Treating acute ischaemic stroke with thrombolytics

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Carole Mongin-Bulewski
PhD
Editor
Hospital Pharmacy Europe

Stroke is the third leading cause of death in western Europe after myocardial infarction and cancer, and it is the leading cause of permanent disability and disability-adjusted loss of independent life-years. 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, with annual estimated total costs (direct and indirect) in Europe of approximately €25 billion in 1998, and costs could increase by 30% over the next 10 years.(3)

Stroke units
Over recent years, there has been considerable improvement in the active care of stroke patients, leading to fewer deaths and less disability for patients who survive. This is because stroke units use 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.

Pharmacists can make a significant contribution to this multidisciplinary team, both in the acute and in the rehabilitation phases. The different roles of the pharmacist in a stroke unit can include:(4)

• Checking compliance with evidence-based medicine guidelines.
• Monitoring newly prescribed and existing drug     therapies.
• Giving advice on the correct management of stroke complications.
• Counselling patients, both through verbal advice and written medication information.
• Assessing potential compliance and concordance problems.
• Liaising with general practitioners and community pharmacists on discharge.
• Liaising with patient support groups.

Drug treatments
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. Thrombolytic agents have been evaluated in several randomised controlled trials (RCTs) in acute ischaemic stroke. Alteplase (Actilyse(®)), an intravenous (IV) recombinant tissue plasminogen activator (rt-PA), has been approved in the USA, Canada, Brazil and Germany for use within zero to three hours of stroke onset. It is also licensed in EU countries. However, the EMEA called for two postlaunch clinical studies, as concerns were raised about safety and efficacy in the RCTs. The SITS-MOST (Safe Implementation of Thrombo­lysis in Stroke Monitoring Study) is an observational cohort study of outcome (safety and efficacy), and the European Cooperative Acute Stroke Study 3 (ECASS 3) is an RCT that will explore further the therapeutic treatment window. The original study design for the latter trial specified that outcomes should be measured in patients in whom treatment was given three to four hours following stroke onset.(5)

RCTs
The National Institute of Neurologic Disorders and Stroke (NINDS) trial is the only RCT to have clearly demonstrated the beneficial effects of IV ­thrombolysis (within three hours) for treatment of acute stroke.(6) The 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) In addition, pooled analysis of six randomised rt-PA trials, meta-analyses and post‑approval data supported the use of ­thrombolysis within three hours.(8)

According to meta-analyses of ischaemic stroke in patients treated with IV rt-PA within three hours, approximately one more in every 10 patients will be independent, one in 22 will suffer symptomatic ­haemorrhage and one 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 RCT (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 4.5 hours after the onset of an ischaemic stroke, although the treatment effect decreases with time.(12,13)

Recruitment into ECASS 3 was slow due to the difficult time window, with only 206 of the planned 800 patients recruited by the end of May 2005. The design of the study has recently been changed, with the time window being prolonged to 4.5 hours.

Conclusion
Although alteplase is approved for routine clinical use to treat ischaemic stroke patients, 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 3 may succeed in widening the treatment window.

References

1. Schellinger PD, Kaste M, Hacke W. Curr Opin Neurol 2004;17:69-77.
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.
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5. Treatment of Acute Ischaemic Stroke. Available from: http://www.actilyse.com
6. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-7.
7. Albers GW, Clarck 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.
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11. Hacke W, Kaste M, Fieschi C, et al. Lancet 1998;352:1245-51.
12. Consensus statements on thrombolysis. Karolinska Stroke Update; 11-12 Nov 2002; Stockholm, Sweden. Available from: http://www.stroke-update.org
13. Hacke W, Donnan G, Fieschi C, et al. Lancet 2004;363:768-74.