Understanding stroke: Management of acute

Five and a half million survivors of stroke are living in the world today. In the second and final part of the series, K A L Carroll and J Chataway ;explain how to manage this emergency

For many years, preventing and managing stroke involved reducing risk factors before the event, supportive treatment through the event, and then rehabilitation after the event. A number of studies have shown that specialist stroke units for rehabilitation greatly increase functional outcome after stroke compared with standard hospital care.¹ In follow-up studies over eight years, specialist stroke units for rehabilitation significantly improve outcome in terms of length of stay, death or dependence, and long term hospitalisation.²

In addition, the options for treating ischaemic and perhaps haemorrhagic stroke in the acute setting are also rapidly developing, resulting in a better prognosis. Because the guidelines often change, it is important for students and doctors to not only know about what is currently available but also what is in the pipeline.

Haemorrhagic stroke

Currently, there is no definitely effective targeted treatment for haemorrhagic stroke. Computed tomography shows that the growth of intracerebral haemorrhage within the first few hours of onset is common and that this is the principal cause of early neurological deterioration. Haematoma volume is also a well established predictor of 30 day mortality.

A recent trial (the international surgical trial in intracerebral haemorrhage, STICH) showed that early surgery (haematoma evacuation) has no overall benefit when compared with initial conservative treatment for intracerebral haemorrhage.³ But evidence does show that early intervention with haemostatic treatment might improve outcome. Recombinant activated factor VIIa is approved for the treatment of patients with systemic bleeding problems, such as haemophilia; however, it may also promote haemostasis in patients with normal coagulation by acting locally at the bleeding site without activation of systemic coagulation.

In a recent trial of 399 patients treated within four hours of the start of haemorrhagic stroke, subsequent growth of haematomas was about 50% less with recombinant activated factor VII (rFVIIa),⁴ which was associated with a significant absolute reduction (38%) in mortality and improved functional outcomes in survivors. But an excess of "thrombotic" events in the treated group caused concern. A phase III trial is currently in progress (the rFVIIa in acute haemorrhagic stroke treatment trial, FAST).

Ischaemic stroke-current treatment

Aspirin

One current targeted treatment for acute ischaemic stroke is aspirin. Large randomised controlled trials have shown that early treatment with aspirin (within 48 hours) has a modest benefit (about 1% absolute reduction in death and recurrent ischaemic stroke⁵). Although this is important because aspirin is affordable and generally well tolerated, more effective treatments for acute stroke are needed.

Antiplatelet treatment

Many randomised controlled trials have tested the benefits of other antiplatelet treatments, but they have been far too small. A recent systematic review by the Cochrane Collaboration studied data from five trials and showed that antiplatelet therapy was associated with a significant reduction in the odds of being dead or dependent at final follow-up.⁶ The indirect comparisons of different agents in this review showed no evidence of significant heterogeneity of effect between the agents (aspirin alone, ticlopidine alone, abciximab alone, and the combination of aspirin and dipyridamole). But the data from the non-aspirin regimens were limited, and no large scale trials have directly randomised patients with acute stroke between one antiplatelet regimen and another.

The MATCH trial (management of atherothrombosis with clopidogrel (Plavix) in high risk patients with recent transient ischaemic attack or ischaemic stroke), however, showed that aspirin with clopidogrel (Plavix, Bristol-Myers Squibb, Uxbridge, and Sanofi-Synthelabo, Guildford) has no net advantage compared with clopidogrel alone.⁷ Further studies in progress include the PROFESS trial (prevention regimen for effectively avoiding second strokes), which is comparing the efficacy and safety of aspirin and dipyridamole with clopidogrel and of telmisartan with placebo in preventing recurrent stroke. Also a recent phase II trial of intravenous abciximab given within six hours of the start of ischaemic stroke has shown a reasonable degree of safety and efficacy at improving outcome at three months. For this reason a larger trial of the acute use of antiplatelet treatment is needed.⁸

Rehabilitation- an essential part of management

Anticoagulants

Anticoagulants have been considered as potential treatments. But the international stroke trial (IST1) showed that although patients given heparin had significantly fewer recurrent ischaemic strokes within 14 days, this was offset by a similar sized increase in haemorrhagic strokes, and so the difference in death or non-fatal recurrent stroke was not significant.⁹

Immobilised patients who are not receiving anticoagulants, such as intravenous heparin or an oral anticoagulant, might benefit from low doses of subcutaneous unfractionated or low molecular weight heparin, which reduces the risk of deep vein thrombosis in patients at high risk. (Although the CLOTS trial) is currently assessing the use of graduated compression stockings for this purpose.) The use of low molecular weight heparin as treatment for acute ischaemic stroke has not yet been studied adequately.

Thrombolysis

Thrombolysis has been a standard treatment for acute myocardial infarction since the late 1980s, however, recombinant tissue plasminogen activator (rt-PA) was only licensed for acute ischaemic stroke in the United States in 1996, and only granted a restricted licence for use in acute stroke by the European regulatory agency in 2003. The National Institute of Neurological Disorders and Stroke ran the first trial to show evidence of benefit for thrombolysis in patients with stroke.¹⁰ More extensive data have been pooled by a Cochrane systematic review, which shows¹¹:

• Thrombolytic treatment within six hours of ischaemic stroke may reduce the proportion of patients who are dead or dependent at three to six months


• Thrombolytic treatment within three hours of ischaemic stroke may be even more effective in reducing death or dependency


• Thrombolytic treatment given more than six hours after ischaemic stroke increased the odds of death at the end of follow-up at three to six months, particularly due to symptomatic intracranial haemorrhage.


• Recombinant tissue plasminogen activator may be associated with slightly less hazard and more benefit than other thrombolytics (urokinase, streptokinase, and recombinant pro-urokinase), when given up to six hours after stroke, but no trial has directly compared this activator with any other thrombolytic agent.

So evidence shows that thrombolysis may be beneficial in treating stroke in the acute setting (particularly if given within three hours of the event). Further trials that support this include DIAS II (desmoteplase in acute ischaemic stroke trial), which has shown that the thrombolytic desmoteplase given three to nine hours after acute ischaemic stroke is associated with a higher rate of reperfusion and better clinical outcome compared with placebo.¹² Ongoing trials are investigating the effectiveness, including ECASS III (European Centre for Analysis in the Social Sciences, to evaluate efficacy and safety of recombinant tissue plasminogen activator between three and four hours after stroke started) and the third international stroke trial (IST-3) to investigate the safety and efficacy of treatment with recombinant tissue plasminogen activator within six hours of the start of acute ischaemic stroke in a much broader range of patients than studied before.

Ischaemic stroke-research phase treatments

Although recent advances have propelled the management of stroke into the acute setting, current options for treating acute stroke offer only marginal effects. Aspirin gives only a 1% absolute reduction in death and recurrent ischaemic stroke, and thrombolysis (assuming ideal timing) only a net reduction of death and dependency in 5% of patients. Once the damage from a stroke has maximised, little can be done to recover premorbid function. As a result, despite immediate medical attention, many patients still have persistent deficits. So there is a compelling need for effective treatments in acute ischaemic stroke.

Embolectomy

An alternative to thrombolysis for opening intracranial vessels after stroke is mechanical embolectomy (after its use in cardiology). Recently, the use of a novel embolectomy device (a Merci Retriever) to open occluded intracranial large vessels within eight hours of the start of symptoms of stroke has been investigated.¹³ Under x ray guidance, the Merci Retriever is manoeuvred into the carotid artery where it can capture the clot. Recanalisation was achieved in 48% of patients. Clinically significant procedural complications occurred in 7.1% of patients, and symptomatic intracranial haemorrhages were seen in 7.8% of patients. Good neurological outcomes (modified Rankin score at most 2) were more common at 90 days in patients with successful recanalisation compared with patients with unsuccessful recanalisation (46% v 10%), however, and case fatality was less (32% v 54%). This treatment may be particularly appropriate for people ineligible for intravenous tissue plasminogen activator, however, randomised controlled trials are needed.

Stem cell treatments

Stem cell treatments, although still in their infancy, have provided the potential for a novel strategy of reversing the damage caused by stroke. A variety of different cell types have been investigated in rodent models, including an immortalised cell line NT2N,¹⁴ fetal porcine xenotransplants,¹⁵ and bone marrow stromal cells.^16-18 These have shown that the cells can migrate into infarcts, differentiate, and cause some functional improvement. But human trials are currently limited. Studies have mainly focused on neurotransplantation of NT2N cells^{19 20} and fetal porcine cells²¹ in patients with persistent deficits of at least six months, in spite of preclinical trials indicating that maximum benefit is obtained within the first 72 hours after an ischaemic event.²² The time scale is currently being reduced, with a recent trial using intravenous administration of autologous bone marrow stromal cells within 32-61 days,²³ and trials currently being proposed that use autologous bone marrow stromal cells in the acute setting.

Remember that although these new treatments may seem promising, their delivery by health systems worldwide is an obvious problem. They will put a great strain on not only human resources within the systems but also financial resources in an ever more demanding medical market place. So a great deal more work needs to be done before new treatments can be implemented.

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