Monday, February 11, 2013

Statistics For tPA & Profit


IST-3 broke new ground for misleading statistics in stroke trials with its secondary ordinal analysis, demonstrating "benefit" in the presence of an overall negative, open-label, randomized trial of over 3,000 patients.  Now, who here can decipher the Cochran-Mantel-Haenszel test?  Team Genentech/Boehringer Ingelheim is hoping you can't.

This is a retrospective, observational cohort from the Virtual International Stroke Trials Registry looking for a way around the pesky "contraindications" to tPA treatment that currently prevent large groups of patients from receiving treatment.  These authors pulled non-treated "controls" from the cohort along with tPA-treated patients who had at least one contraindication or warning to tPA use and compared mRS outcomes at 90 days.  The control group was significantly older and sicker – though their strokes were milder (NIHSS 12 [SD 9] vs. NIHSS 14 [SD 8]) – but the authors adjusted only for age and NIHSS.  Their conclusion?
"Many of the warnings and contraindications of alteplase may not be justified and licences, guidelines, and protocols should be adjusted to accommodate recent data from registries and real-world experience."
As the authors correctly note earlier in the paper, observational data combined from heterogenous trials spread over many years is likely rife with differences in care and selection bias.  This alone renders their results invalid as anything but hypothesis-generating, rather than practice-changing.

The other issue is their primary outcome and statistical tool of choice:
"The primary outcome measure was the mRS at 90 days, analyzed across the whole distribution of scores with the use of the Cochran–Mantel–Haenszel test,"
Here's an example of an unadjusted mRS distribution "favoring" alteplase:


Just at first glance, looks pretty much the same – perhaps even favors placebo (top bar).  How the heck is this significantly positive towards tPA?  Well, the CMH takes into all ordinal levels – even the perturbations between disability/living death/death at the bottom of the scale – as opposed to just the clinically relevant mRS 0-1 or mRS 0-2 that were primary outcomes in other stroke trials.  So, the statistical significance in this test has nothing to do with the clinical efficacy of the treatment in question.  Then, the adjusted OR of 1.29 (95% CI 1.00 - 1.66) is somehow based on a mélange of "dichotomized outcomes at 90 days (mRS 0–1, mRS 0–2, NIHSS 0–1, and mortality)".

I'm afraid this simply looks like the authors dragged the VISTA data through every permutation of statistical tools possible until they found a test and a combined endpoint for logistic regression that came out in favor of tPA.  And, then, sold it as practice-altering.

Disheartening.

Here's the disclosures, for your reading pleasure:
BF has received modest honoraria for participation in clinical trials (Sanofi-Aventis). AVA has served as PI of CLOTBUST trial partially funded by Genentech, and currently serves as PI of CLOTBUSTER funded by Cerevast Therapeutics and consultant to Genentech. EB is an employee of Boehringer Ingelheim. JCG, CW, PL, and NKM have no relevant conflicts of interest. AM has served as a consultant for Boehringer Ingelheim, received speaker’s honoraria from Boehringer Ingelheim, and congress expenses from Lundbeck. NW has received expenses from Boehringer Ingelheim for his role as member of the steering committee in relation to the ECASS III trial with alteplase and served as a consultant to Thrombogenics as chairman of the DSMB. SITS International (chaired by NW) received a grant from Boehringer Ingelheim and from Ferrer for the SITS-MOST/SITS- ISTR. His institution has also received grant support toward administrative expenses for coordination of the ECASS III trial. NW has also received lecture fees from Boehringer Ingelheim and from Ferrer. AS and KRL have received research grants, modest honoraria for participation in clinical trials, and have a consultancy or advisory board relationship with manufacturers from drugs (including Boehringer Ingelheim). KRL administered the grant from Genentech for support of this study.

"Thrombolysis in Stroke Despite Contraindications or Warnings?"
stroke.ahajournals.org/.../STROKEAHA.112.674622.abstract

Friday, February 8, 2013

Lidocaine for Renal Colic

Just when you think you've heard it all – something new and different.  This is a randomized, blinded trial of morphine vs intravenous lidocaine for the management of flank pain associated with ureterolithiasis.  Why, do you ask?  Because, in Iran, they don't have ketorolac as an option for renal colic.

Patients were enrolled based on clinical symptoms, and ureterolithiasis was confirmed by plain radiographs.  240 patients in generally well-balanced groups were enrolled; all patients received 0.15mg/kg IV metoclopramide for nausea, and then the groups were randomized to 0.1mg/kg of morphine vs. 1.5 mg/kg of intravenous lidocaine.  Pain outcomes were measured by visual analog scale at 5, 10, 15, and 30 minutes – and the short answer is, they both worked, and neither treatment had terribly significant side effects.


I am all for expanding the toolbox for Emergency Medicine, however unusual the idea might be.  After all, every so often, you might need an alternative agent for that extra-special patient who is allergic to ketorolac, morphine, acetaminophen, ondansetron, fentanyl, and the color blue....


"Effectiveness of intravenous lidocaine versus 
intravenous morphine for patients with renal colic in the emergency department"

Wednesday, February 6, 2013

Pediatric Blunt Trauma Remains Confounding

The latest output from the Pediatric Emergency Care Applied Research Network is a clinical decision instrument intended to assist clinicians in managing pediatric blunt abdominal trauma.

Like previous PECARN studies, this is a multi-center, prospective, observational study conducted in tertiary pediatric emergency departments.  This study enrolled 12,044 children with blunt trauma and prospectively collected structured data regarding their mechanism, external injuries, and physiologic variables.  Using the magic of statistical partitioning, the authors derived a decision instrument for use in risk-stratifying a patient as "very low risk for intra-abdominal injury requiring acute intervention."  If the patient meets all criteria, the prediction rule is 97.0% sensitive, missing 6 out of 203 abdominal injuries.

This is critically valuable data – but, as a decision-instrument in a zero-miss environment, I'm not sure if it helps.  The authors note that use of their CT decision-instrument actually increased resource utilization if retrospectively applied to the derivation cohort, if the requirement is held that a patient be negative for every variable.  If the threshold is raised to 1 or 2 variables present, then sensitivity drops to 82% and 77%, respectively.  Only about half received a CT scan, and a small percentage were lost to follow-up – though, given the outcome of "injuries requiring intervention", the methodology is reasonable.  However, because intervention-requiring injuries only represented 26% of all radiographically-identified intra-abdominal injuries, this study is still going to be ignored out-of-hand by folks who want to identify all injuries, not just intervention-requiring injuries.  After all, the grade 1 splenic laceration may be intervention-free, but remains important regarding activity restrictions to prevent future morbidity.

The authors also note these findings require external validation – wherever they're going to find another pedatric emergency care network to enroll 12,000 patients!

"Identifying Children at Very Low Risk of Clinically Important Blunt Abdominal Injuries"
http://www.ncbi.nlm.nih.gov/pubmed/23375510

Monday, February 4, 2013

UTI: Yet Another Windmill?

Medicine is full of windmills re-imagined as dragons – and two of the most prominent voices of reason in Emergency Medicine are David Newman and Jerome Hoffman.  This skeptical take on pediatric urinary tract infections is David Newman's latest, which covers content reflective of his SMART EM podcast on the same topic.

The premise of his argument is rather straightforward:

  • There's substantial overlap between UTI and asymptomatic bacteruria, leading to overdiagnosis.
  • Even when the diagnosis is correctly made, prompt treatment does not prevent complications.
The complications in question are urosepsis and renal scarring.  Urosepsis, in David's literature review only results from urinary tract infections from the otherwise immunosuppressed, or in infants with congenital anomalies.  Renal scarring, purportedly from pyelonephritis, has little or controversial evidence in supporting antibiotic use from preventing it.

This will be published in an upcoming issue of Annals of Emergency Medicine.

"Pediatric Urinary Tract Infection: Does the Evidence Support Aggressively Pursuing the Diagnosis?"
www.ncbi.nlm.nih.gov/pubmed/23312370


Friday, February 1, 2013

Don't Waste the Saline

This is a study that follows-up and confirms the prior "mythbusting" literature regarding the management of minor soft-tissue lacerations in the ED.  Specifically, this article evaluates the need for wound irrigation with sterile saline ($) as compared with tap water (free).

Unsurprisingly – and consistent with prior literature – this relatively contemporary study of 663 patients at Stanford University hospitals shows no difference in subsequent rates of wound infection, regardless of irrigation solution.  The sterile saline group suffered 6.4% (9.1 to 3.7%) subjective wound infections in follow-up, compared to 3.5% (5.5 to 1.5%) infections in the warm tap water irrigation.  A few patients were lost to follow-up, and the study has some generalizability limitations due to predefined exclusion criteria – frequently seen ED comorbidities such as diabetes, alcoholism, and immunocompromise were excluded.

But, it's another piece of the puzzle that tells us suturing of uncomplicated wounds needs not be made more complicated.  There's no evidence to suggest that anything more than tap water, absorbable sutures, and non-sterile techniques are needed for optimal patient outcomes.

"Water is a safe and effective alternative to sterile normal saline for wound irrigation prior to suturing: a prospective, double-blind, randomised, controlled clinical trial"
http://bmjopen.bmj.com/content/3/1/e001504.full

Wednesday, January 30, 2013

MOPETT – Half-Dose tPA for PE

It's not very often I read an article and decide to I'd like to incorporate it into my practice.  EMCrit covered this last month, but I reserved judgement until I had a chance to read the primary literature for myself.

This is the MOPETT trial – half-dose (?"safe dose") tPA for "moderate" pulmonary embolism.  We already know what to do for "massive" PE – full-dose thrombolytics when not otherwise contraindicated.  However, the data for full-dose thrombolytics in "submassive" PE is less conclusive.

These authors enrolled relatively ill PE patients – tachypneic, hypoxic, tachycardic patients with >70% thrombotic occlusion of lobar or main pulmonary arteries – but did not apply regularly applied measures of "submassive" – RV dysfunction, elevated troponins, elevated BNP.  Their primary outcome was long-term development of pulmonary hypertension, with mortality and bleeding as their secondary outcomes.  They dosed tPA at 50mg, rather than 100mg – 10mg bolus and 40mg infusion.

Their two cohorts were rather well matched.  Outcomes favored the thrombolysis group, with 16% subsequent pulmonary hypertension compared with 57% in the control group.  Mortality, recurrent pulmonary embolism, and bleeding complications were similar and at rates too low to detect a difference given the power of the study.

I'd like to start doing this.  I wish they published the troponin/BNP/RV dysfunction rates in the two cohorts to provide better context with the other submassive literature.  I also would have preferred to see this study registered with clinicaltrials.gov.  But, in a nice change, none of the authors declare any conflicts of interest!

"Moderate Pulmonary Embolism Treated With Thrombolysis (from the “MOPETT” Trial)"
www.ncbi.nlm.nih.gov/pubmed/23102885

Monday, January 28, 2013

Etomidate, Safe for Sepsis?

Sadly, the jury is still out.  Just months after Critical Care Medicine published the systematic review demonstrating an association between use of etomidate and mortality in sepsis, now they're back with a retrospective data-mining expedition that draws the opposite conclusion.

This is a multi-center prospective registry of critically ill patients entered into a research database who were retrospectively data-mined for septic, intubated patients.  Of the 42,000 patients in the database, approximately 2,000 met this definition, and about half were identified as receiving etomidate as their induction agent.  In their cohort, there was no in-hospital mortality difference between the patients who received etomidate and the patients who received a different induction agent for intubation.

Unfortunately, as an observational, retrospective study of imperfectly matched cohorts, there are far too many uncontrolled confounders to base clinical practice on these findings.  Studies such as these, even robust, prospective cohorts, are capable of doing little more than suggesting a hypothesis contrary to the findings of prior work.

If you believe etomidate has a chance to harm patients in sepsis, this doesn't change your practice.

"Single-Dose Etomidate Is Not Associated With Increased Mortality in ICU Patients With Sepsis: Analysis of a Large Electronic ICU Database"
www.ncbi.nlm.nih.gov/pubmed/23318491

Friday, January 25, 2013

Copy & Paste Medicine

Mostly unrelated to Emergency Medicine – but an interesting descriptive study of a downstream phenomenon I see on a frequent basis.  

For example, I'll intermittently follow-up a patient to see how they fared as an inpatient.  I'll read the inpatient documentation, consultant reports, etc. – and find the tiny EM HPI perpetuated throughout the chart with minimal modification.  This anecdotal experience is backed up by these authors who used text-compare software to identify copied passages in daily progress notes from an ICU setting.  In this ICU at MetroHealth in Cleveland, 82% of resident notes copied at least >20% of the text from the previous days' progress note – and copied 55% of the prior content on average.  Attending notes were slightly less frequently copied (74%), but tended to copy more content (61%).

There's no conclusive data regarding whether this copy/paste practice affects patient outcomes, but it's an interesting symptom of evolving medical care and documentation in the EHR era.  I hope that, as HIT evolves, documentation tools trend towards encouraging concise, effective communication, rather than this sort of (likely ineffective) chart bloat.

"Prevalence of Copied Information by Attendings and Residents in Critical Care Progress Notes"
www.ncbi.nlm.nih.gov/pubmed/23263617

Wednesday, January 23, 2013

New ACEP tPA Clinical Policy


If you're still skeptical about the use of tPA in stroke patients – too bad.  If you're not on the bus, it would seem now you're under it.  ACEP has published their new Clinical Policy regarding tPA use in the most recent issue of Annals of Emergency Medicine.  tPA should be offered to folks in the 0-3 hour window who meet NINDS criteria as a Level A recommendation.  This is based on the following Class I evidence:
  • Two studies that are negative for benefit (ECASS, ATLANTIS)
  • The post-hoc analysis of ATLANTIS B with 61 patients,
  • NINDS
The Level B recommendation is that tPA be considered for use off-label in the 3-4.5 hour window, based on ECASS III.

If you'll travel backwards in time a couple days (by scrolling down), you'll see I did a quick review of two articles concerning the "trustworthiness" of clinical practice guidelines.  The Institute of Medicine names eight criteria – and, for the most part, this guideline does OK.  It does, unfortunately, fare less well at the conflict of interests declared:
  • Dr. Smith – Served on scientific advisory board for Genentech.
  • Dr. Gronseth – Speakers' bureau for, and honoraria from, Boehringer Ingelheim.
  • Dr. Messe – Former speakers' bureau for Boehringer Ingelheim.
Three out of eight guideline writers directly involved with the pharmaceutical manufacturer.   As far as indirect support, however, if they wanted to be more transparent, Dr. Edlow, Dr. Jagoda, Dr. Stead, Dr. Wears, and Dr. Decker also ought to have disclosed their association with the Foundation for Education and Research in Neurologic Emergencies – supported by multitudinous pharmaceutical manufacturers, including Genentech.

If you're irritated that pharmaceutical manufacturers are helping write our clinical guidelines, make your voice heard.

"Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department"

Monday, January 21, 2013

What Are "Trustworthy" Clinical Guidelines?

This short article from JAMA and corresponding study from Archives is concerned with advising practicing clinicians on how to identify which clinical guidelines are "trustworthy".  This is a problem – because most aren't.  

The JAMA article paraphrases the eight critical elements in the 2008 Institute of Medicine report required to generate a "trustworthy" article, such as systematic methodology, appropriate stakeholders, etc.  Most prominently, however, several deal specifically with transparency, including this paraphrased bullet point:
  • Conflicts of interest:  Potential guideline development group members should declare conflicts. None, or at most a small minority, should have conflicts, including services from which a clinician derives a substantial proportion of income. The chair and co-chair should not have conflicts. Eliminate financial ties that create conflicts.
The Archives article cited by the JAMA article reviews over 100 published guidelines for compliance with the IOM.  The worst performance, by far, was compliance with conflicts of interest, and notes that 71% of committee chairpersons and 90.5% of committee co-chairpersons declared COI – when declarations were explicitly stated at all.  Overall, less than half of clinical guidelines met more than half of the IOM recommendations for "trustworthiness".

Sadly, another dismal addition to the all-too-frequent narrative describing the rotten foundation of modern medical practice.

"How to Decide Whether a Clinical Practice Guideline Is Trustworthy"
www.ncbi.nlm.nih.gov/pubmed/23299601

"Failure of Clinical Practice Guidelines to Meet Institute of Medicine Standards"
www.ncbi.nlm.nih.gov/pubmed/23089902

Friday, January 18, 2013

Lactate – Is There Any Death It Doesn't Predict?

Turns out – apparently, no!

Continuing the run on pulmonary embolism articles, we find that – in addition to all the things we know prognosticates increased mortality in PE patients – elevated plasma lactate levels also predict poor outcomes.  This is generally unsurprising, because elevated lactate levels are associated with increased mortality, even in unselected ED patients.  What is interesting, however, is that lactate levels >2 mmol/L were more associated with 30-day mortality than shock/hypotension, hypoxia, or right-ventricular dysfunction.  It's a small cohort, but it's a reasonable finding, regardless.

However, what's sort of odd regarding the Editor's Summary for this article is that it specifically mentions the lactate level does not outperform a simplified pulmonary embolism severity index clinical tool.  The "truth" is that an AUC of 0.84 is better than an AUC of 0.71 – but that (0.72 to 0.95) and (0.60 to 0.83) overlap.  Rather than trash the lactic acid level compared with the PESI, it might have been more accurate to simply state the current study was underpowered to confirm the advantage of lactic acid over PESI, and further research is necessary.

Can you buy stock in lactate level assays?  It's clearly the new favorite all-purposes prognostication tool.


"Prognostic Value of Plasma Lactate Levels Among Patients With Acute Pulmonary Embolism: The Thrombo-Embolism Lactate Outcome Study" 
http://www.ncbi.nlm.nih.gov/pubmed/23306454

Wednesday, January 16, 2013

Inadequate "Overuse" Reduction Strategies

This study was featured in Academic Emergency Medicine as one of their CME articles – theoretically, an article with additional value presented with incentives to motivate a closer reading of the content.  I don't mean to imply this is somehow a bad article – but it's just interesting to step back out of the tunnel vision of statistics and boggle at the inadequacy of the current state of medicine. 

 This is a prospective study of patients evaluated for pulmonary embolism attempting to evaluate how many patients were "inappropriately" scanned.  This definition of "inappropriate" scanning was determined by patients who were either PERC negative or had low-risk Wells' score followed by a negative d-Dimer.  Overall, of 152 patients, 11.8% were ultimately diagnosed with PE.  However, the authors state that application of the PERC rule might have eliminated 9.2% of these scans while Wells'/d-Dimer would have obviated 13.8%.

While I certainly don't discount the beneficial effect of even small reductions in the number of individuals evaluated for pulmonary embolism, these are still terrible numbers.  90% of CT scans for PE are negative?  And using these decision instruments gets us to ~75% negative scans?  This would be comically wasteful performance and innovative performance improvement in any other industry.

We pretty clearly need to do better.

"Overuse of Computed Tomography Pulmonary Angiography in the Evaluation of Patients with Suspected Pulmonary Embolism in the Emergency Department"
www.ncbi.nlm.nih.gov/m/pubmed/23167851/

Monday, January 14, 2013

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"