Category: Stroke

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

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

To Lyse Before Endovascular Intervention … or Not

I’ve been of the general opinion that, no, thrombolytics are of low utility prior to endovascular intervention for stroke. The typical candidate for endovascular intervention has a clot in a large vessel. Thrombolytics are overwhelmingly ineffective at treating such lesions, hence, the entire foundational need for endovascular intervention. Then, absent indication creep, the patients for whom endovascular intervention is intended are those with salvageable tissue as resulting from excellent collateral circulation – i.e., the sort of patients for whom the “time is brain” mantra does not strictly apply. Therefore, thrombolytics prior to the definitive procedure are effectively low-value, and deplete the fibrinogen likely needed to reduce serious procedural adverse events.

But, this is just opinion – useful evidence is profoundly lacking.

This article, unfortunately, does not add much to the current body of evidence. These authors present a post-hoc analysis from the ASTER trial, which tested clot aspiration versus stent retrieval. As is typical for these types of trials, those who arrived within 4.5 hours of symptom onset were treated with thrombolytics prior to their procedure, while others were excluded as “outside the window”. There were 381 patients here, 250 of whom were eligible for thrombolytic therapy. These authors pull out all the stops with regard to data analysis, breaking down their outcomes by procedural attempts, reperfusion, complications, clinical outcomes, and hemorrhagic complications. Then, they further generate forest plots for adjusted outcomes depending on the arm of the trial – aspiration or stent retriever.

And, after all this, it’s still just a retrospective data dredge for meaningless signals replete with unmeasured confounders and selection bias. The patients who received thrombolysis initially are different than those who did not, full stop – and no multivariate regression can reliably produce precise estimates of their likely outcomes. I could have told you “we need a prospective trial design” to shed further light on this question, arriving at the same conclusion in six words, rather than in these seven pages.

“Mechanical Thrombectomy Outcomes With or Without Intravenous Thrombolysis Insight From the ASTER Randomized Trial”
https://www.ahajournals.org/doi/10.1161/STROKEAHA.118.021500

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

tPA in Under 20 Minutes is Recklessness

In my book, “safe” translates to a lack of attributable harm. Therefore, going as fast as possible while still claiming safety – should mean no excess harms resulting from the rush.

There’s no way to precisely tell whether or not this is the case here in Helsinki, where the stroke neurologists have cut their door-to-needle time for thrombolysis to under 20 minutes. The results as described here, however, are not promising, and the authors agree with my impression:

“Our findings support the safety of highly optimized door-to-needle times.”

Ha ha! Of course they don’t.

This is a retrospective review of 1,015 stroke code patients arriving over a two-year period between 2013 and 2015. This institution, incorporating elements of pre-hospital assessment into their initial evaluation, have had door-to-needle times below 20 minutes since 2011. How do they perform?

Of the 1,015, there were 150 (14.8%) patients with misdiagnosis on the initial assessment. Of these, 90 were ultimately diagnosed with a stroke mimic, 59 were eventually diagnosed with a stroke or TIA, and one small basal ganglia hemorrhage was missed. These initial misdiagnoses led, as you might imagine, to both unnecessary treatment and delays to the correct treatment. The most profound effects of these delays were in the context of stroke mimics, whose median delay until a correct diagnosis was 39 hours. Thirteen stroke mimics received thrombolysis, and diagnostic inertia from the initial misdiagnosis led 13 more to have median delays of up to 56 hours for the initiation of condition-specific treatment.

Now, there are limitations here that likely tilt these statistics in favor of the institution. There is no described standard follow-up evaluation to confirm cerebral ischemia, and likely some of those with TIA (146 patients) or who received tPA (331 patients) and improved could further be lumped in with the stroke mimics based on their clinical evaluation and whether they ever underwent MRI. Conversely, even though these authors are speeding headlong in order to give tPA, we can’t actually attribute all these misdiagnoses to their rushed evaluation. It is likely some of these cases would remain clinically challenging, even with a few extra minutes of careful consideration.

However, if they are trying to prove their implementation is safe, this comparison group is exactly what is necessary. They’ve shown their protocol is results in a substantial number of misdiagnosis and documented patient harms; the onus is on this team to prove their pursuit of a handful fewer minutes to tPA is not a contributing factor.  Finally, any possible advantage to shaving a handful of minutes off door-to0-needle times pales in comparison to these obvious misses.

“Diagnosing cerebral ischemia with door-to-thrombolysis times below 20 minutes”
http://n.neurology.org/content/early/2018/07/11/WNL.0000000000005954

Stopping the Alteplase Indication Creep

Ever since the narrow approval and strict inclusion criteria of the first trials for alteplase in stroke, our benevolent corporate overlords have been doing their utmost to expand its indications – all while continuing to unilaterally boost its price. This includes sponsoring “expert” convocations to whittle down contraindications, as well as sponsoring, and then cancelling, trials destined to futility.

This is another example of the latter.

This is the remnants of PRISMS, a trial testing the alteplase versus aspirin in a randomized, placebo-controlled trial of mild stroke. In this trial, “mild stroke” included a NIHSS of ≤5 and the absence of any disabling deficits. That is to say, rather, every patient entered in this trial met, in theory, the primary outcome of an mRS of 0-1 at entry. The trial expected to find an advantage to treatment of 9% and incidence of sICH of 2%, a NNT of 11, NNH of 50, and a requirement of 948 patients for the statistical power to validate such findings.

The trial, however, was stopped after 313 patients due to “slow enrollment”. Of these, 32 were lost to follow-up, leaving 281 available for 90-day assessment without imputation. The bulk of patients ranged in NIHSS 1 to 3, with sensory symptoms, facial palsy, and dysarthria the most frequently represented stroke symptoms. Of those with 90-day follow-up, 83.1% of the aspirin arm achieved mRS 0-1, compared with 77.5% of those randomized to alteplase. Conversely, 3.4% of these mild strokes were ultimately mRS 4-6 – a typical definition of “poor outcome” – in the aspirin arm, compared with 10% of those randomized to alteplase. The 5 patients with sICH following alteplase administration contributed to these poor outcomes, compared with none following administration of aspirin.

So, very clearly, there is no evidence here to support a presumption of benefit from alteplase administration, but quite clearly evidence of harm. The authors – with hardly any conflict-of-interest to speak of – go to great lengths to assure us:

“The findings from the current trial cannot be extrapolated to all patients with lower stroke severity based on an NIHSS score of 0 to 5.”

Please continue, they say, treating this population despite the virtual absence of evidence. Even more comically, they also conclude this ought not be the last word in this patient population:

“… the very early study termination precludes any definitive conclusions, and additional research may be warranted.”

Although these authors go to great lengths to assure us there was no tomfoolery at work in the sponsor’s decision to terminate the trial, it strains credibility to suggest Genentech would be so willing to abandon potential profit relating to an expanded indication. Such decisions to cut their losses would hardly be warranted if an expectation of potential return were in store.

At the very least, this clearly shows not only diminishing returns, but likely harms relating to the use of alteplase in minor stroke. Given the sparse RCT data in this realm – NINDS, for example, included only 58 cases with a NIHSS below 5, and nearly 3,000 patients were actively excluded from other RCTs – these data still ought to move the needle of equipoise with regard to treating a spectrum of low NIHSS, but potentially disabling, deficits.  It would be entirely defensible not to treat this population while awaiting robust trial evidence in support.

Also: 13% stroke mimics!

“Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits”

https://jamanetwork.com/journals/jama/fullarticle/2687354