Category: Neurology

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

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

Intracranial Angioplasty, Where Did We Go Wrong?

This week The Lancet published a friendly reminder from the SAMMPRIS investigators warning us that it is a bad idea to go putting stents in places they do not belong. This unintended favor came in the form of the publication of the long term follow-up from the Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis trial online this week in The Lancet.

The SAMMPRIS trial, originally published in the NEJM in 2011 applied the frequently  attempted, but rarely accurate mantra,“If it works on the heart then it should work on the brain.” The authors took high risk TIA patients with radiologically confirmed intracranial stenosis and randomized them to “aggressive” medical management or percutaneous transluminal angioplasty and stenting (PTAS). The trial was stopped early because of the exorbitant amount of periprocedural strokes and death among those in the PTAS group. Specifically there was an 8.9% absolute increase in stroke and 1.8% increase in mortality within the first 30 days of enrollment. The authors’ summary of this dramatic failure was that the true benefits and harms could not be assessed at the time of initial publication, as there was not enough data to determine if the long term benefits outweighed these initial harms.

The recent paper is the 2-year follow up of this cohort and specifically addresses these presumed “long term benefits”. The overall occurrence of stroke was 19% in the medically managed group vs 26% in the PTAS group. It is apparent no clinically significant benefit exists especially when considering the devastating early harms. Yet another example of our limited understanding of the pathophysiology of atherosclerotic disease, and the ramifications of introducing thrombogenic objects into already tight spaces.

“Aggressive Medical Treatment With or Without Stenting in High-Risk Patients with Intracranial Artery Stenosis (SAMMPRIS): the Final Results of a Randomized Trial” http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62038-3/fulltext

Nihilism, Emergency Medicine, and the art of doing nothing at emnerd.com and @CaptainBasilEM

Intracranial Angioplasty, Where Did We Go Wrong?

This week The Lancet published a friendly reminder from the SAMMPRIS investigators warning us that it is a bad idea to go putting stents in places they do not belong. This unintended favor came in the form of the publication of the long term follow-up from the Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis trial online this week in The Lancet.

The SAMMPRIS trial, originally published in the NEJM in 2011 applied the frequently  attempted, but rarely accurate mantra,“If it works on the heart then it should work on the brain.” The authors took high risk TIA patients with radiologically confirmed intracranial stenosis and randomized them to “aggressive” medical management or percutaneous transluminal angioplasty and stenting (PTAS). The trial was stopped early because of the exorbitant amount of periprocedural strokes and death among those in the PTAS group. Specifically there was an 8.9% absolute increase in stroke and 1.8% increase in mortality within the first 30 days of enrollment. The authors’ summary of this dramatic failure was that the true benefits and harms could not be assessed at the time of initial publication, as there was not enough data to determine if the long term benefits outweighed these initial harms.

The recent paper is the 2-year follow up of this cohort and specifically addresses these presumed “long term benefits”. The overall occurrence of stroke was 19% in the medically managed group vs 26% in the PTAS group. It is apparent no clinically significant benefit exists especially when considering the devastating early harms. Yet another example of our limited understanding of the pathophysiology of atherosclerotic disease, and the ramifications of introducing thrombogenic objects into already tight spaces.

“Aggressive Medical Treatment With or Without Stenting in High-Risk Patients with Intracranial Artery Stenosis (SAMMPRIS): the Final Results of a Randomized Trial” http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62038-3/fulltext

Nihilism, Emergency Medicine, and the art of doing nothing at emnerd.com and @CaptainBasilEM

The “Ottawa SAH Rule”

This is a rather dangerous article for many reasons.  Firstly, it’s published in a high-impact journal and received a fair bit of coverage in the news media.  Secondly, it concludes its discussion by suggesting this ought to be adopted as a standardized rule for the evaluation of acute headache – this isn’t just a descriptive study on features of subarachnoid hemorrhage, it’s been given an official-sounding title, the “Ottawa SAH Rule”.  Because of this, there’s significant potential for the rule described here to be adopted as widespread practice.

Therefore – it better be nearly perfect.

This is a prospective cohort from 10 university-affiliated Canadian hospitals.  They looked at non-traumatic headaches reaching maximal intensity within 1 hour not part of a recurrent headache syndrome, and found 132 patients with SAH out of 2,131 assessed.  They specifically gathered information on three previously-derived prediction rules and found none of them were 100% sensitive – so they chose the required elements from each to reach 100% (95% CI 97.2-100) sensitivity.  The cost of this 100% sensitivity?  Degeneration of specificity from the 28-35% in the three individual rules down to 15% (95% CI 13.8-16.9) in the final rule.  The authors observed application of the derived rule would have decreased investigations for SAH from 84% of the enrolled cohort down to 74% of the enrolled cohort, and thusly their rule is superior to routine clinical practice by maintaining 100% sensitivity while decreasing resource utilization.

I think their inclusion criteria are fine – a rapid-onset, severe, atraumatic headache is the classical population of interest.  Patients without this feature have such a low incidence of SAH that it’s unreasonable to evaluate for it.  Their outcome measures, unfortunately, were a little softer.  The positive diagnoses are reasonable – CT proven SAH or positive lumbar puncture with a source feature on cerebral angiography.  However, only 82% underwent CT and 39% underwent LP, with a six month telephone follow-up – and a small number were lost to follow-up.  Many would argue that CT alone is not sufficient for ruling out SAH, and 6-month survival is a limited proxy.  This weakens its claim for 100% sensitivity.

Then, of course, a 15% specificity is awful.  This isn’t necessarily a criticism of the authors, but more a recognition of the limitation of distilling diverse clinical data into concise decision instruments.  19 different patient features were significantly different between the SAH and no-SAH groups; reducing this to just 6 features discards so much information that an instrument designed for a complex clinical prediction is bound to fail.  There were 1,694 false positives by the rule compared with 132 true positives.  If this rule is applied without the strict exclusion criteria specified in the publication, there may be a huge number of inappropriate investigations.

Then, the rate of investigation comparison is also probably invalid.  These institutions underwent specific 1-hour orientation to the study being performed and were actively involved in gathering clinical data for the study.  I’m certain the 84% rate of investigation observed was conflated by the ongoing research at hand.  The previous Perry study from 2011 had an evaluation rate of 57%, so it’s hard for me to believe the statistics from the current publication.

Finally, the kappa values for inter-observer agreement were rather mixed.  Based on only sixty cases where two physicians evaluated the same patient, four of the six final rule elements had kappas between 0.44 and 0.59, representing only moderate agreement.  This is a significant threat to the internal validity of the underlying data in support of their rule.

Overall, yes – the elements they identify through their observational cohort are likely to capture most cases of SAH.  However, the limitations of this study and the poor specificity make me reluctant to buy in completely – and certainly not adopt it as a standardized “rule”.

“Clinical Decision Rules to Rule Out Subarachnoid Hemorrhage for Acute Headache”
http://www.ncbi.nlm.nih.gov/pubmed/24065011

ACEP/AAN Guideline Writers Respond

Some of the authors of the new ACEP/AAN clinical policy have responded to the BMJ report discussing conflict-of-interest in guidelines, focusing on the science behind the tPA portion.

If you haven’t already visited, it’s truly a star-studded sort of discussion, with David Newman, Jerome Hoffman, Robert Solomon, Jeffrey Saver, Stephen Messe, Peter Sandercock, and James Grotta, among others.

Most Positive LPs Aren’t SAH

There’s still active debate regarding whether CTs are now sensitive enough to pick up all subarachnoid hemorrhage, and whether lumbar puncture is about to go the way of the dodo.  Their argument is based on the premise that, despite the imperfect gold standard of this practice changing study, very few negative CTs result in positive lumbar punctures.

However, as this chart review study shows, in real-world practice, most positive LPs may in fact be false positives.  This is a 10 year review at Barnes Jewish Hospital, where they were able to identify 57 patients with negative CT and positive LP, who subsequently underwent angiography for diagnostic confirmation.  Of these, three patients had positive findings – only two of which were ultimately determined to be true positives.

This is a little different than previous reviews, in which 53% of negative CT/positive LP represented true positives.  These authors suggest the previous higher-yield results are likely the result of dependence on xanthrochromia as part of the diagnostic evaluation, and a cohort with a longer duration of symptoms prior to LP.

The truth is likely somewhere in the middle, splitting the difference between useless and half-wrong.  This probably aids the “CT, no LP” camp – of which I tend towards – by demonstrating the preponderance of false positives inherent to LP for SAH.

“Yield of Cather Angiography After Computed Tomography Negative, Lumbar Puncture Positive Subarachnoid Hemorrhage”
www.ncbi.nlm.nih.gov/pubmed/23619131‎

Rewriting The Inconvenient Rules on tPA

Stroke neurologists spent the first decade of the tPA era explaining away negative studies and excluding patients from meta-analyses secondary to “protocol violations”, emphasizing that strict adherence to NINDS criteria supports clear benefit to tPA.  As we’ve seen, however, the new push is rather to take back the night, expanding the treatment window out to 4.5 hours, 6 hours, the extreme elderly, and all sorts of previously excluded patients.

But we don’t need evidence to do that – we just need Genentech to fly a select group of experts out to a meeting so they can issue a report in support of throwing out the previous exclusion criteria: The Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force.  The astute reader might already recognize the prevailing bias just from the acronym for their group.

This is the first report, specifically addressing “rapidly improving stroke symptoms”.  I agree with the general concept – if a severely disabled patient has shown some improvement, but are still profoundly limited – it is reasonable to consider them a candidate for treatment.  The original NINDS group was interested primarily in excluding TIAs – folks they thought would go on to have zero residual disability.  However, these authors are already over the cliff on treating nearly every improving and mild stroke symptom.  In true flabbergasting lunacy, a majority of surveyed participants wouldn’t even randomize patients who rapidly improved to an NIHSS of 0 into a clinical trial comparing outcomes with tPA vs. placebo – unless the patient had zero disability, they would simply treat.

I’m no longer surprised by such extreme viewpoints.  After all, here are the authors’ significant COIs:

Broderick: Genentech, Novo Nordisk, Schering Plow, PhotoThera
Grotta: none
Kasner: Genentech
Khatri: Genentech (for a study called “Potential for rtPA to Improve Strokes with Mild Symptoms”!), Penumbra, Jannsen, Lake Biosciences, Medical Dialogues
Levine: Genentech
Meyer: Genentech, The Medicines Company
Panagos: Genetench
Romano: Genentech
Scott: none
Kim: none

“Logistical support for the in-person meeting was provided by Infusion, An InforMed Group Company, who was funded by Genentech, Inc. Travel funds (lodging, airfare, and food) to this meeting were also provided to some participants by Genentech, Inc.”

I cannot fathom why stroke neurologists are still befuddled by continued skepticism towards their tPA recommendations when they persist in pumping out recommendations saturated by bias.

“Review, Historical Context, and Clarifications of the NINDS rt-PA Stroke Trials Exclusion Criteria : Part 1: Rapidly Improving Stroke Symptoms”
www.ncbi.nlm.nih.gov/pubmed/23847249‎

23.4% – The Next Great Hypertonic Saline

Mannitol and hypertonic saline are the most commonly used medications to ward off the catastrophic complications of malignant increased intracranial pressure.  Hypertonic saline, in my experience, has typically been 3%, but there are multiple different concentrations in use.

These authors perform a systematic review and meta-analysis of 23.4% saline.  After all, the theory goes, a more osmotically powerful concentrated solution will exert greater physiologic effects.  They identified 11 articles, six of which they included in a meta-analysis to identify an effect size for intracranial pressure reduction.  Using the pooled data, the measured effect was a 55.6% (CI 44%-67%) decrease in ICP within 60 minutes.  Their systematic review uncovered few adverse effects of 23.4% – transient hypotension and rare hemolytic anemia – and even reported acute reversal of herniation syndromes with good neurologic outcomes.

There is a ton of heterogeneity between studies – both in dosing of 23.4% saline, co-administration of mannitol, and underlying pathophysiology of ICP.  Most studies are also tiny, ranging between 8 and 68, and either retrospective reviews or prospective non-random selection.  Many studies did not report patient-oriented outcomes, so it’s hard to truly compare this practice to the current standard of care.

That being said, it seems interesting for potential use as “rescue” therapy when the alternative is permanent cerebral asphyxiation – and further study is needed to describe the appropriate (if any) population for use.

For reference: the salinity of seawater is about 3.5%, the Great Salt Lake varies between 5-27%, and the Dead Sea is approximately 33.7%.  Definitely not appropriate for a peripheral intravenous line!

“High-Osmolarity Saline in Neurocritical Care: Systematic Review and Meta-Analysis”

BMJ, Clinical Guidelines & tPA

A little hullabaloo today regarding a new report in the BMJ regarding problems with the creation of clinical practice guidelines, including a substantial portion of the article devoted to the conflicts of interest swirling about the use of tPA in acute ischemic stroke.

There have already been personal attacks – even from ACEP’s official twitter account – against the author.  These seem to be motivated by the author’s coverage of the new ACEP/AAN clinical practice guidelines for tPA – and miss the overall point that patients are best protected and served by guidelines that are formulated in the absence of conflict-of-interest.  tPA for acute stroke, erythropoetin endorsement by the National Kidney Foundation, the errant one-man crusade for steroids in spinal cord trauma, and cholesterol treatment guidelines are all discussed in the context of cautionary tales regarding the influence of conflict-of-interest.

Whichever side of the expand/limit tPA in acute stroke debate you fall upon, the issues of sponsorship bias, one-sided panelists on a still-controversial practice, and lack of open peer review for the ACEP/AAN guidelines ought to be unacceptable.  Patients and practicing clinicians benefit from healthy debate and recognition of the limitations of the science, which seems clearly to have been lacking in the creation of these guidelines.

“Why we can’t trust clinical guidelines”
http://www.bmj.com/content/346/bmj.f3830