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

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!

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

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

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

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

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

A Window Into Your EHR Sepsis Alert

Hospitals are generally interested in detecting and treating sepsis.  As a result of multiple quality measures, however, now they are deeply in love with detecting and treating sepsis.  And this means: yet another alert in your electronic health record.

One of these alerts, created by the Cerner Corporation, is described in a recent publication in the American Journal of Medical Quality.  Their cloud-based system analyzes patient data in real-time as it enters the EHR and matches the data against the SIRS criteria.  Based on 6200 hospitalizations retrospectively reviewed, the alert fired for 817 (13%) of patients.  Of these, 622 (76%) were either superfluous or erroneous, with the alert occurring either after the clinician had ordered antibiotics or in patients for whom no infection was suspected or treated.  Of the remaining alerts occurring prior to action to treat or diagnose infection, most (89%) occurred in the Emergency Department, and a substantial number (34%) were erroneous.

Therefore, based on the authors’ presented data, 126 of 817 (15%) of SIRS alerts provided accurate, potentially valuable information.  Unfortunately, another 80 patients in the hospitalized cohort received discharge diagnoses of sepsis despite never triggering the tool – meaning false negatives approach nearly 2/3rds the number of potentially useful true positives.  And, finally, these data only describe patients requiring hospitalization – i.e., not including those discharged from the Emergency Department.  We can only speculate regarding the number of alerts triggered on the diverse ED population not requiring hospitalization – every asthmatic, minor trauma, pancreatitis, etc.

The lead author proudly concludes their tool is “an effective approach toward early recognition of sepsis in a hospital setting.”  Of course, the author, employed by Cerner, also declares he has no potential conflicts of interest regarding the publication in question.

So, if the definition of “effective” is lower than probably 10% utility, that is the performance you’re looking it with these SIRS-based tools.  Considering, on one hand, the alert fatigue, and on the other hand, the number of additional interventions and unnecessary tests these sorts of alerts bludgeon physicians into – such unsophisticated SIRS alerts are almost certainly more harm than good.

“Clinical Decision Support for Early Recognition of Sepsis”
http://www.ncbi.nlm.nih.gov/pubmed/25385815

Again With the Claim tPA is “Safe” in Mild Strokes

In yet another exercise in asking the wrong questions, these authors put forth a rather great deal of effort to regurgitate a vast quantity of mostly meaningless data.

Neurologists, generally those well-supported by Genentech and Boehringer Ingelheim (as in this article), are keen to expand the use of tPA beyond the license criteria.  One of the easiest targets is the giant cohort of stroke patients excluded from treatment for low NIHSS.  In some respects, it seems reasonable to discard an ordinal cut-off in a measure of stroke severity having a non-linear relationship with disability.  But, when media coverage describes an expansion of tPA to mild stroke patients as “saving hundreds of millions of dollars” or “having no downside”, even the hypothetical best intentions have clearly gone awry.

This is a retrospective review of the Get With the Guidelines-Stroke registry, a voluntary, prospective quality improvement project used by hospitals in the U.S.  Between 2010 and 2012, 7,621 patients were treated with IV tPA for AIS having an NIHSS of 5 or less, with 5,910 having data for analysis.  Ranging from 192 patients with an NIHSS to 0 to 1,800 having NIHSS of 5, treatment complications were fairly consistent: 1.3% died, 1.8% suffered sICH, 0.2% suffered serious systemic hemorrhage, and 1.8% suffered other serious complications (e.g., angioedema).

So, of course, for a treatment with no demonstrated efficacy in this population, the authors conclude a number-needed-to-harm somewhere between 30 and 50 “provide[s] reassurance about the safety of IV rtPA in patients with low NIHSS scores”.

Interestingly, this data is essentially an update of the authors’ prior work, published using the 2003 to 2009 GTWG-Stroke registry data.  That publication provided a helpful data supplement comparing outcomes of tPA-treated patients with non-tPA-treated patients with NIHSS 5 or less.  Within the limitations of such a comparison, tPA treatment was associated with significantly increased odds of death, decreased discharges to home, and decreased ambulation at discharge.  The authors have in no way muddled this article with such negativity, nor did they perform any sort of gross comparison between the ambulatory and independence outcomes in the present study with the prior, non-treated population – as they are essentially identical.

But, when you’re fed free money from your sponsors, including free airfare to Chicago, why report or suggest anything that might disrupt the narrative?

“Outcomes in Mild Acute Ischemic Stroke Treated With Intravenous Thrombolysis: A Retrospective Analysis of the Get With the Guidelines–Stroke Registry”
http://www.ncbi.nlm.nih.gov/pubmed/25642650

A Laughable tPA “Systematic Review”

Over 200,000 physicians belong to the American Medical Association.  The Journal, therefore, of this Association has a significant audience and a long tradition.  Continuing Medical Education inserts in JAMA may represent the basic education of many new developments for general practitioners.

Unfortunately, the authors of this most recent CME portion seem to require their own education on the conduct of a “systematic review”.

A properly performed systematic review utilizes a precise, replicable, well-described search strategy with which to canvass the evidence for synthesis.  The assembled evidence is then evaluated based on pre-specified criteria for inclusion or exclusion.  The end-result, hopefully, is a knowledge translation document based on the entire scope of published literature, accounting for controversy and irregularity in the context of a larger summary.

These authors perform a systematic review on “acute stroke intervention”.  They identify and review 145 abstracts utilizing multiple combinations of MeSH terms and synonyms for “brain ischemia/drug therapy, stroke drug/therapy, tissue plasminogen activator, fibrinolytic agents, endovascular procedures, thrombectomy, time factors, emergency service, treatment outcome, multicenter study, and randomized controlled trial”.  A massive undertaking, to be sure – considering these authors are also including intra-arterial and mechanical therapy in their review.

Yet, as indicated in their evidence review chart in the supplement, this strategy managed to identify only 17 RCTs – in the whole of systemic and endovascular therapy.  As an example for comparison, the latest Cochrane Review of thrombolytics for acute ischemic stroke included 27 trials of fibrinolytic agents alone.  And, as covered in their text and cited in their References, the RCT evidence regarding systemic therapy for acute stroke consists of: NINDS and ECASS III.

That’s it.

No MAST-E, MAST-I, or ASK.  No mention of the smaller imaging-guided trials, EPITHET, DEDAS, DIAS, or DIAS II.  Or, even excluding non-tPA trials, no ECASS, ECASS II, ATLANTIS, or, even the largest of flawed acute stroke trials, IST-3.  And, even with such limited coverage, certainly no mention of any of the controversy over imbalances in NINDS, nor flaws in ECASS III pertaining to tPA’s persistent non-approval by the FDA for the 3-4.5 hour time window.

If this were simply a commentary for the lay press regarding the bare minimum highlights of the last 20 years of stroke treatment, perhaps this would suffice.  And, frankly, these authors do much better regarding their reporting on the recent endovascular trials.  But, a CME publication in a prominent medical journal failing to address 90% of the evidence on a particular topic – yet calling itself a “systematic review” – is retraction-worthy.

“Acute Stroke Intervention – A Systematic Review”
http://jama.jamanetwork.com/article.aspx?articleid=2247149