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Thrombolytic therapy for stroke
  1. Martin Brown

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    Edited by Patrick D Lyden (Pp 398, US$125.00). Published by Humana Press, New Jersey, 2001. ISBN 0-896-03746-0

    The end of the 20th century saw a transition in the approach to acute stroke from therapeutic nihilism to enthusiasm. Stroke is now seen as an emergency, warranting urgent assessment, investigation, and treatment. The positive results of the major randomised trial of thrombolysis in acute stroke have played a major part in stimulating this new approach, which is the topic of this publication. This is very much a hands on book, with much practical advice, ranging from detailed advice about the assessment and selection of patients for thrombolysis to how to set up and deliver an emergency service for stroke. The book ranges from a detailed description of the evidence from clinical trials to advice based on personal experience (for example, what questions to ask to determine the time of onset accurately).

    The book starts with a review of the pharmacology and haematology of thrombolysis, the causes of ischaemic stroke, and a description of the ischaemic penumbra. The last is the holy grail of thrombolysis and refers to the concept that a portion of ischaemic brain can be salvaged before undergoing irreversible infarction if treatment can be started early. As becomes evident on reading further, the evidence from the thrombolysis trials suggests that ischaemic penumbra is rarely present for longer than 2 or 3 hours after the onset of stroke. The book then proceeds to an excellent account of the early trials of thrombolysis. These included only a few patients, but the results show the thinking behind some of the protocol requirements proposed for the safe use of thrombolysis. Streptokinase proved to have a very high rate of haemorrhage and was abandoned. By contrast, early studies of recombinant tissue plasminogen activator (rt-PA) were more encouraging. It was certainly a surprise to read that the first attempt to treat stroke using thrombolysis in three patients was in 1958 and that there were another 30 case series before the larger randomised trials were started. The results of the randomised National Institute of Neurological Diseases and Stroke (NINDS) Trial are described in detail. The positive results of this trial led to the licensing of rt-PA for acute stroke in the United States. The two ECASS trials conducted in Europe, in which the primary analyses were neutral, are dismissed in a few paragraphs because they primarily randomised patients within 6 hours and included very few patients within 3 hours of onset. Given the detailed discussion of each of the trials, it is surprisingly that the book does not include a meta-analysis putting together the results of the different trials, but others have done so in reviews and confirmed that there seems to be benefit in patients treated under 3 hours, with an unproved trend to benefit in patients treated from 3 to 6 hours. Nevertheless, the uncertainty about the interpretation of the different results from the trials of rt-PA in North America and Europe is probably the main reason which has prevented rt-PA from receiving a licence for acute stroke in Europe.

    Most of the studies have concentrated on intravenous thrombolysis. Intra-arterial thrombolysis has the advantage of being able to confirm and target the site of persistent arterial occlusion and might reduce the risk of systemic complications, but not necessarily cerebral haemorrhage. The evidence for arterial thrombolysis in stroke is reviewed in a separate chapter and strongly suggests that treatment in selected patients is beneficial up to 6 hours from onset. However, the requirements for an instantly available interventional neuroradiology team limit its applicability to only a few centres.

    It is essential to be able to recognise the early changes of cerebral infarction on CT if thrombolysis is to be used safely and an excellent chapter follows on the techniques and interpretation of CT in acute stroke. However, there is no mention of the role of MR or new imaging techniques such as diffusion weighted imaging. The book concludes withsome interesting case history vignettes, illustrated by the relevant CT, inviting the reader to decide whether or not to thrombolyse the patient. Most cases receive thrombolysis, sometimes outside the NINDS protocol recommended elsewhere in the book, but the cases illustrate the need for detailed and rapid assessment of every patient.

    This book is clearly primarily directed at the North American market, where intravenous thrombolysis is a licensed treatment for stroke. For example, one chapter is entitled “How to run a code stroke”. The term code stroke was a new term to me and was not explained, but it soon transpired that the chapter provided detailed information on how to organise emergency services and respond to the arrival of an acute stroke, so that treatment with rt-PA can be started within the vital 3 hours.

    If there is a criticism of this book, it is that it lacks balance despite the best of efforts of the authors. The benefits of thrombolysis are taken as proved and dramatic, although the fact that some experts are less enthusiastic is acknowledged. Lou Caplan was invited to contribute a chapter arguing against thrombolysis for stroke, but it is clear that by the time he came to write the chapter he was thoroughly in favour of thrombolysis, although he does argue for proper investigation before selection of patients. The disadvantages of concentrating on thrombolysis for stroke receive scant attention. For example, there is no mention of the problem of diversion of resources away from other patients with stroke, or the importance of developing comprehensive stroke services before introducing thrombolysis. Nowhere could I find mention of the importance of the numbers needed to treat for benefit or harm (about eight and 16 respectively) or of the fact that only a small proportion of patients admitted to hospital with stroke are eligible for thrombolysis in the first place (4% in the NINDS study), although there is a chapter with very detailed calculations on the cost effectiveness of rt-PA treatment in the American setting. The book would certainly have been more balanced if contributions had been included describing the European perspective—for instance, from the Cochrane collaboration or from one of the organisers of the International Stroke Trial 3, which plans to re-examine the risks and benefits of intravenous thrombolysis from 0 to 6 hours.

    My criticisms are minor and the book is highly recommended as a guide to current practice for those contemplating introducing thrombolysis into their clinical practice. This will require education of the community, doctors, and emergency services to regard stroke as a “brain attack” requiring urgent admission to a specialised unit. The introduction of thrombolysis has an important influence on the way stroke is perceived. Although only a small proportion of patients benefit directly from thrombolysis, many more benefit from the earlier assessment and care by a specialised team that is an essential component of providing the rapid response needed for thrombolysis. Intravenous thrombolysis is an important advance in stroke treatment, which deserves to be more widely implemented in centres with the appropriate facilities and experience.

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