All prior drug development programs of neuroprotective agents were unsuccessful for a variety of reasons related to both preclinical assessment and the design/implementation of clinical trials. The ...neuroprotection hypothesis of improving functional outcome related to salvaging ischemic brain tissue is strongly supported by robust preclinical data for many agents. In the future, monotherapy neuroprotection trials will be difficult but could be performed in underused centers with drugs that have very promising and complete preclinical results. Additional approaches for the testing and use of neuroprotective agents should be considered. Novel approaches would include extending penumbral survival for the later use of reperfusion therapy, reducing reperfusion injury after successful reperfusion, and using drugs with both neuroprotective and recovery enhancing effects, as exemplified by granulocyte colony-stimulating factor and citicoline. To maximize outcome after stroke, the combined use or reperfusion and neuroprotection is likely to be needed, so we must begin to perform carefully designed trials with this combination.
The treatment of acute ischemic stroke has undergone dramatic changes recently subsequent to the demonstrated efficacy of intra-arterial (IA) device-based therapy in multiple trials. The selection of ...patients for both intravenous and IA therapy is based on timely imaging with either computed tomography or magnetic resonance imaging, and if IA therapy is considered noninvasive, angiography with one of these modalities is necessary to document a large-vessel occlusion amenable for intervention. More advanced computed tomography and magnetic resonance imaging studies are available that can be used to identify a small ischemic core and ischemic penumbra, and this information will contribute increasingly in treatment decisions as the therapeutic time window is lengthened. Intravenous thrombolysis with tissue-type plasminogen activator remains the mainstay of acute stroke therapy within the initial 4.5 hours after stroke onset, despite the lack of Food and Drug Administration approval in the 3- to 4.5-hour time window. In patients with proximal, large-vessel occlusions, IA device-based treatment should be initiated in patients with small/moderate-sized ischemic cores who can be treated within 6 hours of stroke onset. The organization and implementation of regional stroke care systems will be needed to treat as many eligible patients as expeditiously as possible. Novel treatment paradigms can be envisioned combining neuroprotection with IA device treatment to potentially increase the number of patients who can be treated despite long transport times and to ameliorate the consequences of reperfusion injury. Acute stroke treatment has entered a golden age, and many additional advances can be anticipated.
For several years, the only therapy with proven efficacy for acute ischaemic stroke was alteplase, which is approved for use within 4·5 h after stroke onset in many countries, but only within 3 h in ...the USA. However, the recanalisation rate with alteplase is modest. Several trials have shown substantial clinical benefit of neurothrombectomy within 6 h of ischaemic stroke onset, which has initiated a new era of acute stroke therapy. As neurothrombectomy becomes part of standard practice, additional trials will be needed to determine the best way to organise delivery of this care. Continuing clinical trials with several types of advanced MRI and CT imaging to enhance patient selection are investigating alteplase, other thrombolytic drugs, and novel endovascular devices, for use in later time periods from stroke onset. Consequently, the organisation and implementation of future clinical trials will need to adapt to what has been learned from the present generation of trials. The delivery of care to patients with acute stroke will also need to incorporate newly proven therapies, and much additional work is needed to maximise outcomes in as many patients as possible.
For over 40 years, attempts to develop treatments that protect neurons and other brain cells against the cellular and biochemical consequences of cerebral ischaemia in acute ischaemic stroke (AIS) ...have been unsuccessful. However, the advent of intravenous thrombolysis and endovascular thrombectomy has taken us into a new era of treatment for AIS in which highly effective reperfusion therapy is widely available. In this context, cytoprotective treatments should be revisited as adjunctive treatment to reperfusion therapy. Renewed efforts should focus on developing new drugs that target multiple aspects of the ischaemic cascade, and previously developed drugs should be reconsidered if they produced robust cytoprotective effects in preclinical models and their safety profiles were reasonable in previous clinical trials. Several development pathways for cytoprotection as an adjunct to reperfusion can be envisioned. In this Review, we outline the targets for cytoprotective therapy and discuss considerations for future drug development, highlighting the recent ESCAPE-NA1 trial of nerinetide, which produced the most promising results to date. We review new types of clinical trial to evaluate whether cytoprotective drugs can slow infarct growth prior to reperfusion and/or ameliorate the consequences of reperfusion, such as haemorrhagic transformation. We also highlight how advanced brain imaging can help to identify patients with salvageable ischaemic tissue who are likely to benefit from cytoprotective therapy.
BACKGROUND AND PURPOSE:When the coronavirus disease 2019 (COVID-19) outbreak became paramount, medical care for other devastating diseases was negatively impacted. In this study, we investigated the ...impact of the COVID-19 outbreak on stroke care across China.
METHODS:Data from the Big Data Observatory Platform for Stroke of China consisting of 280 hospitals across China demonstrated a significant drop in the number of cases of thrombolysis and thrombectomy. We designed a survey to investigate the major changes during the COVID-19 outbreak and potential causes of these changes. The survey was distributed to the leaders of stroke centers in these 280 hospitals.
RESULTS:From the data of Big Data Observatory Platform for Stroke of China, the total number of thrombolysis and thrombectomy cases dropped 26.7% (P<0.0001) and 25.3% (P<0.0001), respectively, in February 2020 as compared with February 2019. We retrieved 227 valid complete datasets from the 280 stroke centers. Nearly 50% of these hospitals were designated hospitals for COVID-19. The capacity for stroke care was reduced in the majority of the hospitals. Most of the stroke centers stopped or reduced their efforts in stroke education for the public. Hospital admissions related to stroke dropped ≈40%; thrombolysis and thrombectomy cases dropped ≈25%, which is similar to the results from the Big Data Observatory Platform for Stroke of China as compared with the same period in 2019. Many factors contributed to the reduced admissions and prehospital delays; lack of stroke knowledge and proper transportation were significant limiting factors. Patients not coming to the hospital for fear of virus infection was also a likely key factor.
CONCLUSIONS:The COVID-19 outbreak impacted stroke care significantly in China, including prehospital and in-hospital care, resulting in a significant drop in admissions, thrombolysis, and thrombectomy. Although many factors contributed, patients not coming to the hospital was probably the major limiting factor. Recommendations based on the data are provided.
Stroke remains the second-leading cause of death and the third-leading cause of death and disability combined (as expressed by disability-adjusted life-years lost – DALYs) in the world. The estimated ...global cost of stroke is over US$721 billion (0.66% of the global GDP). From 1990 to 2019, the burden (in terms of the absolute number of cases) increased substantially (70.0% increase in incident strokes, 43.0% deaths from stroke, 102.0% prevalent strokes, and 143.0% DALYs), with the bulk of the global stroke burden (86.0% of deaths and 89.0% of DALYs) residing in lower-income and lower-middle-income countries (LMIC). This World Stroke Organisation (WSO) Global Stroke Fact Sheet 2022 provides the most updated information that can be used to inform communication with all internal and external stakeholders; all statistics have been reviewed and approved for use by the WSO Executive Committee as well as leaders from the Global Burden of Disease research group.
Reperfusion therapy for acute stroke has evolved from the initial use of intravenous tissue plasminogen activator (tPA) within 3 hours of symptom onset to more recent guideline‐recommended use up to ...4.5 hours. In addition, endovascular therapy is increasingly utilized for stroke treatment and is typically initiated up to 8 hours after onset. Recent studies demonstrate that imaging of the ischemic penumbra with diffusion/perfusion magnetic resonance imaging (MRI) can identify subgroups of patients who are likely to improve following successful reperfusion (Target Mismatch profile) and others who are at increased risk for hemorrhage and poor clinical outcomes (Malignant profile). New data indicate that stent retriever devices provide better recanalization efficacy and clinical outcomes than the previously available mechanical thrombectomy devices. Going forward, we believe that the use of penumbral imaging with validated MRI techniques, as well as the currently less well‐validated computed tomography (CT) perfusion approach, will maximize benefit and reduce the risk of adverse events and poor outcomes when used both early after stroke onset and at later time points. New trials that feature diffusion/perfusion MRI or CT perfusion‐based patient selection for treatment with intravenous tPA and or endovascular therapies versus nonreperfused control groups are planned or in progress. We predict that these trials will confirm the hypothesis that penumbral imaging can enhance patient selection and extend the therapeutic time window for acute ischemic stroke. ANN NEUROL 2013.
The concept of neuroprotective therapy for acute ischemic stroke to salvage tissue at risk and improve functional outcome is based on sound scientific principles and extensive preclinical animal ...studies demonstrating efficacy. The failure of most neuroprotective drugs in clinical trials has been due to inadequate preclinical testing and flawed clinical development programs. The Stroke Therapy Academic Industry Roundtable (STAIR) group has outlined rational approaches to preclinical and clinical studies. The positive results from the first Stroke‐Acute‐Ischaemic‐NXY‐Treatment (SAINT‐I) trial of the free‐radical spin‐trap drug, NXY‐059, which followed many of the STAIR guidelines, reinvigorated enthusiasm in neuroprotection, but the SAINT‐II trial did not replicate the positive effect on the same primary prespecified outcome measure. This has led to concerns about the future of neuroprotection as a therapeutic strategy for acute ischemic stroke. We discuss new suggestions to bridge the chasm between preclinical animal modeling and acute human stroke trials to potentially enhance the future assessment of novel neuroprotective drugs. Ann Neurol 2007
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