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”
http://www.acep.org/workarea/DownloadAsset.aspx?id=102373

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”
http://www.ncbi.nlm.nih.gov/pubmed/25827595

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”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60732-2/abstract

“Idarucizumab for Dabigatran Reversal”
http://www.nejm.org/doi/full/10.1056/NEJMoa1502000

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”
http://www.ncbi.nlm.nih.gov/pubmed/26061835

“Mobile-Phone Dispatch of Laypersons for CPR in Out-of-Hospital Cardiac Arrest”
http://www.ncbi.nlm.nih.gov/pubmed/26061836

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”
http://jama.jamanetwork.com/article.aspx?articleid=2320315

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”
http://www.ncbi.nlm.nih.gov/pubmed/26034913