Emergency Medicine Literature of Note
Musings on Emergency Medicine, Clinical Informatics, & High-Value Care.
The Annals of Emergency Medicine Journal Club regarding IST-3 has been published as free fulltext online. This article was written by myself, Yashwant Chathampally, and Gregory Press at The University of Texas Health Science Center at Houston.
It may be downloaded here:
“rt-PA and Stroke: Does IST-3 Make It All Clear or Muddy the Waters?“
Suppose you’re “lucky” enough to be taken to an experienced stroke center if you have stroke-like symptoms. After all, they see strokes every day, are experts in the diagnosis of stroke, and have given thousands of patients thrombolytics. However, how often might they be wrong, you ask?
Oh, they estimate about 1 in every 50. But, truthfully, it’s probably much worse.
This is a multi-center observational cohort that purports to identify the percentage of patients treated with tPA and subsequently diagnosed with stroke mimics. Out of the 5518 patients in their cohort, 100 were identified as stroke mimics. Two of the 100 had sICH by NINDS criteria, but none died. Therefore, these authors confirm, tPA is safe even when they’re wrong, and the collateral damage of racing to tPA is low.
Of course, their methodology for identifying a stroke mimic is hugely skewed towards maintaining the diagnosis of ischemic stroke. Only patients in whom clinical details did not suggest a vascular etiology or a clear alternative diagnosis were labeled mimics. Patients with nonspecific features, non-contradictory imaging, or lacking definite evidence favoring stroke mimic remained as diagnoses of acute stroke.
So, even at experienced stroke research institutions – 1 in 50 with the most generous of criteria. What’s the chance real-world performance approaches anything close to this level of diagnostic skill?
The authors, of course, declare multiple financial conflicts of interest with the manufacturer of tPA.
“Safety of Thrombolysis in Stroke Mimics : Results From a Multicenter Cohort Study”
www.ncbi.nlm.nih.gov/pubmed/23444310
Interestingly, it especially killed people who were going to have a favorable outcome with standard care.
This is MR-RESCUE, a trial evaluating the efficacy of endovascular mechanical thrombectomy for acute ischemic stroke. Patients were eligible for this trial up to 8 hours from stroke onset, and most were enrolled because they were outside the window for tPA – or received tPA but failed to recanalize. One of the special features of this study was using emergent MRI to identify a patient subgroup that had a potentially viable “penumbra” of brain tissue surrounding the original infarct. The imaging hypothesis in this study was that patients would particularly benefit from mechanical intervention in the presence of a penumbra such as this.
However, they were wrong. Oddly, the authors reported their primary outcome differences in mean mRS. As discussed on the last blog post, mean and median mRS aren’t used in stroke trials because the profound disability/living death/death numbers at the bottom of the scale don’t represent the clinically relevant treatment effects. Regardless, they failed to show benefit of mechanical embolectomy.
Overall, patients simply did poorly. This is a fine example of the exquisite relationship between NIHSS and outcomes, as the median NIHSS in this trial was 17, less than 20% of the patients had good outcomes (mRS 0-2), and 21% died with in 90 days. Looking at Figure 2, it’s clear the penumbra was an excellent prognostic feature – until the mechanical embolectomy occurred. Then, mortality jumps from 9% to 16%, and the favorable mRS drops from 23% to 15%.
These authors used the MERCI and Penumbra systems. You might already be familiar with the MERCI retriever from earlier, negative trials with significant device complications. Someday we might see the last of it – but, I’m guessing, where there’s already money sunk into a device, there’s more patient harms to come.
“A Trial of Imaging Selection and Endovascular Treatment for Ischemic Stroke”
IST-3 broke new ground for misleading statistics in stroke trials with its secondary ordinal analysis, demonstrating “benefit” in the presence of an overall negative, open-label, randomized trial of over 3,000 patients. Now, who here can decipher the Cochran-Mantel-Haenszel test? Team Genentech/Boehringer Ingelheim is hoping you can’t.
This is a retrospective, observational cohort from the Virtual International Stroke Trials Registry looking for a way around the pesky “contraindications” to tPA treatment that currently prevent large groups of patients from receiving treatment. These authors pulled non-treated “controls” from the cohort along with tPA-treated patients who had at least one contraindication or warning to tPA use and compared mRS outcomes at 90 days. The control group was significantly older and sicker – though their strokes were milder (NIHSS 12 [SD 9] vs. NIHSS 14 [SD 8]) – but the authors adjusted only for age and NIHSS. Their conclusion?
“Many of the warnings and contraindications of alteplase may not be justified and licences, guidelines, and protocols should be adjusted to accommodate recent data from registries and real-world experience.”
As the authors correctly note earlier in the paper, observational data combined from heterogenous trials spread over many years is likely rife with differences in care and selection bias. This alone renders their results invalid as anything but hypothesis-generating, rather than practice-changing.
The other issue is their primary outcome and statistical tool of choice:
“The primary outcome measure was the mRS at 90 days, analyzed across the whole distribution of scores with the use of the Cochran–Mantel–Haenszel test,”
Here’s an example of an unadjusted mRS distribution “favoring” alteplase:
Just at first glance, looks pretty much the same – perhaps even favors placebo (top bar). How the heck is this significantly positive towards tPA? Well, the CMH takes into all ordinal levels – even the perturbations between disability/living death/death at the bottom of the scale – as opposed to just the clinically relevant mRS 0-1 or mRS 0-2 that were primary outcomes in other stroke trials. So, the statistical significance in this test has nothing to do with the clinical efficacy of the treatment in question. Then, the adjusted OR of 1.29 (95% CI 1.00 – 1.66) is somehow based on a mélange of “dichotomized outcomes at 90 days (mRS 0–1, mRS 0–2, NIHSS 0–1, and mortality)”.
I’m afraid this simply looks like the authors dragged the VISTA data through every permutation of statistical tools possible until they found a test and a combined endpoint for logistic regression that came out in favor of tPA. And, then, sold it as practice-altering.
Disheartening.
Here’s the disclosures, for your reading pleasure:
BF has received modest honoraria for participation in clinical trials (Sanofi-Aventis). AVA has served as PI of CLOTBUST trial partially funded by Genentech, and currently serves as PI of CLOTBUSTER funded by Cerevast Therapeutics and consultant to Genentech. EB is an employee of Boehringer Ingelheim. JCG, CW, PL, and NKM have no relevant conflicts of interest. AM has served as a consultant for Boehringer Ingelheim, received speaker’s honoraria from Boehringer Ingelheim, and congress expenses from Lundbeck. NW has received expenses from Boehringer Ingelheim for his role as member of the steering committee in relation to the ECASS III trial with alteplase and served as a consultant to Thrombogenics as chairman of the DSMB. SITS International (chaired by NW) received a grant from Boehringer Ingelheim and from Ferrer for the SITS-MOST/SITS- ISTR. His institution has also received grant support toward administrative expenses for coordination of the ECASS III trial. NW has also received lecture fees from Boehringer Ingelheim and from Ferrer. AS and KRL have received research grants, modest honoraria for participation in clinical trials, and have a consultancy or advisory board relationship with manufacturers from drugs (including Boehringer Ingelheim). KRL administered the grant from Genentech for support of this study.
“Thrombolysis in Stroke Despite Contraindications or Warnings?”
stroke.ahajournals.org/…/STROKEAHA.112.674622.abstract
If you’re still skeptical about the use of tPA in stroke patients – too bad. If you’re not on the bus, it would seem now you’re under it. ACEP has published their new Clinical Policy regarding tPA use in the most recent issue of Annals of Emergency Medicine. tPA should be offered to folks in the 0-3 hour window who meet NINDS criteria as a Level A recommendation. This is based on the following Class I evidence:
The Level B recommendation is that tPA be considered for use off-label in the 3-4.5 hour window, based on ECASS III.
If you’ll travel backwards in time a couple days (by scrolling down), you’ll see I did a quick review of two articles concerning the “trustworthiness” of clinical practice guidelines. The Institute of Medicine names eight criteria – and, for the most part, this guideline does OK. It does, unfortunately, fare less well at the conflict of interests declared:
Three out of eight guideline writers directly involved with the pharmaceutical manufacturer. As far as indirect support, however, if they wanted to be more transparent, Dr. Edlow, Dr. Jagoda, Dr. Stead, Dr. Wears, and Dr. Decker also ought to have disclosed their association with the Foundation for Education and Research in Neurologic Emergencies – supported by multitudinous pharmaceutical manufacturers, including Genentech.
If you’re irritated that pharmaceutical manufacturers are helping write our clinical guidelines, make your voice heard.
“Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department”
We have a fairly robust vascular neurology program at my institution, and – unsurprisingly – they’re rather pro-thrombolysis. While our disagreements over the efficacy of thrombolysis for acute strokes are generally set aside in a truce stemming from academic and research interests, the main philosophical difference between our services remains this: the difference between eligible and indicated.
Vascular neurology tends to treat these terms as synonymous regarding thrombolysis and acute stroke, while it’s clear from the literature that not every patient benefits from thrombolysis. The most recent issue of Neurology features another prognostic tool, the SPAN-100, which is the simplest by far: NIHSS + age. If this score is >100, fewer patients will benefit from tPA than will be harmed. There’s a quality-of-life discussion to be had regarding individualized treatment decisions in SPAN-positive patients, and this is derived from a very small cohort, but it’s consistent with the remaining literature.
The accompanying editorial is also pro-thrombolysis, but does recognize these scoring systems are important clinical tools in educating patients and families regarding the potential for benefits and harms. Most importantly, this table from the editorial summarizes the growing body of literature available to assist the decision-making process:
I look forward to seeing these develop such that clinicians have better tools with which to separate eligible from indicated.
tPA for stroke remains controversial, to say the least. The reasons behind the Emergency Medicine/Neurology disconnect are complex and covered elsewhere. Regardless, thrombolysis is here to stay – and probably helps some patients. The hard part is finding those patients with the most favorable risk/benefit ratio.
This is a study that looked at diffusion-weighted imaging to try and predict which patients were most likely to rapidly improve with tPA. These authors enrolled sixty-six patients with acute stroke eligible for tPA under the Japanese license and performed diffusion-weighted MRI on each of them. Previous studies had suggested an ASPECTS score > 7 predicted response to tPA – and this study confirmed it. Essentially, this translates as larger vascular territories showing greater improvement in NIHSS after tPA than smaller vascular territories.
There’s a bit of a bias in this study, since smaller vascular territories may have produced smaller initial NIHSS. The population was quite old for a stroke study – median age 79. And, truly, the more interesting data presented is the breakdown demonstrating the massively favorable impact of early (within 1 hour) recanalization after tPA administration.
But, mildly interesting paper, important as part of a slow, gradual trend of attempts to delineate which patients have the best potential to benefit from tPA.
“DWI-ASPECTS as a Predictor of Dramatic Recovery After Intravenous Recombinant Tissue Plasminogen Activator Administration in Patients With Middle Cerebral Artery Occlusion”
www.ncbi.nlm.nih.gov/pubmed/23212169
Staying consistent with the “brain attack!” slogan folks developed for stroke, the innovations in treatment continue to progress in their attempts to mimic myocardial infarction. In myocardial infarction, a great deal of focus has been placed on rapid diagnosis and either thrombolysis or interventional catheterization. This extends to the prehospital arena, with experimentation with ECG transmission, pre-hospital lytics, and pre-hospital cath lab activations.
For stroke, they’re still trying to replicate this pre-hospital diagnosis and treatment – made slightly more complex because the diagnostics involved requires CT scanning. However, with enough funding from telehealth and imaging industry, “mobile stroke units” have been created for feasibility evaluations.
And, these authors have certainly demonstrated that it is feasible, diagnosing 48 acute strokes in the prehospital setting and giving half of them thrombolysis. One patient given rt-PA had sepsis rather than an acute stroke, which is of uncertain significance in an underpowered feasibility case series such as this.
However, there’s a difference between can and should. I’m uncertain whether we should even be exploring the can portion in this pilot, considering should means a grossly excessive allocation of resources for a therapy of uncertain benefit. Given the small absolute benefits seen in the handful of trials that even showed a benefit, I can’t possibly see how trials of pre-hospital lytics could favor anything but surrogate endpoints, rather than patient-oriented endpoints. 30 minutes faster to TPA? At what cost, and did outcomes change?
I won’t fault the authors for their interesting experiment – as long as they don’t seriously propose it as The Future based on our current evidence.
“Prehospital thrombolysis in acute stroke : Results of the PHANTOM-S pilot study”
www.ncbi.nlm.nih.gov/pubmed/23223534
This is my favorite sort of article to feature on this site – a probably-overlooked letter about a certainly-overlooked feature of a landmark trial.
This author, from Mt. Sinai, notes last year, the authors of ECASS III updated their online manuscript to change a p-value in their baseline characteristics from 0.03 to 0.003. Since these are p-values for baseline characteristics, they’re only for illustrative purposes – considering, in randomized controlled trials, all the differences do occur by “chance”. However, the conceptual interpretation of this change in ECASS III is the placebo group was inadvertently randomized to have a history of prior stroke by a 7% absolute difference – and the chance of that occurring randomly has now admitted to be 1 in 300 rather than 1 in 30. When tremendously unlikely differences in baseline characteristics occur “by chance”, it raises troubling questions regarding whether they truly occurred randomly.
Additionally, the author of this letter also makes the astute point that, because this difference in baseline characteristics did not reach statistical significance by the ECASS III authors’ definition (0.004), it was not adjusted for in their data analysis. In his adjusted reanalysis (data not shown), the significance of outcomes favoring thrombolysis disappears (OR 1.19, CI 0.89-1.59). Not necessarily surprising, considering the updated meta-analysis including IST-3 data published in The Lancet also makes the statistical significance of the benefit of thrombolysis disappear past 3 hours.
Thrombolysis for acute stroke remains some of the most distorted treatment data in emergency medicine, where this heterogenous patient population is being overtreated based on “eligibility”, rather than “likelihood of benefit”.
“Implication of ECASS III error on emergency department treatment of ischemic stroke.”
http://www.ncbi.nlm.nih.gov/pubmed/23141561