| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2003;34:2847.)
© 2003 American Heart Association, Inc.
Original Contributions |
From the Albuquerque VA and University of New Mexico School of Medicine, Department of Neurology, VA Medical Center, Albuquerque, NM.
Correspondence to Glenn D. Graham, MD, PhD, Albuquerque VA and University of New Mexico School of Medicine, Neurology/127, VA Medical Center, 1501 San Pedro Dr SE, Albuquerque, NM 87122. E-mail graham{at}unm.edu
| Abstract |
|---|
|
|
|---|
Methods This is a meta-analysis of 15 published, open-label studies that broadly followed approved indications and guidelines for tPA use in nonselective patient populations.
Results In 2639 treated patients, the symptomatic intracerebral hemorrhage rate was 5.2% (95% confidence interval, 4.3 to 6.0), slightly lower than the 6.4% rate in the treated group of the randomized, placebo-controlled National Institute of Neurological Disorders and Stroke (NINDS) trial. The mean total death rate (13.4%) and proportion of subjects achieving a very favorable outcome (37.1%) were comparable to the NINDS trial results. Protocol deviations were reported in 19.8%. Comparing across studies showed that the mortality rate was correlated with the percentage of protocol violations (r=0.67, P=0.018).
Conclusions Postapproval data support the safety of intravenous thrombolytic therapy with tPA for acute ischemic stroke, especially when established treatment guidelines are followed.
Key Words: cerebral hemorrhage cerebral infarction cerebrovascular accident meta-analysis tissue plasminogen activator
| Introduction |
|---|
|
|
|---|
The NINDS-sponsored trial3 of tPA in acute stroke was conducted at a relatively small number of experienced stroke centers. One commonly expressed concern is that similar results might not be obtained when tPA is used in a variety of clinical settings. The high symptomatic intracerebral hemorrhage (ICH) rate reported in a series of 70 patients treated at hospitals in the Cleveland area4 is frequently cited as evidence that the risks of tPA may be greater in clinical practice than in a clinical trial setting. Since publication of the NINDS trial results, more than a dozen reports of experience with tPA in open-label, routine clinical use have been published.418 The goal of this project was to examine the overall safety data from this large, collective experience with tPA.
| Methods |
|---|
|
|
|---|
| Results |
|---|
|
|
|---|
|
|
Protocol deviations were reported in 19.8% of the cases overall. Comparison across studies without adjustment for the number of cases showed that mortality rate was correlated with the percentage of protocol violations (r=0.67, P=0.018), as shown in Figure 2. However, the highest mortality rate occurred in the series with the highest percentage of protocol violations,15 and if this data point is excluded, the correlation loses statistical significance. The greatest symptomatic ICH rate was found in the study with the second highest proportion of protocol deviations,4 although the symptomatic ICH rate was not significantly correlated with the frequency of protocol violations overall (P=0.19).
|
| Discussion |
|---|
|
|
|---|
There are several important limitations to these results. As is typical of meta-analyses, data are combined from individual series that used slightly different treatment inclusion and exclusion criteria, although all followed the broad outlines of the NINDS protocol. Five of the case series were collected retrospectively, which may be less accurate than prospective data acquisition. Retrospective surveys may introduce investigator bias in the extraction of data from the medical record and are more likely to rely on estimation of items such as the NIHSS score rather than actual measurement. The threshold and criteria used to determine whether an ICH is symptomatic may vary between individual series, whereas total ICH rates may be unavailable or inaccurate when derived from studies in which not all patients underwent routine follow-up imaging.
Reporting of outcomes was not standardized. Individual studies used modified Rankin scores of 0 to 1 or 0 to 2, NIHSS scores of 0 to 1, or Barthel Index scores of 95 to 100 to define the very favorable outcome group, whereas some provided no outcome data. Failure to report outcomes at a consistent time point (such as 30 or 90 days after stroke) or to use consistent criteria limits any comparative assessment of treatment efficacy. Such comparisons would be problematic even in the best circumstances because of the lack of a control group. It is hoped that future case series of thrombolytic therapies will provide more consistent and detailed data on patient outcomes.
Many of the individual series included here are single-center series rather that multicenter compilations and may be susceptible to publication bias in which only especially favorable, or unfavorable, results are reported. Also, centers treating a high volume of stroke patients, which are more likely to report results, may have better outcomes than lower-volume institutions. A recent pooled analysis of registries incorporating data from 104 German hospitals found a significantly increased risk of in-hospital mortality for stroke patients treated with tPA in institutions using thrombolytic therapy for stroke
5 times per year but no increase for hospitals treating larger numbers.25 These factors may limit the applicability of these results to institutions with small numbers of acute stroke presentations. Even with these limitations, this compilation provides the largest patient experience to date documenting the safety of intravenous thrombolytic therapy for acute stroke outside a clinical trial setting.
The high incidence of protocol violations and the suggestion of a correlation between protocol deviation frequency and adverse outcomes are troublesome. Some patients were treated years after the publication of the NINDS study and approval of tPA in the United States, affording providers sufficient time to become familiar with details of the appropriate use of the drug. Some publications included in this meta-analysis did not have a prespecified goal of accurately detecting the frequency of protocol deviations and may underestimate the true incidence of variance from tPA treatment guidelines. These data support the necessity of adequate provider education and adherence to approved indications in institutions treating acute stroke patients with tPA. For example, in Cleveland, where a 50% protocol deviation rate was initially reported,4 implementation of additional training and quality improvement measures decreased the frequency of protocol violations and reduced the symptomatic ICH rates to levels close to the NINDS results.17 Many physicians, especially nonneurologists, remain hesitant to use tPA in acute stroke patients, suggesting that additional education and training may still be needed in many communities.
Overall, however, the data from open-label tPA use present a compelling argument that thrombolytic therapy for stroke can be used safely across a wide variety of practice settings. Safety results from community hospitals were comparable to those of large, tertiary medical centers.11 Although efficacy claims still must rely on data from randomized trials, the published postapproval experience with tPA in clinical practice compiled here should be considered in assessments of the safety of thrombolytic therapy for ischemic stroke by advocates and skeptics alike.
| Acknowledgments |
|---|
| Footnotes |
|---|
Received June 3, 2003; revision received August 12, 2003; accepted August 13, 2003.
| References |
|---|
|
|
|---|
2. Lenzer J. Alteplase for stroke: money and optimistic claims buttress the "brain attack" campaign. BMJ. 2002; 324: 723729.
3. NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 15811587.
4. Katzan IL, Furlan AJ, Lloyd LE, Frank JI, Harper DL, Hinchey JA, Hammel JP, Qu A, Sila CA. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA. 2000; 283: 11511158.
5. Hill MD, Buchan AM. The Canadian Activase for Stroke Effectiveness Study (CASES): final results. Stroke. 2002; 33: 359. Abstract.
6. Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment With Alteplase to Reverse Stroke (STARS) Study. JAMA. 2000; 283: 11451150.
7. Grotta JC, Burgin WS, El-Mitwalli A, Long M, Campbell M, Morgenstern LB, Malkoff M, Alexandrov AV. Intravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996 to 2000. Arch Neurol. 2001; 58: 20092013.
8. Schmülling S, Grond M, Rudolf J, Heiss W-D. One-year follow-up in acute stroke patients treated with rtPA in clinical routine. Stroke. 2000; 31: 15521554.
9. Koennecke H-C, Nohr R, Leistner S, Marx P. Intravenous tPA for ischemic stroke: team performance over time, safety, and efficacy in a single-center, 2-year experience. Stroke. 2001; 32: 10741078.
10. Buchan AM, Barber PA, Newcommon N, Karbalai HG, Demchuk AM, Hoyte KM, Klein GM, Feasby TE. Effectiveness of t-PA in acute ischemic stroke: outcome relates to appropriateness. Neurology. 2000; 54: 679684.
11. Wang DZ, Rose JA, Honings DS, Garwacki DJ, Milbrandt JC. Treating acute stroke patients with intravenous tPA: the OSF Stroke Network experience. Stroke. 2000; 31: 7781.
12. Akins PT, Delemos C, Wentworth D, Byer J, Schorer SJ, Atkinson RP. Can emergency department physicians safely and effectively initiate thrombolysis for acute ischemic stroke? Neurology. 2000; 55: 18011805.
13. Egan R, Lutsep HL, Clark WM, Quinn J, Kearns K, Lockfeld A, Ireland S, Goins S, Buchholz G. Open label tissue plasminogen activator for stroke: the Oregon experience. J Stroke Cerebrovasc Dis. 1999; 8: 287290.[Medline] [Order article via Infotrieve]
14. Tanne D, Bates VE, Verro P, Kasner SE, Binder JR, Patel SC, Mansbach HH, Daley S, Schultz LR, Karanjia PN, et al. Initial clinical experience with IV tissue plasminogen activator for acute ischemic stroke: a multicenter survey. Neurology. 1999; 53: 424427.
15. Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med. 2002; 162: 19942001.
16. Lopez-Yunez AM, Bruno A, Williams LS, Yilmaz E, Zurrú C, Biller J. Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage. Stroke. 2001; 32: 1216.
17. Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM, for the Cleveland Clinic Health System Stroke Quality Improvement Team. Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke. 2003; 34: 799800.
18. Smith RW, Scott PA, Grant RJ, Chudnofsky CR, Frederiksen SM. Emergency physician treatment of acute stroke with recombinant tissue plasminogen activator: a retrospective analysis. Acad Emerg Med. 1999; 6: 618625.[Medline] [Order article via Infotrieve]
19. Adams HP Jr, Brott TG, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Kwiatkowski T, Lyden PD, Marler JR, Torner J, et al. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 1996; 27: 17111718.[Medline] [Order article via Infotrieve]
20. Quality Standards Subcommittee of the American Academy of Neurology. Practice advisory: thrombolytic therapy for acute ischemic stroke: summary statement. Neurology. 1996; 47: 835839.
21. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 2001; 119: 300S320S.
22. Gladstone DJ, Black SE. Update on intravenous tissue plasminogen activator for acute stroke: from clinical trials to clinical practice. Can Med Assoc J. 2001; 165: 311317.
23. Madhavan R, Jacobs BS, Levine SR. Stroke trials: what have we learned? Neurol Res. 2002; 24 (suppl 1): S27S32.[Medline] [Order article via Infotrieve]
24. Katzan IL, Sila CA, Furlan AJ. Community use of intravenous tissue plasminogen activator for acute stroke: results of the Brain Matters Stroke Management Survey. Stroke. 2001; 32: 861865.
25. Heuschmann PU, Berger K, Misselwitz B, Hermanek P, Leffmann C, Adelmann M, Buecker-Nott H-J, Rother J, Neundoerfer B, Kolominsky-Rabas PL, for the German Stroke Registers Study Group, Competence Net Stroke. Frequency of thrombolytic therapy in patients with acute ischemic stroke and the risk of in-hospital mortality: the German Stroke Registers Study Group. Stroke. 2003; 34: 11061113.
This article has been cited by other articles:
![]() |
L Derex and N Nighoghossian Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update J. Neurol. Neurosurg. Psychiatry, October 1, 2008; 79(10): 1093 - 1099. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Lyden Thrombolytic Therapy for Acute Stroke -- Not a Moment to Lose N. Engl. J. Med., September 25, 2008; 359(13): 1393 - 1395. [Full Text] [PDF] |
||||
![]() |
J. Fiehler, G. W. Albers, J.-M. Boulanger, L. Derex, A. Gass, N. Hjort, J. S. Kim, D. S. Liebeskind, T. Neumann-Haefelin, S. Pedraza, et al. Bleeding Risk Analysis in Stroke Imaging Before ThromboLysis (BRASIL): Pooled Analysis of T2*-Weighted Magnetic Resonance Imaging Data From 570 Patients Stroke, October 1, 2007; 38(10): 2738 - 2744. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. B. van der Worp and J. van Gijn Acute Ischemic Stroke N. Engl. J. Med., August 9, 2007; 357(6): 572 - 579. [Full Text] [PDF] |
||||
![]() |
J. J. Pandit, R. Satya-Krishna, and P. Gration Superficial or deep cervical plexus block for carotid endarterectomy: a systematic review of complications Br. J. Anaesth., August 1, 2007; 99(2): 159 - 169. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Amaro, D. Soy, V. Obach, A. Cervera, A. M. Planas, and A. Chamorro A Pilot Study of Dual Treatment With Recombinant Tissue Plasminogen Activator and Uric Acid in Acute Ischemic Stroke Stroke, July 1, 2007; 38(7): 2173 - 2175. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. L. DeLaPaz and for the Expert Panel on Neurologic Imaging Cerebrovascular Disease AJNR Am. J. Neuroradiol., June 1, 2007; 28(6): 1197 - 1199. [Full Text] [PDF] |
||||
![]() |
H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation, May 22, 2007; 115(20): e478 - e534. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists Stroke, May 1, 2007; 38(5): 1655 - 1711. [Abstract] [Full Text] [PDF] |
||||
![]() |
Z. Qin, M. Karabiyikoglu, Y. Hua, R. Silbergleit, Y. He, R. F. Keep, and G. Xi Hyperbaric Oxygen-Induced Attenuation of Hemorrhagic Transformation After Experimental Focal Transient Cerebral Ischemia Stroke, April 1, 2007; 38(4): 1362 - 1367. [Abstract] [Full Text] [PDF] |
||||
![]() |
M.S.V. Elkind, S. Prabhakaran, J. Pittman, W. Koroshetz, M. Jacoby, K. C. Johnston, and for the GAIN Americas Investigators Sex as a predictor of outcomes in patients treated with thrombolysis for acute stroke Neurology, March 13, 2007; 68(11): 842 - 848. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Kurth, P. U. Heuschmann, A. M. Walker, K. Berger, M. L. Flaherty, B. Kissela, P. Khatri, R. M. Dubinsky, and S. M. Lai Mortality of stroke patients treated with thrombolysis: Analysis of nationwide inpatient sample Neurology, February 27, 2007; 68(9): 710 - 711. [Full Text] [PDF] |
||||
![]() |
G. Thomalla, J. Sobesky, M. Kohrmann, J. B. Fiebach, J. Fiehler, O. Zaro Weber, A. Kruetzelmann, T. Kucinski, M. Rosenkranz, J. Rother, et al. Two Tales: Hemorrhagic Transformation but Not Parenchymal Hemorrhage After Thrombolysis Is Related to Severity and Duration of Ischemia: MRI Study of Acute Stroke Patients Treated With Intravenous Tissue Plasminogen Activator Within 6 Hours Stroke, February 1, 2007; 38(2): 313 - 318. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. J. Audebert, C. Kukla, B. Vatankhah, B. Gotzler, J. Schenkel, S. Hofer, A. Furst, and R. L. Haberl Comparison of Tissue Plasminogen Activator Administration Management Between Telestroke Network Hospitals and Academic Stroke Centers: The Telemedical Pilot Project for Integrative Stroke Care in Bavaria/Germany Stroke, July 1, 2006; 37(7): 1822 - 1827. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Dubinsky and S.-M. Lai Mortality of stroke patients treated with thrombolysis: Analysis of nationwide inpatient sample Neurology, June 13, 2006; 66(11): 1742 - 1744. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Trouillas and R. von Kummer Classification and Pathogenesis of Cerebral Hemorrhages After Thrombolysis in Ischemic Stroke Stroke, February 1, 2006; 37(2): 556 - 561. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. T. Bateman, H. C. Schumacher, B. Boden-Albala, M. F. Berman, J.P. Mohr, R. L. Sacco, and J. Pile-Spellman Factors Associated With In-Hospital Mortality After Administration of Thrombolysis in Acute Ischemic Stroke Patients: An Analysis of the Nationwide Inpatient Sample 1999 to 2002 Stroke, February 1, 2006; 37(2): 440 - 446. [Abstract] [Full Text] [PDF] |
||||
![]() |
Part 9: Adult Stroke Circulation, December 13, 2005; 112(24_suppl): IV-111 - IV-120. [Full Text] [PDF] |
||||
![]() |
W. Kakuda, V. N. Thijs, M. G. Lansberg, R. Bammer, L. Wechsler, S. Kemp, M. E. Moseley, M. P. Marks, G. W. Albers, and the DEFUSE Investigators Clinical importance of microbleeds in patients receiving IV thrombolysis Neurology, October 25, 2005; 65(8): 1175 - 1178. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. Adams, R. Adams, G. Del Zoppo, and L. B. Goldstein 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, April 1, 2005; 36(4): 916 - 923. [Full Text] [PDF] |
||||
![]() |
M. Kaste Thrombolysis: What More Does It Take? Stroke, February 1, 2005; 36(2): 200 - 202. [Full Text] [PDF] |
||||
![]() |
P. U. Heuschmann, P. L. Kolominsky-Rabas, J. Roether, B. Misselwitz, K. Lowitzsch, J. Heidrich, P. Hermanek, C. Leffmann, M. Sitzer, M. Biegler, et al. Predictors of In-Hospital Mortality in Patients With Acute Ischemic Stroke Treated With Thrombolytic Therapy JAMA, October 20, 2004; 292(15): 1831 - 1838. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. Aiyagari, A. Gujjar, A. R. Zazulia, and M. N. Diringer Hourly Blood Pressure Monitoring After Intravenous Tissue Plasminogen Activator for Ischemic Stroke: Does Everyone Need It? Stroke, October 1, 2004; 35(10): 2326 - 2330. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Kaste Reborn Workhorse, CT, Pulls the Wagon Toward Thrombolysis Beyond 3 Hours Stroke, February 1, 2004; 35(2): 357 - 359. [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Stroke Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2003 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |