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Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke.

ABSTRACT: In acute ischemic stroke, the only FDA-approved drug; recombinant tissue plasminogen activator (rt-PA) is limited by restricted time-window due to an enhanced risk of hemorrhagic transformation which is thought to be caused by metalloproteinase (MMP). In experimental stroke inhibitors of the mitogen-activated protein kinase kinase extracellular signal-regulated kinase kinase (MEK) 1/2 pathways reduce the MMPs. This study evaluated whether a MEK1/2 inhibitor in combination with rt-PA can prevent the detrimental effects of delayed rt-PA therapy in stroke. Thromboembolic stroke was induced in C57 black/6J mice and the MEK1/2 inhibitor U0126 was administrated 3.5 h and rt-PA 4 h post stroke-onset. Treatment with rt-PA demonstrated enhanced MMP-9 protein levels and hemorrhagic transformation which was prevented when U0126 was given in conjunction with rt-PA. By blocking the MMP-9 with U0126 the safety of rt-PA administration was improved and demonstrates a promising adjuvant strategy to reduce the harmful effects of delayed rt-PA treatment in acute ischemic stroke.

SUBMITTER: Orset C

PROVIDER: S-EPMC8184783 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke.

Orset Cyrille C Arkelius Kajsa K Anfray Antoine A Warfvinge Karin K Vivien Denis D Ansar Saema S

Scientific reports 20210607 1

In acute ischemic stroke, the only FDA-approved drug; recombinant tissue plasminogen activator (rt-PA) is limited by restricted time-window due to an enhanced risk of hemorrhagic transformation which is thought to be caused by metalloproteinase (MMP). In experimental stroke inhibitors of the mitogen-activated protein kinase kinase extracellular signal-regulated kinase kinase (MEK) 1/2 pathways reduce the MMPs. This study evaluated whether a MEK1/2 inhibitor in combination with rt-PA can prevent ...[more]

PMID: 34099834

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Project description:BackgroundThrombolysis with intravenous rt-PA is currently the only approved acute therapy for ischemic stroke. Re-occlusion after initial recanalization occurs in up to 34% in patients treated with rt-PA, probably caused by platelet activation. In acute myocardial infarction, the combination of thrombolysis and antiplatelet therapy leads to a greater reduction of mortality compared to thrombolysis alone. In patients with acute ischemic stroke, several studies showed that patients already on antiplatelet treatment prior to thrombolysis had an equal or even better outcome compared to patients without prior antiplatelet treatment, despite an increased risk of intracerebral bleeding. Based on the fear of intracerebral haemorrhage, current international guidelines recommend postponing antiplatelet therapy until 24 hours after thrombolysis. Remarkably, prior use of antiplatelet therapy is not a contra-indication for thrombolysis. We hypothesize that antiplatelet therapy in combination with rt-PA thrombolysis will improve outcome by enhancing fibrinolysis and preventing re-occlusion.Methods/designARTIS is a randomised multi-center controlled trial with blind endpoint assessment. Our objective is to investigate whether immediate addition of aspirin to rt-PA thrombolysis improves functional outcome in ischemic stroke. Patients with acute ischemic stroke eligible for rt-PA thrombolysis are randomised to receive 300 mg aspirin within 1.5 hours after start of thrombolysis or standard care, consisting of antiplatelet therapy after 24 hours. Primary outcome is poor functional health at 3 months follow-up (modified Rankin Scale 3 - 6).DiscussionThis is the first clinical trial investigating the combination of rt-PA and acute aspirin by means of a simple and cheap adjustment of current antiplatelet regimen. We expect the net benefit of improved functional outcome will overcome the possible slightly increased risk of intracerebral haemorrhage.Trial registrationThe Netherlands National Trial Register NTR822. The condensed rationale of the ARTIS-Trial has already been published in Cerebrovascular Diseases.

Project description:ObjectiveTo evaluate the clinical efficacy of intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) for acute ischemic stroke.MethodsA total of 76 patients with acute ischemic stroke admitted to the Encephalopathy Dept. of Zhecheng Hospital of Traditional Chinese Medicine between February 2021 and June 2022 were recruited in this prospective trial (ClinicalTrials.gov, NCT03884410) and patients were randomized 1:1 to receive either aspirin plus clopidogrel (control group) or aspirin plus clopidogrel and rt-PA intravenous thrombolytic therapy (experimental group), with 38 cases in each group. The treatment efficiency, National Institute of Health stroke scale (NIHSS) scores, daily living ability, coagulation function, serum Lipoprotein-associated phospholipaseA2 (Lp-PLA2), homocysteine (HCY), hypersensitive C-reactive protein (hsCRP) levels, adverse events, and prognosis were evaluated and compared between the two groups.ResultsIntravenous thrombolysis with rt-PA resulted in a better treatment outcome of patients versus aspirin plus clopidogrel (P<0.05). Patients with rt-PA exhibited better improvement in neurological function than those with aspirin plus clopidogrel, as shown by the lower NIHSS scores (P<0.05). Intravenous thrombolysis with rt-PA resulted in a better quality of life of patients than aspirin plus clopidogrel, indicated by the higher Barthel Index (BI) levels (P<0.05). The lower von Willebrand factor (vWF) and Factor VIII (F) levels indicated better coagulation function of patients with rt-PA versus those with aspirin plus clopidogrel (P<0.05). The lower serum concentrations of Lp-PLA2, HCY, and hsCRP suggested patients with rt-PA had milder inflammatory responses versus those without rt-PA (P<0.05). There was no significant difference in the incidence of adverse events in the two groups (P>0.05). Intravenous thrombolytic therapy with rt-PA better enhanced the prognosis of patients than with aspirin plus clopidogrel (P<0.05).ConclusionCompared with conventional pharmacological regimens, additional rt-PA intravenous thrombolytic therapy improves the clinical outcome of patients with acute ischemic stroke, promotes neurological recovery, and enhances patient prognosis without increasing the risk of patient-related adverse events.

Project description:BackgroundIntravenous administration of recombinant tissue plasminogen activator (rt-PA) within 4.5 h of symptom onset is a standard treatment for acute ischemic stroke (AIS). However, certain patients continue to develop unfavorable outcomes despite timely rt-PA therapy. Identifying those at high risk is essential for developing individualized care plans and establishing appropriate follow-up.MethodsThis retrospective study included AIS patients treated with intravenous rt-PA at 0.9 mg/kg at our center. Outcomes at three months were evaluated using the modified Rankin Scale (mRS). Patients with mRS scores ≤2 were considered to have favorable outcomes, and those with scores >2 were considered to have poor outcomes. Univariable analysis and stepwise logistic regression were used to identify independent predictors of poor prognosis, and a nomogram was subsequently developed. The model's discriminative power was assessed with area under the receiver operating characteristic curves (AUC-ROC), and its calibration was examined using calibration plots. Decision curves and clinical impact curves were applied to determine clinical utility.ResultsAmong 392 enrolled patients, 77 had poor outcomes three months after rt-PA therapy. Fibrinogen (Fg), baseline NIHSS, and a history of hypertension emerged as independent predictors of poor prognosis. The nomogram achieved an AUC of 0.948 (95% CI [0.910-0.985]), with sensitivity of 0.900 and specificity of 0.916 in the training dataset, and an AUC of 0.959 (95% CI [0.907-1.000]), with sensitivity of 0.943 and specificity of 0.947 in the validation dataset. Calibration plots demonstrated close agreement between predicted and observed probabilities, and decision curves indicated a wide range of net benefit threshold probabilities.ConclusionsThis nomogram, incorporating baseline NIHSS, Fg, and a history of hypertension, accurately predicts poor three-month outcomes in AIS patients treated with intravenous rt-PA. Its ease of use may facilitate early risk stratification and assist clinicians in formulating more targeted management strategies and follow-up protocols for patients likely to experience unfavorable outcomes.

Dataset Information

Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke.

Publications

Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke.

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