Treatments in Ischemic Stroke: Current and Future.

BACKGROUND AND AIM: Despite progress made over the last 30 years, stroke is still a leading cause of disability and mortality; likewise, its burden is expected to increase over the next decades, due to population growth and aging. The development of drugs with better safety-efficacy profiles as well as strategies able to improve ischemic stroke management from the pre-hospital setting is needed. SUMMARY: The pathophysiology of ischemic stroke involves multiple pathways resulting in cerebral artery obstruction and brain tissue ischemia. To date, the only approved drug for acute ischemic stroke is intravenous thrombolytic alteplase. Intravenous thrombolysis (IVT) can be administered alone or in combination with endovascular treatment (EVT) with mechanical thrombectomy, in case of large vessel occlusion and generally within 6 h from symptoms onset. The risk of potential bleeding complications, especially symptomatic intracerebral hemorrhage, is one of the reasons for the reluctance to administer IVT. Tenecteplase is a promising alternative fibrinolytic agent, having a better safety profile than alteplase. Moreover, recent evidences have allowed an extension of the IVT ± EVT time window for patients with unknown onset time and for those with a known onset time thanks to the new "tissue-window" approach guided by advanced neuroimaging techniques, which also helps in collateral circulation estimation. Regarding primary-secondary prevention, researchers are focused on improving the efficacy of antithrombotic drugs with a "hemostasis-sparing" approach. Neuroprotective agents are also under development, particularly stem cells. The COVID-19 pandemic has critically stressed global healthcare systems, with collateral damage resulting in access delivery of only emergency care, such as ischemic stroke. Regarding telemedicine, it has had a minor role in acute stroke management, and with the onset of COVID-19, this role will most likely be adopted to increase access and delivery in stroke assessment, but also in the follow-up.

The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1.

BACKGROUND: Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system. METHODS: This prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor-1 (PAI-1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy. RESULTS: PAI-1 and its cofactor, vitronectin, are significantly elevated in patients with COVID-19 disease compared with those with non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID-19 disease relative to healthy controls. PAI-1 and tissue plasminogen activator (tPA) were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant (tPA) variant, tenecteplase, over alteplase lysis. CONCLUSION: This study shows that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the possibility of using pre-existing drugs, such as tenecteplase, to treat COVID-19 disease and potentially other respiratory diseases.

Tenecteplase use in the management of acute ischemic stroke: Literature review and clinical considerations.

PURPOSE: Several research articles have been published within the last decade comparing the use of tenecteplase to alteplase in ischemic stroke management. Prior reporting on the comparative therapeutic efficacy and safety profiles of tenecteplase and alteplase is reviewed. SUMMARY: Tenecteplase is a variant of native tissue-type plasminogen activator, which rapidly promotes thrombolysis by catalyzing formation of the serine protease plasmin. Tenecteplase has theoretical advantages over alteplase as it has greater fibrin specificity and has a longer half-life than alteplase. This allows the administration of a single bolus over 5 to 10 seconds, as opposed to a bolus followed by a 1-hour infusion with alteplase. While currently approved by the Food and Drug Administration for the treatment of ST-segment elevation myocardial infarction, tenecteplase has also been studied in the treatment of acute ischemic stroke and has extensive data for this off-label indication. The most comprehensive trials to date evaluating the use of tenecteplase in acute ischemic stroke include the TNK-S2B, Australian TNK, ATTEST, Nor-Test, and EXTEND-IA TNK trials. Findings from these randomized controlled studies suggest that tenecteplase is at least as efficacious as alteplase in terms of neurological outcomes. The majority of these studies also reported a trend toward improved safety profiles with the use of tenecteplase. CONCLUSION: Current clinical evidence shows that tenecteplase is not inferior to alteplase for the treatment of ischemic stroke and suggests that tenecteplase may have a superior safety profile. Furthermore, tenecteplase also has practical advantages in terms of its administration. This can potentially lead to a decrease in medication errors and improvement in door to thrombolytic time.