United Kingdom Revisiting Safety of tPA

This odd and tragic saga continues: nearly 20 years after the original NINDS publication, we’re still going around and around with re-reviews of the same evidence.  The recent news of this past week is the Medicines and Healthcare products Regulatory Agency in the United Kingdom will set up an expert panel to reevaluate the evidence in support of tPA for stroke.  In light of a recent positive Cochrane Review, a positive individual patient meta-analysis, and a paucity of substantial new data – I cannot imagine what new insight will be uncovered.

This seems to have been brought about by correspondence, written by a British stroke neurologist, in The Lancet, describing the same series of arguments skeptics have been making for the last decade and a half.  There are concerns over inadequate blinding of investigators, noting the alteplase infusion may be visually different from placebo, or that patients treated with alteplase possibly had observable minor bleeds from venipuncture sites.  The manufacturer-sponsored nature of ECASS, ECASS II, and ECASS III is again cited, along with baseline imbalance regarding prior strokes favoring the treatment group in ECASS III.  ATLANTIS is also mentioned as a negative trial, stopped early by interim futility analysis.  He further mentions the lack of difference between <3h and 3-4.5h windows in observational registries, suggesting the underlying time-dependent hypothesis behind treatment with alteplase is flawed.  And, most interestingly, he provides a funnel plot of outcomes by treatment center from NINDS, suggesting certain centers suspiciously had disproportionately positive findings.

Again, these are many of the same arguments made by other  experts in their critiques of the evidence behind thrombolysis for stroke.  As such, the responses – headlined by Peter Sandercock and Joanna Wardlaw – provide some of the same rebuttals as previously seen.  Essentially, what it boils down to – again – is you either trust the data, or you don’t.  And, given the suppressed evidence associated with Boehringer Ingelheim’s dabigatran product, not trusting the data remains a reasonable standpoint.

Whether the the MHRA enquiry will change any regulatory statutes is another issue entirely, and Ian Hudson states there will be a fair re-appraisal.  However, Prof. Simon Brown points us to this interesting blog entry covering Mr. Hudson’s prior time at GlaxoSmithKline.  This journalistic endeavor covers his potential role in overlooked safety concerns regarding paroxetine, as well as other conflicts of interest, and implies the enquiry is unlikely to be truly balanced.

Not to sound like a broken record, but only one thing will settle this debate, once and for all – a large, multi-center, randomized trial conducted independently from the manufacturers of alteplase and otherwise biased institutions.  And, since the chance of that happening is basically nil – I imagine another decade from now, we’ll still be picking apart stroke research and debating the quality of the evidence.

“Questions about authorisation of alteplase for ischaemic stroke”




Emergency Department or Return-to-Daycare Department?

Have you ever seen a child brought to the Emergency Department for pinkeye?  Not only that, but specifically to fulfill the requirement they receive a prescription for antibiotic ointment in order to return to daycare?  You would not be alone, my friends.

In this convenience sample of 303 surveyed parents, 26% reported taking their child to an Urgent Care, and 25% reported taking their child to an Emergency Department, rather than primary care, for minor ailments – including pinkeye.

These parents were also asked several questions regarding how they dealt with illness in children outside the home, where they would take the child for care, and what sort of requirements were placed upon them by daycare.  Most parents would send their children to daycare with a minor upper respiratory infection, but, fever, ringworm, and gastroenteritis were not accepted.  Most parents would either keep the child at home or seek primary care, but at least 10% of those surveyed would utilize some urgent or emergent services.  Significant predictors of utilizing emergency services for minor pediatric ailments were requirements for a “return to daycare” note or a parent “work excuse”, African American ethnicity, single/divorced parents, and those with tenuous job situations.

As such, the authors recommend improved guideline adoption by child care facilities to allow improved management of infectious disease – and reduced resource utilization from harried parents.

“Emergency Department and Urgent Care for Children Excluded From Child Care”

Failing Our Profession Through Futile Care

It is not always feasible to serve all masters in medicine.  From a resource utilization standpoint, unfortunately, one missed opportunity is with regard to how we approach futile care.  We have all experienced the care of a patient who, regardless of testing and therapy, has zero chance of meaningful recovery.  To terminate care for these patients sometimes requires difficult conversations, and can snowball out of control with adverse legal and public relations consequences.

But, as this report from UCLA and RAND details, our failures to properly address futile care and end-of-life issues result in direct downstream harms to other patients.  These authors surveyed ICU physicians each day across 5 different ICUs, enquiring as to whether any of the patients under their care were receiving futile treatment.  Overall, 1,136 patients over 3 months were assessed – with 123 reported to be receiving futile treatment.  On 72 days during the survey period, an ICU was full and providing futile care – and these periods of ICU capacity resulted in 33 patients boarding >4 hours in the Emergency Department, 9 patients waiting >1 day to transfer in from an outside hospital, and 15 additional transfer requests being cancelled after waiting >1 day.  Two patients died while awaiting transfer during times in which an ICU was at capacity while a patient was receiving futile care.

While this is just a single-center experience, I am certain we have all experienced ED boarding or transfer difficulties as a result of ICU capacity.  These patients are subject to proven harms due to delays in care, and, as such, I agree with the authors’ conclusion:

“It is unjust when a patient is unable to access intensive care because ICU beds are occupied by patients who cannot benefit from such care….The ethic of “first come, first served” is not only inefficient and wasteful but it is also contrary to Medicine’s responsibility to apply healthcare resources to best serve society.”

“The Opportunity Cost of Futile Treatment in the ICU”

Hypoxia & Overtreatment in Bronchiolitis

“Treat the patient, not the number” works for many things in medicine – asymptomatic hypertension, hyperglycemia, and anemia, among others.  However, hypoxia is less frequently dismissed as clinically irrelevant.

And, that perfectly explains the results in this study, which evaluated clinician dependence on oxygen saturation to guide disposition in pediatric bronchiolitis.

Bronchiolitis, a viral process of large airway inflammation, can be challenging to treat.  For the most part, the disease simply must run its course, and it’s a matter of the secondary effects of the infection determining need for admission – work of breathing and hydration status.  Clinicians have been encouraged to accept low oxygen saturations (>90%) in the absence of other sequelae as part of their decision-making process leading to safe discharge home.

But, apparently, we’re still married to “normal” numbers.  In this study, researchers in Ontario randomized patients to the pulse oximeter providing either a true oxygen saturation, or an “altered oxygen saturation” – altered, specifically, to display 3% higher than the true value.  Over four years, 345 patients in respiratory distress with a clinical diagnosis of bronchiolitis met screening criteria, although only 213 agreed to participate.  As you might expect, patients with the true oxygen saturation were much more likely to be hospitalized than the patients with the falsely elevated oxygen saturation – 41% vs 25%.  Patients whose true oxygen saturation was displayed also tended to have increased resource utilization within 72-hours.  Zero adverse patient-oriented outcomes were observed in either group.

This is a small, single-center study, so, strictly speaking, its generalizability is limited.  However, it probably accurately reflects practice in many settings – where hypoxia, independent of more important clinical factors, is inappropriately sufficient cause for admission or observation.  This is a worthy reminder of such a flaw in our practice as respiratory viral season begins to ramp up this fall.

“Effect of Oximetry on Hospitalization in Bronchiolitis: A Randomized Clinical Trial”

Highly Sensitive Troponins – False Positive Bonanza

The “highly sensitive” troponin has received a great deal of publicity, hyped ad nauseum, see: “Simple test could help rule out heart attacks in the ER.”

But, as sensitivity increases – invariably, specificity decreases.  However, that is not the fault of the test – it is a failure of clinicians to ask the correct question of the test.  When asking “does this patient have an acute myocardial infarction?”(most commonly Type 1 MI in the ED), our training and education has been outpaced by assay technology – the test no longer provides a dichotomous “yes” or “no”.

This publication provides a lovely window into precisely the added value of the hsTnI compared with conventional TnI, both assays by Abbott Laboratories.  In this study, the authors simultaneously drew research samples of blood any time a cTnI was ordered.  The sample was frozen, and then analyzed at least 1 month following presentation.  Authors performed hospital records review, telephone follow-up, and vital records search to evaluate adverse events in patients with hsTnI or cTnI elevation.

Overall, they enrolled 808 patients, 40 of which received an adjucated diagnosis of “acute coronary syndrome” – 26 with AMI and 14 with unstable angina.  61 patients had acute heart failure, 7 had volume overload, 7 had pulmonary emboli, and 41 had other non-ACS cardiac diagnoses.

All told, there were 105 elevated cTnI samples – and 164 elevated hsTnI samples.  This means, essentially – in the acute setting, asking our question of interest – there were 50% greater false positives associated with hsTnI.  No patients would have been reclassified as nSTEMI based on the hsTnI result.  The authors sum this up nicely in their discussion:

“The preponderance of novel elevations (roughly 10% in this study) will be observed mainly in subjects with non-ACS conditions.”

The authors go on to note the value in detecting these novel or detectable troponin levels – essentially, non-ACS, subclinical disease – with a much poorer long-term prognosis.  This is almost certainly the case, although it will require further investigation to reliably demonstrate cost-effective management strategies based on these results.

“Troponin Elevations Only Detected With a High-sensitivity Assay: Clinical Correlations and Prognostic Significance”

Addendum:  As Stephen Smith points out, it may be possible to use the greater precision of hsTnI at the low end of the assay to more accurately adjudicate some MI.  Great insight!

Should the 48-hour Cardioversion Window Be Revised?

It has become generally accepted practice to treat new-onset atrial fibrillation and atrial flutter with electrical cardioversion in the acute setting – provided the known onset of atrial fibrillation is less than 48 hours.  Beyond that, caution tends to be advised – whether through use of transesophageal echocardiography to rule out left atrial thrombus, or through pre- and post-procedural anticoagulation.

However, this data from a research letter in JAMA suggests – possibly we ought to be even more cautious regarding time-of-onset.

This is a re-analysis of FinCV, a 7 year trial registry of cardioversion for atrial fibrillation from Finland.  The study cohort is comprised of 2,481 patients undergoing 5,116 electrical cardioversions, all without peri-procedural anticoagulation for symptom onset <48 hours.  Outcomes were gathered from vital records review, evaluating for cerebrovascular thrombotic complications within 30 days.

Of these patients undergoing cardioversion, there were 38 definite thrombotic complications.  30 of these 38 occurred in patients whose symptom onset was >12 hours.  There were few apparent pro-thrombotic differences between groups, and thus, the authors very reasonably conclude – we should be cautious regarding cardioversion after 12 hours.  Other predisposing factors in their multivariate analysis include female sex, heart failure, and diabetes – but increasing length of time showed the strongest association.

The 12-48 hour window in this study still only represented a 1.1% risk for 30-day thromboembolism, compared to the ~2% risk after 48 hours.  However, it still exceeds the ~0.3% risk of thromboembolism with peri-procedural anticoagulation.  There are other risks associated with anticoagulation, but it is reasonable to suggest the management strategy is no longer as clear-cut around 48 hours.

“Time to Cardioversion for Acute Atrial Fibrillation and Thromboembolic Complications”

The BATiC Score for Pediatric Trauma – Promising, But Not Prime-Time

Excluding significant intra-abdominal trauma on the basis of clinical evaluation is a lost art in the realm of zero-miss.  Nowhere is this more important than in a pediatric population, considering the small, but real, potential from harms due to exposure to ionizing radiation from CT.

This is the Blunt Abdominal Trauma in Children (BATiC) score, derived in 2009 by a Swiss group.  This rule promotes use of clinical exam, ultrasonographic findings, and laboratory results to determine need for CT.  In this study, authors from the Netherlands retrospectively applied the rule to 216 pediatric trauma patients presenting in a four-year span between 2006 and 2010.  All told, this cohort contained 18 patients for whom intra-abdominal injury were identified, and a BATiC score cut-off of 6 would have a sensitivity of 100% and specificity of 87%, with an AUC of 0.98.  So, this all sounds splendid.

But, only 34 of these patients even received a CT scan as part of their evaluation – and, with the standard outcome definition being injuries diagnosed on CT or as part of hospitalization, there is potential for a fair number of missed diagnoses.  A reasonable case may be made whether any missed injuries were clinically significant, given lack of observed morbidity, but it would be difficult to have confidence based on such as small sample.  Furthermore, just as a simple cultural issue, trauma surgeons in the U.S. tend to feel any injury is clinically significant.

Then, 18.5% of observations used to validate this rule were missing from the retrospective data collection and required imputation.  The extent of this missing data further degrades the reliability of the observed diagnostic characteristics.  No confidence intervals are presented along with their results – but, rest assured, they are quite wide.  Ultimately, this decision-instrument may indeed be valid – but requires specific prospective evaluation.

As an interesting Costs of Care side note, the additional charge for a such a trauma encounter including a CT scan in the Netherlands?  A mere 148 euros.

“External validation of the Blunt Abdominal Trauma in Children (BATiC) score: Ruling out significant abdominal injury in children”

Nitric Oxide Supplies No Miracles in Sepsis

An interesting context to end-organ dysfunction in sepsis stems from microcirculatory dysfunction, secondary to endothelial activation and vascular disruption as part of the inflammatory cascade.  Even though abnormal vasoconstriction in sepsis may be pharmacologically ameliorated, microcirculatory perfusion remains impaired.

This interesting trial attempted to modulate microcirculation through the use of inhaled nitric oxide.  Authors enrolled patients whose macrocirculation had been optimized, using objective targets consistent with contemporary care in septic shock, and randomized them to inhaled nitric oxide or sham.  Using a custom device for 40 ppm nitric oxide inhalation – for which authors all deny COI – an enrollment of 138 patients was planned.

However, after 49 patients, the trial was stopped due to futility.  The device was a success – as measured by circulating nitrite levels.  Unfortunately, from a microcirculation perfusion endpoint, there was no difference.  Likewise, there were no obvious differences or trends in secondary clinical outcomes.  There were, at least no obvious harms related to therapy.

Next steps in evaluation of this therapy – if any – are as of yet unclear.

“Randomized Controlled Trial of Inhaled Nitric Oxide for the Treatment of Microcirculatory Dysfunction in Patients With Sepsis”

Just Another Advertisement for tPA

As with last week’s coverage of the updated Cochrane Systematic Review for tPA in acute ischemic stroke, the key question is: what’s new?

The first pooled meta-analysis, published in The Lancet in 2004, included NINDS, ECASS I, ECASS II, and ATLANTIS.  It was subsequently updated in 2010 to add ECASS III and EPITHET.  Now, these authors have decided to add IST-3.

I am actually a huge fan of individual-patient meta-analyses.  Depending on the data availability, the similarity of trial protocols, and other issues associated with heterogeneity, this is the gold-standard for aggregating data and increasing power.  Individual-patient analyses also allow for more reliable exploration of subgroup effects not otherwise possible through regular meta-analyses or systematic reviews.

But, at the crux of it, a meta-analysis is only as good as the included trials – and this is a topic much debated over the last twenty years.  Entertainingly, the 2014 publication includes this bland statement:

Role of the funding source 

The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data and responsibility for the decision to submit for publication.

Yes, the funding source had nothing to do with the study design, excepting all the folks receiving speaker fees and honoraria – and the fact the original idea and refinements to the approach were contributed by one of the authors who is an employee Boehringer Ingelheim:

KRL has received speaker fees from and has served on the data monitoring committee of trials for Boehringer Ingelheim; his department has received research grant support from Genentech.  GA has received research grant support from Lundbeck, fees for consultancy and advisory board membership from Lundbeck, Covidien, Codman, and Genentech, fees for acting as an expert witness, and owns stock in iSchemaView. EB is employed by Boehringer Ingelheim. SD has received honoraria from Boehringer Ingelheim, EVER Pharma, and Sanofi and has received fees for consultancy and advisory board membership from Boehringer Ingelheim and Sanofi. GD has received research grant support from the NHMRC (Australia) and honoraria from Pfizer and Bristol-Myers Squibb. JG has received fees for consultancy and advisory board membership from Lundbeck. RvK has received speaker fees and honoraria from Penumbra and Lundbeck. RIL has received honoraria from Boehringer Ingelheim. JMO has received speaker fees from Boehringer Ingelheim. MP has received travel support from Boehringer Ingelheim. BT has received honoraria from Pfizer.  DT has received speaker fees and fees for consultancy and advisory board membership from Boehringer Ingelheim and Bayer.  JW has received research grant support from the UK Medical Research Council and from Boehringer Ingelheim to the University of Edinburgh for a research scanner bought more than 10 years ago. WW has received research grant support from the UK Medical Research Council. PS has received honoraria for lectures which were paid to the department from Boehringer Ingelheim. KT has received research grant support from the Ministry of Health, Labour, and Welfare of Japan, and speaker fees from Mitsubishi Tanabe Pharma.  WH has received research grant support from Boehringer Ingelheim, and speaker fees and fees for consultancy and advisory board membership from Boehringer Ingelheim.

The same level of COI was present in previous versions – including employees of the sponsor as authors – but, interestingly, at least the 2004 version explicitly acknowledges a critical issue:

Role of the funding source 

For the ATLANTIS trials, Genentech provided full support for the study and Genentech employees participated to some extent in study design, data collection, data analysis, and data interpretation, writing of the report, and in the decision to submit the manuscript for publication. For the ECASS trials, Boehringer Ingelheim provided full support. Employees of Boehringer Ingelheim participated in study design, in data collection, data analysis, data interpretation, writing of the report, and in the decision to submit the report for publication.

Nothing has changed.  If you trusted the data then, you trust the data now – and vice-versa.

So, what is new?  If anything, what’s new is worse than preceded it.  The authors have nearly doubled the cohort for analysis – by the inclusion of a decade-long trial crippled by the bias introduced by an open-label, mostly unblinded design.  Despite the massive resources invested in conducting it, unfortunately, IST-3 is too flawed for inclusion – due to the unfortunate likelihood any small positive signals regarding tPA are certain to be exaggerated.  And, simply put, that’s where the astute reader ought to stop reading this publication.  There’s no point in trying to interpret their results, to fuss over the heterogeneity between trials, missing baseline characteristics for their many subgroup analysis, or whether the trials stopped early for harm or futility – ATLANTIS – are properly acknowledged.  The authors also omit several planned secondary analyses described in their statistical protocol – although, considering the garbage-in/garbage-out nature of this work, it’s of debatable importance.

The last decade of prospective research – ECASS III and IST-3 – has done nothing but degrade the quality of evidence describing tPA in acute ischemic stroke.  If there is, indeed, anyone left on the fence regarding the pro/con tPA debate, this effort ought move the needle zero to none.  Very early treatment with tPA probably benefits a properly selected subset of patients with acute ischemic stroke.  The rest – whether increasing age, high-or-low NIHSS, specific stroke syndromes, or time-dependent factors – have much smaller, if any, chance of benefit exceeding chance of harm.  Until we have unbiased evidence, we’ll never truly know how to best select patients for this therapy – and neurologists will continue to lament low treatment rates, while Emergency Physicians continue to reject pro-tPA clinical policies.  Only new, independent data has a chance to substantially change our approach to acute ischemic stroke.

“Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials”

Get to the Choppa! Or … Maybe Not?

Helicopter transport is entrenched in our systematic management of trauma.  It is glamorized on television, and retrospective National Trauma Data Bank studies seem to suggest survival improvement – and those with head injury seem to benefit most.

But, these NTDB studies encompass heterogenous populations and are challenged in creating truly equivalent control groups.  This study, on the other hand, is a single-center experience, allowing greater consistency across divided cohorts.  In a novel approach, these authors collected all HEMS trauma transfer requests to their facility across their 30-county catchement area – and specifically looked at occasions when weather precluded HEMS.  This therefore created two cohorts of patients eligible for HEMS, with a subset that was transported by ALS due to chance events.  The paramedic crews manning the HEMS and ALS transfers were staffed by the same company, and therefore had roughly equivalent training.

This created a cohort of 2,190 HEMS transports and 223 ground transports.  Across ISS, GCS, initial transfusion requirements, and vital signs, the two groups had generally minor differences.  However, there was some potentially important variability of initial operative intervention upon arrival at the Level 1 trauma center – 27.4% of HEMS underwent craniotomy, compared with 15.4% of ALS transfers.  Based on multivariable logistic regression, type of transport did not enter into a best fit model of survival – and, thus, there was no difference (9.0% vs 8.1% mortality) between HEMS or ALS transport of trauma patients, despite the additional hour added from call time to arrival at the Level 1 trauma center.

Unfortunately, there are potentially critical flaws in their methods for patient selection.  They report 3,901 patients had a request for trauma transfer – but the number of patients transferred by HEMS or ALS only sums to 2,398.  An additional 49 were transported by BLS.  Then, another 208 died while awaiting transfer.  How many of these 208 died during weather delays awaiting ALS?  Are those deaths, in some fashion, related to the paucity of craniotomies performed on ALS transports?  And, what of the other 965 patients?

I tend to agree with their conclusion – HEMS is expensive and far over-utilized for patients who receive no particular benefit from the time savings.  However, I’m not sure this analysis includes all the data needed to be reliable evidence.

“When birds can’t fly: An analysis of interfacility ground transport using advanced life support when helicopter emergency medical service is unavailable”