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Stroke Mimics and Intravenous Thrombolysis
Correspondence Jonathan R. Hiatt, MD Henry G. Cryer, MD, PhD Areti Tillou, MD, MSEd Department of Surgery David Geffen School of Medicine at UCLA Los Angeles, CA doi:10.1016/j.annemergmed.2012.02.021
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). Dr. Schriger receives funding from the Korein Foundation.
Stroke Mimics and Intravenous Thrombolysis To the Editor: In their report on stroke mimics and intravenous thrombolysis, Artto et al1 conclude that patients with stroke mimics were infrequent in their study and that none of the 14 patients with diagnoses of stroke mimic was harmed by receiving tissue plasminogen activator (tPA).1 They acknowledge a potential bias in their study, though, toward misclassifying stroke mimics as actual strokes, noting that “ѧthe diagnosis might have been biased toward ischemic stroke because making an alternative diagnosis after applying intravenous thrombolysis may have been difficult.” Artto et al1 state in the introduction to their article that 5 other small studies, including a total of 145 stroke mimic cases treated with tPA, also reported no symptomatic intracranial hemorrhage in such patients. Artto et al1 fail to note, though, that the other 5 studies also used the same retrospective methodology and are subject to the same bias toward misclassifying stroke mimics as actual strokes. Such a bias is even more likely in patients who develop intracranial hemorrhage after receiving tPA. As difficult as it might be to recognize and acknowledge that a patient who improves after receiving tPA actually had a stroke mimic, it is undoubtedly more difficult to recognize and acknowledge that a patient who deteriorates because of an intracranial hemorrhage shortly after receiving tPA was not actually having a stroke when he or she initially presented. Large studies of administration of tPA for acute myocardial infarction have reported that about 1% of patients develop clinically symptomatic intracranial hemorrhage.2,3 One might reasonably expect a similar incidence in patients with stroke mimics who receive tPA. The greatest bias in the report by Artto et al,1 though, is in the sweeping statement in the introduction: “Intravenous thrombolysis is an effective and safe treatment for acute ischemic stroke when current guidelines are followed properly.”1 As a reference for this statement, the authors cite a report of a pooled analysis of data from the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke, European Cooperative Acute Stroke Study, and National Institute of Neurological Disorders and Stroke studies.4 In the disclosures of the funding sources, affiliations, and potential conflicts of interests for the participants in the original studies and the pooled analysis, the names “Genentech” and “Boehringer Ingelheim” (the US 246 Annals of Emergency Medicine
and European manufacturers of tPA, respectively) occur a combined 25 times. One of the coauthors in the study by Artto et al1 also reports receiving honoraria and consulting fees from Boehringer Ingelheim.1 A graphic reanalysis of the NINDS data by Hoffman and Schriger5 has been published in this journal. This reanalysis showed that there was no significant difference between tPA patients and controls in the degree of improvement at 90 days when baseline differences in stroke severity were taken into account. Physicians who treat patients with strokelike symptoms should not be reassured by the results reported by Artto et al1 that it is safe to administer tPA to patients with stroke mimics, and they should remain skeptical of the claim repeated by Artto et al1 that tPA has been shown to be safe and effective in treating patients who actually do have acute ischemic strokes. William Durston, MD Emergency Department Kaiser Foundation Hospital Sacramento, CA doi:10.1016/j.annemergmed.2012.02.022
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The author has stated that no such relationships exist. 1. Artto V, Putaala J, Strbian D, et al. Stroke mimics and intravenous thrombolysis. Ann Emerg Med. 2012;59:27-32. 2. Assessment of the Safety and Efficacy of a New Thrombolytic Investigators. Single-bolus tenecteplase compared with frontloaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999;354:716-722. 3. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med. 1997;337:1118-1123. 4. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363:768-774. 5. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS trial. Ann Emerg Med. 2009;54:329-336.
In reply: Thank you for the opportunity to answer the letter of Dr. Durston. He raised a few points that deserve to be challenged. We do not advocate thrombolysis in stroke mimics but report that when we have mistakenly treated stroke mimic patients with thrombolysis, no harm has been done. The results of the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (rt-PA) trial have been denied also, but a reanalysis conducted by an independent committee has reached the same conclusions as the National Institute of Neurological Disorders and Stroke rt-PA investigators.1 All European Cooperative Acute Stroke trials were sponsored by Boehringer Ingelheim. The results of all those trials were published, although European Cooperative Acute Stroke and European Cooperative Acute Stroke 2 were negative and only European Cooperative Acute Stroke 3 was positive.2-4 The first pooled Volume , . : August
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). Dr. Schriger receives funding from the Korein Foundation.
Stroke Mimics and Intravenous Thrombolysis To the Editor: In their report on stroke mimics and intravenous thrombolysis, Artto et al1 conclude that patients with stroke mimics were infrequent in their study and that none of the 14 patients with diagnoses of stroke mimic was harmed by receiving tissue plasminogen activator (tPA).1 They acknowledge a potential bias in their study, though, toward misclassifying stroke mimics as actual strokes, noting that “ѧthe diagnosis might have been biased toward ischemic stroke because making an alternative diagnosis after applying intravenous thrombolysis may have been difficult.” Artto et al1 state in the introduction to their article that 5 other small studies, including a total of 145 stroke mimic cases treated with tPA, also reported no symptomatic intracranial hemorrhage in such patients. Artto et al1 fail to note, though, that the other 5 studies also used the same retrospective methodology and are subject to the same bias toward misclassifying stroke mimics as actual strokes. Such a bias is even more likely in patients who develop intracranial hemorrhage after receiving tPA. As difficult as it might be to recognize and acknowledge that a patient who improves after receiving tPA actually had a stroke mimic, it is undoubtedly more difficult to recognize and acknowledge that a patient who deteriorates because of an intracranial hemorrhage shortly after receiving tPA was not actually having a stroke when he or she initially presented. Large studies of administration of tPA for acute myocardial infarction have reported that about 1% of patients develop clinically symptomatic intracranial hemorrhage.2,3 One might reasonably expect a similar incidence in patients with stroke mimics who receive tPA. The greatest bias in the report by Artto et al,1 though, is in the sweeping statement in the introduction: “Intravenous thrombolysis is an effective and safe treatment for acute ischemic stroke when current guidelines are followed properly.”1 As a reference for this statement, the authors cite a report of a pooled analysis of data from the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke, European Cooperative Acute Stroke Study, and National Institute of Neurological Disorders and Stroke studies.4 In the disclosures of the funding sources, affiliations, and potential conflicts of interests for the participants in the original studies and the pooled analysis, the names “Genentech” and “Boehringer Ingelheim” (the US 246 Annals of Emergency Medicine
and European manufacturers of tPA, respectively) occur a combined 25 times. One of the coauthors in the study by Artto et al1 also reports receiving honoraria and consulting fees from Boehringer Ingelheim.1 A graphic reanalysis of the NINDS data by Hoffman and Schriger5 has been published in this journal. This reanalysis showed that there was no significant difference between tPA patients and controls in the degree of improvement at 90 days when baseline differences in stroke severity were taken into account. Physicians who treat patients with strokelike symptoms should not be reassured by the results reported by Artto et al1 that it is safe to administer tPA to patients with stroke mimics, and they should remain skeptical of the claim repeated by Artto et al1 that tPA has been shown to be safe and effective in treating patients who actually do have acute ischemic strokes. William Durston, MD Emergency Department Kaiser Foundation Hospital Sacramento, CA doi:10.1016/j.annemergmed.2012.02.022
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The author has stated that no such relationships exist. 1. Artto V, Putaala J, Strbian D, et al. Stroke mimics and intravenous thrombolysis. Ann Emerg Med. 2012;59:27-32. 2. Assessment of the Safety and Efficacy of a New Thrombolytic Investigators. Single-bolus tenecteplase compared with frontloaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999;354:716-722. 3. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med. 1997;337:1118-1123. 4. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363:768-774. 5. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS trial. Ann Emerg Med. 2009;54:329-336.
In reply: Thank you for the opportunity to answer the letter of Dr. Durston. He raised a few points that deserve to be challenged. We do not advocate thrombolysis in stroke mimics but report that when we have mistakenly treated stroke mimic patients with thrombolysis, no harm has been done. The results of the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (rt-PA) trial have been denied also, but a reanalysis conducted by an independent committee has reached the same conclusions as the National Institute of Neurological Disorders and Stroke rt-PA investigators.1 All European Cooperative Acute Stroke trials were sponsored by Boehringer Ingelheim. The results of all those trials were published, although European Cooperative Acute Stroke and European Cooperative Acute Stroke 2 were negative and only European Cooperative Acute Stroke 3 was positive.2-4 The first pooled Volume , . : August