Author: Ryan Radecki

Dueling PE Meta-Analyses

A guest post by Rory Spiegel (@EMNerd_) who blogs on nihilism and the art of doing nothing at emnerd.com.

Nothing sparks controversy quite like a discussion on the utility of thrombolytics. No sooner had the wave of debate brought on by the publication of the PEITHO trial and its finding of no overall mortality benefit died down, did JAMA stoke these flames with the publication of a meta-analysis including the entirety of the literature on thrombolytic use for pulmonary embolism. Examining 16 trials, the authors found a statistically significant absolute mortality benefit of 1.12% or an NNT of 59 patients. This benefit was offset by the increase in major bleeding events observed in those given thrombolytics (9.24% vs 3.42%) with a 1.27% absolute increase in ICH.



The cascade of incendiary events continued when one week later a second meta-analysis examining the very same question was published in Journal of Thrombosis and Haemostasis. Only these authors claimed to find the exact opposite of their JAMA counterparts. In this case the authors found no statistical improvement in mortality in the patients given thrombolytics when compared to those given a placebo. Despite these contradictory claims, a more comprehensive inspection reveals these meta-analyses are extensively saying the same thing. A comparison of the two serves as a timely reminder that conclusions reached from any meta-analysis is primarily dependent on the trials selected for inclusion.  The JAMA meta-analysis included 2115 patients in 16 trials, while the Journal of Thrombosis and Haemostasis examined only 1510 patients in 6 trials. Interestingly, the absolute risk reduction in mortality was 1.12% in the JAMA publication vs 1.4% in the Journal of Thrombosis and Haemostasis publication. Though the JAMA analysis had an overall smaller absolute risk reduction, the result reached statistical significance due to the larger sample size.



More importantly the results of these publications should not come as a surprise. Before the publication of PEITHO the data on thrombolytics for PE was sparse. Most of the trials suffered from small sample sizes and questionable methodology. It is the amalgamation of these small trials that accounts for the mortality benefit in both meta-analyses. In the JAMA publication the mortality difference consisted of 17 fewer deaths in the thrombolytic arm compared to the placebo. All of which originated from these small underpowered studies. Conversely, the two large high quality trials (PEITHO and MSPPE) consisting of 1005 and 256 patients respectively made up the majority of patients meta-analyzed, neither of which found a mortality benefit with the use of thrombolytics. Moreover the 2% absolute increase in ICH seen in the PEITHO cohort is only diluted by the inclusion of these small trials, whose sample sizes were not powered to detect such rare events. A more elegant design would be to utilize a weighted average or one of the various statistical methods that takes into account each study’s sample size and event rate, allocating a greater weight to the hardier cohorts. Though one might argue an equally elegant solution would be to not include such flawed trials in the first place.


The publication of these dueling meta-analyses highlights the flaws of such statistical endeavors. Small trials with flawed methodological designs are prone to fall victim to publication bias and the fluctuating whims of chance. Collecting this data and attaching a statistical judgment to it does not correct these imperfections, it augments them. The overall benefit of thrombolytics in PE is yet undetermined, but the answer will not be elucidated in such analysis. We require further large randomized controlled trials like the PEITHO trial. Adding small flawed cohorts to this robust dataset does nothing but muddy the already murky waters.

“Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis.”
http://www.ncbi.nlm.nih.gov/pubmed/24938564

“Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism: a meta-analysis.”
http://www.ncbi.nlm.nih.gov/pubmed/24829097

Lives Saved … or Profiteering by Overdiagnosis?

Following an initial acute ischemic stroke, a search for the cause must be undertaken – for small vessel vasculitis, atherosclerotic emboli, thrombi from the systemic circulation, and so forth, beyond the domain of the Emergency Physician.  However, what the Emergency Physician does encounter is the sequelae of this search, in the form of oral anticoagulants.

These two articles from the New England Journal of Medicine, on their own, seem to reflect advances in diagnostic yield following acute ischemic stroke or transient ischemic attack.  The authors point out approximately 25% of patients suffering AIS and half of those suffering TIA never receive an ultimate identified etiology for stroke – and are classified as “cryptogenic”.  The authors in each of these studies suppose this may be due to the paroxysmal nature of atrial fibrillation, and that short-term electrocardiographic monitoring is missing this diagnosis.  In each study, some type of long-term monitoring technology is utilized, and, ultimately, the rate of diagnosis for paroxysmal atrial fibrillation jumps from 1-3% in each cohort to 8-12% in each cohort.

The catch – scads of authors for each report conflict-of-interest with both manufacturers of novel oral anticoagulants, or device manufacturers likely related to continuous ambulatory monitoring.  There is clear benefit to each of these parties, considering potential expanded indication for both monitoring and for anticoagulation.  These articles will likely be used to support both activities, despite not measuring any patient-oriented benefit.  How much of a primary or recurrent stroke risk is attributable to these very-infrequent paroxysms of atrial fibrillation?  Do they benefit equally from anticoagulation?

Given the conflict-of-interest enshrined in these articles, I am certain the advertised presumption will be they do.  They may, of course, be right – or, this may turn into yet another example of overdiagnosis and high-cost, low-yield medicine.

“Atrial Fibrillation in Patients with Cryptogenic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1311376

“Cryptogenic Stroke and Underlying Atrial Fibrillation”
http://www.nejm.org/doi/full/10.1056/NEJMoa1313600

Independence Day History Lesson

July 4th, for our worldwide readers, is Independence Day in the United States.  This means the trauma centers fill up with all manner of traumatic and alcohol-related injuries.  Just as the Founding Fathers intended.

However, for your reading enjoyment today, I give you the medical biography of John Jones, the first Professor and Chair of Surgery in the American Colonies – as part of the group establishing the Columbia University College of Physician and Surgeons in 1767.

“John Jones, M.D.: pioneer, patriot, and founder of American surgery.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860285/ (free full text in PubMed Central)

How Much Money Is Wasted By Endovascular Treatment for Stroke?

If you recall, last year was a bumper crop of prospective, randomized, controlled trials testing the efficacy of endovascular devices versus tPA alone for acute ischemic stroke.  These trials – SYNTHESIS, MR-RESCUE, and IMS-III – were unified by demonstrating no additive benefit.  Of course, these trials proved nothing to proponents of endovascular therapy, owing to the “outdated” devices used.

Interestingly, IMS-III also prospectively gathered costs associated with both treatment modalities.  Presumably, the authors expected to show a treatment advantage despite increased costs, and would follow-up with a cost-effectiveness analysis.  Now, since there was no advantage with endovascular treatment, this is simply a fascinating observational report.

So, how much did everything cost?  The answer, like everything in medicine:  depends on who’s paying.  Hospital charges for patients receiving tPA were a mean of $86,880, with a median of $58,247, and ranged from $13,701 to $830,652.  Hospital charges for endovascular treatment would have been a mean of $113,185, with a median cost of $86,481, and ranged from $23,350 to $552,279.  Thankfully, this is the funny money that few patients are realistically expected to pay.  Costs, on the other hand, are based off the negotiated Medicare reimbursements, and were estimated at a mean cost of $25,630 for IV tPA and $35,130 for endovascular therapy.  So, a fair bit of extra cost to the system for a therapy that isn’t providing any proven benefit.

Given the lack of efficacy and increased costs, you’d think it should be obvious we ought not be deploying endovascular therapy widely – but, clearly, this is unfortunately not the case.  Medicare and Medicaid still reimburse for endovascular interventions – and its use is bolstered by its sponsors and other such propaganda in the NEJM.  Until proven otherwise, this is all simply money down the drain.

“Drivers of Costs Associated With Reperfusion Therapy in Acute Stroke: The Interventional Management of Stroke III Trial”
http://stroke.ahajournals.org/content/early/2014/05/13/STROKEAHA.113.003874.abstract

Enoximone Miracle for Asthma: Science? Advertising? Both?

Potential leaps forward in medical science are noteworthy.  They should be peer-reviewed, disseminated, and developed – and those responsible, rewarded, to be sure.  But, the medical literature is full of grey areas between science and advertising – including routine publication of sponsored trials, to a “Clinical Evidence Synopsis” composed solely by those with COI, to this latest egregious sample.

Enoximone is a phosphodiesterase inhibitor currently in clinical trials for advanced heart failure.  However, the author of this report documents eight cases of its use in the setting of catastrophic status asthmaticus – three of which progressed to respiratory arrest.  After initiation of medical therapy without improvement, the author gave each of these patients one or multiple doses of intravenous enoximone – with profound improvement.  Anecdotally.

This is all very fine, and case reports are an important step in the chain of evidence.  Enoximone very well may be an important future therapy for selected patients with severe bronchospasm.  However, there’s one slight problem with this publication, stemming from the Declaration of Interest by the author (J.B.):

J.B. received lecture fees from the following companies: Carinopharm GmbH, Germany; Carinopharm, UK; Incapharm, Italy; and Devrimed, The Netherlands, distributors of enoximone. J.B. contributed to a syllabus concerning enoximone for which he received a fee from Carinopharm GmbH, Germany. Carinopharm GmbH filed an IP for the use of enoximone in status asthmaticus in which J.B. is named as the inventor, without financial consequence. J.B. is co-founder and shareholder of Advanced Perfusion Diagnostics at Lyon, France.

So, the publication ultimately represents unfettered promotion of a therapy for whom the author has multiple personal financial conflicts of interest.

Science?  Advertising?  Both?

“Emergency treatment of status asthmaticus with enoximone”

Highly-Sensitive, But Not Highly Valuable

There is a great deal of continuing debate raging over the use of “high sensitivity” troponins in the Emergency Department.  But, it’s not the test alone at fault – the responsibility for interpreting and acting upon the results lay with clinicians.  In the era of conventional troponins, the test was a powerful tool to rule-in myocardial infarction.  With high sensitivity troponins, the greater value in the tool is in ruling-out.

However, while much is made of the theoretical beneficial test characteristics of high sensitivity troponins, few have measured actual patient-oriented outcomes.  This group from Valencia, Spain, prospectively evaluated consecutive patients at a single institution as their laboratory switched from a conventional TnI assay to a highly sensitive one.  Comparing 699 consecutive patients from the pre-hsTnI period to 673 consecutive patients in the post-hsTnI … there were too many baseline differences to draw any useful conclusions.

But, in an effort to salvage the paper, the authors perform a propensity-score matching algorithm to balance to cohorts.  Based on these matched cohorts, for which they do not offer much in the way of detail, there were no differences in major adverse cardiac events or death at 6-month follow-up.  Regarding management decisions after the change, they note patients were less likely to undergo non-invasive testing in a chest pain observation unit, but substantially more likely to undergo invasive procedures.

This is just a single-center experience, and their observations are incontrovertibly corrupted by the unfortunate change in patients characteristics across their study periods.  It does, at least, provide some small window into how hsTnI might impact the management pathway for patients presenting with chest pain.

“High-sensitivity versus conventional troponin for management and prognosis assessment of patients with acute chest pain”
http://heart.bmj.com/content/early/2014/06/19/heartjnl-2013-305440.abstract

Should Paramedics Intubate Out-of-Hospital Cardiac Arrest?

Airway management of out-of-hospital cardiac arrest is a controversial topic.  Most patients transported for OHCA have receive prehospital airway management.  However, attempts at establishing an airway can interrupt compressions, over-ventilation can decrease cerebral perfusion, and delays in airway acquisition impact transport to definitive care.

This study retrospectively evaluates the CARES surveillance group, a multi-site registry from North America, comparing neurologically intact survival after prehospital endotracheal intubation, supraglottic airway, or no advanced airway.  In the unadjusted results, survival rates were 5.4% for intubated patients, 5.2% for supraglottic airway, and 18.6% for no advanced airway.  After statistical adjustments and propensity scores, the authors report the ultimate winner is not attempting an advanced airway – and then endotracheal intubation is superior to supraglottic airway.

But, really, this study tells us nothing.  Even though the authors attempt several methods of statistical adjustment, the likely presence of massive unmeasured confounders invalidates these observations.  There is an entire host of patient-level and situational factors that impact the type of airway attempted, the number of airway attempts, and the aggressiveness of care provided both pre-hospital and in-hospital.  The profound differences in unadjusted outcomes, between those not receiving an advanced airway and those requiring one, paints the most obvious picture of the likely underlying differences in unfavorable physiology at work.

This is hardly the first observational report regarding the impact of prehospital airway management.  And, frankly, we’ve seen enough – this type of retrospective cohort does not hold the answer, unless the registry was specifically designed to answer such questions.  To the authors credit, they do not overstate the level of evidence provided – but an unsophisticated reader might draw the wrong conclusions.

“Airway management and out-of-hospital cardiac arrest outcome in the CARES registry”
http://www.ncbi.nlm.nih.gov/pubmed/24561079

Guideline Recommendations Are Written in Dry Erase Marker, Not Stone.

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

Medicine is filled with guidelines, professional recommendations and expert consensus statements. These documents guide clinical practice. In Emergency Medicine, we often rely on non-EM specialty guidelines. For instance, we often state that a patient in whom you consider ACS should get evocative testing (i.e. stress test) within 72 hours of presentation according to the American College of Cardiology/American Heart Association (ACC/AHA) guidelines. As more guidelines and subsequent revisions are released a number of questions arise. Should we adopt the guidelines immediately? If so, which pieces are ready for immediate incorporation into clinical care? At the heart of these questions is the strength and durability of the recommendations.
This article is unique in the question it asked: what is the durability of class I recommendations from the ACC/AHA? The looked at 11 guidelines published between 1998 and 2007 along with revisions to these guidelines from 2006 to 2013. What they found was surprising. Out of 619 original class 1 recommendations, about 80% were retained in subsequent revisions. About 9% were downgraded or reversed and about 11% were omitted.  Not surprisingly, recommendations with multiple randomized studies backing them up tended to stick around (90.5%) but those recommendations supported by opinion only did not (73.7%).
What can we take away from this? First, we shouldn’t adopt recommendations (even level 1) that don’t have good evidence backing them up. Secondly, guidelines should be updated frequently (these authors suggest every 3 to 5 years) to incorporate new evidence that may up or downgrade recommendations. Guideline adherence shouldn’t be used as a performance measure since the recommendations are anything but written in stone. Lastly, this is a further call for our specialty to take the reigns and start writing our own, high-quality guidelines from which we can base clinical practice.
“Durability of Class 1 American College of Cardiology/American Heart Association Clinical Practice Guideline Recommendations”

Stroke MRI in 6-Minutes or Your Money Back

Despite the advances of modern medicine, the non-contrast CT of the brain is a crude tool.  It is especially poor in the setting of acute stroke – infrequently providing helpful diagnostic information, while serving primarily to rule out intracranial hemorrhage.

These authors, however, offer us a glimpse of the MRI of the future – a useful diagnostic test without long delays of image acquisition time.  These authors report on a single-center, convenience sample of patients with acute neurologic deficits who were able to undergo MRI.  They use a 3.0T MRI to acquire DWI, FLAIR, GRE, perfusion, and MRA sequences using a 6-minute protocol on 62 patients, and two radiologists rated image quality as moderate or good 94% or greater for each modality.

The authors also provide two sample cases, one of which being an acutely altered, profoundly disabled patient within the 3-hour window for tPA.  The 6-minute MRI, however, showed heterogeneous perfusion abnormalities more suggestive of seizure, rather than stroke.  After treatment with anti-eplipetics, the patient made a full neurologic recovery.

This series is small enough it’s clearly just a technology pilot.  Additional study regarding diagnostic accuracy and feasbility in the acute setting is necessary, but it would certainly be a vast improvement over the current state of the art.  Considering the present rush to judgement for tPA and the likelihood of overtreatment of stroke mimics, a diagnostic modality that adds to clinical assessment is sorely needed.a

“Six-Minute Magnetic Resonance Imaging Protocol for Evaluation of Acute Ischemic Stroke: Pushing the Boundaries”
http://www.ncbi.nlm.nih.gov/pubmed/24916906

No, You Can’t Get Drunk Off Tampons

Yet another bit of YouTube lunacy debunked – the concerning “recent phenomenon” amongst adolescents and young adults to use alternate methods of ethanol absorption to decrease detectability, or increase the rate of intoxication.

Such as “tampons soaked in vodka”.  In the vagina.

So, how viable is this strategy?  A toxicologist from USC investigates this strategy in vitro with a relatively straightforward study – simply measuring the maximum quantity of alcohol that could be absorbed by a tampon prior to insertion.  Commercially available tampons, with the applicator attached, maxed out at 15mL.  Minus the applicator, tampons absorbed up to 31mL – but obviously lost any insertion potential.

Disregarding the likely local irritation and discomfort of this method of administration, 15mL is clearly not enough to result in any appreciable level of intoxication – even assuming complete absorption across the vaginal mucosa, which is another topic of entirely reasonable uncertainty.

Another media-hyped “danger” that clearly isn’t.

“A New Clandestine Route of Ethanol Administration? Volume of Vodka Absorbed in Commercially Available Tampons. An in vitro study”
http://www.ncbi.nlm.nih.gov/pubmed/24928406