tPA Is The Hand That Feeds

No biting!

There are still a few hold-outs on the 0 to 3 hour window, but most folks would agree that battle is lost – the best we can hope for is further clarifying the patients with the greatest likelihood of clinically significant benefit vs. those with the greatest level of potential harms.

But, greater than 3 hours is still a battlefield.  This article in the January Annals uses the gloriously unbalanced ECASS III data for a cost-effectiveness analysis which, unsurprisingly, concludes in favor of tPA treatment.  The problem is, of course, the assumption that ECASS III is infallible – a highly suspect position, considering the baseline differences between groups in ECASS III.  Then, accounting for the the 1200 patients in IST-3 enrolled in the 3 to 4.5 window who did poorly with tPA, I’m guessing an updated meta-analysis wouldn’t look quite as favorable.  But, I will give these authors a bit of a break, as this article was accepted for publication before IST-3 results were available.

Finally, in lieu of my usual rant, I’ll just copy and paste the disclosures portion of the article:
“This project was funded through a contract with Genentech, Inc. Drs. Boudreau and Veenstra and Mr. Guzauskas served as a consultant for Genentech, Inc. Ms. Villa is employed by Genentech, Inc. Dr. Fagan is a consultant for Genentech, Inc.”

“A Model of Cost-effectiveness of Tissue Plasminogen Activator in Patient Subgroups 3 to 4.5 Hours After Onset of Acute Ischemic Stroke”

Who Are the PE Positive PERC Negatives?

This little letter, tucked away in the Correspondence section of Annals delves into the Pulmonary Embolism Rule-Out Criteria – a decision instrument of some controversy in Emergency Medicine.  Specifically, this letter addresses a case report from a previous issue of Annals of, essentially, a large pulmonary embolus diagnosed in a young patient who was otherwise PERC negative.

The authors from Carolinas Medical Center have a registry of 1,880 PE+ patients with which to evaluation, and they performed a retrospective application of the PERC rule.  Overall, 6% of this cohort was PE positive and PERC-negative.  When compared with the patients with PE who were PERC-positive, there are a few statistically significant differences – pleuritic chest pain was more common in PERC-negative patients with PE, along with pregnancy or post-partum status.  Unfortunately, these statistically significant relative differences reflect only small absolute differences of essentially clinically irrelevant magnitude.  The only mildly interesting tidbit from the letter is the statistic that none of PERC-negative PEs died within 30 days, compared with 5.7% of the PERC-positive cohort.

The authors suggest a couple weak clinical implications from the data, but these are limited by the retrospective nature of the analysis.  It is enough to remember that PERC-negative does not actually “rule-out” PE – it is simply a collection of negative likelihood ratios working against a pretest probability, resulting in clinical equipoise regarding the expect benefits vs. harms of CT pulmonary angiogram and the resultant harms of treatment in physiologically uninteresting PE.

“Clinical Features of Patients With Pulmonary Embolism and a Negative PERC Rule Result”
www.ncbi.nlm.nih.gov/pubmed/23260692

Tamliflu Redux

Just as relevant a year later, a quick re-post to the Cochrane Collaboration’s Tamiflu exposé:

“Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.”www.ncbi.nlm.nih.gov/pubmed/22258996

See what I wrote about it last year:
https://www.emlitofnote.com/2012/01/lies-damned-lies-and-tamiflu.html

(spoiler alert:  hardly worth the cost, at best; next to useless, more likely)

Diverticulitis – The Sinusitis of the Colon?

Antibiotics are wonderful things.  They treat and provide life-saving amelioration of symptoms from the common cold, the flu, bronchitis, sinusitis, and otitis – or, more accurately, they don’t.  Rather than generalize the treatment with antibiotics for all these illness, it is rather the avoidance of antibiotics that should be generalized, with specific exceptions made as necessary.

The next “-itis” to go under the microscope is diverticulitis.  These authors from Iceland and Sweden deserve, at the minimum, kudos for innovation in swimming against the tide.  The treatment of acute diverticulitis – a febrile illness with an elevated WBC and left-lower quadrant pain – is generally gram-negative and anaerobic coverage as an inpatient or outpatient, depending on comorbidities.  These authors propose that diverticulitis is most frequently a self-limited process, rather than one that requires antibiotics.

This a non-blinded trial of antibiotics vs. non-treatment for CT-demonstrated acute, uncomplicated diverticulitis.  Over 600 patients were admitted, with half receiving simple observation and symptomatic treatment vs. half with the same plus antibiotics.  1% of patients in the antibiotic group suffered treatment failure – progression to abscess or perforation – compared with 2% of patients in the placebo group.

Unfortunately, we’re not quite done with antibiotics based on just this study.  It is unblinded with variable enrollment between centers, leading to several sources of potential bias.  Then, ten patients in the no-antibiotics group crossed over to receive antibiotics for clinical worsening during hospitalization.  However, this is still below the 6.5% complication rate the authors thought might be an acceptable failure rate for conservative therapy.

Many more questions to be answered regarding external validity, so hopefully this inspires other investigators to further explore which subset patients will derive benefit from antibiotics in diverticulitis.

“Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis”
www.ncbi.nlm.nih.gov/pubmed/22290281

The Future of Heart Failure Admissions

At least, this is how Cardiologists think the Emergency Department should be handling heart failure in The Future.

Specifically, Cardiologists would like us to stop admitting patients with acute exacerbations of established heart failure – and, interestingly, they’re a bit apprehensive about discharging them.  Their earth-shaking, practice-modifying innovation is this:  observation unit management.

This strategy is founded partly out of interest of the patient’s well-being, but mostly out of interest for the hospital’s financial well-being.  In general, heart failure remains one of the most difficult hospital readmissions to prevent.  This is important because, suddenly, readmissions within 30 days are no longer reimbursed by CMS.  Now, rather than, re-admit patients for free, they’ve decided the New Fabulous Idea is to place them in outpatient observation status – which is a lower level of reimbursement, but still better than nothing.  In addition to the other obviously indicated admissions, they also feel some of the gray area discharges would probably benefit from observation, appropriately noting heart failure patients discharged from the ED are at high risk of having subsequent worsening due to a variety of contributing factors.

Overall, as far as actual patient care, there’s probably little difference – somewhat cynically, the entire strategy seems mostly to be an advisory on how to minimize the impact of reimbursement losses from readmissions.


“Is Hospital Admission for Heart Failure Really Necessary?  The Role of the Emergency Department and Observation Unit in Preventing Hospitalization and Rehospitalization”
www.ncbi.nlm.nih.gov/pubmed/23273288

And, just as a rather inspirational aside, this is one of the longest disclosures list I have ever seen for an author:
“Dr. Gheorgiade has received support from Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd., CorThera, Cytokinetics, CytoPherx, Inc., DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Inc, John- son & Johnson, Medtronic, Merck & Co., Inc., Novartis Pharma AG, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, sanofi-aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc., and Trevena Therapeutics; and has received significant (>$10,000) support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, and Takeda Pharmaceuticals North America, Inc.”

Angiography After Cardiac Arrest

This is the worst sort of paper – nuggets of truth mired in systematic flaws.  There’s certainly no ill intent by the authors to mislead, it’s simply the nature of this sort of retrospective review.

The PROCAT consortium has been publishing studies of their post-arrest protocols for several years.  They’re huge proponents of early coronary angiography following resuscitation for out-of-hospital arrest – and this is another in a string of articles demonstrating that patients going to coronary angiography after out-of-hospital arrest have improved outcomes.  Of the 1274 patients in their cohort, 745 received early coronary angiography, 447 identified a culprit lesion, and 347 underwent PCI.  The survival rate was 46% in patients undergoing PCI.

However, this number is conflated by other confounding variables known to be associated with good outcomes following cardiac arrest – coronary lesions are likely to be associated with VT/VF, which were also associated with good outcomes.  Additionally, significantly more survivors received therapeutic hypothermia than non-survivors, illustrating the massive problem with viewing this sort of report with anything other than reasoned curiosity: rampant selection bias.  Patients survived because they were selected for interventions based on individualized prognostic features, treatments were not applied evenly across the population.

There is absolutely a subset of OHCA that benefits from early coronary angiography – but this benefit should not be generalized to the inappropriate allocation of resources associated with taking all OHCA to the cath lab after resuscitation.

“Benefit of an early and systematic imaging procedure after cardiac arrest: Insights

from the PROCAT (Parisian Region Out of Hospital Cardiac Arrest) registry”
www.ncbi.nlm.nih.gov/pubmed/22922264

The Latest Prognostication for Stroke

We have a fairly robust vascular neurology program at my institution, and – unsurprisingly – they’re rather pro-thrombolysis.  While our disagreements over the efficacy of thrombolysis for acute strokes are generally set aside in a truce stemming from academic and research interests, the main philosophical difference between our services remains this: the difference between eligible and indicated.

Vascular neurology tends to treat these terms as synonymous regarding thrombolysis and acute stroke, while it’s clear from the literature that not every patient benefits from thrombolysis.  The most recent issue of Neurology features another prognostic tool, the SPAN-100, which is the simplest by far: NIHSS + age.  If this score is >100, fewer patients will benefit from tPA than will be harmed.  There’s a quality-of-life discussion to be had regarding individualized treatment decisions in SPAN-positive patients, and this is derived from a very small cohort, but it’s consistent with the remaining literature.

The accompanying editorial is also pro-thrombolysis, but does recognize these scoring systems are important clinical tools in educating patients and families regarding the potential for benefits and harms. Most importantly, this table from the editorial summarizes the growing body of literature available to assist the decision-making process:


I look forward to seeing these develop such that clinicians have better tools with which to separate eligible from indicated.

“Stroke Prognostication using Age and NIH Stroke Scale: SPAN-100″
www.ncbi.nlm.nih.gov/pubmed/23175723

Evidence Summary for Bell’s Palsy

Although the incidence of stroke in young people is rising, some of these “strokes” can still be clinically diagnosed with Bell’s Palsy.

However, once the diagnosis is made, the practice variation is extensive.  In light of this, the American Academy of Neurology has published an update to their evidence-based guidelines for the treatment of Bell’s Palsy.

Short answer:
 – Steroids are good, with a 12 to 15% increased chance of functional recovery.
 – Antivirals have no consistent evidence of benefit.

Long answer:
 – Only ~4% of Bell’s Palsy sufferers are left with severe residual deficits, with the remainder fully recovering or with slight/mild deficits.  Some folks would pose the question whether any of these treatments are necessary, considering the minimal absolute benefits, even if relative benefits are consistent.

Another risk/benefit decision to discuss with patients.

“Evidence-based guideline update: Steroids and antivirals for Bell palsy : Report of the Guideline Development Subcommittee of the American Academy of Neurology”

Breast Cancer From Pediatric Trauma Imaging

Evaluations for significant pediatric blunt trauma tend to be rather rare.  However, one flip side to improved vehicular safety is that previously fatal accidents turn into diagnostic dilemmas with otherwise well-appearing children after horrific potential injury mechanisms.

This specific article tries to address the risk/benefit ratio for imaging the pediatric thoracic spine after trauma, with a focus on the lifetime excess attributable risk for breast cancer.  They used estimates of radiation to breast tissue from plain films and CT, and then applied the predictions from the BEIR VII report to determine EAR.  From all these various calculations, their worst-case scenario derived an excess of 79.6 cases of breast cancer per 10,000 CT scans in females aged less than 12 years.

Unfortunately, the proponents of CT imaging cite these studies and say we’ve done nothing but document theoretical risk (based on atomic bomb exposure) – while ignoring that the risk of missed injury is equally theoretical.  As usual, the prudent course of action is to perform additional testing only when explicitly indicated – the additional cases of breast cancer are not trivial, but neither are missed injuries.  The rate of additional breast cancer cases is certainly not so high that CTs should be skipped when clinically indicated.

“Theoretical Breast Cancer Induction Risk From Thoracic Spine CT in Female Pediatric Trauma Patients”
www.ncbi.nlm.nih.gov/pubmed/23184109

Predicting Immediate Improvement After tPA

tPA for stroke remains controversial, to say the least.  The reasons behind the Emergency Medicine/Neurology disconnect are complex and covered elsewhere.  Regardless, thrombolysis is here to stay – and probably helps some patients.  The hard part is finding those patients with the most favorable risk/benefit ratio.

This is a study that looked at diffusion-weighted imaging to try and predict which patients were most likely to rapidly improve with tPA.  These authors enrolled sixty-six patients with acute stroke eligible for tPA under the Japanese license and performed diffusion-weighted MRI on each of them.  Previous studies had suggested an ASPECTS score > 7 predicted response to tPA – and this study confirmed it.  Essentially, this translates as larger vascular territories showing greater improvement in NIHSS after tPA than smaller vascular territories.

There’s a bit of a bias in this study, since smaller vascular territories may have produced smaller initial NIHSS.  The population was quite old for a stroke study – median age 79.  And, truly, the more interesting data presented is the breakdown demonstrating the massively favorable impact of early (within 1 hour) recanalization after tPA administration.

But, mildly interesting paper, important as part of a slow, gradual trend of attempts to delineate which patients have the best potential to benefit from tPA.

“DWI-ASPECTS as a Predictor of Dramatic Recovery After Intravenous Recombinant Tissue Plasminogen Activator Administration in Patients With Middle Cerebral Artery Occlusion”
www.ncbi.nlm.nih.gov/pubmed/23212169