Established treatments for acute ischaemic stroke

This article reviews the recommended management of patients presenting to accident and emergency departments with acute ischaemic stroke, and focuses on thrombolysis. The review includes initial management, recommended clinical, laboratory, and radiographic examinations. Appropriate general medical care, consisting of monitoring of oxygenation, fever, blood pressure, and blood glucose concentrations are examined. Criteria for thrombolysis with intravenous recombinant tissue plasminogen activator (rt-PA) are discussed. Complications of rt-PA therapy, such as haemorrhagic transformation and angio-oedema, are reviewed. An approach to management of rt-PA complications is outlined. Only a small percentage of acute ischaemic stroke patients meet criteria for rt-PA; therefore, alternative acute treatment strategies are also discussed. Acute medical and neurological complications in stroke patients are analysed, along with recommendations for treatment.     

Intra-arterial thrombolysis in acute ischaemic stroke

Several thrombolytic agents for the treatment of acute ischaemic stroke have been examined; however, to date, only the i.v. administration of recombinant tissue plasminogen activator is licensed in Australia. Although no trials directly comparing intra-arterial and i.v. delivery of thrombolytics exist, intra-arterial thrombolysis has several potential advantages, including angiographic assessment of the thrombus and the site of occlusion and collateral circulation, improved recanalization, and delivery of higher local concentrations of thrombolytic agents and extending the therapeutic time window for treatment. We conducted a retrospective audit of our experience with the use of intra-arterial urokinase to treat acute ischaemic stroke at an Australian tertiary-care hospital between June 1993 and June 2003. We examined time from stroke onset to assessment, computerized tomography scan, cerebral angiography and thrombolysis, anatomical classification of intra-arterial thrombus, rates of symptomatic intracerebral haemorrhage, and clinical outcome at 3 months. We believe that in carefully selected individuals in appropriate centres of expertise, intra-arterial thrombolytic therapy holds great promise.     

Antithrombotic treatments in acute ischemic stroke

Ischemic stroke results most commonly from cerebral arterial thrombosis. Antithrombotic agents can reduce the incidence of cerebral embolic events or the extent of tissue injury and neurological outcome. The antiplatelet agents aspirin, ticlopidine, and the combination of dipyridamole and aspirin are associated with a significant reduction in second focal cerebral ischemic events. Oral anticoagulants have a role to reduce the incidence of cardiogenic emboli in patients with mechanical cardiac valves or nonvalvular atrial fibrillation. Both antithrombotics are untested in the acute setting. The recombinant tissue plasminogen activator rt-PA has been shown to significantly increase the number of stroke patients with no or minimal deficit when treated within 3 hours of symptom onset. Additional studies of this and other plasminogen activators by both intravenous and intra-arterial delivery have highlighted limitations to this approach, but also support its role in acute intervention. The risk of intracerebral hemorrhage attends the use of all antithrombotic agents, most notably plasminogen activators. Strategies to decrease this risk are likely to add to beneficial outcome.     

Advances in endovascular treatment of acute ischaemic stroke

Over the past decade, there have been rapid advancements in ischaemic stroke reperfusion treatments. However, clear clinical benefit is yet to be shown in large clinical trials. In this review, the major studies in different types of endovascular treatments including intra‐arterial thrombolysis, aspiration devices, mechanical clot retrievers and the new stent retrievers are discussed. First‐generation mechanical thrombectomy devices such as the MERCI Retriever (Stryker, Kalamazoo, MI, USA) and Penumbra aspiration device (Penumbra Inc., Alameda, CA, USA) demonstrated safety and higher rates of recanalisation in the MERCI and Penumbra Pivotal Stroke Trial; however, there was no significant improvement in clinical outcome. Second‐generation endovascular stent retrieval devices Solitaire (ev3 Neurovascular, Irvine, CA, USA) and Trevo (Stryker) have shown promising results. In preliminary trials, SOLITAIRE with the Intention for Thrombectomy (SWIFT) and Thrombectomy Revascularization of Large Vessel Occlusions (TREVO), both showed rates of recanalisation close to 90% and significantly improved clinical outcomes compared with the MERCI study, but the recent landmark studies for endovascular treatment (Interventional Management of Stroke (IMS III), Mechanical Retrieval and Recanalisation of Stroke Clots Using Embolectomy (MR‐RESCUE) and SYNTHESIS) did not show any clinical benefit from endovascular treatment compared with standard intravenous therapy. However, moving forward, the recent Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR‐CLEAN) study results have shown marked improvements in recanalisation, reperfusion and functional outcome in patients receiving endovascular treatment (97% using stent retrievers) within 6 h in addition to standard medical care. Overall, although evidence regarding the efficacy of endovascular treatment in acute stroke has been equivocal, recent publications of large multicentre randomised controlled trials indicate benefit of intra‐arterial stent retriever reperfusion in patients selected by appropriate imaging and treated early by experienced operators, and it will likely remain an important adjunct to established medical treatment with intravenous tPA.     

Osteoprotegerin concentrations and prognosis in acute ischaemic stroke

Abstract. Jensen JK, Ueland T, Atar D, Gullestad L, Mickley H, Aukrust P, Januzzi JL (Odense University Hospital, Denmark; Rikshospitalet, Oslo, Norway; Massachusetts General Hospital, USA). Osteoprotegerin concentrations and prognosis in acute ischaemic stroke. J Intern Med 2010; 267 : 410–417. Aim. Concentrations of osteoprotegerin (OPG) have been associated with the presence of vascular and cardiovascular diseases, but the knowledge of this marker in the setting of ischaemic stroke is limited. Methods and results. In 244 patients with acute ischaemic stroke (age: 69 ± 13 years), samples of OPG were obtained serially from presentation to day 5. Patients with overt ischaemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all‐cause mortality as the sole end‐point. Multivariable predictors of OPG values at presentation included haemoglobin (T = ?2.82; P = 0.005), creatinine (T = 4.56; P < 0.001), age (T = 9.66; P < 0.001), active smoking (T = 2.25; P = 0.025) and pulse rate (T = 3.23; P = 0.001). At follow‐up 72 patients (29%) had died. Patients with OPG ≤2945 pg mL^?1 at baseline had a significantly improved survival rate on univariate analysis (P < 0.0001); other time‐points did not add further prognostic information. In multivariate analysis, after adjustment for age, stroke severity, C‐reactive protein levels, troponin T levels, heart and renal failure concentrations of OPG independently predicted long‐term mortality after stroke (adjusted hazard ratio, 2.3; 95% CI: 1.1 to 4.9; P = 0.024). Conclusion. Osteoprotegerin concentrations measured at admission of acute ischaemic stroke are associated with long‐term mortality.     

Inflammatory markers and in-hospital mortality in acute ischaemic stroke

BACKGROUND: There is substantial evidence that cerebral ischaemia triggers an inflammatory response. We examined the short-term prognostic value on mortality of C-reactive protein (CRP), interleukin-6 (IL-6) and serum amyloid A (SAA) in patients with ischaemic stroke. METHODS: We recruited 203 consecutive patients, under the age of 66 years (mean age=54.2+/-8.1 years, men=132) who admitted to the Neurology Department with the diagnosis of non-haemorrhagic stroke. Patients in atrial fibrillation or with evidence of inflammatory or malignant disease were excluded. The diagnosis was confirmed with a computed tomography or magnetic resonance imaging of the brain within 24h of admission. CRP, IL-6 and SAA levels were determined within 12h from admission. RESULTS: Fourteen (6.9%) patients died during hospitalization. Serum concentrations of CRP, IL-6 and SAA were significantly higher in patients who died compared with those who survived and were independently associated with early death, after adjusting for various confounding factors. For one unit increase in IL-6, CRP and SAA there was an 18%, 14% and 9% higher risk of dying during hospitalization, respectively. Comparisons of the areas under the ROC curve showed that IL-6 had the best predictive ability. Age-adjusted cut-off point analysis showed that IL-6 levels >13 pg/ml were the optimal point that discriminated those who died from the rest of the patients (sensitivity=85% and specificity=93%). CONCLUSIONS: We demonstrated that in-hospital mortality in ischaemic stroke is associated with an exacerbation of inflammatory response as it is reflected by the higher serum levels of IL-6, CRP and SAA. From the inflammatory markers high IL-6 levels had the strongest independent predictive value for in-hospital mortality.     

Management of acute ischaemic stroke in patients with dementia

An estimated 10% of stroke patients have an underlying dementia. As a consequence, health professionals often face the challenge of managing patients with dementia presenting with an acute stroke. Patients with dementia are less likely to receive thrombolysis (0.56–10% vs. 1–16% thrombolysis rates in the general population), be admitted to a stroke unit or receive some types of care. Anticoagulation for secondary stroke prevention is sometimes withheld, despite dementia not being listed as an exclusion criterion in current guidelines. Studies in this population are scarce, and results have been contradictory. Three observational studies have examined intravenous thrombolysis for treatment of acute ischaemic stroke in patients with dementia. In the two largest matched case–control studies, there were no significant differences between patients with and without dementia in the risks of intracerebral haemorrhage or mortality. The risk of intracerebral haemorrhage ranged between 14% and 19% for patients with dementia. Studies of other interventions for stroke are lacking for this population. Patients with dementia are less likely to be discharged home compared with controls (19% vs. 41%) and more likely to be disabled (64% vs. 59%) or die during hospitalization (22% vs. 11%). The aim of this review was to summarize current knowledge about the management of ischaemic stroke in patients with pre‐existing dementia, including organizational aspects of stroke care, intravenous thrombolysis, access to stroke unit care and use of supportive treatment. Evidence to support anticoagulation for secondary prevention of stroke in patients with atrial fibrillation and antiplatelet therapy in nonembolic stroke will be discussed, as well as rehabilitation and how these factors influence patient outcomes. Finally, ethical issues, knowledge gaps and pathways for future research will be considered.