The New, Improved, ACEP Clinical Policy for tPA in Stroke

Released with minimal fanfare, approved by the ACEP Board of Directors on June 24th, the revised ACEP Clinical Policy regarding the use of TPA for acute ischemic stroke has gone final.

It is, of course, a vast improvement over the 2012 version – but has, unfortunately, changed for the worse since the draft was posted.

The highlights:

  • The Level A suggestion to consider the risk of ICH with tPA administration has been eliminated.  It has been moved, nonsensically into the Level B recommendations for offering tPA – when, frankly, it’s the only consistent finding across all the evidence.
  • The Level B recommendation in which tPA “may be given” within 3 hours has been strengthened to “should be offered and may be given”.  Obviously, a profound difference.
  • The Level B recommendation for 3-4.5 hours remains unchanged, based on only one flawed piece of Class II evidence (ECASS III), and conflicting Class III evidence (ATLANTIS, IST-3, meta-analyses).
  • The Level C recommendation to engage in shared decision-making now states “when feasible”, which is obviously open to interpretation.
  • No further clarification of “carefully selected patients” or “systems … in place to safely administer the medication” is provided.

Some wins, some losses.  Obviously, the shared decision-making supporting any “offer” of tPA can be very different, depending on an individual clinicians’ interpretation of the evidence – and it is nice to see the prior COI-infested husk of rotten guidelines finally, officially, tossed on the compost heap.  Let us hope (irrationally, of course) the efforts underway in the United Kingdom spur further, independent, investigation with which to better understand and individualize the risks and benefits of treatment with tPA.

“Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department”

It’s the Flu! It’s Not the Flu!

Every year, influenza season travels the globe, led by the four horsemen of the apocalypse, bringing toys and good cheer to obedient little girls and boys.  Unfortunately, this very same influenza contributes to hundreds of thousands of hospitalizations and tens of thousands of deaths in the U.S. alone.  And, despite such ubiquity, clinicians are utterly inept at rapid, accurate diagnosis.

This small study reviews the diagnostic performance of clinicians at a single hospital during the influenza season of 2012-13.  A convenience sample of 270 patients presenting with any history of respiratory or febrile illness were screened and swabbed for influenza, and the results of eventual PCR testing were compared with the sensitivity of the CDC definition of “influenza-like illness” and accuracy of subsequent clinical diagnosis.

The highlights:

  • 42 of 228 patients were positive for influenza.
  • Only 40 out of the entire cohort of 270 met the CDC definition of ILI, a cough or sore throat coupled with fever.
  • 15 of influenza positive patients were thought to have influenza by the treating clinician, as well as 50 of the influenza-negative.
  • A third of actual influenza patients received an antiviral, while half were treated with antibiotics.

Certainly not a paragon of medical prowess.

The authors, unfortunately, use their data as a platform for wickedness.  In the context of inadequate diagnostic skill, the authors call for improved rapid diagnostic tools – such as those manufactured by the study sponsor.  Furthermore, the entire need for such rapid tools is predicated on the assumption of benefit from antiviral therapy – which is also espoused by the authors, who have undeclared ROI with Roche.

“Clinical diagnosis of influenza in the ED”

Let’s Reverse: Dabigatran

‘Round EMLoN headquarters, we’re big fans of a few medications.  Oseltamivir.  Ticagrelor.  Alteplase.  And, finally, dabigatran.  After all, a blog needs content – and controversy begets content.  Dabigatran, if you need any reminder, is an irreversible direct thrombin inhibitor, whose sponsored trial results continue to receive “updates” for additional “newly discovered” adverse events.  It was also subject to a $650M legal settlement related to its under-emphasized risks to patients.

This pair of articles, presumably, addresses one critical issue with dabigatran – lack of effective reversal options.  The first, published in the Lancet, relates to controlled pharmacokinetics of the monoclonal antibody fragment binding dabigatran, idarucizumab.  Healthy volunteers, all men, were loaded with four days of dabigatran, and the four cohorts of 12 participants each were assigned to receive various doses of idarucizumab.  By every measure of coagulation function, the two highest-dose cohorts effectively reversed dabigatran.  However, given the small number of participants, it is impossible to claim idarucizumab is safe, even in the setting of only a handful of adverse events.  Entertainingly, almost half the research participants complained of at least two subjective adverse symptoms during the dabigatran load.

The second article, in the NEJM, is bizarrely an interim analysis of the first 90 patients enrolled of a planned 300 patient phase III study of idarucizumab.  The appropriateness of reporting a fraction of enrollment from a sponsored phase III study, let alone in the NEJM, is unfathomable.  Regardless, the study enrolled patients requiring urgent reversal for life-threatening bleeding or urgent surgery.  As in the Lancet publication, administration of idarucizumab reversed coagulation parameters almost instantly.  There was, however, a small rebound in anticoagulation and dabigatran activity approximately 12 hours after the initial dose, suggesting a limit to the durability of the reversal in some patients.

Clinically, outcomes are a little difficult to evaluate without a specific control or comparison group.  The patients generally did poorly – 18 of 90 died – but, probably as expected in an elderly, anticoagulated cohort confronted by acute medical issues.  In the patients with life-threatening bleeding, time to resolution was 11.4 hours following administration of idarucizumab – not dissimilar to the use of prothrombin-concentrate complexes for warfarin or Factor Xa inhibitors.  Of course, nearly a quarter of patients were enrolled despite what turned out to be normal initial coagulation profiles – inflating any measure of apparent reversal or bleeding time cessation.  And, again, in such a small sample, without a control population, no obvious statement on safety may be made, even in the setting of just a handful of thromboembolic events.

In short, Boehringer Ingelheim, having scattered the nails in the street, is almost ready to sell you new tires.  Certainly, whatever the adverse effects of idarucizumab, it is better than uncontrolled bleeding – and will doubtless be a welcome addition to many formularies.  The costs, however, will be quite unwelcome – and without a method to readily detect dabigatran activity in the clinical setting, this expensive antidote will likely be uselessly given to many patients without the possibility of benefit, as seen in a quarter of patients here.

Finally, as a bit of an aside, the accompanying editorial is penned by a physician who receives consulting fees from both Boehringer Ingelheim and Portola specifically for his work on the antidotes for dabigatran and the Factor Xa inhibitors.  Is it really so difficult to identify qualified editorialists without the most egregious possible COI?

“Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy  male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial”

“Idarucizumab for Dabigatran Reversal”

New Text Message: Be a Hero! Go!

This pair of articles from the New England Journal catalogues, happily, the happy endings expected of interventions undertaken to increase early bystander CPR.

The first article simply describes a 21 year review of outcomes in Sweden following out-of-hospital cardiac arrest, measuring by 30-day survival in patients who received bystander CPR prior to EMS arrival, with those who did not.  In this review, 14,869 cases received CPR prior to EMS arrival, with a 30-day survival of 10.5%.  The remaining 15,512 cases did not receive CPR prior to EMS arrival, and survival was 4.0%.  This advantage remained, essentially, after all adjustments.  Thus, as expected, bystander CPR is good.

The second article is the magnificent one, however.  In Stockholm, 5,989 lay volunteers were recruited and trained to perform CPR.  Each of these volunteers also consented to make themselves available by contact on their mobile phone to perform CPR in case of a nearby emergency.  Patients with suspected OHCA were geolocated, along with those enrolled in the study, and randomized into two groups to either contact nearby volunteers, or not.  In the intervention group, 62% received bystander CPR, compared with 48% of the controls.  The magnitude of this difference was statistically significant, but, however, the survival difference of 2.6% (CI -2.1 to 7.8) favoring the intervention was not.

But, I think we can pretty readily agree – if bystander CPR improves survival, and text messages to nearby volunteers improves bystander CPR – it’s a matter of statistical power, not futility of the intervention.  If the cost of recruiting and contacting CPR-capable volunteers is low, it is likely increased neurologically-intact survival is the result.

This a an excellent initiative I hope is copied around the world.

“Early Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest”

“Mobile-Phone Dispatch of Laypersons for CPR in Out-of-Hospital Cardiac Arrest”

The Era of the Appendectomy is Not Over

However, it might also be accurate to say: The Era of the Emergency Appendectomy is Over.

This is the Appendicitis Acuta trial, a multi-center trial from Finland, randomizing CT-diagnosed, suspected acute appendicitis to either antibiotics or immediate open appendectomy.  Randomizing 530 patents, the trial failed to meet its pre-specified endpoint of non-inferiority, as measured by the outcome of need for appendectomy within 1 year of the initial episode.

And, by “non-inferior”, I’m a little uncertain regarding their clinical interpretation of such.  Their statistical threshold, based on prior evidence, was a non-inferiority margin of 24%, and the actual rate of antibiotic treatment failure was 27%.  However, frankly, I’m not certain how even meeting their non-inferiority margin would be considered clinically acceptable.  I am all for innovating new, cost-effective approaches challenging classical dogma, but uncomplicated laproscopic appendectomies are just about the most-practiced, least harmful of surgical procedures.

The general argument in favor of antibiotics stems firstly from economic considerations – it’s far cheaper to use antibiotics – and secondly from avoidance of operative complications.  Even here, in which patients uncharacteristically underwent open appendectomies, the overall complication rate of 20.5% is inflated by 19 of 273 patients with superficial wound infections.  Minor, transient, treatable complications should not be included in such an analysis.  The 23 patients with continued pain and bowel symptoms at 1-year follow-up, however, is concerning.  But, again, whether such numbers from open appendectomies reflect the long-term symptom rate of laproscopic surgery is questionable.

This trial, at least, does seem to show an antibiotics-first strategy is not unreasonable.  Even as this was a negative trial, 72.7% of patients did avoid recurrent appendicitis and surgery – and of those who did require surgery, only a handful crossed-over on the initial hospitalization.  Additionally, the delay in definitive management was not specifically associated with increased complications.  It would be interesting to someday see 5- and 10-year follow-up, and whether further patients ultimately fail non-operative management, as truly, the lifetime recurrence rate is the better measure of a successful delayed antibiotic strategy.

I would not fault adoption of a strategy of offering antibiotics and observation – but, without better long-term data, I personally would be opting for the appendectomy.

“Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis”

Can You Diagnose PE With a Walk Test?

So, no.

You can stop reading now, if that’s enough information to satisfy your curiosity.  There is, however, a little more to it.

These authors describe a prospective evaluation of 114 Emergency Department patients with either suspected or confirmed acute pulmonary embolism.  Patients were enrolled by convenience selection during the hours research assistants were in the ED.  Each enrolled patient underwent a 3-minute walk test while research assistants measured changes in heart rate, respiratory rate, and oxygen saturation.

In short, ambulation induced significant changes in heart rate and oxygen saturation between those who did, and did not, have pulmonary embolism.  A change in heart rate of 10 bpm gave a sensitivity of 97% (95% CI 83 to 99%) and specificity of 31% (95% CI 22-42%), while a drop in O2 saturation of 2% gave a sensitivity of 80% (95% CI 63 to 91%) and specificity of 39% (95% CI 30 to 50%).  Obviously, these test characteristics are poor – excepting, perhaps, a potentially useful negative likelihood ratio, particularly when both variables are utilized.  However, there are also serious issues with their gold-standard for diagnosis of pulmonary embolism – with nearly 30% of their cohort undergoing ventilation/perfusion scans.

I appreciate these authors’ attempt to describe the test characteristics of, essentially, a free, non-invasive physiologic stress – and, even if the current data does not support routine use, it’s probably worth continuing to explore.

“Ambulatory vital signs in the workup of pulmonary embolism using a standardized 3-minute walk test”

Chillin’ Children After OHCA

Once upon a time, many adults suffering an out-of-hospital cardiac arrest received therapeutic hypothermia with a target temperature of 33°C.  Then, along came the Targeted Temeperature Managment trial – in which 36°C seemed to be just as good as 33°C.  Now, just to throw another confounder in the mix, we have a trial comparing 33°C to “therapeutic normothermia” – 36.8°C – and we’re doing it in children to address concerns regarding generalizability from adults.

Very detailed summaries of the numbers, methods, and enrollment can be found on other #FOAMed sites – particularly St. Emlyns and ALiEM.  But, the high points:

  • Many – 1,355 – were screened, but ultimately only 260 were randomized and included in their primary analysis.
  • Adherence to temperature management protocols was good or adequate in ~90% of cases.
  • Hypothermia was implemented for 48 hours, followed by normothermia up to 120 hours total to match the normothermia group.
  • In contrast to adults, the great majority (72%) of this pediatric cohort suffered a respiratory arrest.

The outcome: no statistical difference, with 20% of the hypothermia group alive and functional at 1 year, compared with 12% of the normothermia group, a p-value of 0.14.  Regarding safety, arrhythmias and culture-proven infections favored the normothermia group, 1% vs. 5%, and 39% vs. 46%, but these also did not reach statistical significance.  Finally, both 28-day and 1-year mortality favored hypothermia, with an absolute difference of ~10% in each, but this was not statistically significant, either.

I will let the authors speak for me here:

“One important potential limitation of the trial is that, on the basis of the observed confidence limits for treatment differences, a potentially important clinical benefit cannot be ruled out despite the lack of a significant difference in the primary outcome measure. A larger trial might have detected or rejected a smaller intervention effect. Indeed, there was a significant difference in survival time with therapeutic hypothermia, although this was a secondary outcome measure.”

The relative likelihood of benefit for hypothermia in this trial was 1.54, with a 95% CI of 0.86 to 2.76.  Now, this result crosses 1, and therefore requires interpretation in two contexts.  The first is the normal distribution:

In which we visualize the frequency of potential outcomes, and the important realization the more frequent “true” outcome is most likely to occur near the center of the 95% CI range.

And, the more important context:

In which we interpret these data in the context of prior results, generalized from other settings.  In this case, our prevailing opinion is one in which we suspect hypothermia – with much uncertainty regarding the details – is beneficial.  As you can see, the effects of even “statistically significant” findings have only limited practical impact on the “good bet” or the “long shot”.  Hence, the results of this study – which simply barely fail to reject the null hypothesis – do not hardly move the needle against the prevailing opinion.

I tend to side with the authors of this “negative” study: it is mostly likely underpowered to detect the expected benefit, and it is still reasonable to cool children following OHCA.  There are many questions that remain regarding the temperature, duration, and other details – not limited only to children – but it would be erroneous to say this trial refutes the practice of hypothermia in children.

“Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children”

Where’s the Beef With TXA?

CRASH-2 was a massive, international undertaking, testing the utility of tranexamic acid to improve outcomes in bleeding trauma patients.  When given with 3 hours, there were significant reductions in mortality due to bleeding – and the current push for its widespread use was born.

However, this study, and others like it, is not seeing the same magnitude of success as described in CRASH-2.  This single-center, retrospective evaluation of trauma patients reviewed the mortality benefit associated with implementation of a thromboelastography-based TXA protocol.  In 2011, this institution introduced a TEG-based TXA threshold of estimated percent lysis at 30 minutes of >3.0%, and these authors reviewed all cases of trauma patients between 2009 and 2013 meeting that threshold and eligible for treatment within 3 hours.

These authors identified a cohort of 98 patients who met criteria and received TXA, and compared them with a cohort of 934 patients who met criteria and did not.  In-hospital mortality in the cohort receiving TXA was double those who did not (40% vs. 17%), and this disadvantage persisted despite adjustment for age, gender, mechanism, ISS, hypotension, and base excess.  TXA usage was also not associated with resolution of hyperfibrinolysis, as measured by follow-up TEG, but neither was it associated with an increase in thromboembolic events.

Unfortunately, this retrospective evaluation is biased by confounding and unmeasured selection imbalances.  It is, however, not the only study questioning the value of TXA in the setting of routinely well-resuscitated, modern trauma evaluation.  Nothing in this small review provides compelling evidence regarding cessation or tailoring of TXA therapy in bleeding trauma patients, but it does support its continued evaluation for its role in organized, modern trauma settings.

“The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis”

Still Not Choosing Wisely in Trauma Imaging

We can all agree the advent of CT has improved our diagnostic capabilities, particularly in multi-system trauma.  Few would challenge an assumption that outcomes are positively impacted by timely, accurate identification of clinically important pathology.

Unfortunately, the pendulum has swung so far in favor of CT in trauma, any intelligent reliance on clinical exam skills has been deprecated to obsolete.  As such, the expected fallout includes increases in costs, radiation, and length-of-stay as the zero-miss culture creeps from multi-system trauma into the lightly injured.  This has become such an issue the American College of Surgeons devoted one of five slots in their first Choosing Wisely Guidelines to reducing the use of the trauma “pan-scan”.

Hopefully, the culture change will happen none-to-soon, as this NHAMCS data review indicates – showing steady increases in CT use for both head and body over the 2007 to 2010 review period.  Head CT increased from 9.6% to 11.6% of all injury-related encounters, while body CT increased from 5.5% to 8.1% – without any corresponding increase in positive findings.  Yield for severe injury dropped from 4.9% to 3.4% on Head CT, along with a drop for body CT from 6.4% to 3.3%.

This is the NHAMCS probabilistic sample, of course, and it’s simply a coarse observational cohort without detailed clinical factors.  However, I think the likelihood these observations accurately reflect reality is rather high.

Choose more wisely, please.

“Trends in Advanced Computed Tomography Use for Injured Patients in United States Emergency Departments: 2007–2010”

Oxygen: Friend or Foe?

I’m a huge fan of oxygen.  I breathe oxygen nearly every day, and without it, I would literally, moreso than figuratively, die.

But, oxygen is a highly reactive molecule with many adverse effects in the human body.  Recognition of such seems to be in direct contrast to the otherwise reasonable hypothesis of increased oxygenation providing benefit in ischemic disease states.  The most recognizable of these is acute myocardial infarction, where oxygen is enshrined in the classical (and outdated) MONA mnemonic.

This is the AVOID trial, randomizing patients in the field with prehospital diagnosis of STEMI to either 8L/min inhaled oxygen, or oxygen only as needed to maintain saturations >94%.  All patients received aspirin from paramedics en route to the receiving facility, with further care as per local standards and protocols.  The primary outcome was infarct size, as measured by peak troponin and creatine kinase levels.

Paramedics screened 836, randomized 638, an additional 50 were protocol non-compliant, and then 118 were declared not to be STEMI upon arrival at the receiving facility.  The remaining 470 underwent angiography, and the final cohort for analysis was the 441 for whom STEMI was ultimately confirmed.  Groups were generally similar between interventions, although there was an excess of 8 patients with LAD lesions in the oxygen arm and of 10 patients with circumflex lesions in the no-oxygen arm.  There were 11 excess single-vessel patients in the oxygen arm and 17 excess multi-vessel disease patients in the no-oxygen arm.

The answer?  Oxygen is probably bad.  There was no statistically significant difference in mean peak troponin values, favoring the no-oxygen having a p-value of 0.18.  The mean peak CK difference did, however, reach significance, with a p-value of 0.01.  In the 127 patients for whom follow-up MRI imaging was available, measures of infarct size all favored the no-oxygen group, with p-values ranging between 0.04 and 0.08.  However, clinical outcomes were all over the map.  The no-oxygen arm had higher in-hospital mortality, but the oxygen arm had higher rates of recurrent myocardial infarction.  Long-term, six-month outcomes were likewise similar, with trivial clinical differences.

So, oxygen application during routine pre-hospital transport for chest pain is certainly useless and wasteful – and most likely at least a little bit harmful.

“Air Versus Oxygen in ST-Segment Elevation Myocardial Infarction”