Category: Neurology

Publication Potpourri

Clearing the backlog of mildly interesting articles that will never get a full write-up – here’s a quick hit of the most interesting lucky 13!

“Lactated Ringer vs Normal Saline Solution During Sickle Cell Vaso-Occlusive Episodes”
A “target trial emulation” providing observational evidence supporting the superiority of lactated ringers solution over normal saline for the resuscitation of patients being admitted with sickle cell crises. However, only a small fraction of patients actually received LR, and those who did received smaller amounts overall. Frankly, it’s hard to separate these observations from the general concern euvolemic SCD patients are simply receiving far too much fluid during admission.
https://pubmed.ncbi.nlm.nih.gov/39250114/

“Empathy and clarity in GPT-4-Generated Emergency Department Discharge Letters”
The cold, unfeeling computer generates better feels than emergency clinicians. Bland treacle, no doubt, but generic bland treacle will beat the terse output of a distracted human any day. The question now is how to combine the two to create a better human, where suitable.
https://www.medrxiv.org/content/10.1101/2024.10.07.24315034v1

“Mitigating Hallucinations in Large Language Models: A Comparative Study of RAG- enhanced vs. Human-Generated Medical Templates”
Study number n-million demonstrating retrieval-augmented generation – that is to say, using a relatively sophisticated series of prompts to an LLM – improves output and reduces “hallucinations”. In this specific instance, the LLM was effectively mimicking the output of BMJ Best Practice templates.
https://www.medrxiv.org/content/10.1101/2024.09.27.24314506v1

“Towards Democratization of Subspeciality Medical Expertise”
This is one of the AIME demonstration projects, a Google Deepmind output in which an additional layer of “conversational” training has been superimposed upon the underlying model to improve response to consultation-style questions. In this example, the conversational training is tuned to match the response style of genetic cardiology specialists from Stanford University – and the LLM content and style was arguably rated identically to the human specialists.
https://arxiv.org/abs/2410.03741

“The Limits of Clinician Vigilance as an AI Safety Bulwark”
A nice little commentary effectively articulating the elephant in the room: humans are terrible at “vigilance”. The present state of AI/LLM deployment in clinical medicine is replete with omissions and inaccuracies, and it’s not reasonable to simply trust clinicians to catch the mistakes. That said, the five suggested strategies to address vigilance seem … precarious.
https://jamanetwork.com/journals/jama/fullarticle/2816582

“Reviewer Experience Detecting and Judging Human Versus Artificial Intelligence Content: The Stroke Journal Essay Contest”
Who wins an essay competition on controversial topics in stroke and neurology – humans or LLMs? And can reviewers accurately guess which essays are human- versus LLM-generated? The answer, rather distressingly, is that reviewers mostly couldn’t distinguish between author types, and LLM composition quality was arguably higher than human.
https://pubmed.ncbi.nlm.nih.gov/39224979/

“Invasive Treatment Strategy for Older Patients with Myocardial Infarction”
The amusingly named “SENIOR-RITA” trial in which elderly patients with NSTEMI were randomized to an invasive strategy versus a medical management strategy. While this may seem odd to those in the U.S., frailty and baseline life-expectancy are typical considerations for acute care in other countries. In these frail elderly, invasive strategies reduce downstream non-fatal MI, but had no effect on cardiovascular death or the overall composite outcome.
https://pubmed.ncbi.nlm.nih.gov/39225274/

“Thrombolysis After Dabigatran Reversal for Acute Ischemic Stroke: A National Registry-Based Study and Meta-Analysis”
Just another bit from our neurology colleagues patting themselves on the back for doing backflips in order to give everyone thrombolysis. Registry data paired with a garbage-in-garbage-out systematic review and meta-analysis just amplifies the biases prevalent in the underlying practice culture.
https://pubmed.ncbi.nlm.nih.gov/39255429/

“Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke: The ORIGINAL Randomized Clinical Trial”
This trial makes a claim to be ORIGINAL, but at this point – there’s really no general question remaining whether tenecteplase is a valid alternative to alteplase. It is reasonable to test specific doses in various populations with a goal of minimizing harms, of course.
https://pubmed.ncbi.nlm.nih.gov/39264623/

“Technology-Supported Self-Triage Decision Making: A Mixed-Methods Study”
Can laypersons improve their self-triage decision-making with use of technology? This little preprint tests the Ada Health “symptom checker” app against interaction with a ChatGPT LLM and favors use of the symptom checker. Not hardly rigorous enough to discard the chatbot as a possible tool, but certainly the LLM needs more prompt engineering and/or domain-specific training than just “out of the box”.
https://www.medrxiv.org/content/10.1101/2024.09.12.24313558v1

“Class I Recalls of Cardiovascular Devices Between 2013 and 2022 : A Cross-Sectional Analysis”
A brief report looking at recalled cardiovascular devices is insufficient to make any broad conclusions, but certainly demonstrates the regulatory bar for approval is inadequate. Most did not require pre-market clinical testing, and those that did used surrogate or composite endpoints to support approval.
https://pubmed.ncbi.nlm.nih.gov/39284187/

“Effectiveness of Direct Admission Compared to Admission Through the Emergency Department: A Stepped-Wedge Cluster-Randomized Trial”
A bit of an odd question whether a patient with known requirement for admission needs to stop through the emergency department, or whether the patient can go straight to the ward. Unless a patient requires immediate resuscitation with the resources of an ED, it is very clearly appropriate for a patient to be directly admitted. That said, doing so requires new processes and practices – and this trial demonstrates such processes are feasible and safe (and almost certainly cheaper to avoid ED billing!)
https://pubmed.ncbi.nlm.nih.gov/39301600/

“Restrictive vs Liberal Transfusion Strategy in Patients With Acute Brain Injury: The TRAIN Randomized Clinical Trial”
The optimal cut-off is not known, but in this trial, the threshold for transfusion was 9g/dL – and patients randomized to the liberal transfusion strategy did better. An injured brain does not like hypotension and it does not like anemia.
https://pubmed.ncbi.nlm.nih.gov/39382241/

Don’t Use Lytics in Mild Stroke, Part 3

Well, PRISMS demonstrated unfavorable results.

MARISS tried to ascertain predictors of poor outcome in mild stroke, and intravenous thrombolysis was not associated with an effect on the primary outcome.

Now, again, we examine thrombolysis in “mild” stroke, in this case, NIHSS ≤3 – and fail.

Like MARISS, this is a retrospective dredge of patients selected by the treating clinicians to receive either intravenous thrombolysis or, in this case, dual-antiplatelet therapy with clopidogrel and aspirin. The population included for analysis is the Austrian Stroke Unit Registry from 2018 until 2019, an original cohort of 53,899 patients. Of these, 29,252 were NIHSS ≤3, but exclusions meant nearly 25,000 were left out – primarily those whose strokes were the result of atrial fibrillation, or whose treating clinicians chose platelet monotherapy instead of dual antiplatelet therapy.

The remaining ~4,000 were analyzed both in their unadjusted cohorts, as well as propensity scored cohorts comprised of roughly 20% of the original. In the unadjusted cohorts, efficacy and safety outcomes were universally worse in those selected for thrombolysis – but, of course, were generally more severe stroke syndromes. After propensity score matching, these differences generally disappeared – except a preponderance of sICH in the thrombolysis cohort.

The authors here conclude there’s no evidence of superiority for thrombolysis in mild stroke, and their results fit broadly with those from other cohorts. It’s observational and unreliable, but it ought to be a very reasonable stance to withhold thrombolysis for mild strokes pending trials conclusively demonstrating which, if any, mild strokes do improve with thrombolysis.

“IV Thrombolysis vs Early Dual Antiplatelet Therapy in Patients With Mild Noncardioembolic Ischemic Stroke“

It’s Not OK To Let 25% of tPA Cases Be Stroke Mimics

With all the various competing interests for time, it’s rare to find an article of sufficient note to warrant its own blog post. A notable publication might get a short tweet thread. Collections of other literature find their way into ACEPNow articles or the odd Annals of Emergency Medicine Journal Club. But, every once in awhile, there’s something … else.

This article pertains to the practice of telestroke administration of thrombolysis for acute ischemic stroke. In major hospital centers, there may be in-house neurology hospitalists or stroke and vascular specialists, and the expertise for management of stroke is readily at the bedside. In many community, regional, and rural hospitals, these resources are unavailable – except by telestroke evaluation. These common arrangements allow access to neurology expertise, followed potentially by interhospital transfer.

In this article, the authors review a series of 270 patients receiving intravenous thrombolysis following evaluation via telestroke. Most patients underwent MRI with DWI following transfer to the hub stroke center, while a handful did not – probably those with serious complications arising from stroke, and those with obvious stroke mimic etiologies. Patients otherwise were categorized as a stroke if a lesion was found on MRI with DWI, but could be deemed a TIA or a stroke mimic if no lesion was seen.

Not-so astonishingly, they report 23.7% of their series are stroke mimics. Another ~5% are TIA, another diagnosis for which there is no indication for thrombolysis. While this much collateral damage might horrify some, this sort of blanket use of thrombolytics is routine in the United States, if not encouraged. The proof of such encouragement is evidence in these authors’ Discussion section, with this interpretation of recent guidelines:

In fact, the most recent AHA guidelines in 2019 recognise this and specifically recommend thrombolysis to SM given the low rate of sICH and state that starting IVtPA is preferred over delaying treatment to pursue additional diagnostic studies.

Naturally, the authors go on to propose a threshold of reasonable practice for which their performance fits comfortably within:

In our academic tertiary referral telestroke programme, 23.7% of patients administered thrombolysis had a final diagnosis of SM. We suggest that a reasonable SM thrombolysis rate for telestroke programme should be one in four, similar to the accepted negative appendectomy rate, as that the risk of overtreatment should be accepted over the risk of undertreatment.

This is, of course, nonsensical. Leaving aside their entirely specious comparison to an acceptable negative appendectomy rate, let us ruminate seriously on the response to a poorly performing process being to normalize the poor performance. The authors rightfully cite Jeff Saver’s general musings that, given the advancing state of the specialty, the acceptable stroke mimic rate ought to be around 3%. They then justify their absurdly higher total by noting a small portion – about 7-10% – of eligible strokes are missed for treatment, and it is rather the better practice to simply treat any potential stroke in order not to miss a single one.

Again, this perspective hinges primarily on the concept treating stroke mimics with thrombolysis is “harmless“, owing to a rate of sICH of merely ~0.5-1%. While this is still an unacceptable perspective towards inducing sICH in an otherwise unsuspecting patient, the other harms for thrombolysis in stroke mimics include:

  • Diagnostic inertia, in which evaluation and treatment for the true cause of neurologic dysfunction is delayed.
  • Permanent misdiagnosis, in which a patient treated with thrombolysis, improves, and is labelled an “aborted stroke”. They now carry the diagnosis of prior stroke, making it potentially more difficult to obtain health insurance, not to mention likely unnecessarily being prescribed medications for secondary prevention of stroke.
  • Financial harms from being treated with thrombolysis, which typically requires extended monitoring in a critical care or stroke unit, far exceeding the costs associated with a non-stroke hospitalization.

In short, this is a grossly unacceptable perspective endorsing, frankly, reckless use of thrombolysis. These authors should reconsider the primarily literature they are citing as justification and the framing of their argument, and retract their call to normalize these poorly performing clinical systems.

“Thrombolysis of stroke mimics via telestroke”
https://svn.bmj.com/content/7/3/267

It’s a Stroke – of the Eye?

As we are well aware, a brain globally deprived of oxygen, for even the briefest moments, suffers irreversible damage. Cerebrovascular events, those depriving a smaller distribution of the brain of oxygen, do so likewise – excepting the potential for recovery provided by the so-called “ischemic penumbra”. There is great heterogeneity between stroke syndromes and potential for recovery, but perfusion- and tissue-based treatments quite clearly demonstrate some protective effect of collateral circulation.

Does the eye work like that? That is the working theory – or, at least, working wishes and hopes of the neurology and neuro-ophthalmology community.

There is typically only one blood vessel supplying the inner retina – the central retinal artery. If this vessel becomes occluded, widespread ischemia is inevitable. The outer retina is supplied by the choriocapilaris, derived from separate branches of the ophthalmic artery. A further, non-trivial percentage of individuals have a cilioretinal artery, supplying a part of the macula. These other vessels may provide some additional perfusion to parts of the eye, with intact survival approaching 90 minutes in animal studies. Widespread, irreversible damage seems complete by four hours.

So, is there a window of opportunity for early thrombolysis? The American Heart Association thinks so: “The current literature suggests that treatment with intravenous tissue plasminogen activator may be effective.”

This “current literature” of which they speak is primarily a citation from last year’s Stroke, a single-center cohort study and updated patient-level meta-analysis. In the “cohort” portion, this site treated 16 patients with CRAO with alteplase within 4.5 hours, and compared them with 87 others who received “Standard of Care”. Patients in this treatment cohort did better than those who were not – hardly surprising, considering those treated had fewer signs of damage to the retina on initial fundoscopic examination.

The “patient-level meta-analysis” includes 238 patients from studies dating back to the 1980s. The 9 patients for whom treatment was provided within 90 minutes displayed better outcomes than those treated in later time windows, as well as those patients whose outcomes describe the “natural history” of the disease. The guideline authors’ interpretation of these data: “An updated meta-analysis including these modern cohorts again demonstrated a strong effect with treatment within 4.5 hours.”

Little heed is paid to the 5 patients within their meta-analysis reported as having intracranial hemorrhage, 1 with angioedema, and 1 with extracranial hemorrhage.

CRAO is devastating, and there is no known effective treatment. Thrombolysis may be beneficial, but treatment is associated with well-established harms. Along with all the stroke mimics and low-NIHSS patients currently being treated, it’s not surprising these authors contort themselves into recommendations overstating the strength of the evidence. Clinical trials are underway – wait and see.

“Management of Central Retinal Artery Occlusion”
https://www.ahajournals.org/doi/pdf/10.1161/STR.0000000000000366

“Intravenous Fibrinolysis for Central Retinal Artery Occlusion”
https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.028743

Minor Stroke is Our Favorite Stroke

While most facilities are using non-contrast CT, CT angiograms, and/or CT perfusion as part of their initial triage of possible stroke, there are a few using rapid MRI-based protocols. MRI is vastly superior to CT for its specificity for stroke, quite useful in reducing early diagnostic closure and unnecessary treatment with thrombolytics.

One of these MRI-based stroke systems has published a brief, retrospective look at their tPA cohort – focusing, in this report, on the particularly controversial “minor stroke”. Specifically, they teased out patients with presenting NIHSS 0-6, tried to classify them as “clearly disabling”, “potential disabling”, and “non-disabling”. Then, they looked at 90-day outcomes from these groups, trying to discern any useful conclusions regarding the efficacy and safety of tPA in these patients.

Over the 2015-17 study period, there were 1,440 patients evaluated for potential stroke treatment. Of these, 792 fell into their “minor stroke” definition – only 255 of which received a provisional diagnosis of acute ischemic stroke. The remainder were diagnosed as stroke mimics, transient ischemic attacks, or intracranial hemorrhage. Of these 255, about 80% were able to be evaluated with MRI as their primary mode of evaluation, and about 3/5ths were treated with tPA. Ultimately, they end up with 119 patients in their primary comparison, looking at features and outcomes of 30 patients with “clearly disabling” deficits and 89 without.

How effective is tPA in this cohort? Who knows! This study doesn’t answer that question in the slightest. There is no untreated population with 90-day outcomes gathered for comparison. The authors mostly use this study to tout MRI-based screening technology, along with descriptive statistics of frequent perfusion abnormalities present in their untreated cohort. The general gist of their discussion is akin to the oculostenotic reflex in cardiac catheterization – if a stenosis is seen, it will be treated, regardless of known benefit. For using MRI to screen for stroke, they tend to wax optimistically the identification of these perfusion abnormalities in non-disabling strokes might better encourage acute treatment.

This ought to be considered nonsense, as tPA treatment of non-disabling strokes remains bereft of evidence of value. And, just to describe the scope of the problem – of the 305 patients treated with IV tPA, 75 did not have “clearly disabling” deficits. A full quarter of the tPA treatment population based on wishes and hopes! There was one upside to screening with MRI, at least: 454 of those 792 with “minor stroke” received a diagnosis of stroke mimic. I shudder to think of the unnecessary carnage at hospitals without the capacity to exclude stroke mimics with such ease.

Non-disabling stroke should never be treated with thrombolysis in clinical practice, not after PRISMS, nor after looking at the NIHSS 0-5 group in IST-3. The new European Stroke Organization guidelines recommend against thrombolysis. Just stop!

“Prevalence of Imaging Targets in Patients with Minor Stroke Select for IV tPA Treatment Using MRI”
https://n.neurology.org/content/96/9/e1301

Does My Patient Have Prion Disease?

No, they don’t.

But, they might.

Between the years of 2003 and 2015, the National Prion Disease Pathology Surveillance Center captured 5,212 deaths due to prion disease in the United States. This number is clearly greater than zero, but the average annual incidence is around 1.2 cases per million population.

Not the most profound impact on your practice in the Emergency Department, but just one more element of curiosity to file away as trivia.

“Prion disease incidence in the United States, 2003-2015.”
https://www.ncbi.nlm.nih.gov/pubmed/31757870

Wednesday is for Stroke

It had been a few weeks since I perused the recently published articles in Stroke – and there were so many: 1) not quite enough for their own angry post, but 2) worth noting, so, here we are:

Emergency Department Door-to-Puncture Time Since 2014: Observations From the BEST-MSU Study
https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.025106

This one comes with the nonsensical medical lay press article entitled “Mobile stroke units get patients to hospital faster than ambulances“. No, mobile stroke units do not warp the fabric of space-time. They are bound by the same laws of physics and traffic as the rest of us.

What this study actually shows is the difference between door-to-groin-puncture time in patients arriving via the MSU versus regular EMS. The result: it saved about 10 to 15 minutes to have the pre-hospital neurologist evaluation in-person or via telemedicine. Considering the observational evidence regarding the fragility of collateral circulation within the first few hours of large-vessel stroke, this is obviously favorable – but the actual clinical effect of a few minutes can only be minimal at best.

Functional Outcome Following Stroke Thrombectomy in Clinical Practice
https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.026005

A huge German registry of stroke thrombectomy provides some insights into the “real world” outcomes. These authors spend a little time comparing their outcomes to those observed in the meta-analysis of the trials, but this comparison is obviously challenging due to the entry and perfusion imaging selection criteria of the trials. The big takeaway, however: real world mortality was 28.6% compared with the trial mortality of 15.3%. These findings should prompt further investigation into strategies to reduce risk for death.

Blood Pressure and Outcome After Mechanical Thrombectomy With Successful Revascularization
https://www.ncbi.nlm.nih.gov/pubmed/31318633

This is just an observational series – with a lot of missing data – looking for any association between blood pressure and outcomes following mechanical thrombectomy. The general trend: higher is worse. Something like the normotensive range is associated with the best outcomes and fewest complications. However, such observations cannot be assumed to suggest improving blood pressure control will reduce the frequency of downstream complications. More likely, the blood pressure is rising as a result of the complications – intracranial hemorrhage and cerebral edema – and it is only hypothesis-generating at this stage to say strict control will improve outcomes.

Magnitude of Benefit of Combined Endovascular Thrombectomy and Intravenous Fibrinolysis in Large Vessel Occlusion Ischemic Stroke
https://www.ncbi.nlm.nih.gov/pubmed/31311465

Very few analyses truly spur a full rolling-of-the-eyes, but this is one of them: taking matched cohorts from NINDS and SWIFT-PRIME to conjure up some sort of quantification of the benefit of endovascular therapy in large-vessel occlusion. It isn’t so much the basic principle of the analysis with which I quibble – but the fact they are only able to roll with 80 patients each from their NINDS tPA, NINDS placebo, and SWIFT-PRIME cohorts. Of course, if you recall, large-vessel occlusions were not specifically identified in NINDS, so these authors are imputing their presence based on NIHSS and deficit patterns, which is hardly a reliable means of identification. Then, with only 80 patients in each cohort, the imprecision of each comparison is so great it’s virtually pointless to rely on these findings in the patient-facing shared-decision-making information graphics they created. Without reading too much between the lines regarding why this nonsense was ultimately published, it should be noted the lead author is Jeff Saver’s son.

Déjà vu: The New Cutting Edge Treatment of Migraines

It’s rimegepant again!

As featured in such posts as … yesterday’s … it’s the same calcitonin gene-related peptide receptor antagonist, but in an entirely separate large, multi-center, double-blind, randomized controlled trial.

And, the results are essentially the same. In this trial, 1,466 participants were randomly assigned to rimegepant or placebo for treatment of a single migraine headache of moderate-to-severe intensity. At two hours post-dose, response rates were 21% with rimegepant and 11% with placebo. Adverse events were similarly rare and generally mild.

Yet again, this tells us rimegepant is better than nothing – and in no way informs us regarding efficacy in their hypothetical patient population: those without response to either over-the-counter therapy or non-responsive/intolerant of the triptans.

Yet again, this study is completely funded by Biohaven Pharmaceuticals, with all the authors employed by and owning stock.

So, the same critiques as yesterday apply – and it’s transparently just another page out of the typical pharmaceutical corporation playbook: do enough to obtain approval, and then let the marketing operation kick into high gear.

“Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31606-X/fulltext

Addendum: The protocol does have a non-redacted tidbit of a comparison between rimegepant and sumitriptan, based off some unpublished data from a Phase 2b trial. To be taken with a grain of salt, to be sure, but obviously this would not have looked good for rimegepant if any sort of active comparator would have been used:

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