Time to treatment for stroke and problems with observational data

Here’s a big study suggesting earlier TPA treatment for stroke results in better outcomes. This of course isn’t a new idea but this is new data here to support it:

Saver JL, Fonarow GC, Smith EE, Reeves MJ. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA. 2013. PMID 23780461


  • data from the get with the guidelines registry (ran by American Heart and American Stroke Associations)
  • web based data collection tool for providers to enter patients into
  • from 2003-2012 which should quite the spectrum to include pre ECASS III and post ECASS III data
  • patients got into this either prospectively as they got treated or retrospectively by someone identifying a stroke on discharge documentation and entering them into the regsitry . The retrospective data is what we should be particularly suspicious of – you could easily pick and choose the ones you want to enter into the registry. Ultimately this is a study of patients that someone decided to enter into a registry. Some patients with data relevant to this question may well not be entered and therefore we don’t know what happened to them.
  • excluded patients (for this analysis): poor documentation, sites that had few stroke pts in the registry and those who got intra arterial treatments
  • there are, as usual, a lot of conflicts of interest and indeed the registry itself is funded by a pharmaceutical company (and has been funded by several others in the past)


  • 2000 hospitals submitting 1.2 million patients. So there’s a lot of data in this registry
  • they report 6% of these getting TPA
  • they further examine this 6% but exclude all the ones with dubious times, all the ones post 4.5 hrs and all those discharged to other hospitals (for whom they say they couldn’t get good outcome data). There are various other exclusions along the way.
  • note they don’t use the standard stroke outcomes of modified Rankin scale here. They use “ambulatory at discharge” or “discharge home” as surrogates of good outcome. This is even more dubious than the usual mRS assessed by postal questionnaire.
  • ultimately after all the slicing and dicing we get 58300 pts.
  • median time at treatment was 144 mins. 10% treated before 90 mins
  • they report 8.8% mortality, 4.9% ICH, 33% walking at discharge and 38% discharged home. Remember all the exclusions that went into this before hand so these numbers may be on the slightly optimistic side.
  • by comparing all these they find +ve associations between time to treatment and all of the outcomes. Because of the massive numbers all of these are statistically significant.
  • they even calculate NNTs to compare how much better people do when they are treated quickly.


  • The basic demographic data and the number generated have important audit, governance and even actuarial importance.
  • Registry data that is only as good as what people put into it, and it’s not clear how good that data is.
  • From the colossal numbers involved any difference will be statistically significant. Numerically significant and clinically significant are hardly the same.
  • The silliness comes with the comparisons and the implication of causation.
  • The study has no way to account for the confounding factors invovled in why someone might present to the hospital earlier than someone else, or why they might get treated earlier than someone else.
  • For example, it may well be that those who presented earlier were more likely to be having a TIA rather than an established stroke and it may be natural autoregulation and fibrinolysis that resolved their stroke rather than the TIA. Indeed if there was no actual infarcted brain then it is hardly a surprise that rates of ICH were lower in the TIA…ahem… I mean earlier treated group.
  • The point is that this data cannot answer the question they have asked of it. The only data that can answer this question is the data from the RCTs – the very data that is so contentious and controversial (among emergency physicians at least).
  • The associations presented here are all very interesting but add little real science. Rather it reinforces the rhetoric that makes acute stroke the interesting, frantic and emergent condition that we see every day.

The study did, however, remind of two of my favourite bits on causation. The first from XKCD that gets rolled out every month or so on this blog:


And the most thoughtful and sensible of science writers, the late, great Stephen Jay Gould. This is from an essay critiquing the slightly naive narrative we’ve told of Galileo and his achievements in proving heliocentrism. He interestingly got a little bit carried away and claimed that Saturn didn’t have rings but had two tiny planets at either end. His supportive proof was that he had “observed” it and therefore it must be true. All a touch embarrassing really…

Utterly unbiased observation must rank as a primary myth and shibboleth of science, for we can only see what fits into our mental space, and all description includes interpretation as well as sensory reporting. Moreover, our mental spaces house a complex architecture built of social constraint, historical circumstance, and psychological hope.

P50 The lying stones of Marrakech

Stephen Jay Gould

Further Reading/Listening:

LITFL – CCC Stroke Thrombolysis

LITFL – Michelle Johnston on tPA for stroke


EMCrit Cage Match – Jagoda v Swaminathan


Busting the Clotbusters – Domhnall Brannigan

SMART EM – thrombolytics for stroke


Age Adjusted D-dimer Cut Offs

This paper recently published trying to confirm if it’s OK to raise the d-dimer cut off in older people.

“Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism: the ADJUST-PE Study.” 311, no. 11 (March 19, 2014): 1117–1124. doi:10.1001/jama.2014.2135. PMID 24643601

Hopefully you’ve heard about this already through ER Cast and over on BoringEM (if you want more discussion on d-dimer, then be sure and check out the LITFL page on it.) Basically if you’re over 50 then your new d-dimer cut off is 10 times your age. These guys tested that approach.


  • prospective data on pts with suspected PE from Europe.
  • Stratified to low or high risk
  • D-dimers were sent on the low risk ones and if -ve work up was finished. If +ve they went for CTPA
  • follow up at 3 months by phone
  • 3 blinded ‘experts’ adjudicated if something bad happened to them


  • 3300
    • 2900 were ‘non-high’ probability and went down the d-dimer path
    • 400 were high and went straight to scan
  • 330 fell into the ‘age adjusted’ level and all of these guys (who previously would have got advanced imaging) seemed to do well (for what that’s worth)
  • of note their overall rule in rate for PE was 20%, much higher than many contemporary studies


We all want ways to rule out PE and avoid the CT scans. This might be another way to safely rule patients out, though it’s worth bearing in mind that it’s only going to affect a small number of patients.

This is by no means a perfect study. The group of interest did not actually get the reference diagnostic test (the CTPA) so we’re dependent on the veracity of their follow up to know if it’s truly OK to pursue this new strategy of age-adjusted cut off and forgo more advanced testing. This is a common problem in studies like this (see the Perry CT for SAH article as a great example of controversy over this very issue) and it doesn’t mean that it’s all nonsense but as always be sure to use your noodle when thinking about it.

Salim over at REBEL EM has a great post on this summarising the evidence for age adjusted d dimers. There’s actually a lot more evidence than I thought on this.

[Image Credit: Wikimedia Commons]

The ProCESS Trial

This trial is kind of big news. Big news in the way TTM was. Be sure to get the paper (which is free for now) and the supplement that goes with it.

There has already been some great discussion online so be sure and check it out.

So there’s no shortage of great editorialising already out there.

That being said, I wrote most of this on the plane on the way home from SMACC so figured I may at least get it out there.


Sepsis is big and sexy in critical care. It covers a huge range of patients and has turned individual conditions into one clinical syndrome. This in itself is controversial. Why should we treat pneumonia and gall bladder sepsis with the same bundle. While sepsis evangelism has undoubtedly raised awareness and probably improved care are we dumbing it down? Anyhow, that’s a little bit off topic.

For now the big focus in ED sepsis research is on working out which parts of a bundle of care that includes very different interventions actually makes a difference. Do we need central venous oxygen saturations or is it as simple as antibiotics and fluids? (Never mind the question of which and how much fluid…)

One of three trials (ARISE and PROMISE still to come) looking at early sepsis management, this is the US led version.


  • multi centre RCT, non blinded (as expected, it’s difficult to blind an Edwards catheter)(though as is good practice, the investigators were blinded when doing the analysis)
  • note that these were big academic centres and a requirement to get your centre into the study was use of lactate to screen for cryptogenic sepsis and adherence to the SSC guidelines. The SSC guidelines are not endorsed by Australasia as far I’m aware so this in itself might be a marked difference in practice. What do you think?
  • to get into the trial you had to be early in your sepsis course and have had a decent bolus of fluids
  • three groups:
    1. a protocol based on rivers EGDT model
    2. a protocol  based on international opinion
    3. usual care which would be whatever the doc would normally do.
  • These protocols are as always in a supplementary appendix which you have to search for separately. This is an real personal bug bear of mine –  everyone is reading this electronically and keeping the appendix separate for space saving reasons seem poor form
  • Lead investigators could enrol and manage patients in both protocol based groups but not in the usual care group. I understand why but being looked after by a leading researcher in sepsis is an intervention in itself. [See EMCrits discussion of this on the podcast]
  • primary outcome was in hospital death.
  • they powered the study on the assumption that they’d have a 30-45% mortality (as was the case in the Rivers trial), as happens in a lot of trials this overestimated how sick their patients would be.


  • 31 centres screening 12000 pts and got 1300.
  • no difference in primary outcome (60 day in hospital mortality) 21% v 18.2% v 18.9% for EGDT, protocol, usual care respectively.
  • they report a significant difference in fluid administration but I don’t think the difference is clinically significant. [EMCrit agrees even though the lead author sees a big difference in the three groups] We’re talking a litre difference between the most and the least with the other group half way between. If one group was 6l and one was 2l then that would seem to me a clinically significant difference. Note that the paper reports the numbers as 2.3, 3.3 and 2.8. These figures don’t include the mandatory fluid bolus that was pawrt of the inclusion criteria. So in reality it was more like 4-5 l in each group (HT EMcrit and WessexICS for pointing this out top me.
  • there was a bump in renal failure in the protocol based group but this may well be just noise
  • the only other big difference that caught my eye was differences in transfusion with 10% in the EGDT group and minimal in the other.
  • there was slightly more use of vasopressors in the two protocol used groups but not much.
  • there was an understandably big difference in central line usage. The EDGT protocol mandated a central line whereas the other two left it up to the doc essentially.


  • one big issue here is that it might be difficult to find clear water between the groups. If group 2 was developed following international consensus then it will draw on the principles of group 1 Group 3 will likely be the same as group 2 (a doc doing usual care will hopefully be practising in a manner consistent with international standards) This failure to have a major difference between all 3 groups will make it difficult to find an outcome difference between the three.
  • as a result I didn’t expect a big difference in outcomes as I don’t really think they were treated that differently.
  • maybe if the population had been sicker you might be able to draw out a difference.
  • when i deal with a septic patient I use a number of factors to guide my resus. This includes what happens to the lactate and even an ScvO2 if the line is in. Most docs who manage sepsis have some goal in mind that they’re targeting. Maybe all the goals are roughly equal, or if not equal then at least ‘good enough’ to get these outcomes

PK Talk for SMACC 2014

Here’s my PK talk for SMACC for 2014. The PK talks for those who can’t remember are short, snappy focused presentations on anything – the SMACC ones are of course focused on critical care.

I presented the same material at our  joint ICU/ED meeting a few days ago so I figured I may as well share it as a PK.

Genuinely intersted as to whether people are aiming for the higher MAPs in SCI. Was news to me and no one in our department was that impressed by it. The studies aren’t wonderful after all.

For those interested here’s last years PK too.

See you at SMACC Gold people!

Low yield from cardiac stress testing for ED patients

Title says it all. And it’s all been said before. David Newman is unsurprisingly involved in this paper and the SMART EM on this is well worth your time.

What they did:

  • prospective data on their chest pain unit with some chart review (with good but not fully described methods)
  • their routine was a 6 hour rule out then EST if possible or nuclear testing (which we don’t seem to do much of over here)

What they found:

  • mainly young patients (50) and mainly female and lots of hypertensives
  • about 80% were considered intermediate risk. Which is interesting in itself seeing as so many ended up discharged with negative tests
  • of the 4000 with stress tests ,470 had positive tests
  • ultimately about 130 got angios and only half of them had obstructive disease
  • only 28 got appropriate intervention as defined by cardiology guidelines. Lots of other people got stents but probably shouldn’t have.

Their discussion includes this phrase

While AHA guidelines suggest that provocative testing risk stratifies patients to a potentially near-zero short-term adverse event rate, there is increasing recognition that a negative result on serial bio-marker evaluation (typically a prerequisite for provocative testing) may also achieve this goal, making further risk stratification attempts redundant or inherently difficult.


Hermann, Luke K, David H Newman, W Andrew Pleasant, Dhanadol Rojanasarntikul, Daniel Lakoff, Scott A Goldberg, W Lane Duvall, and Milena J Henzlova. “Yield of Routine Provocative Cardiac Testing Among Patients in an Emergency Department-Based Chest Pain Unit: Yield of Stress Testing in Emergency Department Observation Units..” JAMA Internal Medicine (May 20, 2013): 1–6. PMID 23689690