Ryan Radecki

tPA Equally (In)Effective for Wake-Up Stroke

This is a, yet another, study in Stroke of folks claiming it is “safe” to use thrombolysis on patients who are found to have suffered a stroke while sleeping – the so-called “wake-up stroke” population.

The specific claim made is “This retrospective analysis of data in thrombolysed consecutive acute ischemic stroke patients shows no significant differences in mortality, functional outcomes, or bleeding rates between WUIS patients with no early ischemic change on CT and those treated within 4.5 hours of stroke onset.”

…because their sample size is so small the absolute differences are still within the statistical variation expected by chance. This is, unfortunately, a recurring theme I see in these stroke publications, many of which are retrospective registry reviews. Their groups are statistically not different, but this is owing to failed statistical power in study design, as opposed to clinically meaningful equivalence. This is a major difference between retrospective and prospective studies – in which prospective studies choose specific absolute differences necessary to define clinically meaningful equivalence, and then perform power and sample size calculations based on these constraints.

Their outcomes are, incidentally, also simply terrible. They publish a figure comparing outcomes with their wake-up stroke population to their 0-4.5 hour thrombolysis reference group – a 326 patient reference group with 18% mRS 0-1 and a 26% mortality. But then, they further break out the 197 patients from that group that received tPA within the ECASS III license criteria, showing that compliance with guidelines leads to 32% mRS 0-1 and 18% mortality. This therefore implies the other 129 patients – the ones who received tPA outside the license criteria – had utterly dismal functional outcomes and frighteningly high mortality.

Someone needs to go down to King’s College and check up on them and make sure all this off-label use isn’t just costly killing fields.

“A Case-Controlled Comparison of Thrombolysis Outcomes Between Wake-Up and Known Time of Onset Ischemic Stroke Patients”
http://www.ncbi.nlm.nih.gov/pubmed/23723307

Beware Observational Conclusions

“High achieved SBP after standardized antihypertensive therapy in hyperacute intracerebral hemorrhage was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may ameliorate clinical outcomes.”

Jerry Hoffman has mentioned the exercise to, while reading, expand any instance of the word “may” to “may or may not” – to help erase the positive bias of speculative conclusions. And, this is one of those perfect circumstances where the lukewarm endorsement from this abstract conclusion ought to be predicated with a pound of cautionary conditionality.

These authors call their study SAMURAI-ICH, and it’s a prospective, observational study regarding the safety of early blood pressure reduction in intracerebral hemorrhage. What this really means is they thought aggressive BP lowering was going to be awesome – despite only having various bits of inconclusive evidence – so they made wholesale practice changes, and then started a registry to monitor outcomes. So, you can see the bias already.

And, verily, there is an association between their ability to lower blood pressure in ICH and favorable outcomes. Now, their “favorable outcomes” cohort was also young, less disabled at baseline, and had smaller ICH hematoma volume. Through the magic of statistical models, they attempt to control for all the various prognostic catastrophes, and thusly they arrive at their significant association.

But, finally, this observation doesn’t in the slightest explain whether the blood pressure control improved outcomes – or whether it was simply easier to lower blood pressure in patients whose cerebrovascular physiology was less deranged by smaller insults, and who went on to have good outcomes. Aggressive antihypertensive treatment “may or may not” ameliorate clinical outcomes, indeed.

Beware observational conclusions!

“Systolic Blood Pressure After Intravenous Antihypertensive Treatment and Clinical Outcomes in Hyperacute Intracerebral Hemorrhage : The Stroke Acute Management With Urgent Risk-Factor Assessment and Improvement-Intracerebral Hemorrhage Study”
www.ncbi.nlm.nih.gov/pubmed/23704107

A Lovely Overview of Highly-Sensitive Troponin

Although ranting is fun, I much prefer pointing readers in the direction of useful, educational articles – and dispensing with the lighthearted vitriol.

Today, I don’t have to gripe about JAMA – because they’ve published a succinct and fair assessment of the new highly-sensitive troponins by Dr. Lemos from UT Southwestern. Written for a general audience, he begins with, essentially, a case example of mismanaged Type II MI resulting from non-specific troponin rise, and then progresses through the various confounding causes of elevated troponins and the definition of myocardial infarction. He then proceeds to frame these problems in the context of ruling out ACS and balancing sensitivity and specificity, as I’ve previously covered here, here, and here. He makes a fine point that expanding use of these assays will mean approaching the troponin measurement as a continuous value, rather than dichotomous, and a more nuanced diagnostic process. He also cautions against over-testing and over-diagnosis in the low-risk population.

He also half-proposes the use of troponin testing in the outpatient setting, as elevated baseline troponin levels are associated with poor prognosis. However, he notes it remains uncertain the effect routine measurement might actually have on cost-effective care and outcomes.

The author discloses conflict-of-interest with several firms, including manufacturers of the highly-sensitive assays – but his conclusion is quite restrained, and acknowledges the very real practice limitations.

“Increasingly Sensitive Assays for Cardiac Troponins”
jama.jamanetwork.com/article.aspx?articleid=1693870‎

14 Days of Steroids is Too Many Days

Some of the most common practices in Emergency Medicine are only weakly tested or defined – including steroids for acute respiratory illness. What is the true minimum effective dose? How many days – 3, 5, 7, or 14? Burst or taper? Much of our practice is based on habit and mimicry, along with the general evidence that, despite ourselves, we don’t seem to be doing much harm.

This is the REDUCE trial, a multi-center, randomized, double-blind, non-inferiority comparison between a 5-day and a 14-day course of 40mg oral prednisone for acute COPD exacerbation. And…it found no difference in the primary outcome measure. So, then, all’s well.

Except, their outcome measure is utterly bizarre – re-exacerbation within six months? I cannot fathom how a 1-2 week period of steroids could have any causative association with outcomes more than a handful of half-lives after cessation of treatment. Perhaps they theorize the short-term steroid exposure is insufficient to avoid long-term damage secondary to the acute inflammation?

There are also some potentially confounding differences in baseline characteristics. There were 9% more smokers and 5% more home oxygen in the short-term treatment group – which could favor conventional treatment – but then 4% fewer were on daily steroids during the treatment period and 8% fewer received concurrent antibiotics in the conventional treatment group – which could favor the short-term treatment group. Some of these differences would have more effect on short-term outcomes, while others would affect long-term outcomes. I don’t know if there are true clues in the Kaplan-Meier curves they present – because the sample size is small enough these variations might just be occurring due to chance – but it appears there’s a possible hazard towards early re-exacerbation in the 5-day group, followed by regression towards equivalence by six months.

However, these issues aside, their conclusion is probably valid. Their predefined threshold for non-inferiority was 15% – and they easily cleared that bar. All the confounders are probably not of significant magnitude to affect the overall result at that threshold – even for shorter, more relevant follow-up time periods. Additionally, this is otherwise consistent with the other evidence that short-courses of steroids are absolutely acceptable in this context.

“Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease”
www.ncbi.nlm.nih.gov/pubmed/23695200

4-Factor PCC is Here! Yay?

The self-described “EM Nerd” Rory Spiegel from Newark Beth Israel writes in to point out a fascinating discovery – previously undiscovered clinical trial results for Kcentra, the newly available 4-Factor Prothrombin Complex Concentrate, embedded in the product labeling.

4-factor PCCs are well-known from their use in Europe – capable of rapid reversal of factor-dependent coagulopathy at the expense of increased thrombotic complications. Within the package labeling, however, two new Phase III trials are described – open-label, randomized, non-inferiority comparisons. The trials, for what they’re worth, show no significant outcome difference compared with FFP – but, yet again, no clinically relevant threshold for non-inferiority is established to drive sample size calculations. I’d like to comment more, but they only provide detailed adverse event information on one of the two trials. Perhaps we’ll see these published and peer-reviewed imminently.

It should also be noted the extensive exclusion criteria used to enroll patients in these studies – a far longer list than the few contraindications listed on the package label. These criteria may be noted on the ClinicalTrials.gov site.

Lovely to see we’ve now another costly reinvention of the wheel that will almost certainly be overutilized at the behest of Bering’s marketing army.

“Efficacy and Safety Study of BERIPLEX® P/N Compared With Plasma in Patients With Acute Major Bleeding Caused by Anticoagulant Therapy”
http://clinicaltrials.gov/ct2/show/NCT00708435

“The Sign of Four…”
http://emnerd.tumblr.com/post/50947148065/the-sign-of-four

“CSL Behring 1.14.1.3 Draft Labeling Text”
http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM350239.pdf

Bacterial Meningitis in Complex Febrile Seizure

The AAP has guidelines for simple febrile seizure – “There, there, the frightening demonic possession your child just experienced is nothing to worry about.” Complex febrile seizures, however, are offered far less conclusive guidance.

This little retrospective review from UC San Diego evaluates 193 patients presenting with complex febrile seizure. Lumbar puncture was performed in 136, and 1 patient ultimately received a diagnosis of bacterial meningitis. The authors suggest, cognizant of the limitations, that complex febrile seizures need not routinely undergo LP.

This is entirely reasonable and consistent with the prior literature. The largest retrospective review, from Boston Children’s, identified 3 cases with bacterial meningitis out of 526 children. A systematic review and meta-analysis identified 41 cases of bacterial meningitis out of 1996 children. There are additional cases of viral meningitis and encephalitis in these cohorts as well – of uncertain clinical significance – but the general implication is that otherwise well-appearing children ought not need LP absent other signs of CNS infection.

It would, of course, be fabulous if a consensus guidelines would further reinforce this evidence.

“Necessity of Lumbar Puncture in Patients Presenting with New Onset Complex Febrile Seizures”
www.ncbi.nlm.nih.gov/pubmed/23687537

“Yield of lumbar puncture among children who present with their first complex febrile seizure.”
www.ncbi.nlm.nih.gov/pubmed/20566610‎

“Risk of bacterial meningitis in young children with a first seizure in the context of fever: a systematic review and meta-analysis.”
www.ncbi.nlm.nih.gov/pubmed/23383133‎

INTERACT2: ICH Half-Truths

There have been dueling schools of thought regarding atraumatic intracerebral hemorrhage: let the brain autoregulate its own blood supply and don’t artificially lower the blood pressure, or use intravenous agents to lower blood pressure because there’s evidence it decreases hematoma expansion. However, until now, there’d been no evidence that decreased hematoma size correlated with meaningful patient-oriented outcomes.

So, what are they saying about INTERACT2, the open-label, randomized trial of intensive BP control (SBP <140 mmHg) versus guideline-concordant BP control (<180 mmHg)?

@medwireNews INTERACT2 contradicts “longstanding dogma”, supports intensive BP reduction in ICH #eurostroke2013

@MedscapeNeuro INTERACT2: Intensive Blood Pressure Lowering Benefits ICH

@IctusClnic #ESCLondon2013 Surely INTERACT2 will have a great impact in blood pressure management after intracranial hemorrhage.

Pfffft.

The primary outcome was reduction in death or major disability (modified Rankin scale 3 to 6) at 90 days. Unadjusted outcome was statistically negative, 52.0% to 55.6% (OR 0.87, 95% CI 0.75 to 1.01), but favoring intensive BP control. Their secondary outcomes, which uses the conceptually messy tool of ordinal analysis, essentially magnified the effect of that 3.6% absolute difference in mRS outcomes and goes on to show that folks with less disability end up happier and more functional.

However, the baseline functional characteristics favored the intensive BP group, with median NIHSS score of 10 vs. 11. 68% of the cohort was from China – which has uncertain effects on external validity. Over seven different intravenous antihypertensives – including the most popular agent, urapidil – were used for BP lowering, further muddling precise treatment guidance. Most ICH was small volume hemorrhage, and BP treatment didn’t seem to have much different on hematoma expansion – so it’s hard to say why the intensive control group seemed to have a trend towards superiority.

And, finally, even though approximately half of the 1436 assigned to guideline-recommended treatment group had baseline systolic BP >180 mmHg, only 303 of them received an anti-hypertensive agent within 1 hour of study assignment. It might be more appropriate to describe this study as “intensive” vs. “poorly guideline-concordant” BP control – would outcomes have been more favorable if more of the guideline-concordant group actually had their systolic BP lowered below 180 mmHg?

In any event, to call this a practice-changing paradigm is a only a half-truth. It does appear safe, at least, to make a brisk and reasonable effort to lower BP in atraumatic, intracerebral hemorrhage. Whether “intensive” control is needed with a nicardipine infusion, such as in the upcoming Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II trial, is still uncertain.

“Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage”
http://www.nejm.org/doi/full/10.1056/NEJMoa1214609

Misleading Claims for Coronary CTA

The authors of this article make several discrete claims regarding the utility of coronary CT angiography – simply stated right in the title of the article: “Routine coronary computed tomographic angiography reduces unnecessary hospital admissions, length of stay, recidivism rates, and invasive coronary angiography in the Emergency Department triage of chest pain”. And, essentially all the assertions made in this observational, retrospective review are suspect.

Reduces unnecessary hospital admissions:
The article in no fashion addresses “unnecessary” hospital admissions. After all, of their selected cohort of patients, a tiny fraction – 9 of 1,788 – ruled-in for acute MI. A total of 42 underwent revascularization, but this is a measure reflecting only the aggressiveness of their local cardiology groups. It would seem the real problem regarding “unnecessary” admissions is an inability to select patients with appropriate clinical probability for further evaluation.

Reduces length of stay:
There is a less than 1 hour reduction in length of stay only for discharged ED patients. A true accounting of the LOS and congestion of chest pain patients ought to include admitted patients who depart the ED for their hospital observation bed soon after their initial biomarker result – but that would probably make their overall result contrary to their chosen narrative. The reduction in length of stay is also influenced by the authors exclusion of patients who had ED LOS less than 3 hours – as the authors simply decide no adequate evaluation of low-risk chest pain patients could be performed in that timeframe.

Reduces recidivism rates:
The reduction in recidivism rates may have reached statistical significance, but the absolute difference was only 20 patients, most of whom were discharged from the Emergency Department.

Reduces invasive coronary angiography:
There is a reduction in coronary angiography – mostly, from what I can tell, in that the handful of patients with multi-vessel disease detected on CCTA were referred to CABG, and the use of invasive coronary angiography was obviated. The absolute difference was only 19 angiography episodes – an avoidance of a handful of $2000-$3000 procedures at the cost of nearly a thousand $700-$1200 CCTAs.

Finally, their abstract conclusion claims it reduces healthcare resource utilization:
The authors never explicitly define this endpoint – which is probably for the best, as I count 960 non-invasive and 8 invasive tests in their CCTA cohort versus 368 non-invasive and 27 invasive tests in their “standard evaluation” cohort. The admission rate, however, is more than halved from 40% to 14%. A reduction in resource utilization would be contrary to general consensus from trials of CCTA versus standard care.

Most disturbingly, this article reports “Disclosures: none”. However, a simple internet search reveals multiple authors having prior relationships with Siemens and GE Healthcare. Perhaps by some narrowest definition this isn’t untruthful, but it is certainly misleading.

“Routine coronary computed tomographic angiography reduces unnecessary hospital admissions, length of stay, recidivism rates, and invasive coronary angiography in the Emergency Department triage of chest pain”
http://www.ncbi.nlm.nih.gov/pubmed/23684682

The EM Lit of Note PE Decision Tree

A couple weeks back I posted regarding a study where even intermediate- and high-risk patients with suspected PE had negative CTA in the presence of low d-Dimers. Based on that post, I’ve put together a rough decision tree encapsulating how I (currently) prefer to approach the diagnosis of pulmonary embolism:

Note that “Scan for PE” really means to be “offer patient scan for PE”, considering relevant diagnostic uncertainty and risks in a shared decision-making process. “Other reason why d-Dimer would be elevated” takes into account clinical judgement regarding the uselessness of d-Dimer as an acute-phase reactant or inflammatory marker; many “sick” patients will have elevated d-Dimers, obviating its value as a one-way screen-out. Also, this chart does not account for any medicolegal liability risks – a wonderful perk of practicing in Texas.

Follow-up: Seth Trueger and John Greenwood pointed out on the original that there are some specific moderate- and high-risk cases that satisfy PERC criteria, and perhaps the risk-stratification step should occur before application of PERC, as is traditionally done. Fair enough! They also note the EMCrit flow-chart begins with an exhortation of “Did you really care about PE?” – which, I’d say, is approximated by my value judgement of “Bad miss?” after starting to consider PE. Finally, Scott Weingart chimed in to suggest, for patients in whom you’re playing the minimal-harm game for unexciting pulmonary emboli, a bedside ultrasound to quickly check for an occult DVT that might cause them to come back with clinically significant pulmonary venous thrombosis.

The War on Blood Cultures

There are two problems with blood cultures. The first question is with regard to the likelihood you’ll get a true positive result. That question is covered by this JAMA Rational Clinical Examination.

The second question regards whether the true positive result is clinically meaningful. This retrospective review of 639 cellulitis patients – 325 without medical comorbidities and 314 with – evaluated for changes in therapy as a result of positive cultures. 46 cultures returned positive – with half being judged due to contaminants. Of the 23 true positives, 5 resulted in a change of antibiotic therapy – only 2 of which expanded the initial antibiotic choice to include coverage for a new pathogen. Both changes in therapy occurred in the immunosuppressed group.

Yet another example of the incredibly low yield of an expensive test. We’re clearly simply asking a question for which we already have the answer.

“Blood culture results do not affect treatment in complicated cellulitis”
www.ncbi.nlm.nih.gov/pubmed/23588078