Intravenous Tirofiban After Tenecteplase in Acute Ischemic Stroke: The INSTANT Randomized Clinical Trial

# Intravenous Tirofiban After Tenecteplase in Acute Ischemic Stroke: The INSTANT Randomized Clinical Trial *Published: 2026 May 8* reported receipt of grants from Siemens, SNF, Boehringer Ingelheim, the Swiss Heart Foundation, the Bangerter Foundation, and the Horten Foundation; data collection assistance and statistical analysis support from Cercare; and consulting for Bayer AG. Dr Nogueira reported receipt of consulting fees from Anaconda, Biogen, Boehringer Ingelheim, BMS/Johnson & Johnson, Cerenovus, Genentech, Philips, Hybernia, Hyperfine, Imperative Care, Medtronic, Merck, Phenox, Philips, Prolong Pharmaceuticals, Stryker Neurovascular, Shanghai Wallaby, Synchron, and Takeda Pharmaceutical and stock options for consulting from Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, CrestecBio, Euphrates Vascular, Vesalio, Viz-AI, RapidPulse, Sensome, and Perfuze; being a principal investigator for the ENDOLOW trial with funding provided by Cerenovus to Emory University and for the DUSK trial with funding provided by Stryker to the University of Pittsburgh; and being an investor in Viz-AI, Perfuze, Cerebrotech, Reist/Q’Apel Medical, Truvic, Tulavi Therapeutics, Vastrax, Piraeus Medical, Brain4Care, Quantanosis AI, Unity Medical, and Viseon. Dr Goyal reported receipt of grants from Medtronic and Cerenovus (to institution) and consulting fees from Microvention. Dr Thomalla reported receipt of personal fees from Acandis, AstraZeneca, Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Lilly, and TarGED. Dr Nguyen reported receipt of personal fees as associate editor of Stroke, advisory board fees from Bayer and Route 92, consulting fees from Medtronic, and speaker fees from Genentech. Dr Saver reported receipt of personal fees from Abbott, Aeromics, Amgen, Argenica, Astrocyte, Bayer, Biogen, Boehringer Ingelheim, BrainsGate, BrainQ, CSL Behring, Filterlex, Genentech, Johnson & Johnson, MindRhythm, Medtronic, NeuroMerit, Neuronics, Novo Nordisk, Occlutech, Phillips, QuantalX, Rapid Medical, Roche, and Stream Biomedical and consulting compensation for advising on rigorous and safe clinical trial design and conduct. No other disclosures were reported. 50. JAMA. 2026 May 8:e264292. doi: 10.1001/jama.2026.4292. Online ahead of print. Intravenous Tenecteplase Prior to Endovascular Treatment for Ischemic Stroke at 4.5 to 24 Hours: The TNK-PLUS Randomized Clinical Trial. Xiong Y(1)(2), Che F(3), Wang H(3), Hao M(1), Nguyen TN(4), Fisher M(5), Jin A(2), Cao Z(1), Wang Z(3), Yao X(6), Feng G(6), Xu Y(7), Guo S(7), Qin H(8), Huang X(9), Xu J(10), Chen Z(11), Yuan J(12), Li W(13), Hu W(14), Feng X(1), Zong L(1), Ye W(2), Duan C(12), Wang L(1), Wu S(1), Campbell BCV(15)(16), Wang Y(1)(2); TNK-PLUS Investigators. Collaborators: Li C, Yang H, Kong F, Qiu H, Ni C, Wang H, Liu H, Chu J, Xie F, Dai H, Zhuang S, Liu Y, Ding M, Dong Q, Wang Y, Gao S, Liu S, Zhao Y, Yuan H, Zhang C, Xu D, Mu L, Li J, Zhang G, Shi H, Kong Z, Qiao H, Guan M, Yu J, Wu W, Li X, Wang L, Wang H, Zhang B, Yang L, Chang L, Zhuang J, Zhou L, Man H, Fu X, Guo S, Shi Z, Selim MH, Ding D, Cao W, Xu X, Xu Z. Author information: (1)Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (2)China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Beijing, China. (3)Department of Neurology, Linyi People's Hospital, Linyi, China. (4)Department of Neurology and Radiology, Boston Medical Center, Boston, Massachusetts. (5)Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. (6)Department of Neurology, First People's Hospital of Chenzhou, Chenzhou, China. (7)Department of Neurology, Linyi Central Hospital, Linyi, China. (8)Department of Neurology, Zaozhuang Municipal Hospital, Zaozhuang, China. (9)Department of Neurology, First Affiliated Hospital of Wannan Medical College, Wuhu, China. (10)Department of Neurology, People's Hospital of Queshan, Zhumadian, China. (11)Department of Neurological Intervention and Neurological Intensive Care, Dalian Municipal Central Hospital, Dalian, China. (12)Department of Neurology, Daxing Teaching Hospital, Capital Medical University, Beijing, China. (13)Department of Neurology, Heze Municipal Hospital, Heze, China. (14)Department of Neurology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (15)Department of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia. (16)Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia. Comment in doi: 10.1001/jama.2026.4503. doi: 10.1001/jama.2020.23523. doi: 10.1001/jama.2020.23522. doi: 10.1001/jama.2026.0210. doi: 10.1001/jama.2025.12063. ## IMPORTANCE Whether intravenous tenecteplase prior to endovascular treatment (EVT) for ischemic stroke reduces disability in the late time window is unclear. ## OBJECTIVE To investigate the adverse events and efficacy of tenecteplase prior to EVT in patients 4.5 to 24 hours after ischemic stroke onset due to proximal middle cerebral artery (MCA) occlusion. DESIGN, SETTING, AND PARTICIPANTS Multicenter, phase 3, randomized, open-label, blinded end point, superiority trial conducted at 40 centers in China. Adult (≥18 years) patients with acute ischemic stroke 4.5 to 24 hours after last known to be well due to MCA-M1 or proximal M2 occlusion with salvageable brain tissue (ischemic core volume <70 mL, mismatch ratio ≥1.8, and mismatch volume ≥15 mL) identified on computed tomography-perfusion or magnetic resonance-perfusion-diffusion imaging were enrolled from January 25, 2024, through July 21, 2025, and followed up for 90 days. Final follow-up occurred on October 14, 2025. ## INTERVENTIONS Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous tenecteplase (0.25 mg/kg; maximum dose, 25 mg) before EVT (n = 199) or EVT alone (n = 192). MAIN OUTCOMES AND MEASURES The primary outcome was functional independence, defined as a score of 0 to 2 on the modified Rankin Scale (range, 0-6, with higher scores indicating greater disability) at 90 days. Adverse events outcomes included symptomatic intracranial hemorrhage and death. ## RESULTS All of the 391 patients enrolled (median age, 68 years [IQR, 59-75]; 155 [39.6%] females) completed the trial. Functional independence at 90 days occurred in 88 patients (44.2%) in the tenecteplase before EVT group and 83 patients (43.2%) in the EVT alone group (adjusted relative rate, 1.01 [95% CI, 0.83-1.24]; P = .89; risk difference, 0.99% [95% CI, -8.84% to 10.83%]). Mortality within 90 days was 12.7% (25/197) in the tenecteplase before EVT group and 14.2% (27/190) in the EVT alone group. Symptomatic intracranial hemorrhage within 36 hours was 5.1% (10/197) and 2.6% (5/190), respectively. CONCLUSIONS AND RELEVANCE In patients presenting to EVT-capable centers 4.5 to 24 hours after stroke onset with proximal MCA occlusion, intravenous tenecteplase before EVT did not improve clinical outcomes vs EVT alone. ## TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT06221371. DOI: 10.1001/jama.2026.4292 PMCID: PMC13156799 DOI: 10.1001/jama.2026.5245