Huang H, Xu S, Qin T
… +31 more, Wang M, Li G, Liu C, Deng G, Wang Y, Ao D, Xie Y, Zhang Y, Kong Q, Lan L, Yu Y, Huang S, Yu Z, Yi T, Chen W, Zhao W, Su J, Zhou P, Li F, Mei B, Jing P, Zhang J, Du J, Goyal M, Nguyen TN, Wang D, Saver JL, Tang Z, Wang W, Luo X, ATTRACTION Investigators
BACKGROUND: Successful reperfusion after endovascular thrombectomy does not consistently result in functional independence in acute ischaemic stroke. We aimed to assess the efficacy and safety of tirofiban, a glycoprotei...BACKGROUND: Successful reperfusion after endovascular thrombectomy does not consistently result in functional independence in acute ischaemic stroke. We aimed to assess the efficacy and safety of tirofiban, a glycoprotein IIb/IIIa receptor antagonist, given to patients with acute ischaemic stroke who had had a successful endovascular reperfusion. METHODS: This multicentre, double-blind, randomised controlled trial at 82 hospitals in China included patients with acute ischaemic stroke due to anterior-circulation large-vessel occlusion who had had a successful reperfusion after thrombectomy. Eligible patients were randomly assigned (1:1) to receive either tirofiban (intra-arterial bolus 5 μg/kg followed by intravenous infusion 0·1 μg/kg per min for 24 h) or placebo (administered with the same volume and according to the same bolus and infusion procedures as tirofiban), using computer-generated randomisation with fixed blocks stratified by study site. Patients, treating clinicians, investigators, and outcome assessors were masked to group assignments. The primary efficacy outcome was functional independence at 90 days (with a modified Rankin Scale score of 0-2), assessed in all randomly assigned participants (intention-to-treat population). Safety outcomes were symptomatic intracranial haemorrhage within 48 h, any evidence of intracranial haemorrhage on imaging within 48 h, and death within 90 days, and they were assessed in patients having received the study treatment with at least one safety evaluation. The Adjunct Tirofiban Treatment after Successful Endovascular Thrombectomy Recanalisation in Acute Anterior Circulation Ischaemic Stroke (ATTRACTION) trial is registered with ClinicalTrials.gov, NCT06265051 and is now completed. FINDINGS: Of 1686 patients assessed, 1380 were randomly assigned to either the tirofiban group (689 patients) or the placebo group (691 patients) between April 9, 2024, and Sept 29, 2025. Median age was 71 years (IQR 62-77), 591 (43%) patients were female and 789 (57%) were male, and 1367 (99%) were of Han Chinese ethnicity. No patients were lost to follow-up at 90 days. Functional independence at 90 days was recorded in 340 (49%) of 689 patients in the tirofiban group and 299 (43%) of 691 patients in the placebo group (unadjusted absolute risk difference 6·1 percentage points, 95% CI 0·8-11·3, p=0·023; adjusted risk ratio 1·15, 95% CI 1·03-1·27, p=0·0092). There was no significant difference between study groups in the proportion of patients with symptomatic intracranial haemorrhage within 48 h (82 [12%] of 687 patients in the tirofiban group vs 65 [9%] of 691 patients in the placebo group), the proportion with any intracranial haemorrhage within 48 h (235 [34%] patients vs 219 [32%] patients), and 90-day mortality (126 [18%] patients vs 131 [19%] patients). INTERPRETATION: In patients with acute ischaemic stroke due to anterior-circulation large-vessel occlusion achieving successful reperfusion, adjunctive tirofiban increased the likelihood of functional independence compared with placebo. Although symptomatic intracranial haemorrhage occurred numerically more often with tirofiban, the between-group difference was not significant, and this finding warrants caution when weighing potential benefit against bleeding risk. FUNDING: Tongji Hospital Clinical Research Fund.
Lund LH, Barandiarán Aizpurua A, Bollano E
… +27 more, Braun O, Brouwer JLP, Buikema JW, Cannata A, Gardner RS, Handoko ML, Lang CC, Metra M, Sinagra G, Thorvaldsen T, van der Boon RMA, van Essen BJ, Shah SJ, Voors AA, Lam CSP, Pitt B, Solomon SD, Hage C, Stahlberg M, Bernareggi A, Gordon A, Del Sole M, Rosendahl E, Stromberg P, Westerberg G, Edfors R, Petrie MC
BACKGROUND: The central problem in heart failure with reduced ejection fraction (HFrEF) is reduced contractility. Existing inotropes are associated with adverse effects. In this exploratory study, we aimed to assess the...BACKGROUND: The central problem in heart failure with reduced ejection fraction (HFrEF) is reduced contractility. Existing inotropes are associated with adverse effects. In this exploratory study, we aimed to assess the safety and tolerability of AC01, a novel oral calcium-sensitising inotrope and ghrelin receptor agonist, in patients with HFrEF. METHODS: In this phase 1b/2a, randomised, double-blind, placebo-controlled study, adults aged 18-80 years with heart failure for at least 6 months and an ejection fraction of 40% or lower were enrolled at 14 sites in the Netherlands, the UK, Sweden, and Italy. All patients had a transvenous implantable cardioverter defibrillator for primary prevention, with back-up pacing to protect against excessive bradycardia. Other eligibility criteria included sinus rhythm or permanent, persistent, or paroxysmal atrial fibrillation or flutter (only allowed in phase 2a), with a mean resting heart rate of 55-90 beats per min. Randomisation used permuted blocks, with block sizes of four for phase 1b and three for phase 2a. In phase 1b, patients were enrolled in four sequential dose cohorts and randomly assigned 3:1 to ascending doses of AC01 (0·1 mg, 0·3 mg, 1·0 mg, or 3·0 mg) or placebo twice daily for 7 days. In phase 2a, patients were randomly assigned 1:1:1 to parallel groups receiving 1·0 mg AC01, 3·0 mg AC01 (1·0 mg AC01 on days 1 and 2 and 3·0 mg thereafter), or placebo orally twice daily for 28 days. Patients, study personnel, outcomes assessors, those analysing the data, and the sponsor were masked to treatment assignment. The primary outcome was safety and tolerability. Safety was monitored by physical examination, vital signs, safety laboratory assessments, and 12-lead electrocardiograms (ECGs) periodically during the treatment period and until the end-of-study visit (day 12 in phase 1b and day 42 in phase 2a), and cardiac rhythm was continuously monitored remotely using a patch device until day 9 in phase 1b and until day 4 in phase 2a. Adverse or unexpected events, signs, or symptoms were recorded. This study is registered with ClinicalTrials.gov, NCT05642507, and has been completed. FINDINGS: Between Feb 23, 2023, and Aug 28, 2025, 58 patients (53 [91%] male and five [9%] female patients with a median age of 66·0 years [IQR 60·3-72·0]) were randomly assigned: 32 in phase 1b and 26 in phase 2a. In phase 1b, four cohorts of eight patients were enrolled; in each cohort, six patients were allocated to AC01 and two to placebo, with AC01 dose cohorts of 0·1 mg, 0·3 mg, 1·0 mg, and 3·0 mg. In phase 2a, nine patients were allocated to 1·0 mg AC01, eight to 3·0 mg AC01, and nine to placebo. There were 12 AC01-related adverse events in phase 1b and 18 in phase 2a. There were no AC01-related serious adverse events; one treatment-related serious adverse event of increased high-sensitivity cardiac troponin I concentration occurred in a patient receiving placebo in phase 1b. Mild or moderate treatment-emergent adverse events were reported in 33 (80%) of 41 patients receiving AC01 and 12 (71%) of 17 patients receiving placebo. The most common treatment-emergent adverse events were hypotension, non-sustained ventricular tachycardia, dyspnoea, hyperglycaemia, dizziness or vertigo, and headache. ECG data showed no apparent signs of tachycardia, new-onset tachyarrhythmias, myocardial ischaemia, or morphological or conduction abnormalities. No case of symptomatic hypotension was reported, and there were no apparent effects of AC01 on high-sensitivity cardiac troponin I or NT-proBNP. There were no deaths during the study. INTERPRETATION: In patients with HFrEF, AC01 over 28 days appeared safe and well tolerated, and no major harms were identified in this early-phase study. These findings support further investigations of AC01 in larger studies. FUNDING: AnaCardio.
BACKGROUND: One of the drawbacks of fetoscopic endoluminal tracheal occlusion (FETO) for congenital diaphragmatic hernia (CDH) is the need for a second intervention to establish airway patency. In this first-in-human stu...BACKGROUND: One of the drawbacks of fetoscopic endoluminal tracheal occlusion (FETO) for congenital diaphragmatic hernia (CDH) is the need for a second intervention to establish airway patency. In this first-in-human study, we aimed to evaluate a novel tracheal occlusion device (Smart-TO) that spontaneously deflates when in close proximity to a strong magnetic field. METHODS: We conducted two parallel single-centre, single-arm, open-label trials in Paris, France, and Leuven, Belgium. Eligibility criteria included patient age 18 years or more, singleton pregnancy with CDH, and severe or moderate pulmonary hypoplasia in left-sided CDH; in Leuven, eligibility criteria also included severe hypoplasia in right-sided and bilateral CDH. Fetal lung size was assessed by measuring the observed-to-expected lung-to-head ratio by ultrasonography. Data for baseline demographics were self-reported and collected at the screening visit. Insertion of the Smart-TO balloon was scheduled between 27 weeks and 31 weeks of gestation. Balloon deflation was scheduled between 34 weeks and 34 weeks (or earlier, if clinically indicated) by exposure to the magnetic field of a MRI machine, and ultrasonography was then done to confirm balloon deflation. The primary endpoint was balloon deflation, with expulsion of the balloon from the fetal airways at birth as a coprimary outcome in the Paris arm of the study. The primary outcome was reported with its 95% CI using the continuity-corrected score method for all patients with the investigational medical device in place at the time of deflation. Safety analysis was conducted for all patients in whom FETO was attempted. These trials are registered with ClinicalTrials.gov (NCT04931212 [Paris]) and NCT05100693 [Leuven]) and have been completed. FINDINGS: Between Aug 4, 2021 and Jan 15, 2024, 48 patients were enrolled. Of these, 47 patients underwent FETO, and the Smart-TO was successfully placed in 46 fetuses. Median gestational age at FETO was 29 weeks (28-30 weeks). After placement, there was one spontaneous balloon deflation and one unexplained intrauterine fetal death. In all other patients, MRI machine-induced balloon deflation was attempted. The deflation rate was 100% (95% CI 92-100). At birth, the empty balloon was outside the airways in all infants. There were two cases of tracheomalacia in survivors, both with symptom resolution by the time of discharge from neonatal intensive care. There were 14 neonatal deaths, all attributed to pulmonary hypoplasia. Five adverse events were considered likely related to the device (of a total of 84), and no serious adverse events (of a total of 40) were related to the Smart-TO device. INTERPRETATION: This study shows effective magnetic resonance-induced deflation of the Smart-TO balloon and supports short-term safety. These findings constitute an important advance in fetal surgery for CDH, eliminating the need for a second intrauterine procedure. FUNDING: Clinical Council for Research and Education (Klinische Onderzoeks-en Opleidingsraad) of the University Hospitals of Leuven and Assistance Publique-Hôpitaux de Paris. Investigational devices (Smart-TO) were provided free of charge to patients and institutions by BS-MTI.
BACKGROUND: Current surgical treatments for terminal bladder dysfunction include intestinal-based reconstructive approaches that carry substantial morbidity, particularly in immunosuppressed patients. These limitations p...BACKGROUND: Current surgical treatments for terminal bladder dysfunction include intestinal-based reconstructive approaches that carry substantial morbidity, particularly in immunosuppressed patients. These limitations prompted investigation into vascularised composite bladder allograft transplantation as a novel reconstructive alternative. METHODS: This is an ongoing phase 0 feasibility trial of decreased-donor bladder or combined bladder-kidney transplantation at two academic medical centres in the USA. Eligible bladder transplant recipients are adults aged 18-70 years with non-functional, poorly compliant bladders. Ideal candidates for this trial include patients with pre-existing or concurrent immunosuppression requirements. The primary endpoints are technical feasibility, defined as completion of the operation with restoration of urinary continuity with graft perfusion, and patient safety, reported through adverse events. Here, we report on the safety, feasibility, and immunological and functional outcomes from the first-in-human kidney and bladder transplant as part of the study. This study was registered with ClinicalTrials.gov, NCT06337942 and NCT05462561, and is ongoing. FINDINGS: The surgery was carried out in May, 2025. The patient was a 41-year-old anephric male with a terminal bladder and end-stage kidney disease from hypertension who had been on peritoneal dialysis for 7 years. Kidney and bladder were recovered from an ABO compatible 35-year-old female donor with terminal anoxic brain injury. The 8 h surgery was successful, with both organs having excellent perfusion and no intraoperative complications. On postoperative day 25, the patient developed a urine leak from the suprapubic tube tract and wound breakdown (Clavien-Dindo 4), which was managed surgically with good recovery. More than 6 months post-transplantation, the patient maintained appropriate renal (estimation glomerular filtration rate 52-55 mL/min per 1·73 m) and bladder allograft function, with intact sensation and appropriate urge, bladder capacity of 600 mL, complete continence, spontaneous voiding with maximum flow rate 17 mL/s, and complete emptying with negligible post-void residual urine. The patient is maintained on triple therapy immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone. Serial bladder biopsies have remained negative for cell-mediated or antibody-mediated rejection. INTERPRETATION: The first-in-human combined bladder-kidney transplantation demonstrates the technical feasibility of vascularised composite bladder allograft transplantation, with sustained bladder allograft function, sensation, continence, and voiding parameters, and no evidence of rejection beyond 6 months. These findings suggest bladder transplantation might represent a viable option for select patients with terminal bladder dysfunction, particularly those already requiring immunosuppression. FUNDING: American Urological Association's Research Scholar Award, the National Kidney Registry, OneLegacy, and University of California Los Angeles Department of Urology.