Neurology – Page 2 – Emergency Medicine Literature of Note

The New Cutting-Edge Treatment for Migraines

The new sexy business – by which I mean “profitable” – in the treatment of chronic migraine is therapy targeted at the calcitonin gene–related peptide receptor. The past few years have brought several of these to market as ongoing maintenance therapy. This looks at a different application – acute migraine. Their proposed unmet need – the slice of patients for whom various triptans are ineffective.

This is a multi-center, randomized, double-blinded, placebo-controlled trial of rimegepant, an orally-administered CGRP antagonist, administered as a single-dose for acute migraine headache of moderate-to-severe intensity. These authors randomized 1,186 patients in a 1:1 ratio, with the primary end point being freedom from pain at 2 hours after the initial dose.

The winner: rimegepant.

Yes, rimegepant is superior to doing nothing at all for your migraine headache.

And just barely – 19.6% response to rimegepant, compared with 12.0% response to placebo.

The clinical value here is virtually negligible. And, helpfully, the authors provided the primary limitation of this trial for you in the text:

“First, the trial did not include an active comparator to rimegepant.”

The authors note in their introduction many patients receiving triptans do not have a response – 34%! This, however, implies 60+% of patients do have a response – far superior to rimegepant. Then, patients also have an array of over-the-counter options including acetaminophen, ibuprofen, and various caffeine-containing combination therapies. Treating moderate-to-severe migraine attacks with placebo borders on – if not crosses into – unethical territory. Even if this therapy didn’t have a dismal response rate, we still need to generalize it one step further to those who are non-responders to triptans to even have an indication – which would then be the proper enrollment criterion for a trial to ensure the same physiologic features making a patient a triptan non-responder weren’t also a CGPR antagonist non-responder.

Now, no one opposes further exploration of alternative, effective treatments for migraine – headaches, particularly migraine headaches, are relatively common presenting complaints in the Emergency Department. While we have effective abortive treatments for such, there is tremendous value in having a wider array of options for use at home, considering the direct and indirect resource costs and human suffering associated with headaches requiring Emergency Department evaluation and treatment.

But this is junk science – an advertorial in a journal continually proving itself to have virtually no worthy editorial standard:

“Biohaven Pharmaceuticals sponsored the trial, supplied the trial agents, reviewed the trial design, collected the data, and performed data management and analysis. The manuscript was written with the assistance of a medical writer funded by Biohaven Pharmaceuticals. All the authors have confidentiality agreements with Biohaven Pharmaceuticals, either as a condition of employment or in their role as consultants.”

Yet another utter embarrassment for the New England Journal of Medicine.

“Rimegepant, an Oral Calcitonin Gene–Related Peptide Receptor Antagonist, for Migraine”

https://www.nejm.org/doi/full/10.1056/NEJMoa1811090

Addendum: There’s a second study, as well, published in The Lancet with similar results. And, furthermore, deep in a non-redacted part of the protocol, the authors share these unpublished Phase 2b trial results. To be taken with a grain of salt, to be sure, but obviously any comparison with an active drug would have looked much worse for rimegepant:

The EXTEND Alteplase Meta-Analysis

Did you miss the publication of EXTEND a couple weeks ago – a publication I helpfully labeled as “shenanigans“? Well, these same authors have wasted little time performing a systematic review and meta-analysis of individual patient data in the 4.5-9 hour timeframe. Their search, specifically limited to hemispheric stroke and pretreatment perfusion/diffusion evaluation, identifies: EXTEND, ECASS4-EXTEND, and EPITHET.

EXTEND we’ve already heard from – and, since most of the patients for this IPD meta-analysis come from EXTEND, it should be no surprise the overall results effectively mirror EXTEND. EPITHET, of which you may have some faint familiarity, has been pulled from the dusty archives of 2008. Then, there’s ECASS4-EXTEND, of which you probably hadn’t heard, since it was published with zero fanfare about a month ago.

So, what is ECASS4-EXTEND? These were again 4.5-9h patients screened with MRI and enrolled between 2014 and 2017, with early termination recommended by the Data Safety Monitoring Board when enrollment slowed to a trickle following publication of the endovascular trials. Before discontinuation, these authors enrolled 120 and analyzed 116, 60 receiving tPA and 56 placebo. Most of them were “wake up” strokes, and the “time-to-treatment” variable is again facetiously estimated by taking the midpoint between sleep onset and time of waking. There are small increases in patients with reduced disability in the tPA arm, but these unsurprisingly do not reach statistical significance. Likewise, deaths within 90 days are double – 11.5% versus 6.8% – another technically non-significant result. The authors, naturally, focus on the promise of the treatment if a sufficient sample were recruited, rather than the potential threat to patient safety.

And then there’s this all-too-familiar editorial failure:

Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

…in direct contradiction to the third author having this affiliation:

Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany

And this little snippet in the body of the article:

Role of the funding source
… The trial was supported with a restricted grant from Boehringer Ingelheim (Germany), the funder. The funder approved the study design…. Two employees of the funder were members of the steering committee and thus involved in data interpretation and preparation of the publication.

Finally, amusingly enough, ECASS4-EXTEND doesn’t technically meet criteria for their inclusion in the systematic review and IPD meta-analysis – they report they searched for trials “published in English between Jan 1, 2006, and March 1, 2019”, while ECASS4-EXTEND was published on April 4th.

Nitpicking aside, despite the relative frequency and prominence of these publications, this is mostly much ado about nothing – it should be obvious from the early termination of ECASS4-EXTEND these data primarily reflect a cohort we’re sending to endovascular therapy. Therefore, what we really need for these data to be relevant is a confirmatory trial performed specifically in the resource-austere settings thrombectomy might not be available.

“Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31053-0/fulltext

“Extending the time window for intravenous thrombolysis in acute ischemic stroke using magnetic resonance imaging-based patient selection”
https://www.ncbi.nlm.nih.gov/pubmed/30947642

EXTEND Alteplase Shenanigans!

Do you remember EXTEND-IA? Or EXTEND-IA TNK? This is, well, their neglected little brother, regular old EXTEND, stumbling along to “completion” and publication in the New England Journal of Medicine, as is apparently their birthright.

EXTEND-IA was part of the enormously important series of trials launching the endovascular revolution for acute ischemic stroke. EXTEND-IA TNK is another piece of evidence probably pushing us slowly, inexorably, towards tenecteplase rather than alteplase. This, despite its provocatively titled editorial, is not a grand event.

This trial, which started enrolling way back in 2010, essentially mirrors EXTEND-IA, but gives alteplase to patients with a mismatch on perfusion imaging, rather than referring them to thrombectomy. Over 8 years at 16 centers, mostly in Asia-Pacific, the authors were able to randomize a mere 113 patients to alteplase and 112 to placebo. The primary outcome, a modified Rankin Scale of 0 or 1 at 90 days, favored the alteplase cohort, 35.4% to 29.5%. Deaths, partly related to a 6% absolute excess of intracranial hemorrhage, were higher in those treated with alteplase, 11.5% vs 8.9%. The efficacy results do not meet statistical significance prior to adjustment, but the median NIHSS was 12 for alteplase and 10 for placebo. So, you can probably guess the bulk of their discussion focuses on their adjusted effect size, which does reach statistical significance at 1.44 (1.01 – 2.06). Interestingly enough, this wasn’t their original planned adjusted analysis – the 95% CI for that traditional logistic regression crosses unity at 0.99 – leading to questions whether this fortuitous p-value is innocent serendipity, or found because it was findable.

Regardless, this trial – stopped early, per the authors, because of the publication of WAKE-UP – is already mostly obsolete. Systems of stroke care have changed immensely since this trial was planned. About 80% of patients in this trial had large vessel occlusions on imaging – patients who in this modern era would simply go straight to thrombectomy. These results do not support the use of alteplase as an alternative to thrombectomy, as recanalization rates – as we’ve known forever – are simply not good enough with medical therapy. Therefore, in modern systems of stroke care, this trial probably has zero effect on care. The better approach to tailoring treatment to individual patient heterogeneity in our modern systems is to find new ways of integrating MRI into the rapid assessment of stroke.

However, much of the world does not have access to timely thrombectomy for stroke, for a variety of reasons. In rest of the world, in that narrow slice with a modern system for acute evaluation with perfusion imaging and alteplase administration, but not timely thrombectomy, then you could consider changing protocols to include alteplase administration like here in EXTEND. It is not clear from these data whether generalization of these data to such lower-resource settings would accurately reflect effectiveness and safety, but that is the conceivable application of these results. Then, you have to consider the typical disclaimers affecting the reliability of their presented findings:

Dr. Parsons reports receiving consulting fees from Apollo Medical Imaging Technology, Boehringer Ingelheim, Canon Medical Systems, and Siemens; Dr. Wong, receiving grant support, paid to Royal Brisbane and Women’s Hospital, from Boehringer Ingelheim; Dr. Sabet, receiving travel support from Boehringer Ingelheim; Dr. Christensen, holding stock in Ischema- view; Dr. Mitchell, receiving lecture fees from Medtronic USA and Stryker; Dr. Thijs, receiving advisory board fees from Amgen and Bristol-Myers Squibb, advisory board fees and lecture fees from Bayer and Pfizer, advisory board fees, lecture fees, and travel support from Boehringer Ingelheim, and advisory board fees and travel support from Medtronic; Dr. Meretoja, receiving advisory board fees, lecture fees, and travel support from Boehringer Ingelheim and Stryker; Dr. Davis, receiving advisory board fees from AstraZeneca and Boehringer Ingelheim; and Dr. Donnan, receiving advisory board fees from AstraZeneca Australia, Bayer, Boehringer Ingelheim, Merck, Pfizer, and Servier.

At the minimum, at least, it is another bit of evidence regarding the importance of salvageable brain for the utility of any intervention for stroke – a principle that probably ought be applied for those treated within 4.5 hours of stroke, as well.

“Thrombolysis Guided by Perfusion Imaging up to 9 Hours
after Onset of Stroke”
https://www.nejm.org/doi/full/10.1056/NEJMoa1813046

“Image-Guided Intravenous Alteplase for Stroke — Shattering a Time Window”
https://www.nejm.org/doi/full/10.1056/NEJMe1904791

Addendum 5/15/09: Minor updates in response to Twitter discussion and comments below.

Add Clopidogrel to Aspirin, Temporarily

In the Emergency Department, we’re not necessarily spending a lot of our time sending home patients with minor stroke or high-risk transient ischemic attack – or, even if we are, we’re usually not doing it independently. That said, our scope of practice always seems to be expanding, observation units are frequently run by emergency physicians, and hospitals are looking to take advantage of opportunities to discharge patients rather than admit.

Regardless, this is a meta-analysis supporting the findings of CHANCE, looking specifically at the short-term use of aspirin and clopidogrel after a minor stroke or high-risk TIA. CHANCE enrolled 5,170 patients, while this meta-analysis effectively combines these with POINT, while also tossing in the patients from FASTER.

The main takeaway here is the combination of the evidence from the long-term treatment observing it was effectively a wash between stroke prevention and bleeding complications, and the observation that stroke risk was highest immediately following the index event. A reasonable interpretation, as highlighted by the guidelines, is to use dual-antiplatelet therapy short-term after the index event. The evidence does not specifically describe the optimal duration, but anywhere between 10 and 21 days seems reasonable.

Just wanted to toss this one out there with a little more prominence, as this isn’t particularly new, but I also wouldn’t want it to be overlooked.

“Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta-analysis”
https://www.bmj.com/content/363/bmj.k5108

“Guideline: Starting dual antiplatelet therapy ≤ 24 h after high-risk TIA or minor ischemic stroke is recommended.”
https://www.ncbi.nlm.nih.gov/pubmed/30986828

Levetiracetam vs. Phenytoin

The epic, classic showdown from time immemorial: new vs. old.

But, more specifically, these are two trials set to determine relative utility of each in pediatric seizures, vying for the coveted “second-line” therapy recommendation once benzodiazepines have failed. The thought and hope is, of course, the newer agent – levetiracetam – is at least as efficatious, if not moreso, as it can be infused more quickly. The authors then propose levetiracetam is associated with fewer long-term adverse effects and medication interactions during oral maintenance, and, as such, allows for convenient continuation after intravenous initiation.

Generally speaking, these two trials are very similar – both open-label trials randomizing pediatric patients with ongoing seizures, both analyzing about 250 patients … and both demonstrating effectively similar results by different routes. EcLiPSE, interestingly, was designed as a superiority trial, with a primary outcome of time from randomization to seizure cessation. Median time to seizure cessation not statistically different at 35 minutes for fosphenytoin and 45 minutes for levetiracetam, with similar numbers of treatment failures for additional anticonvulsants or intubation. In ConSEPT, the primary outcome was cessation of seizure activity within 5 minutes of the end of the infusion, and here results favored phenytoin at 60% versus 50% for levetiracetam.

Effectively, however, the sample sizes are small enough, the types of patients heterogenous enough, and the differences small enough, the Bayesian interpretation is probably a wash. These are both fine second-line options, but these trials do not provide any data supporting levetiracetam as a superior option.

“Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30724-X/fulltext

“Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30722-6/fulltext

Lacunar Infarcts & Thrombolysis

For some period of time, folks have debated the utility of thrombolysis in lacunar infarcts. The underlying concern is with regard to their underlying suspected pathology relating to non-thrombotic occlusion of small perforating arteries, in contrast to the process seen in small- or large-vessel stroke. This little subgroup analysis of WAKE-UP – the MRI-driven tissue-based trial of alteplase for ischemic stroke – tries to shed further light on this specific concern.

Of the 503 patients included in WAKE-UP (out of 1,362 patients screened), 108 had imaging-defined lacunar infarcts. The median NIHSS of these patients was 4 to 5, and about half were randomized to alteplase and half to placebo. Overall, this subgroup – underpowered for any definitive conclusion – demonstrated similar outcomes as those whose stroke subtype was not lacunar.

The issue is not so much the finding observed here, but the effort in the Discussion and accompanying editorial to generalize WAKE-UP to all strokes. There is only a loose association between DWI and FLAIR findings and predicting time of stroke onset in their cited reference. A little fewer than 2/3rds of strokes of ≤4.5h age seem to have positive DWI and negative FLAIR, and this study enrolled only a tiny fraction of patients with potential lacunar infarcts.

Long story short, a treatment effect observed in this tissue-based enrollment cohort cannot reliably predict treatment response for lacunar strokes screened and treated based on routine non-contrast imaging. Most patients screened for WAKE-UP were excluded based on not meeting imaging criteria, potentially around half of whom were otherwise within 4.5 hour stroke onset (based on their citation above). Thrombolysis does benefit the patients in WAKE-UP, overall, but this almost certainly represents the ceiling for a positive effect size – and in routine practice, effectiveness is likely much lower.

Related aside: when we start routinely screening strokes with MRI in that happy future time, do we exclude DWI+/FLAIR+ from thrombolysis, even if within the “treatment window”? I would think so.

“Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial”
https://jamanetwork.com/journals/jamaneurology/fullarticle/2729091

Emergencies in Medicine

Just a quick note to follow-up this splendid little conference in Park City, UT, where I featured in a debate regarding the utility of tPA for stroke. We had a generally respectful discussion about the state of stroke care and our vision for the future.

Unfortunately, it – as you might expect – looks a lot like a future where tPA flows like water.

The overall gist of the presentation by Chris Lewandowski, one of the original NINDS investigators: pool the trial data, and the benefit is clear. My gripes, well-chronicled on this site: benefit is not uniformly distributed, we should tailor its use, rather than expand it.

Interesting tidbits from the follow-up discussion:

No one is going to re-do NINDS in this country. They couldn’t even complete PRISMS because too many mild, non-disabling strokes were already being treated.
Treating vast numbers of stroke mimics is not troublesome to them – Lewandowski claims to have never heard of one ever having a bleed.
The expected benefit to mobile stroke units relates to “fresh” clot being more likely to lyse, as much as the brief time savings.
Studies like TIMELESS and other tissue-based thrombolytic studies will likely extend the treatment window, just like WAKE-UP.
No qualms about treating NIHSS scores of 1 causing only mild disability (say, unilateral leg weakness). They’ve seen that some NIHSS 1 deteriorate, and believe tPA will prevent it.
They are utterly comfortable with forever using NINDS as their default NNT/NNH consent – and no problem using the same numbers now matter what the NIHSS. Except, they just reduce their risk number for harm, as ICH is generally related to infarct size/NIHSS. This drives me mad.
They feel strongly tPA has been proven “cost-effective”, while I would note those analyses are based on assumptions and models not matching current practice and treatment population.
Treating cervical artery dissection with tPA is favored to them because they expect the clot that showers distally will benefit from lysis, though they agree there is no evidence to support their claims.
They agreed that, overall, the recommendations issued by the AHA overstate the strength of the evidence.

Would be fun to do again – even if it is effectively just shouting into the wind!

Who Recanalizes with Just tPA?

The original argument: tPA helps all strokes, we must give it to everyone as quickly as possible!
The updated argument: tPA doesn’t not help all strokes, so it should still be given!

Specifically, as applies to the cohort of patients with large vessel occlusions being considered for mechanical thrombectomy. This small, pooled registry sample looked at cases from four centers, evaluating the rate and predictive characteristics for recanalization prior to cerebral angiography. The stated purpose of their study was to develop a predictive score, with the reasonable goal of reducing unnecessary tPA exposures prior to thrombectomy.

The numbers, in their score derivation and validation cohorts:

ICA: 6.4%/1.0%
M1 proximal: 16.1%/13.7%
M1 distal: 30.3%/30.7%
M2: 33.7%/34.0%

But, an even more powerful a predictor was thrombus length, as measured by T2 MRI susceptibility vessel sign. Recanalization was seen at over 80% for clots <5mm, 30% for 6-10mm, and below 10% for clots longer than 10mm, with particular futility for >20mm.

Interesting data – and a nice look at how not all sites of occlusion and clots are created equal. Whether, and how, we ought to treat them differently remains uncertain until the results of a prospective trial.

“Post-Thrombolysis Recanalization in Stroke Referrals for Thrombectomy”
https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.118.022335

Tenecteplase vs. Alteplase For … Stroke Mimics?

Bless their little hearts.

It’s almost as though this is a submission fo the IgNobel Prize, rather than a serious scientific manuscript. “How well does a medicine work when the patient doesn’t have the disease?” is basically a joke, right?

Not in the magical world of stroke neurology, replete with its array of meretricious interventions.

This is a secondary analysis of NOR-TEST, a phase III trial comparing alteplase with tenecteplase. A few folks believe tenecteplase has superior fibrinolysis to alteplase, and therefore ought to be potentially favored in acute ischemic stroke. NOR-TEST, for what it’s worth, could not detect any statistically significant difference between the two.

What is notable in this trial, of course, is the 17% rate of stroke mimics. And, this is a Very Important publication comparing the safety of these two medications when given to patients inappropriately. And, of course, there is no difference. There were three cases of intracerebral hemorrhage and three cases of extracranial bleeding, none of whom – you know – died, but were clearly all unnecessary iatrogenic injury.

Some more interesting notes, at least, from their analysis of stroke mimics. The average NIHSS in this entire study was 4, with the IQR for mimics 2-6 and for acute ischemia 2-8. There’s no useful evidence to suggest thrombolysis is superior to placebo in this sort of mild stroke cohort, but, here we are. Absent this evidence, some neurologists make an argument based on the Get With the Guidelines-Stroke registry, observing many patients with mild stroke are ultimately unable to be discharged to home due to persistent disability. In the NOR-TEST cohort of mimics, however, only 79% were assessed to have mRS 0-1 at 3 months, while their treated stroke cohort achieved mRS 0-1 only 60% of the time. It would seem the base rate of mimic- or mild-stroke disability is effectively as observed in the GWTG-Stroke registry, regardless of treatment.

In sum, these authors have basically provided us with an unwitting glimpse into how acute stroke treatment has gone utterly off the rails in Norway. Now, I wonder if they’re related to the group trying to push tPA in less than 20 minutes ….

“Safety and predictors of stroke mimics in The Norwegian Tenecteplase Stroke Trial (NOR-TEST)”

https://www.ncbi.nlm.nih.gov/pubmed/30019629

Starting Treatment on First-Time Seizures

We see a fair bit of ostensibly “first-time” seizure in the Emergency Department. With some room for nuance and debate, general practice is typically still to defer initiation of anti-epileptic therapy.

This decision analysis in the neurology literature ultimately comes to the alternative conclusion – initiation of AEDs is reasonable even absent a clear or likely diagnosis of epilepsy. Based on their cases and parameters regarding seizure recurrence, the degradation of quality-of-life relating to seizure recurrence, and the features of modern AEDs, these authors find in favor of initiation of AEDs. Specifically, they find the previous threshold of ≥60% or greater chance of seizure recurrence after a first seizure is likely too high, and 30-40% may be more reasonable.

These conclusions are appropriate, considering the decision analysis model parameters – but, of course, by definition they also depend on the validity of these parameters. Then, whether this decision analysis can be applied clinically in the Emergency Department is another question, considering the challenges with regard to determine whether a seizure is truly unprovoked. Regardless, as AEDs evolve, have fewer adverse effects, and reach generic status, more liberal strategies of AED initiation in the Emergency Department may be in our future.

“Antiepileptic drug treatment after an unprovoked first seizure: A decision analysis”
http://n.neurology.org/content/early/2018/09/12/WNL.0000000000006319