tPA for TIA?!

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

Over the last year, the debate over the use of alteplase in acute ischemic stroke has continued to heat up. The issue really boiled over in June after BMJ reporter Jeanne Lenzer wrote a scathing evaluation of clinical guidelines after the publication of the new ACEP Clinical Policy on the use of alteplase in ischemic stroke. Now, to muddy the waters further, enter the discussion of giving alteplase to transient ischemic attacks (TIAs).

That’s right, this week, the American Journal of Emergency Medicine published a case report discussing the administration of alteplase to a patient that the treating physicians agreed had a TIA. Before we get into the article itself, let’s take a stroll back in time to 1995.

On December 14th, 1995, the NEJM published the NINDS trial and ushered in the era of alteplase for acute ischemic stroke. One of the major exclusions in the study, and one that few have argued with, was “rapidly improving or minor symptoms.” In essence, NINDS sought to exclude patients with TIAs. The reason for this is elegantly stated by Dr. David Liebeskind (UCLA Stroke Center):

“Thrombolysis is not a rational or evidence-based therapeutic option for transient ischemia irrespective of vascular status . . . The prevailing obsession with arterial occlusion has erroneously focused attention on clots rather than ischemia . . . Imaging of occlusion without consideration of clinical details or pahtophysiolgical mechanisms may therefore be misleading.” (Stroke 2010).

From a pathophysiological and outcome standpoint, there is no good reason to administer alteplase to a patient with a TIA regardless of imaging. If the patient has an NIHSS of 0, there is no room for improvement, only harm.

In spite of this, the authors of the above case report recount the story of a 37-year-old woman who presented with a TIA. Her presenting NIHSS was 0. CT angiogram showed a “near total occlusion of the M2 segment of the MCA.” There is no report about the presence of an ischemic penumbra.  After the CTA was completed, the patients’ symptoms returned but then rapidly resolved. At this point, the physicians decided to administer alteplase in spite of the absence of symptoms. She was then transferred to a stroke center for consideration of neurointerventional care (a therapy proven not to work. See NEJM March 2013). Interestingly, the authors base their decision to treat on imaging findings but never discuss the resolution of these findings after therapy (i.e. no mention of repeat CTA or MRI/MRA).

What does this tell us about alteplase for TIA? Not much. This is a case report and gives us no information about causality of treatment. It doesn’t even show efficacy of concept because pathophysiologically the idea of giving alteplase to a TIA doesn’t make sense.  The authors talk about weighing risks and benefits outside of standard indications and contraindications. But what they have done is give a potentially dangerous, life-threatening medication to a patient with no disability at the time of administration. They have taken on all the risk of the drug without any potential benefit.

What this report really shows is the concept of “indication creep.” Earlier this year, the TREAT task force recommended that patients with rapidly resolving symptoms (but some continued deficit) should be considered for thrombolytic treatment (Stroke 2013). This recommendation wasn’t based on any literature but rather an expert consensus from a meeting sponsored by Genentech (Boehringer-Ingelheim in Europe). This case report is simply the logical extension of an illogical idea: if thrombolytics should be given to a patient with rapidly resolving symptoms, why not give it to one with no symptoms but imaging abnormalities?

The authors conclude by pointing the finger at EM physicians stating that we, “have been historically slow in adopting thrombolytic therapy for CVA.” We haven’t embraced this treatment because we don’t see definitive evidence that it works and we do see the potential harms. A month ago at ACEP, a group of EPs voted 75% to 25% to reconsider the ACEP clinical policy on tPA. The authors go on to suggest that this patient did well and required no further treatments because she received “off-label” thrombolytics. This link violates everything we know about research. Just because something happens after you do something, doesn’t mean the thing you did caused the outcome. Domhnall Brannigan told a wonderful story during his lecture at SMACC last year about a patient who presented with stroke-like symptoms and nausea. Dr. Brannigan gave the patient ondansetron for the nausea and minutes later the patient had resolution of his symptoms. None of us, though, are rushing to give ondansetron for ischemic CVA. The proposition by these authors is just as ludicrous.

“TPA for TIA: The case for “off-label” use of thrombolytics.”
http://www.ajemjournal.com/article/S0735-6757(13)00747-X/fulltext

References
Sobel RM, Wu DT, Hester K, Anda K. tPA for TIA: The case for “off-label” use of thrombolytics. Am J EM 2013; 06 November 2013 (10.1016/j.ajem.2013.10.046

The National Institute of Neurological Disorders and Stroke, rt-PA Stroke Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. NEJM 1995; 333(24): 1581-7.

Liebskind DS. No-Go to tPA for TIA. Stroke 2010; 41(12): 3005-6.

The Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force. Levine SR, Khatri P, Broderick JP, Grotta JC et al. Review, historical context, and clarifications fo the NINDS rt-PA stroke trials exclusion criteria: part 1: rapidly improving stroke symptoms. Stroke 2013; 44: 2500-2505

14 thoughts on “tPA for TIA?!”

  5. Derek, you're not missing much on this one. Basically, they say that no one knows if it's safe to give tPA with New Oral Anticoagulants (NOACs) and they have an 83 year old with a dense MCA stroke (aphasia, gaze paresis). They're conclusions are much more limited and they say that there should be more studies on the subject before making any recommendations. One of the interesting things is that they don't take her for neurointerventional stating that it was contraindicated based on age. The last author has COI as a consultant for Boehringer, Pfizer, Bristol Myers Squib and Bayer. That's a lot of COI.

  6. Derek, you're not missing much on this one. Basically, they say that no one knows if it's safe to give tPA with New Oral Anticoagulants (NOACs) and they have an 83 year old with a dense MCA stroke (aphasia, gaze paresis). They're conclusions are much more limited and they say that there should be more studies on the subject before making any recommendations. One of the interesting things is that they don't take her for neurointerventional stating that it was contraindicated based on age. The last author has COI as a consultant for Boehringer, Pfizer, Bristol Myers Squib and Bayer. That's a lot of COI.

  9. First, do no nothing.

    Then treat the side effects of the first treatment.

    Then treat the side effects of the treatment of the side effects of the first treatment.

    Then . . . .

    If the patient survives, publish.

    Dr. Lucy VanPelt is prescribing that Charlie Brown kick a football to get better.

    .

  10. First, do no nothing.

    Then treat the side effects of the first treatment.

    Then treat the side effects of the treatment of the side effects of the first treatment.

    Then . . . .

    If the patient survives, publish.

    Dr. Lucy VanPelt is prescribing that Charlie Brown kick a football to get better.

    .

  11. "…After the CTA was completed, the patients’ symptoms returned but then rapidly resolved…"

    Playing devil's advocate:

    Those clinicians might argue "The patient wasn't asymptomatic — she was very symptomatic! She was having intermittent focal neurological deficits! And we have a CTA showing us a near-total occlusion! It was like the wheel on Price is Right, spinning, spinning… will it stop on $1.00 or will we miss the Showcase Showdown?"

    But I agree; giving this woman tPA is not supported by the literature and was not a good idea.

  12. "…After the CTA was completed, the patients’ symptoms returned but then rapidly resolved…"

    Playing devil's advocate:

    Those clinicians might argue "The patient wasn't asymptomatic — she was very symptomatic! She was having intermittent focal neurological deficits! And we have a CTA showing us a near-total occlusion! It was like the wheel on Price is Right, spinning, spinning… will it stop on $1.00 or will we miss the Showcase Showdown?"

    But I agree; giving this woman tPA is not supported by the literature and was not a good idea.

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