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”