Category: Stroke

Winter Recap

Spring is here down in this nuclear-free hemisphere. This blog is still effectively in stasis – but the productivity continues elsewhere!

Don’t forget the Annals of Emergency Medicine Podcast, a lighthearted feel-good romantic comedy with Rory Spiegel, available for free on your choice of streaming platforms:

Bimonthly #FOAMed in ACEPNow:

And, lastly, everyone’s favorite part of their residency curriculum, the Annals of Emergency Medicine Journal Club – in which we update folks from the wider world of medical literature in concise summaries for emergency medicine practice:

Enjoy!

Why Isn’t tPA in Minor Stroke Questioned?

A couple months back, this little report – MaRISS – was published with minimal fanfare in Stroke. Considering the effort necessary to fund and conduct a prospective study, it’s rather remarkable these data are so uninformative.

The stated purpose of this study:

“The objective of this study is to describe multidimensional outcomes, identify predictors of worse outcomes, and explore the effect of thrombolysis in this population.”

Reading between the lines – and considering the study and virtually every author here are sponsored by Genentech – the hoped-for outcome was likely some observational support for the pervasive practice of treating mild stroke with alteplase. Considering all the bias of their study design, it’s actually rather surprising they were unable to do so.

To be included in MaRISS, patients with mild stroke were approached after initial treatment, within 24 hours of hospital admission. However, it is grossly obvious the vast majority of patients meeting eligibility criteria were not even approached. Their “CONSORT diagram” doesn’t actually describe their study population prior to the “consented” step of the process – meaning it only describes those patients dropping out or excluded subsequent to consent. How many patients with mild stroke were admitted to participating hospitals during the study period? How many patients were approached, but declined participation? This information is conspicuously and irresponsibly absent.

The resulting convenience sample, then, ultimately reflects the selection biases of those enrolling. For example, out of 1,765 patients included, only 3 (0.3%) developed symptomatic intracranial hemorrhage. This clearly indicates these data are flawed, as the PRISMS trial demonstrated a 3.3% rate of sICH, and even the Get With the Guidelines-Stroke registry of minor stroke shows a 1.8% rate of sICH. The authors provide the understated: “it is possible that individuals with early complication from thrombolytic treatment were not enrolled.”

Sometimes, possibilities are near certainties – and this is one of those cases.

Regardless, the authors then attempt to discern a beneficial effect of alteplase by comparing their treated (57%) and untreated (43%) final study population. Again, the bias of these authors is quite clear because they create eight different adjustment models and use mRS, Barthel Index, European Quality of Life 5 Dimensions, a Visual Analogue Scale version of stroke assessment, and the Stroke Impact Scale to create an 8 x 5 grid of tests for alteplase to display its superiority. In only one of these boxes was their model able to shake out a benefit for alteplase – and, of course, this chance finding gets escalated into the abstract with “a suggestion of efficacy was noted in the NIHSS 3–5 subgroup.” Nor was any effect on outcomes from time-to-treatment with alteplase identified.

So, an observational trial unable to obtain a representative sample nor describe a hoped-for treatment effect. What little remains is a page and a half of mostly previously-described associations of clinical features with poor functional outcomes, fractionally moving the science forward. If anything, these data ought to enhance calls for better prospective clinical trials versus placebo in minor stroke – if anyone weren’t already entrenched in their clinical opinions.

“Predictors of Outcomes in Patients With Mild Ischemic Stroke Symptoms”

https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.032809

All Glory to the MSU

It has apparently become time for the mobile stroke unit to go from niche to prime-time. Previously consigned to the pages of Stroke and similar journals, the latest and most comprehensive trial now graces the pages of the New England Journal of Medicine.

A flagship study for a flagship journal. Not to mention, a positive study – almost too good to be true.

Which, of course, means it probably isn’t.

In brief, the BEST-MSU trial presented is a series of nested protocols and substudies under the umbrella of purpose to test and refine the deployment of a mobile stroke unit. Amongst its many substudies are those testing time-to-tPA administration, early administration of reversal agents for intracerebral hemorrhage, and whether an on-board neurologist can be replaced by a telemedicine neurologist. The trial design is one of those “one week on, one week off” non-randomized designs – not truly randomized, but generally hoping these temporal controls generate basically similar patient populations. The primary outcome is “utility weighted modified Rankin Scale score” at 90 days, a probably-unnecessary rejiggering of what amounts to chasing a mRS 0-1.

The clear and obvious winner: mobile stroke units, the manufacturer of which two authors are consultants. In fact, MSUs were profoundly better – 55% of modified intention-to-treat patients ultimately achieved mRS 0-1 during MSU deployment weeks, compared with only 44% of those treated during traditional EMS response weeks. This treatment effect was basically driven by an 11% absolute excess of patients achieving mRS of 0.

The dramatic enhancement of treatment provided by MSU? 97.5% of those in the MSU cohort received tPA, compared with a mere 80% in the EMS cohort – and those receiving tPA did so within 60 minutes of symptom onset for 30% of those in the MSU cohort, compared with 2.6% of those with EMS. Proponents of MSUs would point to this dramatic improvement in outcomes to be associated with such “hyperacute” stroke treatment.

And, effectively, that is the principle upon which interpretation of this trial hinges. Nearly 17% of patients in the MSU cohort analysis received a final diagnosis of “stroke reversed by tPA”, as compared to 9% in the EMS cohort. There were a few more patients in the MSU cohort whose pre-existing mRS scores were 0, as well as a small excess of NIHSS 0-5, but it’s fairly clear most of the effect size on the primary outcome is driven by those final diagnoses of “stroke reversed by tPA”. This concept of “stroke reversed by tPA” is not specifically defined anywhere in the protocol or paper, somewhat limiting appraisal, unfortunately.

The traditional definition used by neurologists for “stroke reversed by tPA”, also sometimes known as “aborted stroke”, is usually equivalent to “neuroimaging negative cerebral ischemia”. NNCI occurs when patients have resolution of clinical symptoms of stroke, yet follow-up MRI shows no diffusion-weighted imaging lesions. The tPA, therefore, has saved all the brain and there is no indication there was ever any injury. However, this concept is controversial, and both emergency physicians and neurologists believe this to be relatively rare – and that these NNCI are in fact stroke mimics whose presence in study cohorts systematically bias the outcomes.

Another clue regarding those “stroke reversed by tPA” patients comes from the BEST-MSU substudy evaluating the feasibility of teleneurology versus on-board vascular neurologist. When the vascular neurologist was on-board, only 4% were “stroke reversed by tPA”, along with 10% stroke mimics. With the teleneurologist, 26% became “stroke reversed by tPA”, along with 12% stroke mimics. The sample sizes in this substudy were small, but it does not take much imagination to hypothesize there is a diagnostic accuracy component driving the “stroke reversed by tPA” final diagnoses.

There are also various issues with their CONSORT diagram. There were 10,443 stroke alerts, with 8,928 excluded as non-stroke, stroke with exclusions, or stroke mimics. Then, even though the time periods for enrollment were equal, the MSU cohort accumulated 886 enrollments versus 629 in the EMS cohort. This excess in enrollment accumulation in the MSU group is curious, and raises suspicions regarding the presence of a systematic bias towards study enrollment and treatment during MSU deployment weeks. The study protocol then trims down these enrollment cohorts into the modified-intention-to-treat population with a retrospective adjudication of tPA eligibility, further reducing the size of each cohort by approximately 30% – many of whom actually did receive tPA. This unbalanced, retrospectively tweaked cohort represents the mITT population for their primary analysis.

So, the final perspective on the utility of these multi-million dollar technological marvels comes down to, after minor whinging about their study population, the values in Table 5 of their Supplementary Appendix: did early tPA “reverse” strokes – or did their enthusiasm for MSU bias their cohort towards early treatment of stroke mimics?

“Prospective, Multicenter, Controlled Trial of Mobile Stroke Units”
https://www.nejm.org/doi/full/10.1056/NEJMoa2103879

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

Settling the Thrombolysis Before Thrombectomy Question

… taking a quick break from combating misinformation in our age of public health emergency to note this important non-COVID-19 article from the New England Journal of Medicine. Today’s question: is alteplase necessary prior to endovascular thrombectomy in acute ischemic stroke?

“It depends”.

This isn’t the first study to hit the light of day, but the largest. Previously, the “Randomized Study of Endovascular Therapy with Versus Without Intravenous Tissue Plasminogen Activator in Acute Stroke with ICA and M1 Occlusion (SKIP)” was presented at the International Stroke Conference earlier this year. Their study enrolled 204 patients and found no clinically important differences, particularly with respect to their primary outcome of mRS 0-2. Symptomatic intracranial hemorrhage was increased by a couple percent in those with bridging therapy, and there was a small excess of deaths – but, of course, none of these were “statistically significant”.

This study is three times the size, with 656 enrolled. Specifically, these are patients with large-vessel, anterior circulation occlusions for whom treatment can be initiated within 4.5 hours – the role for which alteplase is currently enshrined in the guidelines. And, these results are remarkably consistent with the prior observations. The mRS scores were, again, virtually identical. There was, again, an 2% absolute increase in sICH favoring the direct to endovascular therapy group, likely contributing to an observed ~1% excess deaths in the alteplase cohort.

The only element in “favor” of alteplase bridging is the surrogate outcome of successful reperfusion. There was a 4.6% excess of successful reperfusion before thrombectomy in the alteplase cohort, an advantage maintained to final angiographic recanalization at 24-72 hours. However, this small difference simply has minimal reliable effect on clinical outcomes – reperfusion is not synonymous with tissue salvage.

The net result of these observations ought to be the exclusion of thrombolytic therapy prior to endovascular intervention for those patients with immediate catheterization lab availability. Many patients, however, have prolonged transport times prior to endovascular intervention, and this study does not address this situation. However, prior studies likely demonstrate tenecteplase is more effective at obtaining early reperfusion in patients with large vessel occlusion, and probably should be the thrombolytic of choice in a “drip and ship” situation – if not all situations.

At this point, at least, the onus ought to rather be on proving clinical advantage to alteplase/tenecteplase prior to endovascular intevention. Given the consistent costs and harms of thrombolytic therapy, it is time to prove its value, rather than the converse.

“Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke”
https://www.nejm.org/doi/full/10.1056/NEJMoa2001123

2019 Early Management of Acute Ischemic Stroke

Well, it’s 2019 – for another couple months – so there’s still time to update your Early Management of Acute Ischemic Stroke.

For what would otherwise sound to be a potentially underwhelming interval update, there is, in fact, a ton to unpack in here. Institutional stroke committees and regional EMS systems thrive on constant change, after all. Most of the changes are “clarity”, but there are many new recommendations, some of which are bland – promoting the use of EMS for stroke symptoms, for example – whereas others are even potentially controversial.

Some of the meat:

  • Expert opinion-based recommmendations to bypass local hospitals in preference of thrombectomy-capable facilities for patients ineligible for IV thrombolysis, but with symptoms of large vessel occlusions.
  • Several new recommendations promoting telestroke as a reasonable means of patient evaluation, even if it’s just telephone consultation.
  • A handful of new recommendations incorporating the use of MRI for stroke assessment, based on WAKE-UP, including the use of IV thrombolysis beyond 4.5 hours.
  • Two new recommendations regarding multimodal imaging in acute ischemic stroke. The first, non-controversial recommendation includes the use of CT perfusion or MRI-DWI for assessment of patients between 6 and 24 hours from symptom onset. However, when symptom onset is less than 6 hours, the new recommendation is to perform endovascular intervention based just on vessel status and ASPECTS. Throw out the high-value care guided by REVASCAT, SWIFT PRIME, EXTEND-IA, and ESCAPE and just treat based on the smaller effect sizes seen in THRACE and MR-CLEAN!
  • Surprisingly, explicit recommendation to withhold thrombolysis of mild non-disabling stroke based on PRISMS.
  • Thrombolysis with tenecteplase makes its first appearance as a reasonable alternative to alteplase.
  • A new recommendation to cover initiation of short-term dual antiplatelet therapy for minor stroke not treated with alteplase.
  • An entire massive new section with recommendations regarding in-hospital imaging modalities to help regarding secondary prevention of ischemic stroke.

There’s something in here for just about everyone!

“Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke.”
https://www.ncbi.nlm.nih.gov/pubmed/31662117

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.

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.