Maddening Lack of Perspective in Endovascular Stroke Therapy

Despite three negative trials in the New England Journal of Medicine last year, accompanied by an editorial calling for a moratorium on reimbursement for endovascular therapy for acute stroke, proponents of this therapy forge ahead.  The negative trials, at the very least, have encouraged researchers to recognize – where tPA advocates fail to see – that patient selection is key, and not all candidates eligible for endovascular therapy are likely to benefit.

However, these authors, despite their well-intentioned effort to better target endovascular interventions, completely miss the mark.  This is a retrospective review of patients undergoing endovascular therapy between 2008 and 2012, stratified by selection protocols.  In 2010, the institution switched from an “all-comers” strategy to an MRI diffusion-weighted imaging-guided protocol.  The hypothesis: patients selected for endovascular therapy on the basis MRI-guided infarct characteristics would display better outcomes than the “all-comers” selection cohort.

And, their registry provides them the necessary substrate.  Between 2008 and 2010, 85 patients with median NIHSS 17 underwent endovascular therapy with dismal outcomes:  9.5% mRS 0-2 at 30 days and 47.6% mortality.  After implementation of the imaging-based protocol, only half of eligible patients qualified – and of the 92 patients with median NIHSS 15.5 who eventually underwent endovascular therapy under the new protocol, 23.9% had mRS 0-2 and mortality dropped to 19.7%.  Victory!  So say these authors.

However, there’s another cohort visible only by its absence in their tabular data – the post-protocol group that did not undergo endovascular therapy.  These 87 patients, with a median NIHSS ~16.5, had imaging characteristics thought by these authors to not qualify for endovascular therapy.  For this group, 23.1% had mRS 0-2 and 30% mortality.  These outcomes are not statistically different from the endovascular group.

The authors do not in any manner address this inconsistency in their data set – and the seemingly favorable intervention of lack-of-intervention.  Rather than the authors’ conclusion imaging could guide therapy – the better conclusion is that endovascular therapy was frighteningly harmful to many in the pre-protocol phase, and simply reducing the number of patients undergoing unnecessary intervention improved global outcomes.  And, for just added perspective: the placebo group in NINDS, with median NIHSS 15, had 26% mRS 0-1 and 21% mortality at 3 months – and this is before the modern post-stroke care that does more to improve outcomes than tPA could ever claim.

The madness continues.

“Addition of Hyperacute MRI Aids in Patient Selection, Decreasing the Use of Endovascular Stroke Therapy”
http://stroke.ahajournals.org/content/early/2014/01/09/STROKEAHA.113.003880.short

The “Padding” on Obese Patients is not Protective in Blunt Trauma

Everyone has an anecdotal tale of a morbidly obese patient who suffered penetrating injury that transversed only adipose tissue, leaving the small person living beneath unharmed.  However, these isolated incidents do not appear to apply to blunt trauma.

This study is a retrospective analysis of the National Trauma Data Bank, evaluating 32,780 morbidly obese (BMI >40) and non-obese patients matched 1:1 on age, sex, ISS, GCS, and blood pressure on arrival.  Baseline characteristics – as much as could be gleaned retrospectively – showed no substantial imbalance between the two cohorts.  And, by nearly every measure, patients with morbid obesity suffered poorer outcomes.  ARDS, decubitus ulcers, infectious complications, and thromboembolic complications were all significantly more frequent in this population.  These carried forward with increased hospital LOS and increased mortality – 3% vs. 2.2%

Unsurprising, and yet another manner in which obesity shortens lifespan and degrades quality of life.

“Morbid obesity predisposes trauma patients to worse outcomes: A National Trauma Data Bank analysis”
http://www.ncbi.nlm.nih.gov/pubmed/24368375

Shared Decision-Making to Reduce Overtesting

Medicine, like life, is full of uncertainty.  Every action or inaction has costs and consequences, both anticipated and unintended.  Permeating through medical culture for many reasons, with the proliferation of tests available, has been a decreased tolerance for this uncertainty and the rise of “zero-miss” medicine.  However, there are some tests that carry with them enough cost and risk, the population harms of the test outweigh the harms of the missed diagnoses.  CTPA for pulmonary embolism is one of those tests.

In this study, these authors attempt to reduce testing for pulmonary embolism by creating a shared decision-making framework to discuss the necessity of testing with patients.  They prospectively enrolled 203 patients presenting to the Emergency Department with dyspnea and, independent of their actual medical evaluation, attempted to ascertain their hypothetical actions were they to be evaluated for PE.  Specifically, they were interested in the “low clinical probability” population whose d-Dimer was elevated above the abnormal threshold – but still below twice-normal the threshold.  For these “borderline” abnormal d-Dimers, the authors created a visual decision tool describing their estimate of the benefit and risk of undergoing CTPA given this specific clinical scenario.

After viewing the benefits and risks of CTPA, 36% of patients in this study stated they would hypothetically decline testing for PE.  Most of the patients (85%) who planned to follow-through with the CTPA did so because they were concerned regarding a possible missed diagnosis of PE, while the remaining hoped the CT would at least also provide additional information regarding their actual diagnosis.  The authors conclude, based on a base case of 2.6 million possible PE evaluations annually, this strategy might save 100,000 CTPAs.

I think the approach these authors promote is generally on the right track.  The challenge, however, is the data used to discuss risks with patients.  From their information graphics, the risks of CTPA – cancer, IV contrast reaction, kidney injury and false positives – are all fair to include, but can be argued greatly regarding their clinical relevance.  Is a transient 25% increase in serum creatinine in a young, healthy person clinically significant?  Is it the same as a cancer diagnosis?  Is it enough to mention there are false-positives from the CTPA without mentioning the risk of having a severe bleeding event from anticoagulation?  Then, in their risk of not having the CTPA information graphic, they devote the bulk of that risk to a 15% chance of the CT identifying a diagnosis that would have otherwise been missed.  I think that significantly overstates the number of additional, clinically important findings requiring urgent treatment that might be identified.  Finally, the risks presented are for the “average” patient – and may be entirely inaccurate across the heterogenous population presenting for dyspnea.

But, any quibbles over the information graphic, limitations, and magnitude of effect are outweighed by the importance of advancing this approach in our practice.  Paternalism is dead, and new tools for communicating with patients will be critical to the future of medicine.

“Patient preferences for testing for pulmonary embolism in the ED using a shared decision-making model”
http://www.ncbi.nlm.nih.gov/pubmed/24370071

An Abbreviated IV Acetylcysteine Regime for Acute APAP Toxicity. Short, Sweet, and…. Safe?

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.
Anyone who has perused the literature on APAP toxicity will notice the protocols we use to guide us in the diagnosis and treatment of acute APAP overdose are based primarily on ultra-conservative estimates of risk rather than true clinical data. As a result we are left with acetylcysteine (NAC) treatment regimes that, though effective are cumbersome and convoluted. The current IV NAC regime consists of 3 different weight-based doses over various time periods within the first 25 hours. This regime is costly and frequently causes vomiting and anaphylactoid reactions. In a move towards practicality, authors from the Royal Infirmary of Edinburgh (the birthplace of the Rumack-Matthew Nomogram) performed a RCT comparing this traditional dosing scheme to a far more rational one.

These authors propose the initial bolus dose of NAC to be infused over a longer period (2 hours vs 15 min) followed by a maintenance infusion delivered over 12 hours in contrast to the traditional 24. They theorized that these modifications would reduce the amount of adverse reactions, primarily due to the initial rate at which NAC is infused and at the same time, limit the duration of treatment required. In a 2X2 factorial design, the authors also examined the effects of ondansetron on the rates of adverse reactions in both the traditional and modified NAC regimes.

From September 2010 to December 2012, 222 patients underwent randomization at three different UK hospitals. The authors found that both the modified dosing regiment and ondansetron prophylaxis decreased the rate of vomiting and retching in patients undergoing treatment for acute APAP intoxication. More impressively the modified dose regime seemed to dramatically reduce the incidence of serious anaphylactoid reactions from a frighteningly high 31% to 5%.

As far as safety is concerned there was no difference between the traditional and modified dosing regimes in the number of patients with an elevation in AST levels or microRNA miR-122 harpega(a more sensitive marker of hepatic injury as per the authors’ claims). There was an interesting increase in both AST levels and microRNA miR-122 levels in those given ondansetron when compared to placebo. Though this did not translate into any long term hepatic injuries and it is unclear if this increase was just noise secondary to the small sample size, the authors warn against its prophylactic use before further studies are performed to assess its safety.

Given that the Rumack-Mathews Nomogram was designed to be highly sensitive at the cost of its specificity, and very few patients above treatment threshold go on to clinically relevant hepatic toxicity, it is hard to say how many of these patients actually benefited from treatment. In addition 30% of this population were under the 4 hr 200mg/L level and were only treated because of the recent changes in the UK guidelines to lower the treatment threshold to 100mg/L. Due to the poor specificity and small sample size, it is difficult to truly assess the safety of this refined protocol. Using surrogate endpoints thought to be more sensitive for hepatic injury like a 50% rise in AST  (in contrast to the more traditional measurement of AST > 1000 IU) and microRNA miR-122, may provide us with some idea of efficacy, but does not answer the more pressing question. Are the patients treated with this modified regime at a higher risk for clinically relevant hepatic injury? This would require a much larger study population.

“Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial”
www.ncbi.nlm.nih.gov/pubmed/24290406

 

The Optimal Blood Pressure After OHCA Is …

… normal.

This article is a lot of science for not a lot of insight.  These authors gathered 3,620 out-of-hospital cardiac arrest patients who were transported to the Emergency Department after return of spontaneous circulation.  Patients that arrived to the Emergency Department with ROSC and a normal blood pressure had the best survival, with a linear decrease in survival for patients arriving with SBP below 90 mmHg.

However, the authors take this finding to the next step and conclude patients might benefit from more aggressive post-resuscitation blood pressure management.  Yes – any subgroup association identified on retrospective data dredging may reveal a true finding – but, rather than implicitly hype the positive result, it would be more appropriate to significantly downplay the finding as of uncertain significance and only hypothesis generating for future study.  After all, chances are – sick patients are sick, and those that persist in hypotension after OHCA are declaring themselves as such.  Prehospital blood pressure management does not address the underlying pathophysiology of the arrest and, given what we know about coronary and cerebral vasoconstriction, is more likely to be deleterious than beneficial.

“The association between systolic blood pressure on arrival at hospital and outcome in adults surviving from out-of-hospital cardiac arrests of presumed cardiac aetiology.”
http://www.ncbi.nlm.nih.gov/pubmed/24333351

Stop Using the Antibiotic Sledgehammer

There’s an interesting cultural phenomenon regarding inpatient treatment of respiratory illnesses – a sense that monitoring and close evaluation for treatment failure isn’t enough, and we must immediately deploy the nuclear option when the admission decision is made.  This includes nonsense use of intravenous administration when oral is equivalent and unnecessary use of broad-spectrum agents.

This comparative-effectiveness study evaluated the necessity of broad-spectrum agents versus narrow-spectrum antibiotics for the treatment of pediatric community-acquired pneumonia.  492 CAP admissions from four children’s hospitals in 2010 were retrospectively reviewed for outcomes, stratified by antibiotic choice.  Narrow-spectrum antibiotic choices were penicillin-like agents +/- macrolide, while broad-spectrum included cephalosporins or fluoroquinolones.

In their propensity-matched cohort, with the acknowledged limitations of unmeasured baseline characteristics, there were no useful differences in outcomes.  Most trends favored narrow-spectrum antibiotics, but these are at best statistical noise, and at worst reflect underlying unmatched treatment-episode confounders.

Current consensus-based recommendations are for initial treatment with narrow-spectrum agents – follow them.  I’d also note 51% of the population received blood cultures – 2.8% of which were positive.  I’m sure these were also entirely a waste of money.

“Comparative Effectiveness of Empiric Antibiotics for Community-Acquired Pneumonia”
http://www.ncbi.nlm.nih.gov/pubmed/24324001

Sharp Things are the Best Medicine

Rather, they’re the best fake medicine.

This is a mildly entertaining review of placebo responses from migraine trials, looking to compare the effect size of various forms of placebo.  These authors identified 79 studies with appropriate response-to-therapy data for analysis, and evaluated the relative influences of pharmacologic therapy, cognitive-behavioral therapy, and acupuncture or surgery versus their placebo/sham versions.

Sham cognitive-behavioral therapy was ineffective and all the confidence intervals crossed unity.  Pharmacologic placebo was only superior to no treatment at all.  Then, sham acupuncture or surgery was superior to both no treatment and pharmacologic placebo.  Hence, the authors conclude the expectation of benefit is enhanced by the elaborate rituals associated with invasive therapies – and ought to be considered and cautioned against when designing trials that attempt comparisons between invasive and medical therapies.

Or, you could simply use this knowledge for evil – and conduct almost guaranteed-success non-inferiority trials for any manner of medically useless device for provision of symptom relief.

The choice is yours.

“Differential Effectiveness of Placebo Treatments: A Systematic Review of Migraine Prophylaxis”
http://www.ncbi.nlm.nih.gov/pubmed/24126676

No, You *Still* Don’t Need Antibiotics For That URI

A guest post by Justin Mazzillo, a community doc in New Hampshire.

Perhaps you’ve seen a case or two this year – a child brought to the emergency department for a cold lasting more than a day. Little Johnny’s parents dragged him in to see you at three in the morning, in hopes of obtaining the instant cure of antibiotics. 
These authors out of Washington and the United Kingdom conducted a systematic review to determine the duration of symptoms of earache, sore throat, cough and common cold in children less than 18 years of age. They included only trial arms that used no treatment, symptomatic treatment or placebo. Their findings include:
·      Symptoms of earache resolved by day three in 50% of patients and day seven to eight in 90%.  
·      Sore throat resolved in two to seven days.
·      General cough resolved by day 10 in 50% and day 25 in 90%. Symptoms of croup were gone in 80% by day two.
·      Bronchiolitis symptoms were gone in 50% by day 13 and estimated to be gone in 90% of patients by day 21.
·      Lastly, it took 10 days for 50% of symptoms of the common cold to resolve and 15 days for 90% to be symptom free.
The authors found this data to differ significantly from estimates by the UK National Institute for Health and Care Excellence and the US Centers for Disease Control. This information may go a long way in preventing parents from convincing doctors to put little Johnny on a myriad of antibiotics while his virus runs its course.
“Duration of symptoms of respiratory tract infections in children: systematic review”

http://www.bmj.com/content/347/bmj.f7027

A Rapid Response Fantasyland

Rapid response teams sound good in theory – specifically skilled nurses as back-up providers for floor emergencies, intervening and escalating patients in times of unexpected deterioration.  However, the largest cluster-randomized trial and multiple meta-analyses have failed to show any benefit to rapid response teams.

The response to this high-quality evidence?  Irresponsible conclusions based on low-quality retrospective data.

These authors have so much enthusiasm for their product – a rapid response team that proactively rounds on patients – they’re blind to the most obvious holes in their data.  They try to retrospectively compare pre- and post-RRT implementation outcomes, despite having essentially only data on floor codes.  And, backing up their main conclusion, floor codes are lower post-RRT proactive rounding – of course, floor codes were already trending downwards at the time of implementation.

What happened when the RRT intervened?  The same thing as all other studies show – they moved patients to a higher level of care.  How did patients fare in the ICU?  A third died or were transferred to hospice.  Utterly overlooked in the discussion, in which these authors praise their product and their RRT nurses profusely, is the end result of their RRT product appears to be an unchanged mortality – a simple shuffling around the location of in-hospital deaths.  Their title implies a result that is simply demonstrated nowhere in the article, yet they continue to lavish themselves with accolades right up through the final conclusion:

“Our study demonstrates proactivity and innovation as an overall approach to inpatient cardiac arrests  ….  Innovation stems from a dedicated managerial team who routinely evaluates trends in the code data and creatively seeks ways to prevent cardiac arrest from occurring.”

Managerial buzzword self-aggrandizing nonsense.

“Proactive rounding by the rapid response team reduces inpatient cardiac arrests”
http://www.ncbi.nlm.nih.gov/pubmed/23994805