Category: Stroke

Shaking Out Stroke Mimics

In a world of continued aggressive guideline- and pharmaceutical-sponsored expansion of stroke treatment with thrombolytics, this article fills and important need – better codifying the predictors of stroke mimics. While other editorials espouse the need to be fast without being sure, this is frankly irresponsible medicine – and, in resource-constrained environments, unsustainable.

These authors at two academic centers performed a retrospective clinical and imaging review of 784 patients evaluated for potential acute cerebral ischemia. Patients were excluded if they had signs of acute stroke on initial non-contrast imaging, and if they did not subsequently undergo MRI. Based on review of the totality of clinical information for each patient, 41% of this cohort were deemed stroke mimics. The authors scoring system, then derived 6 variables – and 3 or more were present, the chance of stroke mimic being cause of the current presentation was 87.2%. Their criteria:

  • Absence of facial droop
  • Age <50 y/o
  • Absence of atrial fibrillation
  • SBP <150 mm Hg
  • Presence of isolated sensory deficit
  • History of seizure disorder

When the rate of tPA administration to stroke mimics is ~15%, and 30-40% of patients evaluated for stroke are stroke mimics – there is a lot of waste and potential harm occurring here. These authors suggest the use of this score could potentially halve these errant administrations for 94% sensitivity, or cut errant administrations down to 2% with 90% sensitivity. Considering the patients for which stroke/stroke mimic is an ambiguous diagnosis, it is reasonably likely the symptoms are of lesser severity – and in the range for which tPA is of most tenuously “proven” value. While their rule has not been prospectively validated, some of these elements certainly have face validity, and can be incorporated into current practice at least as a reminder.

“FABS: An Intuitive Tool for Screening of Stroke Mimics in the Emergency Department”

http://stroke.ahajournals.org/content/early/2016/08/04/STROKEAHA.116.013842.abstract

Don’t Stop at the Headline

The verdict is in: “Aspiration Thrombectomy No Help for Large-Clot Strokes”, reports MedPage Today.

Except, they’re not precisely correct – in a way, you could even say they’re wrong.

This is THERAPY, an endovascular trial in acute stroke featuring the Penumbra aspiration device.  This is somewhat unique, as the technology differs from the otherwise popularized Solitaire retrieval system. This trial is also different from the most contemporary comparators, as its imaging criteria did not rely on perfusion imaging, but, rather, simply large-vessel occlusion with a clot length of 8mm or greater.

The results of the trial, as you might have picked up from the lay press headline, were negative – that is to say, they did not reach statistical significance. Their primary endpoint for modified Rankin Scale of 0-2 was achieved in 38% receiving endovascular treatment and 30% receiving intravenous thrombolysis alone, and this 8% absolute difference produced a p-value of only 0.52. However, the trial was initially scheduled to enroll 692 patients to be powered to detect a 10.6% difference, but stopped enrollment after 108 based on the publication of other positive endovascular trials.

So, simply put, this trial tells us hardly anything. Is the Penumbra system just as good as Solitare? Probably, but perhaps we’ll never know for certain. Does the 8% difference seen in this trial reflect the lower magnitude of effect of treatment relating to lack of perfusion imaging? Probably, as well, based on the the larger evidentiary context.

But, at the minimum, the medical reporting has simply gone off course with their headline.

“Aspiration Thrombectomy After Intravenous Alteplase Versus Intravenous Alteplase Alone”
http://www.ncbi.nlm.nih.gov/pubmed/27486173

The tPA Pushback Begins

It isn’t news to anyone in the Emergency Medicine community that tPA isn’t as effective as its efficacy trials suggested, and its overuse is driven by “quality” measures and medicolegal concerns more than any true belief in its usefulness.  However, it remains rare in the Neurology literature to challenge the primacy of tPA – it is much more frequent to see articles promoting and/or defending its expanded use.

This small retrospective series looks at a registry of stroke patients eligible for alteplase who received a CT perfusion study as part of their initial evaluation.  As criteria for review, the CT perfusion lesion needed to be <15mL in calculated volume.  Their final cohort included 366 patients with mostly mild-to-moderate strokes (NIHSS median 8 in each), and a little over half were treated with alteplase, while the remainder were not.  As a retrospective and confounded study, the level of evidence is weak, but the untreated population had significantly better outcomes (mRS 0-1 in 57% vs. 69%), and avoided such complications as parenchymal hemorrhage.

The authors conclude:

“we suggest that neither CTA nor standard clinical/NCCT assessment can appropriately define a relatively large sub-group of patients who are clinically eligible for alteplase, yet appear to have no benefit from treatment.”

Yes, if the volume of acutely injured tissue is quite small, the potential benefit of any therapy has an obvious ceiling – even before considering the viability of the affected tissue or the potential effectiveness of reperfusion.  But the key point here is one I’ve made, most recently at #smaccDUB: we can better individualize care, and avoid costs and risks, with more information.

Thanks to Robert Goulden for sending this in!

“Too good to treat? Ischemic stroke patients with small CT perfusion lesions may not benefit from thrombolysis”
http://onlinelibrary.wiley.com/doi/10.1002/ana.24714/abstract

ENCHANTED – Positive or Negative?

I am probably the last person to comment on ENCHANTED, the trial testing low-dose vs. standard-dose tPA in “Asians”.  When it was released, to some fanfare in the New England Journal of Medicine, I had little to say – it is, frankly, a rather bland contribution to the science.  What has been fascinating, however, is the unusually divergent interpretation of the results.  To wit, the accompanying editorial in the NEJM states:

“ENCHANTED provides no compelling evidence for using low-dose alteplase for acute ischemic stroke in Asian or other populations on the basis of safety considerations or clinical outcomes.”

This is a relatively reasonable interpretation of the results – hinging on the word “compelling”.  No one’s hearts are to be set a-flutter over these results, but that does a disservice to the ultimate clinical question of which dose is appropriate.  The lay press, however, is here to clear things up – or is it?

“ENCHANTED: Low-Dose tPA Now a Viable Option in Stroke?” 
“ENCHANTED results challenge reduced alteplase dose in Asian stroke patients”
“Low-Dose tPA Not as Effective, Even for Asians”
“Lower Dose of Clot-Busting Drug Reduces Brain Bleeding”
“Low-dose alteplase fails to prove noninferiority to standard dose, shows some benefit in stroke”
“Low-Dose Alteplase Not as Effective as Standard-Dose in Acute Ischemic Stroke”

The question, simply, comes down to how easily one interprets “non-inferiority” – a point made nicely by Rory Spiegel in his post – and, further, how one interprets these findings in a Bayesian sense.  The prevailing opinion going into this trial was that low-dose tPA was safer and similarly efficacious in certain ethnic subpopulations on the Asian continent.  The nonsignificant difference (OR 1.09; 95% CI 0.95 to 1.25) in patients having excellent outcomes (mRS 0-1) and the even smaller difference (OR 1.03; 95% CI 0.89 to 1.19) in those having good outcomes (mRS 0-2) does nothing to move the needle on the prevailing clinical hypothesis.  If there is unlikely to be a profound difference in clinical outcomes, what of the safety outcomes?  Here, low-dose alteplase is obviously a winner – significant reductions in hemorrhage and a corresponding decrease in 90-day mortality (p=0.07).

If ECASS failed gloriously due to adverse effects at 1.1 mg/kg, subsequent trials found some favorable risk/benefit at 0.9 mg/kg, and the (supposed) clinical efficacy seems preserved with even greater safety at 0.6 mg/kg, it seems logical to expand interest in lower doses of tPA.  I disagree with those who would dismiss this trial as an unimportant “failure”.

“Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1515510

Stroke – Reversed!

Breathless miracle treatment coverage!  Walk, talk, have a baby, win the Olympic decathalon – all despite having severe stroke!  All it takes is a “simple procedure”!

The lay coverage reads like clickbait.  In contrast – at least – the published abstract Results section leads off with “All patients in the safety population (N=18) experienced at least 1 treatment-emergent adverse event.”

So, not quite such exaggerated hyperbole.

This is the PISCES II trial, implantation of modified bone marrow–derived mesenchymal stem cells directly into the brain.  Cells were implanted via craniostomy, and five 20 μL cell deposits were made at 5 to 6 mm intervals along each of three cannula tracks into the peri-infarct area.  18 patients were enrolled after 379 were screened, and three differing dose concentrations of stem cells were used.  The baseline NIHSS of the population had a mean of 9.44, and patients were all mRS 3 or 4.

With regards to that aforementioned “treatment-emergent adverse event”, thankfully, the vast majority were headache related to the procedure, along with nausea and vomiting.  A few patients developed muscle spasticity, and among relevant serious adverse events, one patient had a seizure and one an asymptomatic subdural/hygroma.  NIHSS improved by 2.00 points among the 16 patients available for 12 month follow-up, and there were other motor improvements and global functional improvements measured on the Fugl-Meyer score.  MRI changes seemed to correlate with improvements in functional status, as well.

Literally every aspect of this trial was controlled by SanBio Inc., the purveyors of this recovery technology.  The manuscript was ghostwritten by professionals funded by SanBio, and SanBio funded almost everything.  Several authors are full-time employees of SanBio, and other authors are former employees and/or stockholders.  It is nice to think this might offer promise and hope for stroke survivors, but this small trial is far from the breathless coverage provided.

“Clinical Outcomes of Transplanted Modifed Bone Marrow–Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study”
http://stroke.ahajournals.org/content/early/2016/06/02/STROKEAHA.116.012995.abstract

tPA – For Minor Strokes, With Many Caveats

It is well-established many patients with minor or rapidly improving stroke fail to thrive.  The NIHSS is a crude tool, and its correlation with infarct size and ultimate disability is limited.  It is not inconceivable some patients with minor stroke could be candidates for intervention.  However, these patients would need to fit our critical requirements: 1) there must be substantial at-risk territory preserved by collateral perfusion, and 2) the occluded vessel must be reliably opened at a greater rate and timelier fashion than the body’s natural recanalization process.

This brief report is an interesting stepping stone on the pathway towards the practical realization of some of these issues.  These authors present a retrospective review of patients with minor stroke (NIHSS ≤ 3) evaluated at their institution.  Their institution routinely performs CT imaging with perfusion (RAPID software) on most stroke evaluations.  They further trim out 73 of these patients for whom the CT perfusion demonstrated substantial volumetric deficits.  Generally, these were patients with small (<5 mL) core infarcts surrounded by 20-40 mL of delayed perfusion, as would be reasonably expected for patients with minimal clinical symptoms.

There were 34 patients in this cohort who received tPA and 39 who were admitted without.  Patients were generally similar, although the tPA cohort had twice the prevalence of prior stroke (29.4% vs. 16.7%) and – most importantly – double the area of delayed perfusion (41.3 mL vs. 25.1 mL with wide standard deviation).  Despite these poorer prognostic features, 90-day mRS 0-1 were 91.2% in the tPA cohort and 71.8% in the standard care.

This is hardly practice changing in its crude, non-randomized, retrospective form.  It does, however, have face validity for informing future study.  It also fits with the paradigm of stroke care I’ve been promoting on this blog for years – the inanity of unselected tPA – and the requirements as above – to maximize potential benefit by ensuring those offered tPA have salvageable tissue (read: small core, large mismatch) and likely to recanalize (read: small vessel).  There’s virtually no question CTP or its equivalent needs to become part of the treatment decision-making process, rather than simple non-contrast CT or even CTA without evaluation of collateral flow.

“Utility of Computed Tomographic Perfusion in Thrombolysis for Minor Stroke”
http://stroke.ahajournals.org/content/early/2016/05/19/STROKEAHA.116.013021.abstract

Triaging Large Artery Occlusions

Endovascular intervention for acute stroke can be quite useful – in appropriately selected patients.  However, few centers are capable of such interventions, and the technology to properly angiographically evaluated for large-artery occlusions is not available in all settings.  Thus, it is just as critical for patients to be clinically screened in some fashion to prevent over-utilization of scarce resources.

These authors retrospectively reviewed 1,004 acute stroke patients admitted to their facility since 2008, 328 of which had large-vessel occlusions: ICA, M1, or basilar artery.  They calculated the accuracy, sensitivity, and specificity of multiple different potential clinical scoring systems, cut-offs.  Unfortunately, every score made some trade-off – either in the rate of false-negative results excluding patients from potential intervention, or in the rate of false-positive results serving to simply subject every patient to advanced imaging.  The maximum accuracy of all their various scores topped around around 78%.

The authors’ conclusions are reasonable, if a little limited.  They feel every patient presenting with an acute stroke within 6 hours of symptom onset should undergo vascular imaging.  These are both reasonable, but ignore one of the major uses for simple clinical scoring systems: prehospital triage.  Admitting none of these are perfect, _something_ must be put to use – and, probably, given the current bandwidth for endovascular intervention, something with the highest specificity.

For what it’s worth, we use RACE to triage for CT perfusion, but CPSSS, ROSIER, or just NIHSS cut-offs around 10 would all be fair choices.

“Clinical Scales Do Not Reliably Identify Acute Ischemic Stroke Patients With Large-Artery Occlusion”
https://www.ncbi.nlm.nih.gov/pubmed/27125526

Endovascular for Stroke – Even Better than the Evidence

What happens when you let Medtronic, et al, author an article on endovascular therapy in The Lancet:  exactly what you’d expect.

We are, in principle, fans of endovascular therapy for acute stroke as presented in the major trials: ESCAPE, EXTEND-IA, and SWIFT-PRIME.  These trials carefully selected eligible patients by use of advanced perfusion imaging and demonstrated high rates of revascularization.  Viable brain plus restored flow has face validity for improved outcomes.

However, these sponsored authors use the meta-analysis for its most nefarious purpose: to obfuscate the important subtleties and eligibility criteria of its included trials.  These authors pool the aforementioned trials, along with MR CLEAN and REVASCAT to provide the following conclusion:

“Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location.”(emphasis mine)

The authors also provide a staggering number-needed-to-treat for endovascular therapy of 2.6.

But, of course, this was written to shock and awe the lay press and general medicine community, rather than edify the astute clinician.  Their NNT is not based on the typical dichotomous cut-off used in stroke trials of mRS 0-1 or 0-2 – but rather the hopelessly flawed ordinal shift analysis.  As the decades turn, apparently, we have forgotten why this approach was frowned upon from the start: it is not appropriate to equate the outcome value difference between mRS 5 and 4 with the difference between mRS 3 and 2, and the limitations in inter-rater reliability in the mRS introduce a vast additional amount of measurement error.  Then, by burying any mention of the strict imaging criteria responsible for the bulk of benefit seen in these trials, they mislead the reader into considering this therapy appropriate for all-comers.

Is there any value to these data as presented?  A little.  There is hypothesis generating evidence that tPA prior to endovascular therapy provides no additive benefit.  There is also evidence that increasingly distal sites of occlusion may not benefit from intervention.

Unfortunately, the flaws in this article outweigh the few potentially usable insights.  This is just yet another piece of direct-to-physician marketing masquerading as scientific evidence.

“Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials”
https://www.ncbi.nlm.nih.gov/pubmed/26898852

Try to Avoid tPA When Already Bleeding

Coming to us from the Department of Common Sense: don’t give tPA to stroke patients who already have intracranial hemorrhage.  There’s a little more subtlety here, of course, because in this instance, we’re dealing with cerebral microbleeds – tiny foci of angiographic damage visualized only on MRI.

These authors performed a pooled and individual-patient meta-analysis of those undergoing MRI prior to treatment with intravenous thrombolysis.  When stratified by CMB burden, arbitrarily divided into “none”, “1-10”, and “>10”, the obvious is … obvious: patients who are already bleeding are more likely to continue bleeding.  In the unadjusted raw numbers, patients with no CMB had a symptomatic intracranial hemorrhage rate of 4.3%, those with 1-10 CMB had 6.1%, and those with >10 had 40.0%.

There are many technical limitations inherent to the retrospective nature of their study, as well as likely other confounding variables – but, the basic gist: our current practice relying only on non-contrast CT likely misses an important safety indicator in the setting of tPA use.

“Risk of Symptomatic Intracerebral Hemorrhage After Intravenous Thrombolysis in Patients With Acute Ischemic Stroke and High Cerebral Microbleed Burden”
https://www.ncbi.nlm.nih.gov/pubmed/27088650

Hospitalization or Home After TIA

In the pursuit of “value-based care”, innovators are consistently looking for ways to deliver similar outcomes without the risks and resource utilization of inpatient hospitalization.  One of these realms is the evaluation of transient ischemic attack.  Most of the recommended follow-up tests are only relatively urgent in nature, and with medical management the typical mainstay of therapy.  As serious considerations go, it seems ripe a candidate for outpatient management.

This retrospective look at outcomes from Canada, however, suggests there may be pitfalls to such a strategy.  These authors reviewed the outcomes of 8,540 patients presenting with TIA or minor stroke, and compared those either admitted to the hospital at the index visit with those discharged, and among those discharged, referral to a specialized follow-up clinic or not.

Patients admitted to the hospital, by all measures, had more severe cerebrovascular disease – as evidenced by duration of symptoms, ABCD2 scores, diagnosis of minor stroke, and other comorbidities.  However, despite this, following hospitalization, these patients had the lowest risk or recurrent stroke or TIA within one year.  The benefit, presumably, comes from increased likelihood of undergoing risk stratification and treatment – carotid imaging, echocardiography, appropriate anticoagulation, appropriate antithrombotic therapy, and the like.  Then, among the discharged, various adjusted and propensity matched analysis demonstrated a protective effect of referral to specialty outpatient follow-up against death, but not for stroke or TIA.  These data do not have the granularity to fully describe whether the excess deaths were in some fashion related to cerebrovascular disease.

Most of the absolute differences in outcomes between groups are small – a few percentage points each, and smaller after adjustment.  That said, it’s probably clearly superior care, as configured in Ontario during this time frame, to have been admitted to the hospital.  As TIA evaluation, and other similar conditions, move to outpatient pathways rather than traditional hospitalization, this represents an important reminder of potential risks of degradation in thoroughness and quality.

“Association between hospitalization and care after transient ischemic attack or minor stroke”
https://www.ncbi.nlm.nih.gov/pubmed/27016521