Category: Stroke

Stretch That Thrombectomy Window

It’s the thing to do in stroke – wedge new treatments into practice with a narrow time window and strict eligibility requirements, then expand, expand, expand.

This latest publication/advertising supplement in the Journal of the American Medical Association pools together the endovascular trials MR CLEAN, ESCAPE, EXTEND-IA, REVASCAT, and SWIFT-PRIME for an individual-patient meta-analysis to explore the various nuances of the treatment effect. After much cleaning and tweaking, the authors come around and say “Whoa! We found a benefit out to 7.3 hours from symptom onset, not just the 6 hour limit recommended by the American Heart Association!”

These were all positive trials, so it’s no surprise the overall outcome is positive – nor is these authors ability to drag out favorable outcomes beyond the 6-hour cut-off, considering some of these trials enrolled patients out to twelve hours. However, in their clumsy calisthenics to marry these data to the time-based hypothesis of acute stroke practice, these authors are clearly dancing around the most important bit of evidence emerging from these trials: imaging selection. They spend a handful of sentences discussing the imaging selection eligibility criteria of the included trials, but one benefit of meta-analyses is its use as a tool to obfuscate such inconvenient aspects in favor of words, words, words relating to the methods of their statistical analysis.

As I described in my #smaccDUB talk, you need two things for stroke therapy to be effective: viable tissue and effective reperfusion. These trials – ESCAPE, EXTEND-IA, and SWIFT-PRIME – finally hit that sweet spot with small infarct cores and safe, effective recanalization. Some of that viable tissue absolutely decays over time, so the time-based hypothesis is not entirely untrue, but it’s a low-value oversimplification. As many of use in Comprehensive Stroke Centers have seen, perfusion imaging can direct therapy for patients far outside the general AHA recommendations. The obvious corollary to this, however, is that perfusion imaging similarly identifies patients for whom intervention is futile, regardless of time window. This second point runs contrary, however, to the financial interests at stake here.

The authors do mention imaging-based criteria is being investigated in multiple clinical trials, e.g.: NCT02142283, NCT02586415.  However, these trials are carefully designed not to enroach upon established time-based criteria, and to use imaging only to further extend the treatment windows.

Other fun tidbits:

  • A few patients randomized to endovascular intervention did not receive one. After all, most received pre-intervention tPA – some would be expected to recanalize with medical therapy alone. However, this publication gives another lovely window into our clot-buster that doesn’t bust clots: only 6.8% could be reasonably concluded to have had clot thrombolysis after medical therapy alone. We probably should not be giving tPA to patients for whom endovascular intervention is planned.
  • All five studies cited here were published in the New England Journal of Medicine.  This meta-analysis is in JAMA. Presented without comment.

“Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis”

http://jama.jamanetwork.com/article.aspx?articleid=2556124

 

Coda – there were just a couple relevant conflict of interest disclosures:

Dr Saver reports being an employee of the University of California; serving as an unpaid site investigator in multicenter trials run by Medtronic and Stryker for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled; receiving stock options for services as a scientific consultant regarding trial design and conduct to Cognition Medical; receiving funding for services as a scientific consultant regarding trial design and conduct to Covidien/Medtronic, Stryker, Neuravi, BrainsGate, Pfizer, Bristol Myers-Squibb, Boehringer Ingelheim (prevention only), ZZ Biotech, and St Jude Medical; serving as an unpaid consultant to Genentech advising on the design and conduct of the PRISMS trial; neither the University of California nor Dr Saver received any payments for this voluntary service. The University of California has patent rights in retrieval devices for stroke. Dr Goyal reports receiving grants from Covidien/Medtronic, consulting payments from Covidien/Medtronic, and having patent rights in systems and methods for diagnosing strokes (PCT/ CA2013/000761) licensed to GE Healthcare. Dr van der Lugt reports grant funding from the Dutch Heart Foundation, AgioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/LAMEPRO/Penumbra, Stryker, and Top Medical/Concentric. Dr Menon reports serving as an unpaid member of in the ESCAPE trial, which received support from Covidien/Medtronic, receiving grant support from AstraZeneca, honoraria from Penumbra, a submitted patent for triaging systems in ischemic stroke, and serving on the board of QuikFlo Health. Dr Majoie reports that his institution has received honoraria for his service on a Speaker’s Bureau from Stryker. Dr Dippel reports that his institution has received honoraria for his speaking from Stryker and grant funding from the Dutch Heart Foundation, AgioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/ LAMEPRO, Penumbra, Stryker, and Top Medical/ Concentric. Dr Campbell reports that his institution received a grant to support the EXTEND-IA trial from Covidien/Medtronic. Dr Campbell reports grant funding from the National Health and Medical Research Council of Australia and Medtronic and fellowships from the National Heart Foundation of Australia, National Stroke Foundation of Australia, and Royal Australasian College of Physicians. Dr Nogueira reports receiving fees for service on steering and data safety monitoring committees to Medtronic, Stryker, Penumbra, and Rapid Medical. Dr Demchuk reports receiving grant support and personal fees from Covidien/Medtronic and personal fees from Pulse Therapeutics. Dr Devlin reports that his institutions received clinical trial payments for patients enrolled in clinical trials from Medtronic, clinical trial support from Brainsgate and Genervon, and holding a patent. Dr Frei reports personal fees from Penumbra, Stryker, Codman, MicroVention, and Siemens. Dr Jovin reports receiving fees for service on steering committees from Silk Road Medical, Covidien, Stryker Neurovascular, Air Liquide; personal fees from Neuravi and Johnson & Johnson; nonfinancial support from Fundacio Ictus; and serving on the advisory board for Anaconda. Dr Siddiqui reports personal fees from StimSox, Valor Medical, Neuro Technology Investors, Cardinal Health, Medina Medical Systems, Buffalo Technology Partners, International Medical Distribution Partners, Codman & Shurtleff, Medtronic, GuidePoint Global Consulting, Penumbra, Stryker, MicroVention, W. L. Gore & Associates, Three Rivers Medical, Corindus, Amnis Therapeutics, CereVasc, Pulsar Vascular, the Stroke Project, Cerebrotech Medical Systems, Rapid Medical, Lazarus, Medina Medical, Reverse Medical, Covidien, Neuravi, Silk Road Medical, Rebound Medical, Intersocietal Accreditation Committee; other fees from Penumbra, 3D Separator Trial, Covidien, SWIFT PRIME and SWIFT DIRECT trials, MicroVention, FRED trial, CONFIDENCE study, LARGE trial, POSITIVE trial, COMPASS trial, INVEST trial. Dr van Zwam reports that his institution has received honoraria for his speaking from Stryker and Codman. Dr Davis reports lecture fees and research support from Covidien/Medtronic; travel support from Bristol Myers-Squibb and Pfizer; and advisory board fees from Boehringer Ingelheim and Medtronic. Dr Silver reports personal fees from Boehringer Ingelheim. Dr Donnan reports nonfinancial support from Boehringer Ingelheim; grants from the Australian National Health and Medical Research Council; and fees for service on advisory boards for Boehringer Ingelheim, AstraZeneca, Bristol Myers-Squibb, Pfizer and Merck Sharp & Dohme. Dr Brown reports receiving consulting fees from Medtronic/Covidien and personal fees from the University of Calgary. Dr Mitchell reports that his institution received a grant to support the EXTEND-IA trial from Covidien/Medtronic; his institution has received unrestricted research funding and grants from Codman Johnson and Johnson, Medtronic, and Stryker; and serving as an unpaid consultant to Codman Johnson and Johnson. Dr Davalos reports receiving payments for serving on a multicenter study steering committee and grant funding from Medtronic. Dr Roos reports grant funding from Medtronic. Dr Hill reports unrestricted grant funding for the ESCAPE trial to University of Calgary from Covidien/Medtronic, and active/in-kind support consortium of public/charitable sources (Heart and Stroke Foundation, Alberta Innovates Health Solutions, Alberta Health Services) and the University of Calgary (Hotchkiss Brain Institute, Departments of Clinical Neurosciences and Radiology, and Calgary Stroke Program); personal fees from Merck, nonfinancial support from Hoffmann-La Roche Canada. In addition, Dr Hill has a submitted patent for triaging systems in ischemic stroke, and owns stock in Calgary Scientific, a company that focuses on medical imaging software. No other disclosures were reported.
Funding/Support: The HERMES pooled analysis project is supported by a grant from Medtronic to the University of Calgary.

But Where is the Antidote to the Poison @NEJM?

Andexanet alfa is the long-awaited antidote for the Factor Xa inhibitors – rivaroxaban, apixaban, edoxaban, and their ilk. This publication, featured at the European Stroke Congress and in the New England Journal of Medicine, is Portola’s latest update regarding its utility. Is it better than their previous update – their failure to receive initial FDA approval – or just another “incomplete” like their publication last fall?

This is ANNEXA-4, an open-label, single-group study purporting to evaluate the efficacy and safety of andexanet for clinical hemostasis in actively bleeding patients with concomitant use of Factor Xa inhibitors. Or, more specifically, these are interim results – the first 67 of 250 planned for enrollment. The clinical efficacy endpoint is a complex series of adjudicated judgements regarding the cessation of bleeding, hematoma expansion, or change in hematocrit, depending on the type of bleeding enrolled. The primary safety endpoint is death or thrombotic event within 30 days – stroke, myocardial infarction, venous thromboembolism, etc.

There is virtually nothing positive to relate here. The authors, of course, relate that somewhere around 80% of the 47 patients included in their efficacy analysis obtained “good” or “excellent” hemostasis with 12 hours following their andexanet infusion. But, these essentially arbitrary labels at a potentially clinically unimportant timepoint tells us virtually nothing regarding its value versus observation, or an alternative treatment such as prothrombin concentrate complexes.

On the negative side, the list is endless. There is the baffling offensiveness of publishing what amounts to a quarter of a trial in the New England Journal of Medicine.  The mean time to andexanet bolus was nearly 5 hours, raising concern regarding the acuity and severity of bleeding in enrolled patients.  The vague, patient-oriented endpoints are meaningless – with or without a comparator – and thus, this boils down to basically a pharmacokinetic observational study. Even then, the pharmacokinetics don’t appear terribly favorable – andexanet dramatically reduces Factor Xa activity during infusion, but pops back to therapeutic anticoagulation following cessation. A concerning 18% had thrombotic events within 30 days – but, again, without any control group, little can be concluded regarding safety.

Finally, clearly, the NEJM has given up publishing the conflicts-of-interest for the authors because it would sum up to half the journal – this article directs the reader to the disclosure forms on the web. For the eagle-eyed reader, however, they can pick out this text as part of the author affiliations: “Portola Pharmaceuticals, San Francisco (J.T.C., A.G., M.D.B., G.L., P.B.C., S.G., J.L., B.L.W.)”. Yes, eight of the authors are employees of Portola Therapeutics, the manufacturer. Better even, are their ICJME form disclosures. John Curnutte, the Head of Research and Development, has checked the box stating he has no relevant conflicts of interest with the work under consideration for publication – but, you know, outside the submitted work he happens to be an employee for Portola. In fact, from what I can tell, every employee authoring this article declared they have no COI with the work under consideration for publication.

Inconceivable!

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors
http://www.nejm.org/doi/full/10.1056/NEJMoa1607887

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