Thrombolysis for acute stroke with special emphasis on the very old: experience from a single Dutch centre

R J van Oostenbrugge; R M M Hupperts; J Lodder

doi:10.1136/jnnp.2005.070292

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Thrombolysis for acute stroke with special emphasis on the very old: experience from a single Dutch centre

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Thrombolysis in the very old; prudence rather than fearlessness.
Jan Lodder
Published on: 13 April 2016
Great-Grandparents and Thrombolysis for Stroke
Bijan Vatankhah
Published on: 13 April 2016
Certainty in the face of uncertainty will not answer questions in acute stroke treatment
William N Whiteley
Published on: 13 April 2016

Published on: 13 April 2016
Thrombolysis in the very old; prudence rather than fearlessness.
- Jan Lodder, neurologists
- Other Contributors:
  Robert J van Oostenbrugge, Raymond M Hupperts, and Jan Lodder
Dear Editor,
We appreciate Drs Schwark and Schellinger’s comments on our paper, but we are not convinced by their argument that, because thrombolysis benefits patients younger than 80 years, there is no reason to withheld the treatment in those over 80 since their prognosis is even worse (1,2). So far, observational data question the validity of their view. We agree with Dr. Vatankhah et al. and Dr. Whiteley et...
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Dear Editor,
We appreciate Drs Schwark and Schellinger’s comments on our paper, but we are not convinced by their argument that, because thrombolysis benefits patients younger than 80 years, there is no reason to withheld the treatment in those over 80 since their prognosis is even worse (1,2). So far, observational data question the validity of their view. We agree with Dr. Vatankhah et al. and Dr. Whiteley et al. that we need additional controlled data (3,4); even if one adheres strongly to observational data, SITS-MOST will not provide these, as patients older than 80 are excluded from this registry. Faced with the inability not to decide, fear may indeed not be an option. However, with regard to trombolysis in most of the elderly patients there may be “more courage in avoiding danger than in conquering it”(5).
References
1. Thrombolysis for acute stroke with special emphasis on the very old: experience from a single Dutch centre. R J van Oostenbrugge, R M M Hupperts, and J Lodder. J Neurol Neurosurg Psychiatry 2006; 77: 375-377.
2. Is old age really a reason to withhold thrombolytic therapy? C Schwark and P D Schellinger. J. Neurol. Neurosurg. Psychiatry 2006 77: 289.
3. Certainty in the face of uncertainty will not answer questions in acute stroke treatment. William N Whiteley, Peter Sandercock, Joanna Wardlaw, Richard Lindley. JNNP Online, 14 Mar 2006.
4. Great-Grandparents and Thrombolysis for Stroke. Bijan Vatankhah, Michael S. Dittmar, Nando P. Fehm, and Markus Horn. JNNP Online, 27 Mar 2006.
5. Oracle 47 in the The Art of Wordly Wisdom. Balthasar Gracian (1601-1658). Translated by Ch. Maurer. Doubleday Publ. New York 1992.
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Conflict of Interest:
None declared.
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Published on: 13 April 2016
Great-Grandparents and Thrombolysis for Stroke
- Bijan Vatankhah, Registrar
- Other Contributors:
  Michael S. Dittmar, Nando P. Fehm, and Markus Horn.
Dear Editor,
We thank van Oostenbrugge, Hupperts and Lodder for their fine work on thrombolysis for stroke (1). They add another piece to the puzzle of this therapy for the elderly. The major studies on recombinant tissue plasminogen activator (rtPA) in stroke therapy included only 42 patients over 80 years (2), thus this therapy is only licensed for patients being younger in most countries. Later series by Tann...
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Dear Editor,
We thank van Oostenbrugge, Hupperts and Lodder for their fine work on thrombolysis for stroke (1). They add another piece to the puzzle of this therapy for the elderly. The major studies on recombinant tissue plasminogen activator (rtPA) in stroke therapy included only 42 patients over 80 years (2), thus this therapy is only licensed for patients being younger in most countries. Later series by Tanne et al.(3), Simon et al.(4), our centre (5) and the current one (1) examined the outcome in further 153 very elderly. The in-hospital death and symptomatic bleeding rates were comparable to younger patients, but the long-term functional outcome was often not examined. I agree with Schwark and Schellinger (6) that we should be open to perform this therapy as well on the senior patients if the inclusion criteria are rigidly applied. Nevertheless, we have to bear in mind that the very elderly chosen for this treatment so far were probably carefully selected and thus do not represent the common senior patient. We might have treated senior patients that were indeed in a much younger state concerning their biological system. We therefore cannot project the preliminary results on the majority of older stroke patients. We need to gain further data as cerebrovascular events are among the major causes of death in seniors. For now, we recommend informed consent for thrombolysis in the very elderly as it cannot be seen as a standard treatment for this cohort yet.
Sincerely,
Bijan Vatankhah, M.D.
Department of Neurology, University of Regensburg / Germany
Universitaetsstrasse 84
D-93053 Regensburg / Germany
e-mail: Bijan.Vatankhah@medbo.de
Michael S. Dittmar, M.D.
Department of Anaesthesiology, University of Regensburg /Germany
Nando P. Fehm, M.D.
Department of Neurology, University of Regensburg / Germany
Markus Horn, M.D.
Department of Neurology, University of Regensburg and Bad Hersfeld Medical Centre / Germany
References
(1) van Oostenbrugge RJ, Hupperts RM, Lodder J. Thrombolysis for acute stroke with special emphasis on the very old: experience from a single Dutch centre. J Neurol Neurosurg Psychiatry. 2006 Mar;77(3):375-7.
(2) The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. N Engl J Med 1995; 333:1581-1588.
(3) Tanne D, Gorman MJ, Bates VE, Kasner SE, Scott P, Verro P, Binder JR, Dayno JM, Schultz LR, Levine SR. Intravenous tissue plasminogen activator for acute ischemic stroke in patients aged 80 years and older : the tPA stroke survey experience. Stroke. 2000 Feb;31(2):370-5.
(4) Simon JE, Sandler DL, Warwick Pexman JH, Hill MD, Buchan AM for the Calgary Stroke Programme. Is intravenous recombinant tissue plasminogen activator (rt-PA) safe for use in patients over 80 years old with acute ischaemic stroke ? – The Calgary experience. Age and Ageing. 2004; 33: 143-149.
(5) Vatankhah B, Dittmar MS, Fehm NP, Erban P, Ickenstein GW, Jakob W, Bogdahn U, Horn M. Thrombolysis for stroke in the elderly. J Thromb Thrombolysis. 2005 Aug;20(1):5-10.
(6) Schwark C, Schellinger PD. Is old age really a reason to withhold thrombolytic therapy? J Neurol Neurosurg Psychiatry. 2006 Mar;77(3):289.
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Conflict of Interest:
None declared.
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Published on: 13 April 2016
Certainty in the face of uncertainty will not answer questions in acute stroke treatment
- William N Whiteley, Specialist Registrar in Medical Neurology
- Other Contributors:
  Peter Sandercock, Joanna Wardlaw, Richard Lindley
Dear Editor,
Many doctors treating elderly patients with acute stroke are uncertain whether the risk of alteplase outweighs its benefits. The European Medicines Evaluation Agency agrees with their position – alteplase does not have a licence in Europe for use in acute stroke patients over the age of 80. Many cases series, including the one from Maastricht (1) recently published in the JNNP, show that older patient...
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Dear Editor,
Many doctors treating elderly patients with acute stroke are uncertain whether the risk of alteplase outweighs its benefits. The European Medicines Evaluation Agency agrees with their position – alteplase does not have a licence in Europe for use in acute stroke patients over the age of 80. Many cases series, including the one from Maastricht (1) recently published in the JNNP, show that older patients do worse than younger patients after treatment with alteplase. However, this is frequently seen in many treatments for older people as they generally have greater risks from disease and treatments. Without a randomised control group it is uncertain whether older patients will benefit from alteplase treatment. Registers of thrombolysis in acute stroke such as SITS-MOST will also share the disadvantages of uncontrolled case series.
The MRC Third International Stroke Trial (IST3) – a large, randomised trial of thrombolysis in acute ischaemic stroke – will have the power to address the uncertainty about alteplase treatment for the very old. By mid February 2006, IST-3 had recruited over 500 patients, of whom 171 were aged 80 years or more – more than 4 times the number included in previous randomised trials of alteplase. The uncertainty principle is not – as Schwark and Schellinger (2) suggest - a weakness of its design, but rather a strength. The responsible clinician and the patient must both regard the treatment as ‘promising but unproven’ for recruitment to go ahead. This principle has clear ethical, organisational and scientific advantages over more prescriptive approaches of recruitment to randomised trails. It was an essential design feature in several trials that have provided reliable answers to important questions; it was successfully employed in large- scale trials of carotid surgery (3) , interventional neuroradiology for aneurysmal subarachnoid haemorrhage (4), and corticosteroids for traumatic brain injury (5). We would therefore disagree with Schwark and Schellinger’s assertion that the best course of action is simply to treat selected older patients (2). It is better to consider recruiting patients in whom the treatment is promising but unproven into IST-3, since to do so will add useful and reliable evidence.
Full details of the trial are available at http://www.ist3.com.
Yours sincerely,
William Whiteley
Specialist Registrar in Medical Neurology
Peter Sandercock
Co-Chief Investigator IST-3
Joanna Wardlaw
Professor of Neuroradiology
Department of Clinical Neurosciences
Western General Hospital
Edinburgh
UK
Richard Lindley
Co-Chief Investigator IST-3
Westmead Hospital
Sydney
Australia
Figure 1: Recruitment into the Third International Stroke Trial.
References
1. Van Oostenbrugge RJ, Hupperts RMM, Lodder J. Thrombolysis for acute stroke with special emphasis on the very old: experience from a single Dutch Centre J Neurol Neurosurg Psychiatry 2006;77:375-377
2. Schwark C, Schellinger PD. Is old age really a reason to withhold thrombolytic therapy? J Neurol Neurosurg Psychiatry 2006;77:289
3. European Carotid Surgery Trialists' Collaborative Group . MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet. 1991;337(8752):1235-43.
4. International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002;360(9342):1267- 74.
5. CRASH trial collaborators Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet. 2004;364(9442):1321-8.
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Conflict of Interest:
None declared.
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