Category: Stroke

More Endovascular Junk Science

So far, we’ve seen nothing but poor outcomes in endovascular cerebral reperfusion trials.  The MERCI devices were simply dysfunctional and lethal and, despite advances with newer devices, we’re still waiting for a decisive trial demonstrating clear benefit.  But, the money is out there for the taking if the science will support it – and thus, more “science”.

This is a study involving authors sponsored by Stryker who do a retrospective review of cases at two hospitals, comparing infarct volume and short-term outcomes of patients who underwent either endovascular intervention, conventional thrombolysis, or no treatment for their large-vessel acute ischemic stroke.  The accompanying editorial probably sums up their limitations best:
“Retrospective, nonrandomized nature of the study; the comparison between 2 hospitals in the same health care system in which endovascular interventions were performed in one and not the other, which may have resulted in some unintentional differences in overall care; the combining of data among patients who received intravenous thrombolysis with those who received no reperfusion therapy, which may have diluted treatment responses; … and the lack of long-term clinical outcomes that could be correlated with the imaging findings.”

So, they have a collection of patients for whom it is in no way appropriate to compare outcomes and generalize any sort of conclusions – and that’s precisely what they do.  And, specifically, after reporting full-cohort baseline characteristics, their conclusions are based on subgroups of that cohort – and using an imaging surrogate outcome measure!

I’d tell you these authors conclude patients with an NIHSS of 14 or higher may be the best candidates for endovascular reperfusion therapy – but then I’d be further perpetuating this “science”.  Again, what they claim may be true – but they’re overestimating the ability of their data to claim it.

“Comparison of Final Infarct Volumes in Patients Who Received Endovascular Therapy or Intravenous Thrombolysis for Acute Intracranial Large-Vessel Occlusions”
http://archneur.jamanetwork.com/article.aspx?articleid=1686897

“Neuroimaging Negative” Strokes Are A Lie

Back in 2011, there was an article in Annals of Emergency Medicine discussing what a fantastic job we were doing in diagnosing stroke and avoiding administering tPA to “stroke mimics”.  They reported a rate of 1.4% administration to stroke mimics – none of whom had bleeds.  The problem I pointed out, both on my blog and in a response letter to Annals, was that the authors invented a new category called “neuroimaging negative” acute stroke – which was probably actually all stroke mimics.  This would have changed the rate of tPA administration to stroke mimics from 1.4% to 29.3%.  The authors, having financial conflict of interest with the manufacturers of tPA, disagreed.

This study, part of the “Lesion Evolution in Stroke and Ischemia On Neuroimaging” project, evaluated the progression of lesions on MRI following tPA administration.  These authors found 231 patients with acute stroke who were initially screened by MRI prior to tPA administration and had evidence of infarction on diffusion weighted imaging.  They found that, following tPA administration, only 2 patients had resolution of an MRI DWI lesion.  They therefore conclude that “Patients with a stroke are unlikely to have complete DWI lesion reversal within 24 hours after IV tPA treatment,” and patients with no DWI lesion following tPA administration should be considered to have a diagnosis other than acute stroke.

Thus, this confirms my conclusion that the 27.9% of patients from the prior study with “neuroimaging negative” acute stroke ought to universally be considered to have had a diagnosis other than acute stroke.  The reality is that we are likely treating an ever-greater number of acute ischemic strokes – and further efforts to push Emergency Physicians to treat additional patients more quickly are certainly going to expose additional patients to avoidable harms.

“Negative Diffusion-Weighted Imaging After Intravenous Tissue-Type Plasminogen Activator Is Rare and Unlikely to Indicate Averted Infarction”
http://www.ncbi.nlm.nih.gov/pubmed/23572476

Stroke or Stroke Mimic? Who Cares!

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

Mechanical Embolectomy Kills People

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”

Statistics For tPA & Profit


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

New ACEP tPA Clinical Policy

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:

  • Two studies that are negative for benefit (ECASS, ATLANTIS)
  • The post-hoc analysis of ATLANTIS B with 61 patients,
  • NINDS

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:

  • Dr. Smith – Served on scientific advisory board for Genentech.
  • Dr. Gronseth – Speakers’ bureau for, and honoraria from, Boehringer Ingelheim.
  • Dr. Messe – Former speakers’ bureau for Boehringer Ingelheim.

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”

tPA Is The Hand That Feeds

No biting!

There are still a few hold-outs on the 0 to 3 hour window, but most folks would agree that battle is lost – the best we can hope for is further clarifying the patients with the greatest likelihood of clinically significant benefit vs. those with the greatest level of potential harms.

But, greater than 3 hours is still a battlefield.  This article in the January Annals uses the gloriously unbalanced ECASS III data for a cost-effectiveness analysis which, unsurprisingly, concludes in favor of tPA treatment.  The problem is, of course, the assumption that ECASS III is infallible – a highly suspect position, considering the baseline differences between groups in ECASS III.  Then, accounting for the the 1200 patients in IST-3 enrolled in the 3 to 4.5 window who did poorly with tPA, I’m guessing an updated meta-analysis wouldn’t look quite as favorable.  But, I will give these authors a bit of a break, as this article was accepted for publication before IST-3 results were available.

Finally, in lieu of my usual rant, I’ll just copy and paste the disclosures portion of the article:
“This project was funded through a contract with Genentech, Inc. Drs. Boudreau and Veenstra and Mr. Guzauskas served as a consultant for Genentech, Inc. Ms. Villa is employed by Genentech, Inc. Dr. Fagan is a consultant for Genentech, Inc.”

“A Model of Cost-effectiveness of Tissue Plasminogen Activator in Patient Subgroups 3 to 4.5 Hours After Onset of Acute Ischemic Stroke”

The Latest Prognostication for Stroke

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.

“Stroke Prognostication using Age and NIH Stroke Scale: SPAN-100″
www.ncbi.nlm.nih.gov/pubmed/23175723

Predicting Immediate Improvement After tPA

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