Category: Stroke

On the Other Site …

I’ve taken the opportunity of reboot to try and make smaller, more digestible chunks to highlight what I’m reading – and to post more often.

So, check out:

It’s a Substack, but I’m not trying to milk anyone for money – don’t worry about that!

Mobile Stroke Unit Propaganda Writ Large

This is yet another one of those “Get With The Guidelines” stroke analyses, a retrospective dredge with massive imbalances between groups – followed by statistical adjustments capable of turning out whichever result suits an author list with a full, dense printed page of pharma and stroke technology conflicts of interest.

In that respect, the study is unremarkable. Patients with potential stroke who were transported by Mobile Stroke Units were more likely to be functionally independent at baseline and more likely to be transported to a comprehensive stroke center. Thus, patients transported by Mobile Stroke Unit were more likely to be ambulatory and functionally independent at hospital discharge. Everything between the intake and output is just diversions.

Where it becomes further disagreeable is the accompanying editorial, written by two individuals who run Mobile Stroke Unit programs, arguing federal reimbursement ought to cover their pet projects. After a brief brush with the limitations of these data, they assert:

“it convincingly demonstrates through a large, representative, multicenter study that in real-world clinical practice, MSUs are associated with improved short-term patient outcomes”
… quite the over-glamourization of a secondary analysis of quality improvement registry data.

“the magnitude of benefit conferred by MSUs is comparable to that of other widely accepted acute stroke interventions, such as IVT in a 3-hour to 4.5-hour window and specialized stroke units”
… after multiple statistical adjustments of a grossly imbalanced cohort.

“this study demonstrates that MSUs not only benefit patients with AIS eligible for IVT, but also patients with AIS who are ineligible for IVT and patients with other forms of stroke”
… so, even if the MSU – whose mission in life is to provide tip-of-the-spear IVT – doesn’t provide acute treatment, it still confers benefit due to its soothing glow?

“This may be explained by faster imaging and blood pressure control in patients with intracerebral hemorrhage.”
… admission blood pressure for patients with SAH in this cohort was identical between MSU and EMS.

“this study rebuts concerns that by reaching and treating patients with suspected stroke earlier in their clinical course, MSUs could lead to unnecessary IVT treatments and higher rates of hemorrhagic complications. In fact, this study demonstrated the opposite: MSU care was associated with lower rates of stroke mimics”
… yes, as is the typical approach to coding these data, early administration of IVT virtually dictates a patient be coded. Once a patient has received IVT, only strong evidence to the contrary permits consideration of alternative causes of transient neurologic dysfunction – a happy accident also precluding any sICH occurring in “stroke mimics”, because there are none. To wit: only 24 of 4,218 (0.56%) of all MSU responses were “stroke mimics”, whereas 2,114 of 104,466 (2.0%) of all EMS responses were stroke mimics. When all you have is a hammer, everything you see looks like a stroke.

“Furthermore, for the broader population presenting with suspected stroke regardless of final diagnosis, the data suggest the potential for a lower risk of death.”
Again, this is magical thinking. As above, observing benefits outside the scope of the capabilities of an MSU ought prompt reconsideration statistical adjustments rather than plaudits.

These data are simply unsuited to support this sort of unabashed enthusiasm for MSUs. Rather than this editorial supporting their argument to consider funding and reimbursement structures for these tools, their biases shine through to diminish it. Regrettably, as per usual, guidelines and policy will be made by those sponsored to make the most persuasive contortion of data, rather than the most accurate.

“Mobile Stroke Unit Management in Patients With Acute Ischemic Stroke Eligible for Intravenous Thrombolysis”
https://jamanetwork.com/journals/jamaneurology/fullarticle/2824954

“Mobile Stroke Units—Time for Legislation and Remuneration”
https://jamanetwork.com/journals/jamaneurology/fullarticle/2824955

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.