Stroke – Page 3 – Emergency Medicine Literature of Note

If It Bleeds, It Can Get TXA?

When trauma bleeds: TXA! When women bleed: TXA! When the nose bleeds: TXA! When your freckles need lightening: TXA!

But, what about inside the brain?

This is TICH-2, an international, randomized, placebo-controlled trial testing tranexamic acid versus placebo for patients with primary intracerebral hemorrhage. The intervention arm received 1g of IV TXA as a bolus, followed by 1g over the subsequent 8 hours. The primary outcome was functional status at day 90 measured – inappropriately so, of course – as shift on the modified Rankin Scale. We’ve critiqued the ordinal shift several times as, effectively, statistically magnifying unimportant differences as a crutch for trials struggling to find a difference using a traditional, dichotomous endpoint.

However, regardless, their efforts are for naught: their primary endpoint still failed to reach statistical significance. Across five years and 2,325 randomized participants, nearly all patient-oriented outcomes showed no difference: 29% of TXA patients were mRS ≥2 at 90 days, compared with 29% of placebo. The numbers of deaths by day 90 were virtually identical, as were measures of quality of life, functional status, and days at home. Adjusted analyses and various subgroups generated odds ratios whose confidence intervals almost broke free of unity, but not quite.

The major quirk – over two-thirds of the trial was randomized greater than 3 hours from onset. The trauma literature focuses on early anti-fibrinolytic treatment, and it is reasonable to suggest the delay in treatment was too great to demonstrate a benefit. Then, even though no patient-oriented benefit was observed, hematoma expansion was attenuated in the TXA cohort. This is not the first time an ICH trial has seen benefits with regard to hematoma expansion absent patient-oriented outcome improvements, but it still seems a valid surrogate for, at least, a small effect size for which this trial may (or not) be underpowered to detect.

My takeaway is this trial hasn’t done much to move the needle with regard to evaluating TXA in ICH. It does show, at least, as administered in this trial, it is unlikely to have substantial benefit. However, TXA is inexpensive and seems to demonstrate a reasonable margin of safety. It is still reasonable to consider its use in as timely a fashion as possible, with the expectation the true NNT may be ~50 to 200, while awaiting further data from other trials currently underway.

“Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31033-X/fulltext

Wake Up and Smell the tPA

What happens when you wake up and you’re paralyzed from a stroke? Well, usually nothing. “Unknown time of onset” takes you – for better or worse – out of the game for alteplase, but not necessarily for endovascular therapy should a large-vessel occlusion be identified. Those large vessel occlusions, in the setting of a favorable CT perfusion profile, seem to benefit from endovascular therapy.

But, getting back to the “wake up stroke” – these have had our neurologists gnashing their teeth for some time. They have hypothesized many of these strokes have occurred just before waking and might otherwise be eligible for treatment. Absent reliable presenting information regarding the time of onset, these authors look to MRI – using presence of DWI lesion without corresponding FLAIR signal as a surrogate for tissue viability/stroke recency. Exclusion criteria in addition to the usual alteplase culprits were extremes of age, premorbid functional disability, NIHSS >25, thrombectomy candidates, and those with infarct volumes greater than 1/3rd the MCA territory. The primary outcome was 0 or 1 on the mRS at 90 days, like most trials.

These authors in this multicenter, placebo-controlled planned to enroll 800 patients, but ran out of money after five years and 503 patients. To get to these 503, the authors needed to screen 1362 potential strokes. These 859 exclusions were for various reasons, but over half were because the FLAIR matched the DWI lesion – indicated a completed infarct. Another 137 had negative DWI – i.e., not stroke – and various others had hemorrhage, failed to meet criteria for infarct size, or a scattering of other exclusions. Even despite these exclusions, another 79 snuck through as protocol violations, including 48 who should have been excluded based on imaging criteria.

Now, the meat: About 95% of those included were of the “wake up” variety, nearly all from overnight sleep. Baseline clinical features were generally well-matched. Median NIHSS was 6 in each group, although median lesion volume on DWI was 2.0 mL in the alteplase cohort as compared to 2.5 with placebo. At 90 days, 53.3% of the alteplase cohort achieved an mRS of 0-1 as compared with 41.8% with placebo. Bleeding complications, as typical, favored the placebo cohort – with absolute advantages ranging from 1.6% to 3.6%, depending on the definition of hemorrhage used. Death at 90 days also favored placebo at 1.2% versus 4.1%.

It is difficult to know what to do with these data unless your system is specifically equipped to replicate the conditions of this trial with rapid MRI. Even then, there are some oddities and specific warnings to unpack. If adhering to this protocol, the majority of patients screened will not be eligible for treatment. The number of patients who had completed their infarction was similar to those who had DWI/FLAIR mismatch, and another third had other imaging or clinical findings excluding them from treatment. Incorporating MRI into workflow may not yet represent a high-value approach.

Then, the authors performed a pre-specified subgroup analysis stratifying based on NIHSS – and the 109 analyzed patients with a NIHSS >10 did terrible. Only 13.5% of those in the tPA cohort and 12.3% of those receiving placebo achieved mRS 0 or 1. Unpacking these stratifications further, the authors provide us a whole host of breakdowns:

Generally, not too much should be read into these secondary outcomes, but they are useful for generating equipoise for other investigations. That said, these data should be at least a useful cautionary tale regarding the value of tPA in the setting of mild, but disabling stroke – as these 175 patients represent at least six times more patients than from NINDS, and are of higher quality evidence than any of the Get With the Guidelines publications trying to build the case for tPA in mild stroke.

One takeaway that should definitely not be generated from this is: “well, if there’s an absolute increase in good outcome of 12% on those screened with MRI, then treating all ‘wake up’ patients after screening with just CT could generate about a 6% absolute benefit, and that should be offered to patients.” Unfortunately, I suspect we will hear such calls – probably based on parsing out the low NIHSS patients in the subgroups above, and trying to toss out the ~30% with a large-vessel occlusion identified on MRA as patients who should be triaged to endovascular. Again, trying to pick and choose the secondary outcomes that suit your narrative is fraught with peril, and the fact remains such a treatment strategy is also likely to generate harms greater than those seen in this trial. These data ought to have a very narrow application – but shareholders and executives don’t realized dividends when alteplase isn’t flying off the shelves for expanded indications.

“MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset”
https://www.nejm.org/doi/full/10.1056/NEJMoa1804355

The Futility of Alteplase

This article is mostly a story about tenecteplase, but, effectively, it’s also a scathing indictment of alteplase – you know, the miraculous “clot-buster” we’ve been using for the past 23 years.

Because, despite rumors to the contrary, it doesn’t actually bust clots.

This isn’t news to anyone who actually follows the stroke literature closely. Indeed, the entire endovascular/thrombectomy industry is constructed upon this edifice of failure. And, as we see in this 202-patient study comparing recanalization rates after large-vessel occlusion, tenecteplase appears to be more efficacious than alteplase – 22% vs. 10%.

That is to say, in a population of 24 ICA occlusions, 3 basilar occlusions, 60 M1 occlusions, and 14 M2 occlusions, alteplase successfully “busted the clot” in 10. Most of the difference in recanalization was driven by the M1 and M2 patients, where tenecteplase had a 26% success rate and alteplase languished at 8%. These rates for alteplase are a little lower than most prior literature, so it is reasonable to be suspicious of the superiority margin associated with tenecteplase.

But, regardless, as you can see, both are dismal – and, for the past 20+ years, prior to the advent of even limited endovascular availability, we’ve just been pushing alteplase on these large vessels to no beneficial effect – except to Genentech and their shareholders.

“Tenecteplase versus Alteplase before Thrombectomy
for Ischemic Stroke”
https://www.nejm.org/doi/full/10.1056/NEJMoa1716405

The Magic of Telestroke

The use of telestroke assessment is sweeping the nation, like a meme, it’s viral, it won’t get out of your head.

It is, understandably, difficult to staff 24-hour neurology support with the responsiveness required by the quality guidelines for the evaluation of acute stroke. Likewise, it is difficult to standardize care across all providers in the Emergency Department – giving further fits to those administrators engaged with guideline compliance and certification.

So, remote assessment via telestroke.

This is a brief before-and-after report regarding the use of telestroke at the 21 hospitals in the Kaiser Northern California region. This was rolled out over the course of 2015-16, and compared with a seasonally-adjusted 9-month period for each hospital. As with any before-and-after study, there are always unmeasured confounders impacting care and processes, but these authors presented a few findings:

Daily “stroke alerts” in the system increased from 8.8 per day to 11.7 per day.
The rate of alteplase administration increased from 13.1% to 17.6%.
The rate of stroke mimics receiving alteplase increased from 3.9% to 6.8%.
The rate of symptomatic intracranial hemorrhage increased from 2.2% to 3.8%.
Door-to-needle time decreased from a mean of 63.2 minutes to 41.8 minutes.

Is telestroke responsible for all these “improvements”? Again, with all the other various potential process initiatives, it’s impossible to say for certain. What is apparent, however, is that this vertion of faster is not obviously better – treatment of greater numbers of mimics, along with an increase in bleed rate – is not obviously higher quality care. Whether this, as well, can be blamed solely on telestroke is likewise a reasonable question not specifically answered here.

“Novel Telestroke Program Improves Thrombolysis for Acute Stroke Across 21 Hospitals of an Integrated Healthcare System”
http://stroke.ahajournals.org/content/early/2017/12/14/STROKEAHA.117.018413

More “Time Is (Not) Brain” Nuances

This article is conceptually quite strange – and that’s evident right in the title. Time from imaging, not time from onset, is the determining factor in outcomes from acute stroke? However, despite the overall oddity of their premise, there’s at least one pearl demonstrated here: patients with excellent collateral circulation are far more resilient.

This is a small, retrospective evaluation of patients undergoing endovascular intervention for large vessel occlusion within 18 hours, dichotomized between those with a “target” and a “malignant” mismatch profile on CT perfusion imaging. The “target” profile has a Tmax>10s volume ≤100 mL, while the “malignant” profile was ≥100 mL.

There were only 154 patients for analysis, only 48 of whom had “malignant” profile – and, in their tiny sample, they observed no association between time from CT to reperfusion and functional outcomes in those with “target” profile, while there was an apparent association between time delays and outcomes for the “malignant” profile. Whether this risk for poor outcomes can be truly assigned to these time delays or other features intrinsic to at-risk tissue, it does, again, demonstrate the marked heterogeneity in stroke patients with regard to their underlying tissue viability.

The value in endovascular intervention drops precipitously when, despite otherwise being eligible, the collateral circulation is insufficient. The “time is brain” absolutism continues to weaken, affecting both those traditionally considered appropriate and those in extended time windows.

“Time From Imaging to Endovascular Reperfusion Predicts Outcome in Acute Stroke”

http://stroke.ahajournals.org/content/early/2018/03/15/STROKEAHA.117.018858

How Many 6-to-24 Hour Stroke Patients Are Eligible?

So, DAWN and DEFUSE-3 show it is reasonable to use tissue-based criteria to guide intervention, rather than the quaint, but anachronistic, concept of “time is brain.” However, in expanding this window, what is the yield of screening? How many CT cerebral angiograms with specialized perfusion imaging will need to be performed to identify a patient for intervention?

This single-center report 2014 through 2017 at a DAWN trial-participating center found:

2,667 patients with acute ischemic stroke.
792 arrived between 6 and 24 hours of last known to be normal.
298 of those were NIHSS ≥10.
155 of those had proximal anterior large vessel occlusion.
45 of those were non-disabled at baseline and met clinical and imaging mismatch criteria.

The authors also did an analysis for DEFUSE-3 eligibility, and ended up with similar numbers, although there were 15 DAWN-eligible patients who did not meet DEFUSE-3 criteria and 28 DEFUSE-3 patients who did not meet DAWN criteria, so there’s some fuzziness at the bottom of the pyramid, in addition to the limitations of their retrospective review.

So, effectively, a little more than a third of patients presenting between 6 and 24 hours probably meet criteria for screening for large-vessel occlusion, with about half of those identifying an occlusion, and then another third of those having imaging findings with sufficient viable tissue for intervention.

There are almost certainly opportunities to use clinical evaluation – not just a NIHSS cut-off – to improve yield, but there will inevitably be a balance between sensitivity and specificity with respect to resource utilization.

“Eligibility for Endovascular Trial Enrollment in the 6- to 24-Hour Time Window”
http://stroke.ahajournals.org/content/early/2018/03/15/STROKEAHA.117.020273

DEFUSE-3 is DAWN All Over Again

A couple months ago the stroke community was presented with the results of DAWN – an acute stroke trial leaving us longing wistfully of the simple days where we just bickered over tPA in the 3-hour window. With DAWN, the authors evaluated patients with symptoms of 6 to 24 hour duration and found, with specific perfusion mismatch criteria, revascularization was likely beneficial. DEFUSE-3 is the second member of this club.

This is an open-label, blinded-assessor, randomized trial of patients presenting 6 to 16 hours following “last known well”. Dynamic randomization stratified based on age, core infarct, time from symptom onset, and NIHSS. Proximal middle cerebral artery and internal carotid occlusions were required, as was perfusion imaging demonstrating an ischemic core of less than 70 mL and a clinically important penumbra of at least 15 mL. The primary outcome was the clinically and statistically flawed ordinal shift in the modified Rankin scale.

As is become virtually routine in these endovascular trials, this one was stopped early – after 182 of 476 originally planned. These authors halted enrollment after the DAWN publication, and applied their protocol for interim analysis for early stoppage – which was met. Ignoring their ordinal shift measure and going straight for the typical mRS 0-2, we find 45% meeting that outcome with endovascular intervention, and 17% with medical therapy. Adverse events, including intracranial hemorrhage, were modestly increased in the endovascular arm, although mortality in the endovascular cohort are halved. Revascularization rates at 24 hours, interestingly, were only 79% in the endovascular cohort, and they still had a fair bit of infarct growth – but, sample size limitations notwithstanding, clinical outcomes obviously vastly favor the endovascular cohort. The American Stroke Association has wasted no time updating their guidelines to incorporate new time windows, up to 24 hours, using the DAWN and DEFUSE criteria.

Obviously, in an open-label trial, the scales can be tilted by the intensity of follow-up care – for instance, in IST-3, more stroke patients receiving tPA ended up in intensive care units. ICUs, with their more favorable nursing ratios, are virtually guaranteed to be more likely to be on top of all the other components of high-quality post-stroke care. In open-label trials, as well, it is reasonable to suggest different conversations may be had about comfort care measures, depending on whether an intervention were performed with the hopes of potential downstream improvement. These are just a couple examples of the many ways these sorts of trials may exaggerate the magnitude of potential benefit.

All that said, the Bayesian position – colored by sponsored trials as it is – still suggests these data are on the right track. The key to stroke care is tissue viability, not arbitrary time metrics. Either the collateral flow is there, or it isn’t – with the caveat that, yes, eventually those collaterals can collapse and complete the infarction. How these new tissue-based considerations fit into systems of stroke care – and who needs to be transferred for specialized imaging – is an open question/headache we’ll all be struggling to figure out over the next months/years.

“Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging”
http://www.nejm.org/doi/full/10.1056/NEJMoa1713973

Out of the Way!

The mobile stroke unit is the new, malignant, extravagant reaction to the “Time is Brain” mantra. However, not all locations are endowed with such an embarrassment of resources.

This very brief report details a systems approach in Mashhad, in Northeast Iran. In 2015, these authors reported only 1.2% of all strokes received treatment with IV tPA, and their analysis indicated prehospital delays were their primary issue. Rather than take the CT to the patient, their far more entertaining solution was simply to clear a path. To relieve delays from chronic traffic congestion and gridlock, they designed an online control system for all traffic lights to be activated based on the severity of the emergency medical condition. Green lights in a continuous path from the incident location to the medical facility help activate traffic flow to allow ambulances room to maneuver. These authors report their successful implementation reduced prehospital transfer time by 50%, although absolute measures are not reported.

Now, they do mention their next step is to report on improvements in patient-oriented outcomes. However, unless the traffic is truly catastrophic, I expect improvements in anything but process surrogates will be difficult to detect.

“Time is brain: An online controlling of traffic lights can save lives”
http://emj.bmj.com/content/early/2017/11/24/emermed-2017-206888

“DAWN” of the Mismatch Era

It wasn’t truly so long ago the treatment for an acute stroke was virtually nonexistent. Then, it progressed, with patients eligible for treatment within 3 hours … then 4.5 hours … then 6 … and, now, 24 hours. Whatever happened to “time is brain”? How can we possibly be treating patients out to a day after onset of symptoms?

This is the DAWN trial, randomizing patients with acute ischemic stroke to endovascular intervention or medical management within 6 or 24 hours of symptom onset. Eligibility criteria included occlusion of the internal carotid or proximal middle cerebral artery paired with one of three different clinical syndrome/infarct core mismatches based on CT or MRI perfusion imaging: three cohorts with NIHSS of 10 or 20, with differing sizes of infarct cores. The underlying theory here stems from observations of the viability of cerebral tissue as dependent upon collateral circulation, rather than simply the linear passage of time.

This is, as you might already have gathered from the press releases, a positive study. Unfortunately, it was so positive it was stopped early for benefit based on a primary outcome these authors almost certainly created uniquely to support early termination of these sorts of trials: the “utility-weighted modified Rankin scale”. Rather than use the traditional mRS as in all other stroke trials, or, even, the statistically flawed “ordinal shift analysis”, these authors assigned point values to the various mRS categories, those with the least disability receiving the most points. This resulted in the potential enrollment of 500 patients being stopped at the earliest possible pre-specified interim analysis with a mere 200 patients enrolled.

Tossing out their nonsensical fake outcome measure for the more easily approachable mRS categories, 52 of 107 (49%) of thrombectomy patients were functionally independent (mRS 0-2) at 90 days versus 13 of 99 (13%) of those in the control group. These results were roughly consistent across their various subgroup analyses, although, with such a small trial, the confidence intervals get awfully wide, awfully quickly. That said, despite all the other associated trial shenanigans, it is fairly obvious this sort of treatment is helpful to patients. I’ve been preaching tissue-based approaches to therapy for a couple years now, and despite this trial’s individual issues, in a Bayesian sense these results are consistent with prior evidence.

Of course, this does not actually indicate the window for screening ought to be 24 hours as will likely be justified from these data – the bounds of eligibility for the study do not simply translate subsequently to clinical policy recommendations. The study design does explicitly stratify patients to 6 to 12 hour and 12 to 24 hour cohorts, but the IQR range for “time from symptom onset” for the entire cohort is 10.2 to 16.3 hours, implying approximately half the 12 to 24 hour cohort was actually randomized between 12 and 16 hours. This leaves a paucity – approximately 25 patients in each arm – of data to inform treatment in the 16 to 24 hour window. Contrariwise, these data also do not explicitly exclude patients beyond 24 hours as potential candidates for intervention, as this is a tissue-based, not time-based, paradigm. Further prospective study will be needed to determine the precise time window at which perfusion screening for large vessel occlusions ultimately becomes so low-yield there is no value in the pursuit.

These authors also do not provide useful information regarding the number of patients screened for possible inclusion. Much will be made of these results, with a likely profound impact on our approach to stroke. To properly design stroke systems of care and project resource utilization, physicians and policy makers need data regarding the clinical characteristics of all patients evaluated and those features best identifying those who ought be triaged or transferred to specialized centers.

Finally, of course, there is the perpetual elephant in the room – heavy involvement from the sponsor in the conduct of the study, along with multiple authors on the payroll. These financial conflicts of interest always threaten internal and external validity by limiting generalizability and amplifying apparent effect sizes. All this said, however, this is probably an important step forward in the evolution in our approach to stroke.

“Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct”
http://www.nejm.org/doi/full/10.1056/NEJMoa1706442

The Top “Overuse” of 2016

Another entry in JAMA Internal Medicine’s lovely “Less is More” series, this is a “systematic review” of the previous year’s literature regarding potentially unnecessary care. Living here in the asylum, it seems all our fellow inmates and I are consigned to issuing weather reports from the tempest – but, hey, baby steps.

Their “systematic review” is not particularly rigorous. It’s basically a literature search, followed by a subjective distillation by author consensus to those considered to be the most potentially impactful – but, regardless, their list is worth reviewing. Without further ado, the highlights of their ten selections:

Transesophageal echocardiography is more informative than transthoracic in illuminating the etiology of a stroke, but the additive information does not have a clear downstream benefit on outcomes.
Patients undergoing computed tomography to rule out pulmonary embolism without algorithm-compliant use of D-dimer suffer from overuse and low-value testing.
CT use increased in all Emergency Department patients with respiratory symptoms, with no evidence of downstream change in prescribing, hospital admission, or mortality.
Supplemental oxygen does not demonstrate benefit in patients with chronic obstructive pulmonary disease and mild exertional hypoxia.
Small improvements in antibiotic prescribing were seen when comparisons to peers were performed.
A shared decision-making implementation for Emergency Department patients with chest pain increased patient engagement and demonstrated a secondary effect of diminished admission and cardiac testing.

Wizard.

“2017 Update on Medical Overuse: A Systematic Review”
https://www.ncbi.nlm.nih.gov/pubmed/28973402