Drug treatment for acute ischaemic stroke

teaser

Nils Gunnar Wahlgren
MD PhD
Head of Stroke Research
E:[email protected]

Ahmed Niaz
MD MPH
Stroke Research Fellow
Stroke Research Unit
Department of Neurology
Karolinska Hospital
Stockholm
Sweden
E:[email protected]

Stroke is not only the third leading cause of death in Western Europe but also a major of cause of neurological disability. About 85% of strokes are ischaemic, and the remainder are haemorrhagic.(1) The overall case-fatality of patients with first ever ischaemic stroke is about 15% at 30 days and 30% at one year. The overall risk of recurrence of stroke after first-ever ischaemic stroke is 4% at 30 days and 12% at one year.(2) The burden of stroke on society is huge; the annual estimated total costs (direct and indirect) for stroke in Europe were approximately €25 billion in 1998 and could increase by 30% over the next 10 years.(3)

Stroke unit care
Stroke unit care uses a multidisciplinary team approach to manage stroke patients in a dedicated ward, with a specially educated team aiming at early mobilisation and active and targeted rehabilitation. Stroke unit care, when compared with alternative services, reduces the odds of death by 14%, death or institutionalised care by 20%, and death or
dependency by 22% at one year.(4)

Several factors or treatment strategies may contribute to the beneficial effect of stroke unit care, including:

• Early detection and prompt treatment of factors that may aggravate cerebral damage in the ischaemic brain (ie, hypoxia, hyperglycaemia, hypotension, cardiac arrhythmias and elevated body temperature).
• Prompt identification and treatment of common complications of stroke (eg, deep venous thrombosis, pulmonary embolism and pneumonia).
• Systematic assessment of dysphagia that may reduce the risk of aspiration and subsequent chest infections, and more aggressive management of infections.

Thrombolysis
The major cause of ischaemic stroke is the blockage of an artery in the brain by thromboembolism. Reperfusion by dissolving the thrombus with thrombolytic drugs may reduce brain damage, hence thrombolytic agents have been evaluated in several randomised controlled trials (RCTs) in acute ischaemic stroke. Alteplase, an intravenous recombinant tissue plasminogen activator (rt-PA), has been approved in the USA, Canada, Brazil and Germany for use within 0–3 hours of stroke onset. It is also recently licensed in EU countries, and after three years the EMEA will consider the continued licence of alteplase based on the outcome of two postlaunch clinical studies. One is the SITS-MOST (Safe Implementation of Thrombolysis in Stroke Monitoring Study), an observational cohort study of outcome (safety and efficacy), and the other the European Cooperative Acute Stroke Study–3 (ECASS-III), an RCT that will further explore the therapeutic treatment window, measuring outcome in patients in whom treatment can be given only 3–4 hours following stroke onset.(5)

The National Institute of Neurologic Disorders and Stroke (NINDS) trial is the only RCT that has clearly demonstrated beneficial effects of intravenous thrombolysis (within three hours) for treatment of acute stroke.(6) The recently published ATLANTIS (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke) substudy, in which 61 patients received thrombolysis within three hours, also showed a favourable outcome compared with placebo (p=0.01).(7) Moreover, pooled analysis of six randomised rt-PA trials, meta-analyses and postapproval data supported the use of thrombolysis within three hours. Table 1 shows the results of a recent systematic review of rt-PA trials in acute ischaemic stroke.(8)

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According to meta-analyses of ischaemic stroke patients treated with IV rt-PA within three hours, approximately 1 more in every 10 patients will be independent, 1 in 22 will suffer symptomatic haemorrhage and 1 in 100 fewer may die as a result of the treatment.

A benefit of thrombolysis beyond three hours after stroke could not be clearly demonstrated in any single RCTs (ECASS I, ECASS II and ATLANTIS).(9–11) However, the pooled analysis of the 2,776 patients of the ATLANTIS, ECASS and NINDS rt-PA trials suggests benefit up to four-and-a-half hours after the onset of an ischaemic stroke, although the treatment effect decreases with the time.(12)

Neuroprotection
In the acute stage of occlusive stroke, moderate reduction of blood flow results in a penumbra of neurons, often surrounding a core infarct, in which brain cells survive for a few hours but gradually die if reperfusion is not established. The concept of neuroprotection involves protecting the brain from pathological damage by inhibition of a cascade of molecular events occurring under ischaemia in the penumbra zone, which would otherwise lead to calcium influx, activation of free-radical reactions and cell death. Increased knowledge of the complex pathophysiology in acute ischaemic stroke has led to the development of a great number of candidate drugs for neuroprotective interventions. Many neuroprotective agents have proven efficacious in animal models, but no human study has shown a statistically significant benefit in patients with acute ischaemic stroke on primary endpoint measures. Some neuroprotective agents show a beneficial effect in post-hoc analyses (eg, citicoline and piracetam), and others are still in clinical development, including(13):

• Magnesium and CP-101,606 (noncompetitive NMDA antagonists).
• YM872 (AMPA antagonist).
• Diazepam (GABA agonist).
• Bay x 3072 (serotonin agonist).
• BMS-204352 (potassium channel opener).
• NXY-059 (free-radical scavenger).

Conclusion
Alteplase is now approved for routine clinical use to treat ischaemic stroke patients. However, continuous education and safety monitoring are needed to guarantee the safe and efficient use of thrombolysis.

The three-hour time window is the major limiting factor preventing wider application of thrombolysis in ischaemic stroke. Future trials such as ECASS III, IST-3 (International Stroke Trial) and EPITHET (Evaluating diffusion/perfusion mismatch as a guide to rt-PA treatment) may succeed in widening the treatment window, and combined thrombolysis and neuroprotective agent trials such as ARTIST (AMPA Receptor Antagonist Treatment in Ischemic Stroke Trial) may demonstrate both an increase in efficacy and a wider treatment window.

References

1. Bamford J, Sandercock P, Dennis M, et al. Lancet 1991;337:1521-6.
2. Petty GW, Brown RD, Jr, Whisnant JP, et al. Neurology 1998;50:208-16.
3. Swedish National Board of Health and Welfare. National guidelines for stroke care. 2000.
4. Stroke Unit Trialists’ Collaboration. Organised inpatient (stroke unit) care for stroke (Cochrane Review). In: The Cochrane Library. Issue 1. Oxford: Update Software; 2003.
5. Press release. Europe-wide launch of first treatment for acute ischaemic stroke. Available from URL: http://www.boehringer-ingelheim.com/stroke/.
6. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-7.
7. Albers GW, Clark WM, Madden KP, Hamilton SA. Stroke 2002;33:493-5.
8. Wardlaw JM. An updated systematic review of rt-PA in acute ischaemic stroke. In: Wahlgren NG, Ahmed A, Hårdemark HG, editors. Update on stroke therapy 2002–2003. Stockholm: Karolinska Stroke Update; 2003.
9. Clark WM, Wissman S, Albers GW, et al. JAMA 1999;282:2019-26.
10. Hacke W, Kaste M, Fieschi C, et al. JAMA 1995;274:1017-25.
11. Hacke W, Kaste M, Fieschi C, et al. Lancet 1998;352:1245-51.
12. Consensus statements on thrombolysis. Karolinska Stroke Update; 2002 Nov 11–12; Stockholm, Sweden. Available from URL: http://www.stroke-update.org
13. Internet Stroke Center. Washington University School of Medicine. Available from URL:http://www.strokecenter.org/trials/index_cats.htm.

Resources and events
Karolinska Stroke Update
W:www.strokeupdate.org
SITS International
Stroke Thrombolysis Collaboration
W:www.acutestroke.org
European Stroke Initiative
W:http://eusi-stroke.org/index.shtml
Internet Stroke Center
Independent web resource for information about stroke care and research
W:www.strokecenter.org
European Stroke Conference
Valencia, Spain
21–24 May 2003
W:www.eurostroke.org