Thrombolysis with plasminogen activator (rtPA) in stroke

Findings by SBU Alert

Version: 4

Technology and target group

Although stroke affects approximately 30 000 individuals in Sweden annually, options for treatment in the acute phase have been limited. However, an acute treatment method is now available to dissolve clots (thrombolysis) using recombinant tissue plasminogen activator (rtPA¹) in patients with cerebral infarction, the most common type of stroke. The method has been tested only in younger stroke patients (<80 years) where treatment has been initiated shortly after onset. The Medical Products Agency has approved thrombolysis with rtPA for patients up to 80 years of age and within 3 hours following the onset of symptoms. Based on current estimates, the target group is limited to approximately 1 500 patients per year in Sweden.

Patient benefit and side effects

Eight randomized controlled studies involving 2 955 patients have been conducted where treatment with rtPA was initiated within 6 hours following onset. The most serious risk of treatment is the risk for cerebral hemorrhage. An increase in symptomatic (including fatal) cerebral hemorrhage has been found in 62 of 1 000 patients treated. Nevertheless, a net gain in overall outcome has been shown, namely that an additional 55 of 1 000 patients survived or were not dependent of the help of others if they were treated with rtPA. The highest percentage of positive effects was found in the 957 patients where treatment was initiated within the first 3 hours following onset. Of these, 110 of 1 000 patients treated avoided death or dependency on others.

Economic aspects

There are no studies on cost or cost effectiveness except for a model study with unconfirmed results.

Scientific evidence

Thrombolysis with rtPA within 3 hours of onset in patients up to 80 years of age yields a generally positive result (Evidence grade 2)* despite the increase in severe brain hemorrhages (Evidence grade 1)*. Relatively few patients were included in the studies, and the studies were conducted at specialized centers. Therefore, it is important to follow up the results in general health services by using quality registries (SITS-MOST, Riks-Stroke). Effect size and risk must also be presented with greater precision. Sweden needs to participate in large international randomized trials to acquire further knowledge about which patients benefit, eg, regarding age and longer time periods following onset, and which patients are at higher risk. Knowledge concerning cost effectiveness is greatly limited (Evidence grade 4)*, and further studies are needed.

*Grading of the level of scientific evidence for conclusions. The grading scale includes four levels;
Evidence grade 1 = strong scientific evidence,
Evidence grade 2 = moderately strong scientific evidence,
Evidence grade 3 = limited scientific evidence,
Evidence grade 4 = insufficient scientific evidence.

Footnote
¹rtPA = recombinant tissue plasminogen activator, Alteplase. Some of the referenced studies investigated a different type of tPA. This assessment, however, uses rtPA since it is the substance that has been approved in Sweden.

This summary is based on a report prepared at SBU in collaboration with Prof. Bo Norrving, University Hospital of Lund. It has been reviewed by Prof. Kjell Asplund, National Board of Health and Welfare, Stockholm, Prof. Mona Britton, SBU, Stockholm and Veronica Murray, MD, Danderyd Hospital, Stockholm.

The full report is available only in Swedish.

SBU Alert is a service provided by SBU in collaboration with the Medical Products Agency, the National Board of Health and Welfare, and the Federation of Swedish County Councils.

References

1. Socialstyrelsen, Medicinsk Faktabas MARS; State of the Art - Stroke, 1997.
2. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-7.
3. Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med 2002;162:1994-2001.
4. Donnan GA, Davis SM. Neuroimaging, the ischaemic penumbra, and selection of patients for acute stroke therapy. Lancet Neurol 2002;1:417-25.
5. Gladstone DJ, Black SE. Update on intravenous tissue plasminogen activator for acute stroke: from clinical trials to clinical practice. CMAJ 2001;165:311-7.
6. Hårdemark HG, Nordmark O, Terent A. [Early thrombolysis indicated in threatened cerebral infarction. A study of 60 patients treated at Akademiska sjukhuset in Uppsala]. Läkartidningen 2002;99:4350-5.
7. Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS. Health Technol Assess 2002;6:1-112.
8. Tanne D, Kasner SE, Demchuk AM, Koren-Morag N, Hanson S, Grond M, Levine SR. Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: the Multicenter rt-PA Stroke Survey. Circulation 2002;105:1679-85.
9. Wardlaw JM, Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2003;CD000213.