Abstract
We conducted a post hoc analysis of the ARAIS (Argatroban Plus Recombinant Tissue-Type Plasminogen Activator for AIS) trial to investigate whether diabetes mellitus (DM) affects the efficacy of argatroban plus alteplase in patients with acute ischaemic stroke (AIS). Patients were categorized into DM and non-DM subgroups. In each subgroup, outcomes were compared between the argatroban plus alteplase group and the alteplase alone group. Additionally, the interaction between DM and treatment efficacy was assessed. The primary outcome was excellent functional outcome at 90 days, which was defined as a modified Rankin Scale score of 0–1. A total of 696 patients were included in this study. Regarding the primary outcome, the treatment effect was comparable between the argatroban plus alteplase group and the alteplase alone group both in the DM subgroup (58.4% versus 63.0%; adjusted risk difference, 1.1%; 95% CI, -13.8% to 16.1%; P = 0.88) and the non-DM subgroup (65.8% versus 65.3%; adjusted risk difference, 0.9%; 95% CI, -6.9% to 8.7%, P = 0.81). No significant interaction was observed between DM and treatment effect on the primary outcome (P = 0.93). Compared with alteplase alone, the efficacy of argatroban plus alteplase in achieving excellent functional outcomes at 90 days did not differ by DM status in patients with AIS.
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References
Powers, W. J. et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 50(12), e344-e418 (2019).
Wardlaw, J. M., del Zoppo, G. & Yamaguchi, T. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2, CD000213 (2000).
Goyal, M. et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet 387(10029), 1723–1731 (2016).
Hébert, M., Lesept, F., Vivien, D. & Macrez, R. The story of an exceptional serine protease, tissue-type plasminogen activator (tPA). Rev. Neurol. (Paris). 172 (3), 186–197 (2016).
Wardlaw, J. M., Murray, V., Berge, E. & del Zoppo, G. J. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst. Rev. 2014(7), CD000213 (2014).
Alexandrov, A. V. & Grotta, J. C. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology 59 (6), 862–867 (2002).
Saqqur, M. et al. Clinical deterioration after intravenous recombinant tissue plasminogen activator treatment: A multicenter transcranial Doppler study. Stroke 38(1), 69–74 (2007).
Chen, L., Cao, S. & Yang, J. Argatroban plus aspirin versus aspirin in acute ischemic stroke. Neurol. Res. 40 (10), 862–867 (2018).
Hosomi, N. et al. Efficacy of anti-coagulant treatment with argatroban on cardioembolic stroke. J. Neurol. 254(5), 605–612 (2007).
Barreto, A. D. et al. Randomized, multicenter trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke). Stroke 48(6), 1608–1616 (2017).
Chen, H. S. et al. Effect of argatroban plus intravenous alteplase vs intravenous alteplase alone on neurologic function in patients with acute ischemic stroke. JAMA 329(8), 640–650 (2023).
Xu, Q. & Cheung, R. T. F. Melatonin mitigates type 1 diabetes-aggravated cerebral ischemia-reperfusion injury through anti-inflammatory and anti-apoptotic effects. Brain Behav. 13(9), e3118 (2023).
Sivandzade, F., Prasad, S., Bhalerao, A. & Cucullo, L. NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches. Redox Biol. 21, 101059 (2019).
Vercalsteren, E. et al. The pre-stroke induction and normalization of insulin resistance respectively worsens and improves functional recovery. Int. J. Mol. Sci. 24(4), 3989 (2023).
Skelin Klemen, M., Kopecky, J., Dolenšek, J. & Stožer, A. Human beta cell functional adaptation and dysfunction in insulin resistance and its reversibility. Nephron 148 (2), 78–84 (2024).
Arboix, A. et al. Cerebral infarction in diabetes: Clinical pattern, stroke subtypes, and predictors of in-hospital mortality. BMC Neurol. 5(1), 9 (2005).
Reiter, M. et al. Diabetes and thrombolysis for acute stroke: A clear benefit for diabetics. Eur. J. Neurol. 21(1), 5–10 (2014).
Desilles, J. P. et al. Diabetes mellitus, admission glucose, and outcomes after stroke thrombolysis: A registry and systematic review. Stroke 44(7), 1915–1923 (2013).
Yang, Y. et al. Randomized trial of argatroban plus recombinant tissue-type plasminogen activator for acute ischemic stroke (ARAIS): Rationale and design. Am. Heart J. 225, 38–43 (2020).
Molina, C. A. et al. Thrombolysis-related hemorrhagic infarction: A marker of early reperfusion, reduced infarct size, and improved outcome in patients with proximal middle cerebral artery occlusion. Stroke 33(6), 1551–1556 (2002).
Arenillas, J. F. et al. Prediction of early neurological deterioration using diffusion- and perfusion-weighted imaging in hyperacute middle cerebral artery ischemic stroke. Stroke 33(9), 2197–2203 (2002).
Sacco, R. L. et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44(7), 2064–2089 (2013).
Rao, N. M., Levine, S. R., Gornbein, J. A. & Saver, J. L. Defining clinically relevant cerebral hemorrhage after thrombolytic therapy for stroke: Analysis of the National Institute of Neurological Disorders and Stroke tissue-type plasminogen activator trials. Stroke 45(9), 2728–2733 (2014).
Fiorelli, M. et al. Hemorrhagic transformation within 36 hours of a cerebral infarct: Relationships with early clinical deterioration and 3-month outcome in the European Cooperative Acute Stroke Study I (ECASS I) cohort. Stroke 30(11), 2280–2284 (1999).
American Diabetes Association Professional Practice Committee for Diabetes. Diagnosis and classification of diabetes: standards of care in diabetes-2026. Diabetes Care. 49 (Supplement 1), S27–S49 (2026).
Chen, R., Ovbiagele, B. & Feng, W. Diabetes and stroke: Epidemiology, pathophysiology, pharmaceuticals and outcomes. Am. J. Med. Sci. 351(4), 380–386 (2016).
Capes, S. E., Hunt, D., Malmberg, K., Pathak, P. & Gerstein, H. C. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: A systematic overview. Stroke 32(10), 2426–2432 (2001).
Beckman, J. A., Creager, M. A. & Libby, P. Diabetes and atherosclerosis: Epidemiology, pathophysiology, and management. JAMA 287(19), 2570–2581 (2002).
Undas, A., Wiek, I., Stêpien, E., Zmudka, K. & Tracz, W. Hyperglycemia is associated with enhanced thrombin formation, platelet activation, and fibrin clot resistance to lysis in patients with acute coronary syndrome. Diabetes Care. 31 (8), 1590–1595 (2008).
Guo, Y. et al. Impact of diabetes on platelet function in acute ischemic stroke patients taking dual antiplatelet therapy. Front. Neurol. 12, 712024 (2021).
Jia, Q. et al. Diabetes and poor outcomes within 6 months after acute ischemic stroke: The China National Stroke Registry. Stroke 42(10), 2758–2762 (2011).
Bradley, S. A., Smokovski, I. & Bhaskar, S. M. M. Impact of diabetes on clinical and safety outcomes in acute ischemic stroke patients receiving reperfusion therapy: A meta-analysis. Adv. Clin. Exp. Med. 31(6), 583–596 (2022).
Bhatt, D. L. et al. COMPASS Steering Committee and Investigators. Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease. Circulation 141 (23), 1841–1854 (2020).
Chen, W. et al. CHANCE Investigators. Recurrent stroke in minor ischemic stroke or transient ischemic attack with metabolic syndrome and/or diabetes mellitus. J. Am. Heart Assoc. 6 (6), e005446 (2017).
Emerging Risk Factors Collaboration et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375 (9733), 2215–2222 (2010).
Boulanger, M., Poon, M. T., Wild, S. H. & Al-Shahi Salman, R. Association between diabetes mellitus and the occurrence and outcome of intracerebral hemorrhage. Neurology 87 (9), 870–878 (2016).
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Conceptualization: Hui-Sheng Chen. Methodology: Hui-Sheng Chen, Xiao-Wen Hou, Yu Cui. Software and data curation: Xiao-Wen Hou, Yu Cui. Investigation: Xiao-Wen Hou, Yu Cui, Nan-Nan Zhang. Writing-Original Draft Preparation: Xiao-Wen Hou. Writing-Review and Editing: Hui-Sheng Chen.
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Hou, XW., Cui, Y., Zhang, NN. et al. Efficacy of argatroban plus alteplase versus intravenous alteplase according to diabetes mellitus in acute ischemic stroke. Sci Rep (2026). https://doi.org/10.1038/s41598-026-47016-5
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DOI: https://doi.org/10.1038/s41598-026-47016-5
