Category: Neurology

Time-to-Treatment Effect “Confirmed”

The holy grail of tPA proponents, the time-to-revascularization theory, is the subject of this most recent article in JAMA.  This is a data mining exercise from the Get With The Guidelines-Stroke Registry – and, actually, there’s not a lot to say.  They evaluate 55,000 patients from the registry, and there are significant differences between the cohorts receiving tPA between 0-90, 91-180, and 181-270 minutes – so all their outcomes are dependent on multiple statistical adjustments.

And, when I say multiple, I mean overwhelming:

The variables used in the risk models were patient-level and hospital-level risk adjustors that were expected to be predictive of outcome, based on empirical analysis, prior literature, and clinical judgment.

Patient-level factors included age, race/ethnicity, sex, medical history (including atrial fibrillation, prosthetic heart valve, previous stroke or TIA, coronary heart disease or prior myocardial infarction, carotid stenosis, peripheral vascular disease, hypertension, dyslipidemia, diabetes, and current smoking), stroke severity (NIHSS), an age-by-NIHSS interaction term, arrival time during regular work hours (7 AM-PM Monday-Friday), arrival mode (ambulance, private vehicle), and select classes of vascular risk prevention medications prior to admission.

Hospital-level factors included hospital size, region, teaching status, rural location, certified primary stroke center status, average number of patients treated with tPA annually, and average number of annual stroke dis- charges. All variables were included in the predictive models without use of a stepwise or other formal variable selection process.

The pharmaceutical industry conflict-of-interest disclosure is even longer.

These folks could have made these data say whatever they desired with their statistical weighting.  They report a positive association with time-to-treatment and improved outcomes; the astute reader may interpret this as they are wont.

It is also worth mentioning the earlier time-to-treatment populations are probably more likely to include stroke mimics and TIAs – both of which tend towards excellent outcomes, with or without tPA.  The percentage of stroke mimics treated with tPA ranges between 6.5% and 15.5% at academic centers using MRI as imaging confirmation, and has been estimated to be as high as 25% to 29% in community settings.  The GWTG-Stroke registry specifically fails to account for stroke mimics in their coding instructions – a patient that receives tPA and rapidly improves is to be coded as “aborted stroke”, even though contemporary evidence throws this concept into doubt.

Regardless, the percentage of stroke mimics confounding the results likely dwarfs the magnitude of effect of the proposed time-to-treatment association reported by these authors.

“Time to Treatment With Intravenous Tissue Plasminogen Activator and Outcome From Acute Ischemic Stroke”
http://jama.jamanetwork.com/article.aspx?articleid=1697967

tPA Equally (In)Effective for Wake-Up Stroke

This is a, yet another, study in Stroke of folks claiming it is “safe” to use thrombolysis on patients who are found to have suffered a stroke while sleeping – the so-called “wake-up stroke” population.

The specific claim made is “This retrospective analysis of data in thrombolysed consecutive acute ischemic stroke patients shows no significant differences in mortality, functional outcomes, or bleeding rates between WUIS patients with no early ischemic change on CT and those treated within 4.5 hours of stroke onset.”

…because their sample size is so small the absolute differences are still within the statistical variation expected by chance.  This is, unfortunately, a recurring theme I see in these stroke publications, many of which are retrospective registry reviews.  Their groups are statistically not different, but this is owing to failed statistical power in study design, as opposed to clinically meaningful equivalence.  This is a major difference between retrospective and prospective studies – in which prospective studies choose specific absolute differences necessary to define clinically meaningful equivalence, and then perform power and sample size calculations based on these constraints.

Their outcomes are, incidentally, also simply terrible.  They publish a figure comparing outcomes with their wake-up stroke population to their 0-4.5 hour thrombolysis reference group – a 326 patient reference group with 18% mRS 0-1 and a 26% mortality.  But then, they further break out the 197 patients from that group that received tPA within the ECASS III license criteria, showing that compliance with guidelines leads to 32% mRS 0-1 and 18% mortality.  This therefore implies the other 129 patients – the ones who received tPA outside the license criteria – had utterly dismal functional outcomes and frighteningly high mortality.

Someone needs to go down to King’s College and check up on them and make sure all this off-label use isn’t just costly killing fields.

“A Case-Controlled Comparison of Thrombolysis Outcomes Between Wake-Up and Known Time of Onset Ischemic Stroke Patients”
http://www.ncbi.nlm.nih.gov/pubmed/23723307

Beware Observational Conclusions

“High achieved SBP after standardized antihypertensive therapy in hyperacute intracerebral hemorrhage was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may ameliorate clinical outcomes.”

Jerry Hoffman has mentioned the exercise to, while reading, expand any instance of the word “may” to “may or may not” – to help erase the positive bias of speculative conclusions.  And, this is one of those perfect circumstances where the lukewarm endorsement from this abstract conclusion ought to be predicated with a pound of cautionary conditionality.

These authors call their study SAMURAI-ICH, and it’s a prospective, observational study regarding the safety of early blood pressure reduction in intracerebral hemorrhage.  What this really means is they thought aggressive BP lowering was going to be awesome – despite only having various bits of inconclusive evidence – so they made wholesale practice changes, and then started a registry to monitor outcomes.  So, you can see the bias already.

And, verily, there is an association between their ability to lower blood pressure in ICH and favorable outcomes.  Now, their “favorable outcomes” cohort was also young, less disabled at baseline, and had smaller ICH hematoma volume.  Through the magic of statistical models, they attempt to control for all the various prognostic catastrophes, and thusly they arrive at their significant association.

But, finally, this observation doesn’t in the slightest explain whether the blood pressure control improved outcomes – or whether it was simply easier to lower blood pressure in patients whose cerebrovascular physiology was less deranged by smaller insults, and who went on to have good outcomes.  Aggressive antihypertensive treatment “may or may not” ameliorate clinical outcomes, indeed.

Beware observational conclusions!

“Systolic Blood Pressure After Intravenous Antihypertensive Treatment and Clinical Outcomes in Hyperacute Intracerebral Hemorrhage : The Stroke Acute Management With Urgent Risk-Factor Assessment and Improvement-Intracerebral Hemorrhage Study”
www.ncbi.nlm.nih.gov/pubmed/23704107

Bacterial Meningitis in Complex Febrile Seizure

The AAP has guidelines for simple febrile seizure – “There, there, the frightening demonic possession your child just experienced is nothing to worry about.”  Complex febrile seizures, however, are offered far less conclusive guidance.

This little retrospective review from UC San Diego evaluates 193 patients presenting with complex febrile seizure.  Lumbar puncture was performed in 136, and 1 patient ultimately received a diagnosis of bacterial meningitis.  The authors suggest, cognizant of the limitations, that complex febrile seizures need not routinely undergo LP.

This is entirely reasonable and consistent with the prior literature.  The largest retrospective review, from Boston Children’s, identified 3 cases with bacterial meningitis out of 526 children.  A systematic review and meta-analysis identified 41 cases of bacterial meningitis out of 1996 children.  There are additional cases of viral meningitis and encephalitis in these cohorts as well – of uncertain clinical significance – but the general implication is that otherwise well-appearing children ought not need LP absent other signs of CNS infection.

It would, of course, be fabulous if a consensus guidelines would further reinforce this evidence.

“Necessity of Lumbar Puncture in Patients Presenting with New Onset Complex Febrile Seizures”
www.ncbi.nlm.nih.gov/pubmed/23687537

“Yield of lumbar puncture among children who present with their first complex febrile seizure.”
www.ncbi.nlm.nih.gov/pubmed/20566610‎

“Risk of bacterial meningitis in young children with a first seizure in the context of fever: a systematic review and meta-analysis.”
www.ncbi.nlm.nih.gov/pubmed/23383133‎

INTERACT2: ICH Half-Truths

There have been dueling schools of thought regarding atraumatic intracerebral hemorrhage: let the brain autoregulate its own blood supply and don’t artificially lower the blood pressure, or use intravenous agents to lower blood pressure because there’s evidence it decreases hematoma expansion.  However, until now, there’d been no evidence that decreased hematoma size correlated with meaningful patient-oriented outcomes.

So, what are they saying about INTERACT2, the open-label, randomized trial of intensive BP control (SBP <140 mmHg) versus guideline-concordant BP control (<180 mmHg)?

@medwireNews INTERACT2 contradicts “longstanding dogma”, supports intensive BP reduction in ICH #eurostroke2013 

@MedscapeNeuro INTERACT2: Intensive Blood Pressure Lowering Benefits ICH 

@IctusClnic #ESCLondon2013 Surely INTERACT2 will have a great impact in blood pressure management after intracranial hemorrhage.

Pfffft.

The primary outcome was reduction in death or major disability (modified Rankin scale 3 to 6) at 90 days.  Unadjusted outcome was statistically negative, 52.0% to 55.6% (OR 0.87, 95% CI 0.75 to 1.01), but favoring intensive BP control.  Their secondary outcomes, which uses the conceptually messy tool of ordinal analysis, essentially magnified the effect of that 3.6% absolute difference in mRS outcomes and goes on to show that folks with less disability end up happier and more functional.

However, the baseline functional characteristics favored the intensive BP group, with median NIHSS score of 10 vs. 11.  68% of the cohort was from China – which has uncertain effects on external validity.  Over seven different intravenous antihypertensives – including the most popular agent, urapidil – were used for BP lowering, further muddling precise treatment guidance.  Most ICH was small volume hemorrhage, and BP treatment didn’t seem to have much different on hematoma expansion – so it’s hard to say why the intensive control group seemed to have a trend towards superiority.

And, finally, even though approximately half of the 1436 assigned to guideline-recommended treatment group had baseline systolic BP >180 mmHg, only 303 of them received an anti-hypertensive agent within 1 hour of study assignment.  It might be more appropriate to describe this study as “intensive” vs. “poorly guideline-concordant” BP control – would outcomes have been more favorable if more of the guideline-concordant group actually had their systolic BP lowered below 180 mmHg?

In any event, to call this a practice-changing paradigm is a only a half-truth.  It does appear safe, at least, to make a brisk and reasonable effort to lower BP in atraumatic, intracerebral hemorrhage.  Whether “intensive” control is needed with a nicardipine infusion, such as in the upcoming Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II trial, is still uncertain.

“Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage”
http://www.nejm.org/doi/full/10.1056/NEJMoa1214609

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

Neurosurgery’s Takedown of Steroids in SCI

A brave new day dawns – clinicians who otherwise lived in fear of medicolegal reprisal from failing to administer steroids in acute spinal cord trauma may now safely withhold them.

The steroids in spinal cord debate, a one-man crusade lead by Michael Bracken, distorted by performing Cochrane Reviews of his own articles, has hopefully been definitively settled.  These authors, as part of a comprehensive update on the diagnosis and management of acute spinal cord injury, definitively summarize the flawed literature supporting methylprednisolone administration.  Their recommendation:

Administration of methylprednisolone (MP) for the treatment of acute spinal cord injury (SCI) is not recommended. Clinicians considering MP therapy should bear in mind that the drug is not Food and Drug Administration (FDA) approved for this application. There is no Class I or Class II medical evidence supporting the clinical benefit of MP in the treatment of acute SCI. Scattered reports of Class III evidence claim inconsistent effects likely related to random chance or selection bias. However, Class I, II, and III evidence exists that high-dose steroids are associated with harmful side effects including death. 

We’ve come a long way since the NIH faxed a letter to every Emergency Department in the country instructing physicians to give steroids.  Another amazing saga demonstrating the danger of inadequately reviewed medical evidence.

“Pharmacological Therapy for Acute Spinal Cord Injury”
http://www.ncbi.nlm.nih.gov/pubmed/23417182

Chovstek Sign – Forget It

This entertaining brief communication refers to Chvostek sign – the twitching of the facial muscles after tapping the facial nerve purportedly associated with hypocalcemia.

This neurologist notes, after one of his residents presented with bilateral Chvostek sign, he convenience sampled other residents and medical students on the wards – and 6 out of 11 exhibited Chvostek sign.  He otherwise notes 25-43% of healthy individuals exhibit this sign and 29% of patients with hypocalcemia do not.  He bluntly states Chvostek sign should simply be retired as a clinically relevant entity.

Stick with the Trousseau sign!

“Chvostek sign, frequently found in healthy subjects, is not a useful clinical sign”
http://www.neurology.org/content/80/11/1067.full

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