Tuesday, May 26, 2015

DIAS-3 – Desmoteplase Fails in the Extended Time Window

It seems to be the stroke neurologists' greatest lament – the restricted time windows for tPA, either 3 or 4.5 hours, excluding so many patients from receiving the blessing of thrombolysis.  There have been failed trials in the past in extended time windows, and, even, failed trials in the 3-5h time window.  But, this is desmoteplase, and it is more fibrin specific than alteplase – and this follows up DIAS-2, which seemed to suggest benefit in patients with demonstrated arterial conclusion on vascular imaging.

It is, sadly, negative by the primary outcome of 90-day Rankin score (mRS 0-2), adding another tick mark to the list of failed contemporary trials for systemic thrombolysis.  Safety outcomes, mercifully for the patients involved, were similar, with low rates of neurologic worsening associated with intracranial hemorrhage in each cohort.

The authors, as before, find and focus on a single positive subgroup: patients with ischemic injury volume of less than 25mL on MRI.  There was, interestingly, no positive effect noted for patients whose ischemic injury volume was less than 25mL on CT – and the authors had no specific explanation for the discrepancy.  However, given the recent successful endovascular trials, it is quite reasonable to suggest an imaging-based, tissue-salvage model is more appropriate than the simplistic time-based model suggested by NINDS.  Unfortunately, tissue salvage is dependent upon recanalization – and rates were not significantly different between cohorts, 49% with desmoteplase vs. 42% with placebo.  This is the persistent elephant neurologists fail to acknowledge – that systemic thrombolysis simply rarely works as advertised – greatly diminishing any possible beneficial effect.

The conflict-of-interest statement falls on what probably would have once been considered the extreme side, but now is tragically routine:
The funder was involved in the study design, data collection, data analysis, and data interpretation. Two employees of the funder provided medical writing assistance in the editing of the report. The corresponding author had full access to all study data; all other authors without funder affiliation had access to study data via the corresponding author and authors with funder affiliation had full access to all study data.
Interestingly, review of the ClinicalTrials.gov registration indicates the study was initially planned in 2008 to enroll 320 patients, with an end date in 2010.  In 2010, the planned enrollment was increased to 400, and the study ultimately enrolled 492.  Given the COI involved, it reasonable to suggest the funder was involved in ongoing analysis of the results with the intention of stopping the study at the precise moment a positive outcome – or ultimate futility – was detected.  Despite the best efforts of Jeff Drazen and the NEJM to downplay potential distortions secondary to funding sources, clearly, our vigilance for such likely scientific misconduct should not be diminished.

“Safety and efficacy of desmoteplase given 3–9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial”
http://www.ncbi.nlm.nih.gov/pubmed/25937443

Friday, May 22, 2015

Where Should You Admit the Elderly with Rib Fractures?

In general, trauma results in disproportionately severe injuries in elderly patients despite similar mechanisms.  A frequent concern, specifically, is the risk of pneumonia or intubation associated with rib fractures – previously demonstrated to increase linear for each fracture in patients aged greater than 65.

However, a dichotomous age cut-off paired with a single variable is an obviously simplistic model.  These authors retrospectively reviewed 400 patients aged greater than 55 years of age hospitalized with injuries including rib fractures.  A regression model was developed to determine predictors of respiratory failure or pulmonary complications.

Six variables shook out of their analysis as significant predictors of subsequent complications:  COPD, low serum albumin, use of an ambulatory assist device, a tube thoracostomy in place, injury severity score, and total number of rib fractures.  Transforming these variables into a scoring system resulted in a predictive instrument with and AUC of 0.82 (0.77 - 0.88), with sensitivities and specificities in the 70%s based on their chosen threshold.

While this performance is suboptimal, the model has obvious face validity – the frail, severely injured, with underlying pulmonary disease are the most likely to deteriorate.  Their model also requires external validation.  However, given that most patients do develop pulmonary complications, such a tool could be reasonably used to reduce the costs and resource utilization associated with prophylactic ICU admissions – as long as you were willing to accept the risk of approximately 1 in 20 patients requiring unexpected escalation in care from the floor.

“A pilot single-institution predictive model to guide rib fracture management in elderly patients”
http://www.ncbi.nlm.nih.gov/pubmed/25909417

Wednesday, May 20, 2015

Finally, an End to Tamulosin for Renal Colic?

Most urologic professional societies recommend “medical expulsive therapy” for ureterolithiasis, with an expectation of increased stone expulsion, improved time-to-passage, and reduced need for analgesia.

As I’ve covered before – breaking down a pro-tamulosin Cochrane Review – the evidence in support of this practice is junk.  David Newman, Anand Swaminathan, and Salim Rezaie agree.  The last time I posted, I posited there was probably some small benefit to a subgroup of patient with renal colic, but, alas, we would probably never have high-quality evidence.

I was wrong.

This study in The Lancet tested MET by randomizing patients with CT-confirmed ureterolithiasis to three arms – placebo, nifedipine, or tamulosin.  The randomization algorithm balanced the arms between stone size and stone location.  The primary outcome was need for urologic intervention at 4 weeks, with secondary outcomes of patient-reported time to stone passage and pain medication use.

With 1,167 patients randomized – 31 of which were excluded or lost to follow-up – there was no difference in need for urologic intervention between groups: 20% placebo, 19% tamulosin, 20% nifedipine.  Secondary outcomes – measured by follow-up questionnaire – were likewise similar, with no differences detected in the number of pain medication nor days until stone passage.

Now, urologic intervention is a rather imprecise surrogate outcome for evaluating the efficacy of MET for promoting stone passage.  And, only 62% of patients returned the surveys regarding the secondary outcomes of subjective stone passage and analgesic use.  This is high-quality evidence, but hardly infalliable.  The authors also state no subgroup showed benefit – which is not entirely true.  MET was slightly beneficial (86% vs. 82%) for patients with lower ureteral tract stones, with a p-value of 0.099.  Giving into the tyranny of p-values, yes, there’s no benefit – but using the p-value akin to a likelihood ratio, judged against the larger context of other (albeit, low-quality) trials showing benefit, I would not find it unreasonable to contest the totality of these authors’ conclusion.

Regardless, the empiric use of tamulosin has simply been an urban legend taken one step too far.  Short of large stones in the lower urinary tract, the benefit is fleeting at best – and the magnitude of the benefit may be too low to matter.

“Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60933-3/abstract (oa)

Monday, May 18, 2015

Back to IMS-III: It’s the Collaterals

The year 2012 was dark times for endovascular treatment for acute ischemic stroke.  MR-RESCUE, IMS-3, and SYNTHESIS were all decidedly negative, and their failures trotted out in the New England Journal of Medicine.

This current year has been much better – a trove of trials following the initial positive result of MR-CLEAN, the key features of which were:

  • Improved time from onset to endovascular intervention.
  • Effective recanalization, far exceeding that of tPA.
  • Narrowly selected patients guided by imaging criteria.

Of those three key features, it appears the universally critical items are primarily the last two – recanalization and salvageable tissue.

This is a reanalysis of IMS-3, looking retrospectively at 78 patients from the trial for whom cerebral angiograms were available.  They looked specifically a the “capillary index score”, essentially, an imaging-based classification of the collateral circulation near a lesion.  In an outcomes-blinded fashion, the authors calculated the CIS for each, and then correlated the results with functional outcomes.  The numbers are small, but the numbers achieving good outcomes are consistent and logical:
  • Poor CIS, unsuccessful recanalization: 1/15 (7%)
  • Poor CIS, successful recanalization: 2/15 (13%)
  • Good CIS, unsuccessful recanalization: 5/24 (25%)
  • Good CIS, successful recanalization: 17/24 (71%)
Essentially another brick in the small wall of evidence favoring the necessity of an imaging-based strategy to narrowly select patients for endovascular intervention, rather than a non-selected time-based strategy.

“Relative Influence of Capillary Index Score, Revascularization, and Time on Stroke Outcomes From the Interventional Management of Stroke III Trial”
http://www.ncbi.nlm.nih.gov/pubmed/25953374

Monday, May 11, 2015

EMLitOfNote at SAEM Annual Meeting

The blog will be on hiatus this week – in San Diego!

I’ll be speaking at:
Social Media Boot Camp
May 12, 2015, 1:00 pm - 5:00 pm
with multiple members of the SAEM Social Media Committee

FOAM On The Spot: Integration of Online Resources Into Real-Time Education and Patient Care
May 13, 2015, 1:30 - 2:30 PM
with Anand Swaminathan, Matthew Astin, and Lauren Westafer

From Clicks and Complaints to a Curriculum: Integrating an Essential Informatics Education
May 13, 2015, 2:30 - 3:30 PM
with Nicholas Genes and James McClay

and co-author on an abstract presentation:
Automating an Electronic Pulmonary Embolism Severity Index Tool to Facilitate Computerized Clinical Decision Support
May 14, 2015, 10:30 - 10:45 AM

Hope to see a few of you there between Tuesday and Thursday!

Friday, May 8, 2015

Will You Be My SWEDEHEART?

I may be reviewing this article just because of its acronym – a recognition of the serious efforts expended to derive SWEDEHEART and its full name: “Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies”.

Briefly, this is a prospective registry of patients admitted to coronary care units in Sweden with symptoms suggestive of acute coronary syndrome.  These authors’ goal was to describe the implications and prognostic value of the new, 5th-generation highly-sensitive troponins, specifically the Elecsys hsTnT.  This particular assay has a limit of detection of 5 ng/L, a 99th percentile in healthy controls of 14 ng/L, and less than 10% coefficient of variation at 13 ng/L.  This compares to the prior generation of assays in which positive results were roughly ~50 ng/L.  Overall, the authors reviewed the inpatient stays for 48,594 patients.

There are probably two useful takeaways from this article:
  • Only 18% of patients with "positive" hsTnT between 14-49 ng/L were ultimately diagnosed with MI.  This compares with 81.2% of those with hsTnT >50 ng/L.
  • The one-year mortality of patients with hsTnT between 14-49 ng/L on admission was 10.3%.  This compares to 2.0% for those less than 14 ng/L and 17.1% for those >50 ng/L.
The acute implication for Emergency Medicine is mostly a recognition of the prevalence of elevations >99th percentile outside the context of an acute coronary syndrome.  The less acute, but equally important implication, is recognizing the need for aggressive referral and follow-up for those with small elevations in the absence of ACS.  While no “emergency” intervention is necessary, detection of even low levels of cardiac suffering is a strong predictor of future risk, and should be recognized accordingly.

“Implications of Introducing High-Sensitivity Cardiac Troponin T Into Clinical Practice”
http://www.ncbi.nlm.nih.gov/pubmed/25908071

Wednesday, May 6, 2015

Welcome, Zerbaxa, Let Us Never Speak of It Again

It is time once again to visit the twisted world of pharmaceutical advertorials, this time in the Lancet.  Our subject is ceftolozane-tazobactam, a 5th-generation cephalosporin, approved and marketed as Zerbaxa.  It joins an ever-growing arsenal of antibiotics whose intention is to fight the growing tide of antimicrobial resistance.

And, thus, welcome – and let us never use it.

Of course, this study will be the basis of many mailers, presentations, and lunch visits imploring its use.  This is a phase 3 trial, comparing intravenous ceftolozane-tazobactam versus intravenous levofloxacin for treatment of complicated UTI/pyelonephritis, designed as a non-inferiority trial.  The results, as expected in any such paid advertorial, show “composite cure” favoring ceftolozane-tazobactam – a cure rate of 76.8%, versus 68.4% with levofloxacin.  The authors declare superiority based on confidence intervals, and the accompanying editorial further celebrates its availability and success.

Of course, this is “composite cure”, an endpoint based solely on differences in microbiological eradication of the original pathogens; clinical cure showed a non-significant difference.  And, the cohort for evaluation was only a “microbiological modified intention to treat population”, which ultimately excluded over 300 patients from this 1000 patient trial.  And, even then, the supposed difference in efficacy was based solely on the treatment failures in patients with pathogens with levofloxacin resistance.

So, yes, this is non-inferior to levofloxacin – except in price, where this new agent will likely cost $200-$300 per day per patient.  Superior?  No.  Its only utility will be in those locations where resistance is very high, and, even then, there will likely be other, cheaper alternatives with efficacy.

But, Cubist Pharmaceuticals, the sponsor and co-author of this paper, has no interest in use of such cheaper options.

“Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI)”
http://www.ncbi.nlm.nih.gov/pubmed/25931244

Monday, May 4, 2015

Attempting Decision-Support For tPA

As I’ve wondered many times before – given the theoretical narrow therapeutic window for tPA in stroke, paired with the heterogenous patient substrate and disease process – why do we consent all patients similarly?  Why do we not provide a more individualized risk/benefit prediction?

Part of the answer is derived from money & politics – there’s no profit in carefully selecting patients for an expensive therapy.  Another part of the answer is the reliability of the evidence base.  And, finally, the last part of the answer is the knowledge translation bit – how can physicians be expected to perform complex multivariate risk-stratification and communicate such information to a layperson in the acute setting?

In this paper, these authors describe the development process of an iPad application specifically designed for pictoral display of individualized risk/benefit for tPA administration in acute ischemic stroke.  Based on time from onset to treatment, age, gender, medical history, NIHSS, weight, and blood pressure, manual entry of these variables into the software provides individualized information regarding outcomes given treatment or non-treatment.

Unfortunately, the prediction instrument – S-TIPI – is based on: NINDS, ECASS II, and ATLANTIS.  Thus, as you might expect, in the most commonly used time frame of 0-3 hours, the outcomes essentially approximate NINDS.  The authors mention they used the UK portion of the Safe Implementation of Thrombolysis in Stroke database and the Virtual International Stroke Trials Archive to refine their calculations, but do not delve into a discussion of predictive accuracy.  Of note, a previous article describing recalibration of S-TIPI indicated an AUC for prediction of only 0.754 to 0.766 – but no such uncertainty, nor their narrowly derived limited data set, are described in this paper.

Regardless, such “precision medicine” decision instruments – for both this and other applications – are of great importance in guiding complex decision-making.  This paper is basically a “check out what we made” piece of literature by a group of authors who will sell you the end result as a product, but it is still an important effort from which to recognize and build.

“Development of a computerised decision aid for thrombolysis in acute stroke care”
http://www.ncbi.nlm.nih.gov/pubmed/25889696

Friday, May 1, 2015

Muddying Acute Stroke With Recanalization vs. Reperfusion

The conceptual mainstay of interventions for acute ischemic stroke is recanalization.  The “clot buster” – tPA.  The “clot retriever” – the endovascular stent devices.  These are interventions aimed at opening an occluded vessel and restoring flow.

But, as it turns out, recanalization is only part of the story.  The other half – and the not fully-appreciated utlimate goal – is reperfusion.

This is a small analysis of 46 patients from a prospective, multicenter database undergoing acute magnetic resonance angiography following acute ischemic stroke.  All patients had visible sites of arterial occlusion accompanied by a measurable ischemic penumbra.  Furthermore, each of these patients underwent subsequent MRA within 6 hours to evaluate recanalization and reperfusion.

Most of the occlusions were proximal, large intracranial vessels – ICA, M1, M2, and M3.  Most patients – 34 – received intravenous tPA, while the remaining 12 were managed conservatively.  Recanalization occurred in 29% of patients receiving tPA and 25% of those not.  However, reperfusion occurred regardless of recanalization – 46% of those receiving tPA and 33% of those not.  Univariate analyses regarding improvement in NIHSS and functional outcomes showed the strongest predictor (and, given the small sample, really the only predictor) was not recanalization – it was reperfusion.

Now, recanalization is certainly the most effective method for achieving reperfusion – hence the increasingly favorable results seen in the endovascular trials as device reliability improved.  That said, clearly, some of our thinking regarding patient selection is flawed by a narrow approach focused solely on recanalization.  There are many logistical hurdles and additional studies needed to translate some of this knowledge into practice, but it appears it may be quite reasonable to withhold acute recanalization therapy if reperfusion has already been spontnaeously, naturally achieved.

The goal, after all – despite the best efforts of pharmaceutical backers – should not be to expand the shotgun spread of recanalization therapies to the largest possible cohort.  Rather, we ought to be focusing on finding additional stratification strategies, with a goal of improving patient selection to those with the greatest magnitude of potential benefit.

“Reperfusion Within 6 Hours Outperforms Recanalization in Predicting Penumbra Salvage, Lesion Growth, Final Infarct, and Clinical Outcome”
http://www.ncbi.nlm.nih.gov/pubmed/25908463

Wednesday, April 29, 2015

Getting High, Getting Nauseated

Can you name some of your favorite types of patients in the Emergency Department?  Weak and dizzy?  Syncope?  Low back pain?  How about gastroparesis or cyclic vomiting syndromes?

Well, good news – if drug-induced vomiting is on your list of rewarding patient encounters, then this wave of states with newly legalized marijuana is just for you.

This is a small review of two urban, academic Emergency Departments in Colorado, retrospectively analyzing their diagnoses for encounters involving nausea & vomiting.  The breakpoint in their analysis was the legalization of recreational marijuana in 2009.  Through, frankly, a great number of assumptions involving documentation, drug screens, and other chart review calisthenics, the authors distilled out the patients with multiple ED visits for vomiting associated with drug abuse – clinically, the cyclic vomiting syndrome.  And, if you accept the limitations of their review: the number of visits for cyclic vomiting to their EDs has doubled since the introduction of legalized marijuana.

Hooray.

Interestingly, there is also a small exploratory analysis included in the paper regarding the antiemetic of choice.  They note promethazine use, despite the small sample, was significantly associated with needing admission – with an OR of 5.06 (95% CI 2.01 to 13.63).  Whether this represents unmeasured cofounders or a real effect is uncertain.  Anecdotally, with some evidence to support the practice, I have good experiences with droperidol and haloperidol in these sorts of patients.

“Cyclic Vomiting Presentations Following Marijuana Liberalization in Colorado”
http://www.ncbi.nlm.nih.gov/pubmed/25903855