke Organisation (ESO) data pooled analysis will shed more light on this question. guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J 2021; 6: I-LXII. In conclusion, this phase 3 trial provides evidence 3 Tsivgoulis G, Katsanos AH, Sandset EC, et al. Thrombolysis for acute ischaemic that intravenous thrombolysis with tenecteplase stroke: current status and future perspectives. Lancet Neurol 2023; 22: 418–29. 4 Alamowitch S, Turc G, Palaiodimou L, et al. European Stroke Organisation within 24 h from symptom onset is effective and safe (ESO) expedited recommendation on tenecteplase for acute ischaemic in patients with acute ischaemic stroke and basilar stroke. Eur Stroke J 2023; 8: 8–54. 5 Palaiodimou L, Katsanos AH, Turc G, et al. Tenecteplase vs alteplase in acute artery occulsion, particularly in the subgroup of ischemic stroke within 4.5 hours: a systematic review and meta-analysis of randomized trials. Neurology 2024; 103: e209903. patients not treated with endovascular thrombectomy. 6 Katsanos AH, Psychogios K, Turc G, et al. Off-label use of tenecteplase for The treatment effect of tenecteplase in basilar artery the treatment of acute ischemic stroke: a systematic review and meta- analysis. JAMA Netw Open 2022; 5: e224506. occlusion seemed to be analogous to the treatment 7 Gerschenfeld G, Turc G, Obadia M, et al. Functional outcome and effect of tenecteplase in anterior circulation large- hemorrhage rates after bridging therapy with tenecteplase or alteplase in patients with large ischemic core. Neurology 2024; 103: e209398. vessel occlusion,9 while patient selection was based 8 Rousseau JF, Weber JM, Alhanti B, et al. Short-term safety and effectiveness on a pragmatic approach without mandatory use of for tenecteplase and alteplase in acute ischemic stroke. JAMA Netw Open 2025; 8: e250548. advanced neuroimaging. Should the results of TRACE-5 9 Xiong Y, Campbell BCV, Schwamm LH, et al. Tenecteplase for ischemic stroke be independently confirmed in non-Asian populations at 4.5 to 24 hours without thrombectomy. N Engl J Med 2024; 391: 203–12. 10 Xiong Y, Alemseged F, Cao Z, et al. Tenecteplase versus standard medical harbouring different risk factors and diverse underlying treatment for basilar artery occlusion within 24 h (TRACE-5): a multicentre, prospective, randomised, open-label, blinded-endpoint, superiority, mechanisms of acute ischaemic stroke, they have the phase 3 trial. Lancet 2026; published online Feb 5. https://doi.org/10.1016/ potential to revise stroke guidelines worldwide. S0140-6736(25)02633-9. Testing early haemostatic therapy for acute intracerebral haemorrhage The clinical severity, narrow time window to reduce overcome by treatments for this serious condition. Published Online bleeding, and variable care pathways for patients In this issue of The Lancet, Joseph P Broderick and February 4, 2026 https://doi.org/10.1016/ with spontaneous (non-traumatic) intracerebral colleagues1 present the results of the FASTEST trial, S0140-6736(26)00146-7 haemorrhage (ICH) are enormous challenges to be a monumental effort to establish the safety and See Articles page 773 Comment efficacy of the potent haemostatic agent, intravenous from recombinant factor VIIa,3 constituting a patient recombinant factor VIIa, administered to patients population of potential responders to target in the within 2 h of the onset of ICH. This multicentre, double- FASTEST trial.1 blind, randomised, placebo-controlled, adaptive, Given that clinical trials are a major investment by phase 3 trial was conducted through an international investigators, sponsors, and participants, it is appropriate network of hospitals and mobile stroke units across to gain as much information as possible from them. six countries between 2021 and 2025. Unfortunately, This information typically involves analyses to establish after the first 626 of a planned 860 patients were whether the average effect of the treatment varies more randomly assigned to either recombinant factor VIIa (or less) to the benefit (or harm) of patients. However, or an identical placebo at the time of the second pre- careful thought must be applied to the interpretation planned interim analysis, futility signals in the first of such data because it is difficult to disentangle the 434 patients with available data on the primary outcome influence of low statistical power, multiple testing, of functional recovery at 180 days prompted the steering exposure interactions, confounding, and chance. committee to terminate the trial. Overall, there was One solution is to only accept such results as hypothesis- no benefit of recombinant factor VIIa on either the generating from analyses of prespecified subgroups, and primary outcome (odds ratio 1·09 [95% CI 0·79–1·51]) where there are biological explanations and data relevant or secondary outcomes, despite a significant reduction for guiding clinical decisions. Ultimately, however, large in ICH expansion with recombinant factor VIIa clinical trials and meta-analyses of individual patient (–3·68 mL [95% CI –5·40 to –1·94]; p=0·0011). However, data are required to provide reliable estimates of effects non-significant signals emerged in small, prespecified overall and by patient subgroups. For the use of early subgroups of patients defined by time to treatment intensive blood pressure lowering in patients with acute (<90 min) and the presence of a spot sign indicating ICH, a clear interaction between time from symptom active bleeding on CT angiography. FASTEST, which was onset to randomisation and the effect of recombinant itself based on post-hoc subgroup analyses of the earlier factor VIIa only became apparent after data were pooled FAST trial,2,3 reminds us to be cautious when seeking from 11 312 patients who participated in five clinical trials to substantiate the effects seen in patient subgroups conducted over the past 20 years.7 and to be wary when hoping that significant effects on FASTEST continues to investigate the benefit of ultra- plausible mechanistic surrogates will improve functional early recombinant factor VIIa by recruiting its patient outcomes. population of potential responders within 90 min of The rationale behind the use of recombinant factor VIIa symptom onset or within 2 h if a spot sign is identified. for patients with ICH was based on established safety If ultra-early recombinant factor VIIa is shown to benefit and efficacy in patients with pre-existing coagulation individuals with active bleeding, we will finally have disorders, with an initial proof-of-concept trial evidence that limiting haematoma expansion with a showing that early treatment reduced ICH haematoma haemostatic agent improves functional outcomes in expansion.4 However, a subsequent international, this patient group. However, the generalisability of the phase 3, randomised controlled trial showed no effect population will be minimal worldwide unless code ICH of recombinant factor VIIa on the functional outcomes care pathways can identify people with hyperacute ICH of patients when administered within 4 h after the in the ambulance and convey them rapidly to hospital, onset of ICH, despite further evidence of a reduction where CT angiography will need to be available (as it is for in ICH expansion.2 Furthermore, recombinant factor acute ischaemic stroke due to a large-vessel occlusion), as VIIa produced an excess of serious thromboembolic well as fast-care bundles to effectively control elevated complications that, alongside the neutral effects on blood pressure and other physiological parameters.8 all outcomes in a meta-analysis of all trials to date,5 CSA reports grants from the National Health and Medical Research Council and prompted guidelines to recommend against the use Medical Research Futures Fund of Australia, the Medical Research Foundation of the UK, and AstraZeneca Australia. CSA is also a consultant to Auzone of this agent for ICH.6 Despite these setbacks, post- BioTechnology China; a chair of the data and safety monitoring boards for hoc modelling of data from the FAST trial identified several investigator trials; president-elect of the World Stroke Organisation; and the editor-in-chief of Cerebrovascular Diseases. RA-SS reports grant funding from several subgroups of patients who might benefit the British Heart Foundation and the Chief Scientist Office in Scotland; 736 segamI ytteG aiv nedragnwo yb otohP Comment honorarium for membership of an endpoint committee for a trial sponsored by 2 Mayer SA, Brun NC, Begtrup K, et al, and the FAST Trial Investigators. Novo Nordisk paid to his institution; and membership of the data and safety Efficacy and safety of recombinant activated factor VII for acute monitoring board for the investigator-initiated DO-IT trial. RA-SS is also the intracerebral hemorrhage. N Engl J Med 2008; 358: 2127–37. clinical director of the UK Network of Registered Clinical Trials Units and lectures 3 Mayer SA, Davis SM, Skolnick BE, et al, and the FAST trial investigators. for the European Stroke Masters of the European Stroke Organisation. Can a subset of intracerebral hemorrhage patients benefit from hemostatic CC declares no competing interests. therapy with recombinant activated factor VII? Stroke 2009; 40: 833–40. 4 Mayer SA, Brun NC, Begtrup K, et al, and the Recombinant Activated Factor *Craig S Anderson, Chen Chen, Rustam Al-Shahi Salman VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005; 352: 777–85. canderson@fudan.edu.cn 5 Eilertsen H, Menon CS, Law ZK, et al. Haemostatic therapies for stroke due Institute of Science and Technology for Brain-inspired Intelligence, Fudan to acute, spontaneous intracerebral haemorrhage. University, Shanghai 201203, China (CSA); The George Institute for Global Cochrane Database Syst Rev 2023; 10: CD005951. Health, University of New South Wales, Sydney, NSW, Australia (CC, RA-SS); 6 Steiner T, Purrucker JC, Aguiar de Sousa D, et al. European Stroke Neurology Department, Royal Prince Alfred Hospital, Sydney, NSW, Australia Organisation (ESO) and European Association of Neurosurgical Societies (CSA); Neurology Department, Shanghai East Hospital, School of Medicine, (EANS) guideline on stroke due to spontaneous intracerebral haemorrhage. Tongji University, Shanghai, China (CC); Institute for Neuroscience and Eur Stroke J 2025; 10: 1007–86. Cardiovascular Research, University of Edinburgh, Edinburgh, UK (RA-SS) 7 Wang X, Ren X, Li Q, et al, and the INTERACT Investigators. Effects of blood pressure lowering in relation to time in acute intracerebral haemorrhage: 1 Broderick JP, Naidech AM, Elm JJ, et al. Recombinant factor VIIa versus a pooled analysis of the four INTERACT trials. Lancet Neurol 2025; placebo for spontaneous intracerebral haemorrhage within 2 h of 24: 571–79. symptom onset (FASTEST): a multicentre, double-blind, randomised, 8 Li Q, Yakhkind A, Alexandrov AW, et al. Code ICH: a call to action. Stroke placebo-controlled, phase 3 trial. Lancet 2026; published online Feb 4. 2024; 55: 494–505. https://doi.org/10.1016/S0140-6736(26)00097-8. Supplemental ultrasound screening lowers advanced breast cancers The goals of breast cancer screening are to detect breast Vascular-based imaging is roughly three-times more cancers as early as possible to reduce both mortality sensitive than ultrasound4 but is more invasive and costly.7 and the morbidity of therapy. It is well established Ultras ound is used in some geographical jurisdictions to that mammography is less sensitive in women with screen women who have contraindications for MRI and dense breast tissue. These women have higher rates of average-risk women with dense breast tissue.8 interval cancers and more advanced stage diagnoses Breast cancer mortality reduction in RCTs remains at detection,1 and they derive a smaller breast cancer the gold standard for showing screening benefits. mortality reduction from screening mammography Because modern treatments improve survival even for compared with women with non-dense breasts.2 women with advanced cancers, mortality differences Efforts to reduce screening disparities in women with can take many years to emerge, and RCTs do not capture See Articles page 784 dense breast tissue include more frequent mammo- reductions in treatment morbidity. Declines in interval graphy3 and supplemental imaging modalities to and advanced cancers precede mortality reductions mammog raphy.4 Supplemental ultrasound reduces the and are often used as surrogate markers, although their interval cancer rate: in the J-START trial, a randomised validity remains debated.9 control trial (RCT) from Japan, adding ultrasound to In a prespecified follow-up analysis from the J-START mammography increased sensitivity, reduced speci ficity, trial, published in The Lancet, cumulative incidence of detected more cancers, and lowered the interval cancer advanced cancer (stage 2 or higher [node positive, T2 rate by 75%, compared with mammography alone for all or higher, or both]) up to Oct 4, 2024, was assessed.10 breast tissue densities.5 In the Netherlands, supplemental Data on race and ethnicity were not collected. MRI for women with the most dense breasts reduced the 76 196 asymptomatic women aged 40–49 years were interval cancer rate by 85%.6 Contrast mammography randomised to either mammography plus ultrasound offers similar sensitivity to MRI and is expected to versus mammography alone every 2 years. Among produce similar reduction of interval cancer rate.4 To date, the 36 723 women in the intervention group, however, no RCT has shown a mortality benefit from any 894 cancers were detected, with 234 (26·2%) classified supplemental modality. Ultrasound is widely available, less as advanced. In the 35 938 women in the control group, invasive, and less costly than vascular-based modalities. 843 cancers were detected, with 277 (32·9%) classified segamI ytteG aiv gnaWynoP --- [PDF原文](https://sci-net.xyz/storage/7932541/d0e0a5d637b65037b810e069eda58ede09a726d7b781d4c479ce4cfc3d484a84/Testing-early-haemostatic-therapy-for-acute-intracerebral-haemorrhage.pdf) DOI: 10.1016/S0140-6736(26)00146-7