Published online before print March 23, 2006, doi: 10.1161/01.STR.0000217368.50025.f5
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(Stroke. 2006;37:1151.)
© 2006 American Heart Association, Inc.
Letters to the Editor |
Repeated Tissue Plasminogen Activator Treatment for Early Stroke Recurrence: Protocol Violation Is Not an Option
Unitat Neurovascular, Department of Neurology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
To the Editor:
We read with interest and concern the article by Topakian et al1 in which the authors describe the clinical case of a stroke patient successfully treated with tissue plasminogen activator (tPA) that experienced a recurrence and therefore was treated again with a low dose of tPA 90 hours after the first event. Authors argued that the rationale for the second treatment was the "evidence of vessel reocclusion and profound perfusion/diffusion mismatch"; this statement raises several considerations.
The diffusion/perfusion (DWI/PWI) mismatch concept to select acute stroke patients suitable for reperfusion therapies is currently under investigation with promising expectations.2,3 However, this concept is being applied in patients who do not present subacute ischemic lesion, a major exclusion criterion in all to-date thrombolysis studies. Although DWI/PWI mismatch may represent a surrogate marker of potential salvageable brain tissue if rapid restoration of blood flow is achieved, its presence does not provide by itself safety information. Extent and severity of cerebral ischemia are considered major determinants of symptomatic intracranial hemorrhage (SICH) in stroke patients treated with tPA. Several MRI studies have shown that the analysis of apparent diffusion coefficient maps but not the presence of DWI/PWI mismatch predicts the risk of SICH.4 Even relatively small but profoundly ischemic lesions may reflect areas of severe brain–blood barrier disruption and increased risk of SICH.5 Moreover, a late reperfusion of an already damaged brain tissue has been associated with a higher rate of SICH.6 Although a second IV thrombolytic bolus has been reported successful in patients with acute myocardial infarction,7 several pathophysiological-based safety concerns may preclude its use in patients with recently infarcted brain tissue.
Extension of the time window for reperfusion therapies represents a major goal for stroke treatment. We consider that development of novel approaches to increase the number of patients who may benefit from thrombolysis and reconsideration of some exclusion criteria such as recent ischemic stroke are encourageable. These studies, however, should always be done under strict protocols in order to acquire valuable information. Physicians should beware of isolated heroic measures that expose patients to noncontrolled risks without offering useful data for treatment improvement.
References
- Topakian R, Gruber F, Fellner FA, Haring HP, Aichner FT. Thrombolysis beyond the guidelines: two treatments in one subject within 90 hours based on a modified magnetic resonance imaging brain clock concept. Stroke. 2005; 36: e162–164.
[Abstract/Free Full Text] - Ribo M, Molina CA, Rovira A, Quintana M, Delgado P, Montaner J, Grive E, Arenillas JF, Alvarez-Sabin J. Safety and efficacy of intravenous tissue plasminogen activator stroke treatment in the 3- to 6-hour window using multimodal transcranial doppler/mri selection protocol. Stroke. 2005; 36: 602–606.
[Abstract/Free Full Text] - Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, Fischer M, Furlan A, Kaste M, Lees KR, Soehngen M, Warach S. The desmoteplase in acute ischemic stroke trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005; 36: 66–73.
[Abstract/Free Full Text] - Selim M, Fink JN, Kumar S, Caplan LR, Horkan C, Chen Y, Linfante I, Schlaug G. Predictors of hemorrhagic transformation after intravenous recombinant tissue plasminogen activator: prognostic value of the initial apparent diffusion coefficient and diffusion-weighted lesion volume. Stroke. 2002; 33: 2047–2052.
[Abstract/Free Full Text] - Montaner J, Rovira A, Molina CA, Arenillas JF, Ribo M, Chacon P, Monasterio J, Alvarez-Sabin J. Plasmatic level of neuroinflammatory markers predict the extent of diffusion-weighted image lesions in hyperacute stroke. J Cereb Blood Flow Metab. 2003; 23: 1403–1407.[CrossRef][Medline] [Order article via Infotrieve]
- Molina CA, Alvarez-Sabin J, Montaner J, Abilleira S, Arenillas JF, Coscojuela P, Romero F, Codina A. Thrombolysis-related hemorrhagic infarction: a marker of early reperfusion, reduced infarct size, and improved outcome in patients with proximal middle cerebral artery occlusion. Stroke. 2002; 33: 1551–1556.
[Abstract/Free Full Text] - Banerjee P, Clark AL, Norell MS. Repeat thrombolysis for acute myocardial infarction. Int J Cardiol. 2005; 102: 515–519.[Medline] [Order article via Infotrieve]
Department of Neurology, Wagner-Jauregg Hospital, Linz, Austria
Departments of Neurology, General Hospital, Linz, Austria
Department of Radiology, General Hospital, Linz, Austria
Response:
Off-label use is no protocol violation. Managing early recurrent stroke represents a major challenge to stroke neurologists. For clinical settings like the one described in our article,1 clinicians will hardly find any evidence-based recommendation in current stroke treatment guidelines.2–3 In our patient, after the sudden dramatic neurological deterioration on day 4 attributable to an early recurrent stroke, we faced a difficult management problem.
Our decision to carry out a second recombinant tissue plasminogen activator (rtPA) treatment has nothing to do with heroism or "medical machismo," as some may argue. Taking full responsibility for the consequences, we made our decision after carefully weighing up the arguments for risk and benefit of a second rtPA treatment. There were several arguments in favor of a second treatment with rtPA.
Firstly, we all know that the earlier thrombolysis treatment is started, the higher the chances are for neurological improvement.4 Obviously, the immediate recognition of the patients’ sudden deterioration by our stroke unit staff enabled us to consider another rtPA treatment with a relatively short stroke onset-to-treatment time.
Secondly, there was evidence of vessel reocclusion, a large perfusion deficit and a significant perfusion/diffusion mismatch, all demonstrated by multimodal MRI. Although the confirmation of vessel occlusion does not constitute a prerequisite for thrombolysis in current treatment guidelines, it certainly supports clinicians in their decision-making if the patient is considered for being given a potentially harmful thrombolytic agent.
Thirdly, we took account of the fact that the patient had already been receiving "best medical therapy" before the second stroke, ie, a platelet inhibitor (clopidogrel), an angiotensin-converting enzyme inhibitor (lisinopril), and a statin (simvastatin). Each of these medications is thought to have >1 beneficial effect in stroke patients, but our patient did experience a second stroke in spite of this seemingly "optimal" regime.
Fourthly, as we already stated in our article, we were well aware that repeat intravenous thrombolysis might carry a considerable risk of serious hemorrhage in previously infarcted brain. However, the infarcted area in the 24-hour FLAIR images after the first treatment was rather small. With respect to a presumed higher bleeding risk in case of another full dose of rtPA, the second treatment was carried out with a markedly reduced dose.
In clinical settings like the one described above, stroke neurologists are at a loss when it comes to evidence-based medicine. Time and again physicians face complex clinical situations and patient subgroups to which information derived from controlled clinical trials cannot be applied. It goes without saying that it is not the intention of a single case report to offer novel treatment options to the medical community. However, we may remind our critics that the description of a special case may shed light on difficult and still unsolved aspects of patient care and that case reports do constitute a part of the evidence pyramid.
References
- Topakian R, Gruber F, Fellner FA, Haring HP, Aichner FT. Thrombolysis beyond the guidelines. Two treatments in one subject within 90 hours based on a modified magnetic resonance imaging brain clock concept. Stroke. 2005; 36: e162–e164.
[Abstract/Free Full Text] - Hacke W, Kaste M, Bogousslavsky J, Brainin M, Chamorro A, Lees K, Leys D, Kwiecinski H, Toni P, Langhorne P, Diener C, Hennerici M, Ferro J, Sivenius J, Gunnar N, Bath P, Olsen TS, Gugging M. European Stroke Initiative Executive Committee and the EUSI Writing Committee. European Stroke Initiative Recommendations for Stroke Management-update 2003. Cerebrovasc Dis. 2003; 16: 311–337.[CrossRef][Medline] [Order article via Infotrieve]
- Adams H, Adams R, Del Zoppo G, Goldstein LB. Stroke Council of the American Heart Association; American Stroke Association. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke. 2005; 36: 916–923.
[Free Full Text] - Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S. ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363: 768–774.[CrossRef][Medline] [Order article via Infotrieve]
Related Article:
- Response
- Raffi Topakian, Hans-Peter Haring, Franz T. Aichner, Franz Gruber, and Franz A. Fellner
Stroke 2006 0: 01.STR.0000217369.61669.02v1.[Abstract] [PDF]
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