Month: November 2013

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

It’s Ultrasound Fightin’ Time

Trauma showdown: pneumothorax.  Chest x-ray or ultrasound?

The answer on the surface is pretty clear – unless you delve a little deeper into the precise question asked.

This meta-analysis of head-to-head ultrasound vs. CXR studies for the diagnosis of pneumothorax shows what we all essentially expect: the sensitivity of ultrasound is greatly superior, while specificity is statistically similar.  Sensitivities for ultrasound were better for trauma, using the linear (high frequency) probe, and when performed by Emergency Physicians, and ranged from 73% to 85%.  CXR sensitivities ranged from 32.6% to 49%, with heterogeneity based on study enrollment methods.  Specificities for each were ~99%.

What the study does not address – are these pneumothoracies clinically meaningful?  Ultrasound certainly finds more disease, but the newly identified disease will all be closer to the benign end of the spectrum.  I guarantee there are patients out there with normal CXR in the setting trauma, who then receive an ultrasound positive for pneumothorax, and are then referred to CT scan and surgical evaluation – would have ultimately been fine.  Before we move along to detecting more “disease”, we ought to examine the downstream consequences of missing or detecting these small pneumothoracies.

“Pleural ultrasonography versus chest radiography for the diagnosis of pneumothorax: review of the literature and meta-analysis”
ccforum.com/content/17/5/R208‎

The Curious Story of Diclegis

For no particular reason, I’ve recently become familiarized with the story of Diclegis (Diclectin in this study, and in Canada).  For use in pregnancy-induced nausea and vomiting, Diclegis is a delayed-release combination formulation of 10mg each of doxylamine and pyridoxine.  It was approved by the FDA in April of 2013, and has rapidly become first-line therapy.

The surprising bit – this is precisely the same drug our mothers took in pregnancy.  It was introduced in the 1950s as Bendectin, and it was estimated as many as 30% of pregnant women took this combination pill in the 1970s.  However, in the early 1980s, the manufacturer was the target of innumerable lawsuits alleging fetal malformation – and in 1983, voluntarily withdrew the drug from the market.  This choice was made solely due to the costs of defending against litigation, and not a reflection of the safety of the drug.  The physicians who had published data suggesting fetal risk were eventually discredited, and even the FDA noted in 1999 that Bendectin was not withdrawn for reasons of safety or effectiveness.

So – now it’s back, and, unsurprisingly, it works better than placebo.  This manufacturer-sponsored, double-blind, placebo-controlled trial demonstrated improvement with Diclectin in almost every measure.  And, 48% of Diclegis users asked for compassionate use of the study drug following conclusion of the study (although, so did 32% of placebo).  I’ve also discovered my new favorite disease-severity scoring system: the PUQE Score.

The downside: it costs ~$160 for 30 pills.

A brief perusal of the internet shows doxylamine, a sedating, first-generation antihistamine costs as low as 3 cents per tablet.  Pyridoxine, vitamin B6, costs as little as 6 cents per tablet.  Diclectin costs ~$5 per tablet.  You could pay for Diclegis – after all, it is a special “delayed-release” formulation where doxlyamine reaches peak concentration 6 hours after ingestion.  Or, you could do what obstetricians have been telling their patients to do for the last several decades: make your own equivalent dosing from the component medications at a fraction of the cost.

It certainly seems prudent to try the cheaper option, first.

“Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial”
http://www.ncbi.nlm.nih.gov/pubmed/20843504

Houston Resus Podcast

Featuring ACEP Teaching Award recipients Pratik Doshi & Yashwant Chathampally, I’m happy to point the way to a new University of Texas – Houston Emergency Medicine publication:  the Houston Resus Podcast.

Another new #FOAMed resource, driven primarily by our resident enthusiasm for teaching and critical care.

The full site is here:
http://www.houstonresus.com

And the iTunes link to the Podcast is:
https://itunes.apple.com/us/podcast/houston-resus-ut-houston-emergency/id685819529

Ultrasound First For Pulmonary Embolism?

Akin to the ultrasound first for appendicitis protocol currently in use, the authors of a recently published study in CHEST propose using ultrasound before CTPA in patients where the diagnosis of pulmonary embolism is being considered.

Their protocol consisted of bedside thoracic and lower extremity ultrasounds to identify either a confirmatory DVT or an alternative diagnosis that would account for the patient’s current presentation. In both the ED and inpatient settings,  ICU physicians evaluated this protocol’s performance in 100 patients. The 54 patients who were determined, due to an alternative diagnosis found on ultrasound, not to require further testing, none of them were found to have a pulmonary embolism on confirmatory CT. Of the remaining 40 patients (42%) whose ultrasound revealed no convincing alternative diagnosis or lower extremity DVTs, 12 were found to have pulmonary embolisms on their confirmatory CTPA. The authors conclude that though further studies are needed, an ultrasound first strategy will reduce the number of CTs obtained to rule out pulmonary embolism.

Though I am not opposed to the utilization of ultrasound as a bedside tool, using it to rule out pulmonary embolisms is a flawed paradigm. The proposed protocol is not one which rules out PE, it in fact does just the opposite. This protocol takes advantage of the high specificity of ultrasound for the diagnosis of pneumonia, pulmonary edema, and DVT. It employs the strategy of ruling in an alternative diagnosis or a lower extremity DVT. If no convincing diagnosis is discovered the patient will then move on to the more traditional rule out strategy of CTPA. This study essentially uses bedside ultrasound to address the  two most heavily weighted criteria on the Well’s Score, “an alternative diagnosis that is less likely than pulmonary embolism” and  “signs and symptoms of deep venous thrombosis”. In no way is this protocol fatally flawed. It has the potential to add a great deal to clinical decision making. Unfortunately it does not address the more serious epidemic in the current management of pulmonary embolisms. That is the egregious over-testing and subsequent over-diagnosis of pulmonary embolism in the ultra low risk patient.

“Ultrasound Assessment of Pulmonary Embolism in Patients Receiving Computerized Tomography Pulmonary Angiography”
journal.publications.chestnet.org/article.aspx?articleid=1763837

For more nihilism, emergency medicine and the art of doing nothing see emnerd.com and @CaptainBasilEM

Ultrasound First For Pulmonary Embolism?

Akin to the ultrasound first for appendicitis protocol currently in use, the authors of a recently published study in CHEST propose using ultrasound before CTPA in patients where the diagnosis of pulmonary embolism is being considered.

Their protocol consisted of bedside thoracic and lower extremity ultrasounds to identify either a confirmatory DVT or an alternative diagnosis that would account for the patient’s current presentation. In both the ED and inpatient settings,  ICU physicians evaluated this protocol’s performance in 100 patients. The 54 patients who were determined, due to an alternative diagnosis found on ultrasound, not to require further testing, none of them were found to have a pulmonary embolism on confirmatory CT. Of the remaining 40 patients (42%) whose ultrasound revealed no convincing alternative diagnosis or lower extremity DVTs, 12 were found to have pulmonary embolisms on their confirmatory CTPA. The authors conclude that though further studies are needed, an ultrasound first strategy will reduce the number of CTs obtained to rule out pulmonary embolism.

Though I am not opposed to the utilization of ultrasound as a bedside tool, using it to rule out pulmonary embolisms is a flawed paradigm. The proposed protocol is not one which rules out PE, it in fact does just the opposite. This protocol takes advantage of the high specificity of ultrasound for the diagnosis of pneumonia, pulmonary edema, and DVT. It employs the strategy of ruling in an alternative diagnosis or a lower extremity DVT. If no convincing diagnosis is discovered the patient will then move on to the more traditional rule out strategy of CTPA. This study essentially uses bedside ultrasound to address the  two most heavily weighted criteria on the Well’s Score, “an alternative diagnosis that is less likely than pulmonary embolism” and  “signs and symptoms of deep venous thrombosis”. In no way is this protocol fatally flawed. It has the potential to add a great deal to clinical decision making. Unfortunately it does not address the more serious epidemic in the current management of pulmonary embolisms. That is the egregious over-testing and subsequent over-diagnosis of pulmonary embolism in the ultra low risk patient.

“Ultrasound Assessment of Pulmonary Embolism in Patients Receiving Computerized Tomography Pulmonary Angiography”
journal.publications.chestnet.org/article.aspx?articleid=1763837

For more nihilism, emergency medicine and the art of doing nothing see emnerd.com and @CaptainBasilEM

hsTnI – All Promise, No Proof

At some point, it is true – there are no “bad” tests, only “bad” applications and interpretations of those tests.  One of those tests, as supported by Abbott Laboratories, is the high-sensitivity troponin.  You may also know this test as the “low-specificity” troponin – as, barring small improvements in the assay, a more sensitive test for the same biomarker is bound to result in decreased specificity.

This article describes the populations of ADAPT and APACE for whom high-sensitivity troponins are available.  These trials were part of a prospective derivation of an “accelerated diagnostic protocol,” in which low-risk patients (TIMI 0 or 1) with normal ECGs and two negative hsTnI two hours apart were found to be eligible for discharge from the Emergency Department.  With an approximately 14% of 30-day MACE (mostly nSTEMI) in each cohort, the authors strategy is reasonable:  only ~0.7% of patients meeting these three criteria eventually met a primary endpoint.

Conversation about this article led to this tweet by the primary author:

@EMManchester @240minDoc Precision of hs #troponin assays now shown to have great advantage. ED patients with possible ACS and this assay 1
— Louise Cullen (@louiseacullen) November 7, 2013

… except it isn’t entirely true.  The missing key to this statement is precisely what the “great advantage” entails.  These authors, sponsored by Abbott Laboratories, do not show this diagnostic strategy utilizing hsTnI is in fact superior to the same strategy using conventional troponins.  Quick back-of-napkin math shows the ADAPT conventional troponin cohort using this same strategy gives statistically similar results.  This critique led to the final tweet from the primary author:

@emlitofnote @EMManchester @240minDoc OK have to wait til part II where I can show you larger pop and more narrow CIs.
— Louise Cullen (@louiseacullen) November 8, 2013

Yes, with sufficient statistical power, there will likely be a reproducible difference between the different troponin assays.  When millions of patients are evaluated for chest pain every year, there may be a few for whom this improved sensitivity is clinically significant.  However, it is far more likely this increased sensitivity will end up referring additional patients for testing – resulting in increased costs and harms from overdiagnosis.  This is not the fault of the test – but, rather, simply that we don’t yet know the clinical significance of all small troponin elevations, and there is no appropriate algorithm for managing them in current practice.

I actually like what these authors are doing – using a rapid rule-out plus risk-stratification to safely discharge patients from the Emergency Department.  However, they’re selling hsTnI without proving it’s superior, in this strategy, to conventional troponin testing.  Then, as tests become more sophisticated, our interpretation of them needs to as well – and studies such as these need to do more than simply describe a “minimal-risk” cohort, but also provide useful guidance on the rest of the grey area troponin elevations.

Finally, I’d also like to finally see the TIMI score retired for use in the Emergency Department.  Please. Make it die.

“Validation of High-Sensitivity Troponin I in a 2-Hour Diagnostic Strategy to Assess 30-Day Outcomes in Emergency Department Patients With Possible Acute Coronary Syndrome”

Letter in JAMA

A couple months back, JAMA published Jeff Saver’s time-to-tPA association, derived from the Get With the Guidelines-Stroke Registry.  My critique of this article remains essentially the same, but this past issue JAMA published an edited version as a response to Dr. Saver.

While many of you will find the content behind the JAMA paywall, the basic gist of Saver’s response to my letter is:

  • tPA-treated stroke mimics are not included in the GWTG-Stroke registry during the study period.  It is an optional reporting field.
  • The tiny bit of data from original NINDS showed rapidly-improving patients from the placebo group were equally distributed between 59 to 90 minutes and 91 to 180 minutes (3/145 vs. 4/167).
  • The onset-to-treatment-time and outcome association was consistent between NIHSS 0-14 and NIHSS 15-42, and therefore any effects from TIAs must be insignificant.

In summary: they don’t really know how many TIAs/stroke mimics/aborted strokes there were, but they can draw lines around some numbers to support their conclusion.

These are reasonable responses from their standpoint.  I would point out, however, the NINDS group made specific efforts to exclude “rapidly improving” symptoms from inclusion, probably resulting in extreme extra care in preventing enrollment of TIAs.  This population is unlikely to be generalizable to current tPA-happy practice across medicine.  They do not, unfortunately, address the problem of “aborted stroke” coding, which further received a shout-out on Twitter from Dr. Hsia:

@emlitofnote hit the mark in @JAMA_current with citing our averted #stroke paper: #tPA-treated does not equal #stroke http://t.co/6aE7bFlm7k
— Amie Hsia (@DCStrokeDoc) November 8, 2013

I’ll try and get a peek at the GWTG-Stroke data myself, but with the literature documenting anywhere from 2% to 31% stroke mimic treatment rate – with the actual true rate probably exactly in the middle of that range – it’s critically important to uncover risks and costs of inappropriate tPA administration.  If the GWTG-Stroke registry is a true quality device, it needs to do a better job of measuring adverse events.

Or, you could end up like Houston Texans’ coach Gary Kubiak, who received tPA last week for a stroke mimic (currently reported as having had a TIA – which I find dubious, but I have no personal knowledge of the case).

“Acute Ischemic Stroke and Timing of Treatment”
http://www.ncbi.nlm.nih.gov/pubmed/24193085

Strep Throat? Stay Home!

NBC News covered this useful-seeming innovation last week – a predictive score to help patients decide whether their sore throat might be caused by Group A Strep.  It seems a quite reasonable proposition on the surface – if patients can receive guidance on their pretest likelihood of disease, they might rather not seek unnecessary medical care.  For the 12 million physician visits every year for sore throat, putting a dent in this would account for sizable cost savings.

This study describes retrospective development of a “Home Score” for use by patients, based on a MinuteClinic database of 71,000 sore throat presentations for which a strep swab was performed.  The authors split the data into a derivation and a validation set, and produced a complex mathematic scoring system, from 1 to 100, based off age, fever, cough, and biosurveillance data.  Using a score of 10 as a cut-off, the validation set sensitivity was 99%, specificity was 1%, and the prevalence data used resulted in a validation negative predictive value of 87%.  This NPV, the authors say, is the important number regarding advising patients whether they ought to seek care for GAS.

There are a few issues with this derivation, of course.  First of all, the derivation population is subject to selection bias – as only patients with strep swabs are included.  Then, the MinuteClinic data has to be generalizable to the remaining adult population.  The use of the Home Score also depends on the availability of biosurveillance data for their specialized algorithm.  Finally, their NPV cut-off of 90% would theoretically obviate clinic visits for only 230,000 of the 12 million patients seeking care for sore throat – a large drop, but only a drop in the bucket, nonetheless.

And, the elephant in the room: Group A Strep doesn’t need antibiotics in the United States.  The likelihood of adverse reactions to treatment of GAS exceeds the chance of benefit – whether progression to peritonsilar abscess or rheumatic fever is considered.  A few folks on Twitter chimed in to echo this sentiment when this story was discussed:

@embasic @DrLeanaWen @MDaware @NBCNewsHealth just need to redesign app to say “no you don’t” regardless of sx
— Anand Swaminathan (@EMSwami) November 10, 2013

There are legitimate reasons to visit a physician for sore throat – but, in the U.S., nearly all uncomplicated pharyngitis can safely stay home, GAS or not.

“Participatory Medicine: A Home Score for Streptococcal Pharyngitis Enabled by Real-Time Biosurveillance”
http://www.ncbi.nlm.nih.gov/pubmed/24189592

Another Appeal for Prudent Antibiotics

Bronchitis, deadly scourge of man – at least, considering the quantity of antibiotics prescribed, it must be, right?

Or, the cure is worse than the disease, as these authors seem to demonstrate.  This is a parallel, single-blinded, placebo-controlled trial in 9 primary care centers in Catalonia, Spain, enrolling patients with acute bronchitis.  Non-immunosuppressed patients with a productive cough of less than a week’s duration were randomized to amoxicillin-clavulanic acid, ibuprofen, or placebo for a 10 day course.  The primary outcome was time to cure, with treatment failure and safety outcomes as secondary outcomes.

With approximately 140 patients in each group, the only clinically meaningful significant difference between groups was the incidence of adverse events in the amoxicillin-clavulanic acid group.  These were mostly gastrointestinal events, occurring in 12% of the antibiotic group, compared with 5% of the ibuprofen group and 3% of the placebo group.  Days with cough, treatment failure, and time to overall symptom resolution showed no significant differences between groups.  There was some suggestion of a trend towards benefit from the ibuprofen arm, but this would have to be confirmed in a larger trial.

The main limitation of this article is failure to include a macrolide antibiotic as a comparator, considering the expected bacterial epidemiology of ambulatory respiratory infections.  Regardless, this adds to the body of evidence demonstrating the futility of antibiotics in healthy patients with bronchitis – and I’d expect similar findings even if azithromycin were included.

“Efficacy of anti-inflammatory or antibiotic treatment in patients with non-complicated acute bronchitis and discoloured sputum: randomised placebo controlled trial”
www.ncbi.nlm.nih.gov/pubmed/24097128